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Recent eLetters

Displaying 241-320 letters out of 659 published

  1. Re: NICE, drug-eluting stents and the limits of trial data

    Dear Sir

    Dr Mohindra raises interesting points.

    As regards clinical effectiveness, we must not confuse effectiveness in reducing restenosis and the need for repeat treatment (about which there is no doubt) and the potential for a reduction in later morbidity and mortality (about which there is continuing debate). The point is that we cannot exclude the latter possibility and this raises the issue of sensitivity analyses in cost-effectiveness analyses. The NICE models of cost-effectiveness usually result in a black-and-white view of the world, when there are many criteria that influence treatment decisions in individual patients. There is considerable uncertainty in these economic models, which should be recognised.

    Dr Mohindra writes that any balance to be struck is between value and cost, not between clinical and cost-effectiveness, with value being seen both in terms of effectiveness and how the patient perceives this. Many others have discussed the limitation of relying wholly on an assessment of cost per QALYs in this regard and so there is nothing new here. NICE itself has stated that it does not have a threshold at which cost- effectiveness becomes unacceptable, although greater reliance on other factors is required for costs per QALY of more than £20,000.(1) He is right to point out though that I did not highlight this distinction in my editorial.

    As regards the cost of stents, he is right in pointing out that this is something that currently depends on market forces; because of this, the cost can vary across the country. I am informed that the NICE committee had some difficulty dealing with this issue and ultimately decided to use an “average” cost of a bare metal stent, although for some reason they were provided with costs that were significantly lower than the costs identified by other means.

    The value of a treatment as perceived by the patient is clearly very important. Take a “low risk” scenario where a patient treated with a bare metal stent has a 10% risk of angiographic restenosis and a clinical restenosis rate of 5% (i.e. a 1 in 20 chance of requiring a second treatment). For the same patient a drug eluting stent might offer a 5-6% chance of angiographic restenosis with a 2-3% chance of clinical restenosis (i.e. a 1 in 50 chance of requiring a second treatment). I don’t think many patients would find this choice very difficult but, depending on the relative costs of the stents, the NHS might find the 2-3% absolute difference unacceptable. One would have to be extremely sure of the reliability of cost-effectiveness analyses before denying this benefit to patients.

    Because value is more difficult to establish than effectiveness, the current NICE methodology puts great pressure on clinicians to deny patients a superior treatment. In calling for this difference between effectiveness and value to be considered, Dr Mohindra calls for greater involvement of politicians in the process and yet NICE claims to be an “independent body”. He has not outlined what sort of involvement he would find helpful. There is a possibility that greater political involvement might lead to a reduction in the range of cost per QALYs that is deemed acceptable and so greater political involvement might make matters worse rather than better. Politicians in committee will always ask for a line to be drawn somewhere (although they sometimes react differently when confronted with a specific constituent’s medical problems), whereas patient groups and clinicians will always want what is “best”, regardless of cost. Some system is needed if only to avoid “the tragedy of commons”, whereby the individual demand by every patient for the currently best treatment regardless of cost leads to a level of healthcare spending that cannot be provided.(2) Introducing an ethicist into the process might help, if only to outline the dilemmas when cost-effectiveness analyses fall into the zone when additional justification is required to support the use of a new treatment.

    Dr Mohindra has written elsewhere about the “affordability gap”, i.e. the gap between evidence-based treatments and NICE-approved treatments.(3) This is currently under great scrutiny, especially in the world of cancer treatment, where we might see that the value of a few additional weeks of life outweighs the results of cost-effectiveness analyses. In a recent presentation to the British Cardiovascular Society, I suggested that NICE does affect the clinician’s role as the patient’s advocate, but its system of appraisal, however imperfect, does at least provide a societal framework that both doctors and clinicians can live with as long as it is fair, consistent, intellectually robust and transparent. Many feel that the NICE review of drug-eluting stents has been anything but.

    The debate about how to value a treatment will continue.

    Yours sincerely

    Mark de Belder

    1. Raftery J. Review of NICE’s recommendations, 1999-2005. Br.Med.J. 2006;332:1266-8

    2. Ferner RE, McDowell SE. How NICE may be outflanked. Br.Med.J. 2006;332:1268-71

    3. Mohindra RK, Hall JA. Desmond’s non-NICE choice: dilemmas from drug-eluting stents in the affordability gap. Clinical Ethics 2006;192:105 -8

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  2. Diabetes in Africa: the situation in the Seychelles

    Professor NS Levitt recently reviewed the epidemiology, management and health care challenges related to diabetes in Africa [1], however not including data from the Seychelles. We would like to add some information from the Republic of Seychelles, an island state located 1800 km east of Kenya where more than 80% of the population is of African descent.

    Based on two independent population-based surveys in 1989 and 2004, the prevalence of diabetes (fasting blood glucose >=7 mmol/l and/or treatment) increased from 6.2% to 9.6% in men and from 6.1% to 9.2% in women [2-4]. The prevalence reached 11.5 % in 2004 when also considering results of the oral glucose tolerance test. The prevalence of obesity increased markedly in the interval [4,5] and overweight accounted for 49% of all cases of diabetes in 2004 [4]. Furthermore, pre-diabetes was found in an additional 22% of the population [4].

    Of all cases of diabetes in the population aged 25-64, 54% were aware of the diagnosis [4]. However less than a fifth of diabetic persons under treatment had blood glucose, blood pressure and blood cholesterol below the recommended targets [4]. Furthermore, we found that persons with pre- diabetes already had worsened levels of several cardiometabolic risk factors and were therefore at increased cardiovascular risk [6]. We also confirmed the strong association between diabetes and microalbuminuria in the Seychelles [7] and found a high prevalence of the metabolic syndrome [8].

    Our figures further contribute to map the "diabesity" epidemic in the African region. Limited therapeutic control among diabetic patients in the Seychelles is challenging since this occurred while the population is well aware of diabetes following sustained awareness campaigns since the late 1980s and health care, including medications in all major therapeutic classes, is provided at no direct cost through an easily accessible network of health centers. The situation in the Seychelles may provide a good case study for current and future trends in rapidly developing countries in the continent and, possibly, for middle-income countries in other regions.

    Conflict of interest statement: We declare that we have no conflict of interest

    References 1) Levitt N. Diabetes in Africa: Epidemiology, management and healthcare challenges. Heart 2008;94:1376-82. 2) Tappy L, Bovet P, Shamlaye C. Prevalence of diabetes and obesity in the adult population of the Seychelles. Diab Med 1991;8:448-52. 3) Bovet P, Shamlaye C, Gabriel A, Riesen W, Paccaud F. Prevalence of cardiovascular risk factors in a middle-income country and estimated cost of a treatment strategy. BMC Public Health 2006,6:9. 4) Faeh D, William J, Tappy L, Ravussin E, Bovet P. Prevalence, awareness and control of diabetes in the Seychelles and relationship with excess body weight. BMC Public Health 2007;7:163. 5) Bovet P, Chiolero A, Shamlaye C, Paccaud F. Prevalence of overweight in Seychelles: 15-year trends and association with socio-economic status. Obes Rev 2008; 2008;9:511-7. 6) Faeh D, William J, Yerli P, Paccaud F, Bovet P. Diabetes and pre- diabetes are associated with cardiovascular risk factors and carotid/femoral intima-media thickness independently of markers of insulin resistance and adiposity. Cardiovasc Diab 2007;6:32. 7) Pruijm MT, Madeleine G, Riesen W, Burnier M, Bovet P. Prevalence of microalbuminuria in the general population of Seychelles. J Hypertens 2008;26:871-77. 8) Kelliny C, William J; Riesen W; Paccaud; Bovet P. Metabolic syndrome according to different definitions in a rapidly developing country of the African region. Cadiovasc Diab 2008;18;7:27.

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  3. NICE, drug-eluting stents and the limits of trial data

    SIR, Dr M De Belder asks the question how to determine the worth of drug-eluting stent? (1) The answer to this question does not lie in the trial data. The function of the trial data is to establish the extent of clinical-effectiveness to a given degree of certainty. In this context, whilst a trend may be hypothesis generating it does not establish clinical -effectiveness.

    There is no balance between clinical and cost-effectiveness. Clinical effectiveness necessarily precedes cost-effectiveness. If there is a balance to be struck it lies between value and cost. The cost is set by the market and by negotiation between the respective parties. Once this is settled the remaining key variable left to be determined is the value placed upon the degree of benefit demonstrated by the clinical trial evidence.

    The value of the intervention to the patient as perceived by the NHS has to be balanced against its cost to the NHS as payer. It is this combination of clinical-effectiveness, cost and value (2) that presently falls to be considered by NICE.

    Importantly, observe that the value to the patient of the treatment is judged not by the patient but by the payer. Because of this critical point the process should possess a stronger political component than it presently does. This is because it is the politicians and not NICE who are directly accountable to the key stakeholders i.e. the public whose dual guise as patients and tax payers drives this dilemma. (3)

    Questions of clinical effectiveness can yield to randomised controlled clinical trials. However it is clear, from the principle of fact-value distinction first expressed by David Hume (4), that the value of an intervention cannot be determined from the trial data because trial data only ever returns a factual conclusion. Questions of value do yield to the principles of ethics. Questions of cost yield to principles of economics.

    As the present situation with drug-eluting stents demonstrates there seems to be a need for doctors who can wield the full spectrum of such principles to be engaged with the aim of better protecting the interests of patients.

    References

    (1) Mark A de Belder NICE Guidelines for the use of drug-eluting stents: how do we establish worth? Published Online First: 26 August 2008. doi:10.1136/hrt.2008.144055

    (2) Rawlins M., Culyer AJ. National Institute for Clinical Excellence and its value judgments. BMJ 2004;329:224-227

    (3) Burke K. NICE needs sweeping changes to maintain credibility, say MPs. BMJ 2002;325:5

    (4) Hume D. Treatise on Human Nature.1738. Book III part 1

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  4. Risk assessment in HCM

    Sir, I was interested in Elliott and Spirito's lucid description of the arrhythmogenic substrate in HCM (1) in their recent review article. Although they quote no evidence for their assertions, I have advanced this hypothesis on many occasions in the last 16 years and have gathered substantial clinical evidence that is consistent with the electrophysiological effects of disarray leading to lethal arrhythmias.

    Paced electrogram fractionation in HCM has recently been shown, in a prospective study, to be strongly predictive of arrhythmic events (2). Furthermore, the same study prospectively evaluated the prediction of sudden death by "risk factors" and showed that the predictions of risk factors are only just distinguishable from being purely random. This has clear implications for prevention of sudden death using ICDs.

    Prospective evaluation of hypotheses is a normal part of the scientific process; I wonder why Drs Elliott and Spirito have been unwilling to test their assertions on the prediction of sudden death, constructed by retrospective analysis of databases, in a rigorously designed, properly conducted prospective trial?

    Yours sincerely Richard Saumarez

    1) Elliot P, Spirito P. Prevention of hypertrophic cardiomyopathy- related deaths: theory and practice. Heart; 2008:94;1269-1275. 2)Saumarez R, Pytkowski M, Sterlinski M et al. Paced ventricular electrogram fractionation predicts sudden death in hypertrophic cardiomyopathy. European Heart Journal 2008;29:1653-1661.

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  5. Comment to Acute pulmonary embolism revisited published in Heart 2008;94:795-802

    To the editor,

    Re: Comment to Acute pulmonary embolism revisited published in Heart 2008;94:795-802.

    We have read with great interest the review article by Dr Konstantinides1 on acute pulmonary embolism (PE) published in the June issue of the journal. Unfortunately this very comprehensive review failed to mention the use of levosimendan in the treatment of right ventricular failure and acute pulmonary hypertension in the critically unstable patient with massive PE. Levosimendan has been successfully used as rescue therapy in this particular group of patients. The high mortality of massive PE is correlated with the presence of shock due to right ventricular failure whereas mortality for massive PE without the presence of shock versus submassive PE is approximately the same2 This is important as submassive PE can eventually result in massive PE. Levosimendan is a calcium sentitizer, a new inodilator that displays lusitropic properties by increasing the sensitivity of the myosin filaments to calcium and by activation of the ATP-sensitive potassium channels reducing the afterload3. In both human4 and animal5 l studies levosimendan has shown to restore the right ventricular-vascular coupling via pulmonary vasodilation and enhanced myocardial contractility, hence improving right ventricular performance. Similar findings were seen in patients with ARDS treated with this new inodilator4 . Powell et al6 successfully used Levosimendan as a rescue therapy in a patient with obstructive shock secondary to a massive PE where thrombolysis was not an option due to the presence of active dyspepsia and a known duodenal ulcer. In our experience, the use of levosimendan is relatively safe if no loading dose is given at 0.1 to 0.2 mcg/kg/min. Although the SURVIVE3 trial failed to show a survival difference between dobutamine and levosimendan in acute heart failure, patients with right ventricular failure were not included in the study.

    Dr B L De Keulenaer, MD, FJFICM Dr B P Powell Dr I R Jenkins

    Correspondence to:

    Dr B L De Keulenaer, MD, FJFICM Intensivist Fremantle Hospital Alma street 6160 Fremantle WA Australia Email: bdekeul@hotmail.com Phone +61 08 9431 3333 Fax + 61 08 9431 3009

    References

    1. Konstantinides SV. Acute pulmonary embolism revisited. Heart 2008;94:795-802. 2.Alpert JS, Smith R, Carlson J et al. Mortality in patients treated for pulmonary embolism.JAMA. 1976 Sep 27;236:1477-80. 3. Mebazaa A, Nieminen M, Packer M et al. SURVIVE Investigators. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA 2007;297:1883-1891. 4. Morelli A, Terboul JL, Maggiore SM et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med 2006;34:2287-2293. 5. Kerbaul F, Rondelet B, Demester JP et al. Effetcs of levosimendan versus dobutamine on pressure load-induced right ventricular failure. Crit Care Med 2006;34:2814-2819. 6. Powell BP, Simes D. Levosimendan in acute pulmonary embolism. Anaesth Intensive Care. 2007 Oct;35:771-2. .

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  6. Risk assessment in HCM

    Sir, I was interested to note the omission from the review by Elliot and Spirito (1) of an important paper by Saumarez and colleagues (2) describing an electrophysiological method of risk assessment in hypertrophic cardiomyoptahy(2). The substrate for sudden death is almost certainly fibre disarray and fibrosis. Based on this knowledge, Saumarez and colleagues in 1992 (1) hypothesised that pacing induced electrogram fractionation might predict risk of death from VF or a similar arrhythmia. The results of the small initial investigation were impressive and represented an important step in risk stratification of HCM. The ACC/AHA/ESC guidelines (ESC 2006) referred to by Elliot and Spirito (their ref 25) mention the Saumerez paper but overlook its central point which is pacing induced electrogram fractionation NOT induction of arrhythmia. A large scale multicentre trial published 16 years later has confirmed the initial hypothesis (3). One wonders why this technique of paced electrogram fractionation analysis (PEFA) does not even deserve a mention in the current review?

    1. Elliot P, Spirito P. Prevention of hypertrophic cardiomyopathy- related deaths: theory and practice. Heart; 2008:94;1269-1275. 2. Saumarez R, Camm AJ, Panagos A et al. Ventricular fibrillation in HCM is associated with increased fractionation of paced right ventricular electrograms Circulation 1992;92:467-74. 3. Saumarez R, Pitkowski M, Sterlinski M et al. Paced ventricular electrogram fractionation predicts sudden death in hypertrophic cardiomyopathy. European Heart Journal 2008;29:1653-1661.

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  7. Coronary calcium scoring the first step in case of suspected significant coronary atherosclerosis

    With interest we read the article by Leschka and colleagues concerning the assessment of coronary atherosclerosis by dual-source computed tomography coronary angiography (CTCA) and calcium scoring (CS).[1] The authors propose an imaging pathway consisting of dual-source CTCA and selective CS in patients with suspicion of significant coronary atherosclerosis. We have two remarks.

    Firstly, as the authors indicate in the Results and in Table 1 and 2, no significant stenoses were detected in patients without coronary calcium. However, in Figure 2, six patients without coronary stenosis are considered to have a negative calcium score. We assume this is an error and that this number should be zero. Then, the total number of patients with a calcium score of 0 or >= 400 add up to 46, consistent with the total number of patients mentioned under CS in Table 2.

    The sensitivity of coronary calcium for presence of significant stenoses and the negative predictive value reported by the authors are 100%, in concordance with previous studies that used the gold standard, electron-beam tomography (EBT) to derive calcium scores.[2,3] In view of the reported negative predictive value, we propose that CS should be the initial test in case of suspected significant coronary atherosclerosis. Thus, further diagnostic imaging procedures with associated radiation dose and contrast effects can be withheld in almost one-fifth of the clinical population (14/74). Earlier generations of multi-detector computed tomography (MDCT) up to single source 64-MDCT were found to underestimate the amount of coronary calcium compared to EBT.[4] Thus, the prevalence of coronary calcium is underestimated with single-source MDCT, leading to unability to reliably exclude coronary calcium. With dual-source CT the temporal resolution of EBT is approximated. We recently found that dual- source CT-derived calcium scores are closer to calcium scores derived by EBT than those by MDCT.[5]

    Dual-source CT studies in larger prospective populations should confirm these findings.

    References

    1. Leschka S, Scheffel H, Desbiolles L, et al. Combining dual-source computed tomography coronary angiography and calcium scoring: added value for the assessment of coronary artery disease. Heart 2008;94:1154-61. 2. Breen JF, Sheedy PF II, Schwartz RS, et al. Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease. Radiology 1992;185 : 435-439. 3. Laudon DA, Vukov LF, Breen JF, Rumberger JA, Wollan PC, Sheedy PF II. Use of electron-beam computed tomography in the evaluation of chest pain patients in the emergency department. Ann Emerg Med1999; 33:15 -21 4. Greuter MJ, Dijkstra H, Groen JM, et al. 64 slice MDCT generally underestimates coronary calcium scores as compared to EBT: a phantom study. Med Phys 2007;34:3510-9. 5. Groen JM, Greuter MJ, Vliegenthart R, et al. Calcium scoring using 64- slice MDCT, dual source CT and EBT: a comparative phantom study. Int J Cardiovasc Imaging 2008;24:547-56.

    Competing interests: none.

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  8. Impaired left ventricular energy metabolism in Hypertrophic Cardiomyopathy is not due to fibrosis

    Esposito et al address an important pathophysiological question, i.e., whether altered cardiac energy metabolism in hypertrophic cardiomyopathy (HCM) is primary or secondary, due to fibrosis (1). The authors conclude that “the inverse relation observed between LE extension (LE = late enhancement a measure of fibrosis) and the alteration of PCr/ATP-ratio (PCr = phosphocreatine; ATP = adenosinetriphosphate) suggests that the impairment of myocardial energy metabolism, detected by 31P-MRS (MRS=magnetic resonance spectroscopy) in HCM patients, may be related to the presence of fibrosis rather than to a primary myocardial alteration”. However, this conclusion is not supported by the data presented and is in fact in contrast to experimental data previously published. Using HPLC measurements in rat hearts (2), we showed that myocardial scar tissue contains negligible amounts of ATP (0.2 +/- 0.1 nmol/mg protein, <1% of levels in normal myocardium). Furthermore, ATP is an essential requirement for PCr synthesis, and therefore, cardiac tissue cannot contain PCr if it contains no ATP. In line with this, we also have unpublished data showing that myocardial scar contains negligible amounts of PCr. These experimental data strongly suggest that any signal measured in the HCM patients, whether they show fibrosis or not, must almost exclusively come from the remaining cardiomyocytes and not from the scar. In conclusion, the authors demonstrate an inverse relationship of the PCr/ATP-ratio and myocardial fibrosis, but their data do not support their conclusion, i.e. that altered myocardial energetics in HCM occur secondary to fibrosis.

    1. Esposito A, De Cobelli F, Perseghin G, Pieroni M, Belloni E, Mellone R, Canu T, Gentinetta F, Scifo P, Chimenti C, Frustaci A, Luzi L, Maseri A, Del Maschio A. Impaired left ventricular energy metabolism in patients with Hypertrophic Cardiomyopathy is related to the extension of Fibrosis at Gadolinium Delayed Enhanced MR Imaging. Heart. 2008. 2. Neubauer S, Horn M, Naumann A, Tian R, Hu K, Laser M, Friedrich J, Gaudron P, Schnackerz K, Ingwall JS, et al. Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction. J Clin Invest. 1995;95(3):1092-1100.

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  9. 3 D echocardiography

    We in cardiac imaging have long been grappling with reconstructed two dimensional imaging of the heart for decision making which not only is inaccurate,frought with danger but has a long learning curve.3D Echocardiography has truly come of age and is fast emerging as a "Real imaging" modality.3D echo has the potential of redifining and simplifying cardiac imaging as it adds a new much needed dimension to this otherwise wonderful technique of imaging the heart.The authors need to be congratulated on bringing out the advantages of this advancement in a comprehensive yet simple manner.

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  10. Physiological fetal to neonatal transition is safer.

    Sir,
    Re: Fetal to neonatal cardiac transition is affected by cord clamping and interruption of the placental transfusion.

    In her paper, Gardiner (1) describes “the most dramatic changes in loading occur at birth when there is a sudden increase in distal impedance associated with removal of the placental circulation, a six fold increase in pulmonary blood flow leading to a rise in left atrial pressure and reversal or cessation of flow through the oval foramen, and a more gradual closure of the arterial duct. This new serial arrangement of the circulation demands that both ventricles are suddenly able to receive and eject the entire cardiac output that was previously shared between them.” (our emphases). She is correct in describing the effect on the newborn heart of the usual transition from fetal to adult pattern circulation that occurs in the majority of hospital births in the UK at present. However,, this is NOT a description of the natural or physiological fetal to neonatal transition but of a ‘routine’ and possibly unjustified intervention. After early cord clamping, there is indeed a sudden removal of the placental circulation leading to a sudden increase in distal impedance. By contrast, in a physiological birth the first event is for the newborn baby to initiate ventilation. This results in the marked fall in the impedance of the pulmonary circulation. Most of the output of the right ventricle is now directed into the pulmonary artery and leads to a reduced flow through the arterial duct. None of these changes are sudden although they are largely completed within a few minutes of birth. Oxygenated blood now returns to the left ventricle and is directed into the aorta and umbilical arteries. The high oxygen level of this blood together with substances released from the newly expanded lungs constricts the umbilical artery. The systemic blood pressure, which would otherwise fall with the reduced contribution from the arterial duct, is thus maintained by a slow closure of the umbilical and placental circulation. As the placental circulation closes down and the pulmonary circulation opens up there need be no significant change in the afterload of either ventricle.

    The new serial arrangements of the heart require both sides of the heart to pump out precisely the same volume. Until this happens the shunts of the arterial duct and the oval duct allow compensation of any slight differences in flow. In the term fetus the output of the right ventricle is slightly higher (250ml/minute/kg) than the left (200mls/min/kg). With the shunts in place the circulations work in parallel and allow the outputs to change without any marked changes in tissue flow. In the fetus the cardiac output is therefore described as the total output from both ventricles as the combined cardiac output (CCO). However, in the adult circulation, with the two sides of the heart working in series, the output from the left is the same as the output from the right. The cardiac output is now described as the output from one ventricle and in the newborn will be about 225mls/min/kg. There is no sudden change and certainly nothing like the doubling as suggested.

    The “sudden” changes associated with removal of the placental circulation described in Gardiner's paper are the result of applying a cord clamp to a functional placental circulation; an effect which is exaggerated if the clamp is applied before the baby breathes and the pulmonary circulation has become well established. Applying the clamp throws a large afterload onto both ventricles and it is unnecessary. As the author points out, it may result in ventricular damage (among other effects) from which the recovery is incomplete. Immediate cord clamping is standard practice in most obstetric units. Its lack of apparent harm in the majority of neonates has prevented recognition of the evidence base that it does cause injury in both term (2) and preterm babies.(3)

    Fetal and neonatal cardiology or cardiothoracic specialists need to be aware that midwives, obstetricians and neonatologists may require specific guidance about the management of the third stage of labour, particularly when a baby has an identified cardiac anomaly that might benefit from a gradual placental transfusion (or no placental transfusion). Plans for the management of the third stage should be clearly made and documented in maternal notes in advance.

    Yours sincerely,

    David J R Hutchon FRCOG,
    Consultant Obsttetrician and Gynaecologist,
    Memorial Hospital,
    Hollyhurst Road,
    Darlington. DL3 6HX

    Dr Susan Bewley MA MD FRCOG,
    Consultant Obstetrician/ Maternal Fetal Medicine
    Guy's & St Thomas' NHS Foundation Trust
    Women's Services, 10th Floor North Wing
    St Thomas' Hospital
    Westminster Bridge Rd
    London SE1 7NH

    References
    1. Gardiner HM. Response of the heart to changes in load: from hyperplasia to heart failure. Heart 2005 91(7) 871-873
    2 McDonald SJ, Middleton P Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD004074. DOI: 10.1002/14651858.CD004074.pub2
    3. Rabe H, Reynolds G, Diaz-Rossello J. A Systematic Review and Meta-Analysis of a Brief Delay in Clamping the Umbilical Cord of Preterm Infants. Neonatology 2008;93:138-144

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  11. Thiazolidinediones and cardiovascular disease

    It is very disappointing to read a largely uncritical regurgitation of opinion on the clinical use of thiazolidinediones in type 2 diabetes. Far too often, cardiology based opinions are being published without proper reference to the importance of glycaemic control in the prevention of microvascular complications and the conclusion that thiazolidinediones should be taken off the market or not prescribed pays no heed to these important issues. Additionally, the majority of clinicians now seem to have serious doubts about the veracity of the original meta analysis published by Nissen and colleague for the very same reason that the authors criticise Largo's meta-analysis of heart failure. Im not sure you can have it both ways. However, the bulk of PCTs now support the view that the thiazolidinediones are, at worst, cardio neutral in relation to ischaemic cardiovascular disease and have important beneficial effects on sustained glucose control. Rather than throwing everything out because of limited data from a meta-analysis, these findings indicate the need for better understanding of the diabetes phenotyps and a personalised approach to diabetes care that includes both cardiovascular risk management and the prevention of microvascular complications.

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  12. Acute discrete dissection of the ascending aorta

    We thank Dr Breithardt 1 for his interest in our paper reporting a case of discrete dissection of the ascending aorta 2. In the transoesophageal echocardiographic image published Dr Breithardt has interpreted the presence of a hazy horizontal line located approximately in the middle of the aortic lumen as an intimal flap dividing the aorta into an anterior false lumen and a posterior false lumen suggesting the presence of a “classic” aortic dissection (class 1 in the classification of the European Society of Cardiology 3), instead of a discrete aortic dissection (class 3 in the ESC classification). The structure indicated by Dr Breithardt as an intimal flap was just a linear artefact; it had fuzzy and indistinct borders, it was located twice as far from the transducer as the posterior aortic wall (type A artefact according to Evangelista et al 4), had a displacement parallel to the aortic walls, had a thickness > 2.5 mm 5 , and had a movement parallel to the posterior aortic wall: all features peculiar for linear artefacts. Last, but not least, no intimal flap was detected at surgical inspection. Finally, the arrow indicating the periaortic effusion points to a discrete separation of the pericardial layers representing a small amount of fluid around the ascending aorta; it had been therefore placed correctly.

    With best regards,

    Fabio Chirillo, Loris Salvador, and Francesco Bacchion

    REFERENCES

    1) Beithardt OA. Discrete dissection or overt intimal flap? Heart eLetter 6 August 2008. 2) Chirillo F, Salvador L, Bacchion F. Acute discrete dissection of the ascending aorta. Heart 2008; 94: 924. 3) Erbel R, Alfonso F, Boileau C, et al. Diagnosis and management of aortic dissection. Recommendations of the task force on aortic dissection of the European Society of Cardiology. Eur Heart J 2001; 22: 1642-1681. 4) Evangelista A, Garcia del Cavillo H, Gonzalez-Alujas T, et al. Diagnosis of ascending aortic dissection by transesophageal echocardiography: utility of M-mode in recognizing artifacts. J Am Coll Cardiol 1996; 27: 102-107. 5) Vignon P, Spencer KT, Rambaud G, et al. Differential transesophageal echocardiographic diagnosis between linear artifacts and intraluminal flap of aortic dissection or disruption. Chest 2001; 119: 1778-1790.

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  13. Multislice CT is not essential before atrial ablation

    To the Editor:

    We read with interest Drs. Tops and Schalij’s editorial regarding the use of multislice computed tomography (MSCT) to delineate left atrial and pulmonary vein anatomy prior to catheter ablation [1]. Although we agree with the value of combining three-dimensional (3D) imaging with electro- anatomical mapping techniques to guide catheter ablation, we would suggest that for the majority of patients, the optimal method to achieve this is through cardiac magnetic resonance (CMR) imaging.

    The fundamental advantage of CMR is the ability to produce 3D imaging of the left atrium and pulmonary venous anatomy, without exposure to ionising radiation. This is not a trivial consideration. The recently published AHA scientific statement on cardiac CT states that a 10mSv CT study may be associated with an increase in the possibility of fatal cancer of approximately 1 in 2000 cases [2]. In fact the radiation dose of a ‘typical’ cardiac CT maybe 50% higher than this value; the mean dose in a recent, large scale, prospective, multi-centre trial of 64-slice MSCT was 15±4mSv [3].

    More importantly, this estimation took no account of the additional risk attributable to age, gender or scan protocol. A recent study sought to estimate lifetime attributable risk (LAR) of cancer incidence associated with radiation exposure from a single cardiac MSCT examination, and determine how risk was influenced by these factors [4]. They identified a large variation dependant on these 3 factors, with younger women being particularly vulnerable to breast and lung cancer (LAR for a 20yr female was 0.70% (1 in 143)). Even with the use of tube current modulation algorithms, the estimated risk for a 20yr old female was only reduced to 1 in 219 [4].

    Although the spatial resolution of MSCT (approximately 0.5mm) is higher than that of CMR (approximately 1.5mm), Tops & Schalij correctly point out that the resolution of both techniques is still sufficient considering the diameter of modern ablation catheters (4 to 8mm) [1]. Most current mapping systems are able to integrate CT or CMR images with similar ease. Indeed, Dong et al., showed no difference in the level of registration error when images produced by CMR or MSCT were integrated with electro-anatomical mapping to guide ablation [5].

    As a major reason for performing 3D imaging is to reduce procedural fluoroscopy times (and patient radiation exposure), it is counterintuitive to expose individuals to additional ionising radiation by performing MSCT rather than CMR. Thus in answer to the question, ‘multislice CT: is it essential before atrial fibrillation ablation?’ we would argue no, it should only be considered in those patients for whom CMR is unavailable or contraindicated.

    References

    1. Tops LF, Schalij MJ. Multislice CT: is it essential before atrial fibrillation ablation? Heart 2008;94:973-5.

    2. Budoff MJ, Achenbach S, Blumenthal RS, et al. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation. 2006;114(16):1761-1791.

    3. Hausleiter J, Hermann F, Meyer T et al. International prospective multicenter study on radiation dose estimates of coronary CT angiography in daily practice - results from the PROTECTION 1 study. J Cardiovasc CT. 2008; 2(4S): S19-20.

    4. Einstein AJ, Henzlova MJ, Rajagopalan S. Estimating risk of cancer associated with radiation exposure from 64-slice computed tomography coronary angiography. JAMA. 2007;298(3):317-23.

    5. Dong J, Dickfeld T, Dalal D, et al. Initial experience in the use of integrated electroanatomic mapping with three-dimensional MR/CT images to guide catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:459-66.

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  14. Anticoagulation in Libman-Sacks Endocarditis?

    To the Editor,

    In the April 2008 issue of the Journal, Aldous (1) reported the striking case of a young male with Libman-Sacks endocarditis due to primary antiphospholipid syndrome (PAS) A transesophageal echocardiogram performed on the patient revealed a 1.5 X 1.5cm aortic valve vegetation which had apparently embolized to his left lower extremity. A trial of anticoagulation failed to result regression of the lesion. The patient eventually underwent successful valve-sparing surgery and was again anticoagulated.

    We differ with the author’s contention that long term anticoagulation in PAS will "usually proceed to regression of valve disease". While the effects of anticoagulation therapy on patients with PAS and cardiac involvement have not been extensively studied, several small recent studies have all shown that the cardiac lesions associated with the PAS may not respond to, or may even progress, despite, anticoagulation therapy. In the largest prospective study of which we are aware, Turiel et al (2) followed 47 patients with PAS over a 5 year period with serial transesophageal echocardiography. All patients received oral anticoagulants with or without anti-platelet therapy. Over the period of follow-up, cardiac involvement remained unchanged in 64% (30 subjects). Moreover, new cardiac abnormalities appeared in 36% (17 subjects). These findings reflect the findings of other smaller series (3,4). Hence, it would appear that anticoagulation therapy is ineffective in treating the cardiac lesions associated with PAS.

    1.Aldous S. An interesting presentation of antiphospholipid syndrome Heart 2008; 94:421.

    2.Turiel M, Sarzi-Putin P, Peretti R, Bonizzato S, Muzzupappa S, Atzeni F et al. Five year follow-up by transesophageal echocardiographic studies in primary antiphosphospholipid syndrome. Am J Cardiol 2005;96:574-9.

    3.Espinola-Zavaleta N, Vargas-Barron J, Colmenares-Galvis,T, Cruz- Cruz F, Romero-Cardenas A, Keirns C et al. Echocardiographic evaluation of patients with primary antiphospholipid syndrome. Am Heart J 1998;137:974- 9.

    4.Espinola-Zavaleta N, Montes RM, Soto ME, Vanzzini NA, Amigo MC. Primary antiphospholipid syndrome: a 5-year transesophageal echocardiographic follow-up study. J Rheumatol 2004;31:2402-7.

    Competing interests: None

    Correspondence to: jeffrey.silbiger@mssm.edu

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  15. Discrete dissection or overt intimal flap?

    Dear Editor,

    I am puzzled by the image published by Chirillo et al.(1) which supposedly shows a "discrete aortic dissection", but - according to the authors - no intimal flap.

    My interpretation of the provided image would be that the hazy horizontal line which runs through the middle of the aorta most likely represents a typical intimal flap separating a true lumen (lower part) from the false lumen (with the intimal splitting tear, upper part). A cineloop including both short-axis and longitudinal views, as well as a colour-Doppler study might help to identify the intimal flap more clearly.

    In addition, the arrow pointing to "periaortic effusion"(PE) is obviously misplaced.

    With best regards, Ole-A. Breithardt

    (1) F Chirillo, L Salvador, and F Bacchion. Acute discrete dissection of the ascending aorta. Heart 2008; 94: 924

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  16. Moderate patient-prosthesis mismatch can impact on mortality after aortic valve replacement

    Dear Editor,

    We have read with interest the article of Mascherbauer et al.[1] recently published in Heart and we congratulate our colleagues for an honest effort on shedding some light on an important issue which is still generating some controversy. Nonetheless, based on the title and the conclusions of both the abstract and the paper, we are concerned that the paper may unfortunately convey the wrong message i.e. that moderate prosthesis-patient mismatch should never be a concern in patients undergoing aortic valve replacement. Moreover, from the introduction, justification for the study appears to be based on the perception that our previous papers were recommending “that even left ventricular outflow tract enlargement may be justified to prevent moderate PPM”. In fact, we have never made such an unqualified recommendation. Indeed, our findings as well as those of others [2] show that the impact of moderate PPM on outcomes is most significant in patients with LV dysfunction as compared to patients without dysfunction (e.g. early mortality = 16% vs 5%, p< 0.001) and our recommendation has always been that if PPM is anticipated, alternative options should be considered in light of the patient’s overall clinical condition and the risk to benefit ratio of doing such procedures.

    Unfortunately, the number of patients with LV dysfunction in the present study is too small to do any analysis in this regard. Moreover, LV dysfunction might even be a confounding variable since it was significantly more prevalent (15.2% vs 5.6%, p = 0.003) in the patients without PPM and hence, it could explain the relatively high mortality observed in this group (5.5%). Indeed, operative mortality for AVR in patients without LV dysfunction is usually 1-4% and if such had been the case, the markedly higher operative mortality (10.2%) observed in the group with PPM might have become statistically significant.

    Notwithstanding this consideration, the statistical power of the study is clearly limited. Indeed, the difference in short-term mortality (5.5% vs. 10.2%) between the 2 groups did not reach statistical significance (i.e. p=0.14 with Yates correction in the results section and in Table 4, or p=0.098 without Yates correction in the Table 3). However, considering the previous study of Blais et al. [3] for sample size estimation, the inclusion of 361 patients leads to a statistical power of only 43% for the analysis of operative mortality. Moreover, using the same percentage of operative mortality in the two groups, but with a sample size of 880 patients (i.e. corresponding to the number of patients which would have result in a 80% a priori statistical power), the p-value would have been of 0.009 (without Yates correction). Hence, had the same sample size been closer to that of previous series, the findings and conclusions of the paper could have been entirely different.

    Furthermore, as opposed to the perception given in the article of Mascherbauer et al., aortic root enlargement is certainly not the only and/or first line option to avoid PPM. The preventive strategy should rather be focused primarily on the implantation of prosthesis models providing a better hemodynamic performance and thereby a larger EOA in relation to patient’s annulus size. And in this regard, several recent studies have demonstrated that PPM can successfully be avoided or its severity reduced with the use of such strategy. [4-6]

    Given these limitations, the present paper provides little new information and the findings certainly do not justify the unqualified conclusion that moderate PPM has no impact on short or long term mortality which implies that it can almost be ignored. To the contrary, we reiterate that the projected indexed EOA should always be calculated at the time AVR and that the decision with regards to the prosthesis to be implanted should be made in light of the patient’s overall clinical condition.

    Clearly and based on many concurring data in the literature, every effort should be made to avoid severe PPM in every patient undergoing aortic valve replacement and moderate PPM if LV dysfunction and/or severe LVH is present. Finally, it should be mentioned that the underestimation of EOA in bi-leaflet prosthesis is based on in vitro studies and that this has not been shown to be a consistent finding in vivo. Indeed, recent studies using either the indexed EOA measured at predischarge exam or the projected indexed EOA derived from in vivo reference values demonstrated that the same cut-off values for indexed EOA were valid to predict outcomes in their series of patients with bi-leaflet mechanical prosthesis. [7;8]

    Moreover, in one of these studies, even a moderate PPM was shown to negatively impact long- term survival after adjustment for other risk factors. [8]

    References

    [1]. Mascherbauer J, Rosenhek R, Fuchs C, Pernicka E, Klaar U, Scholten C, Heger M, Wollenek G, Maurer G, Baumgartner H.
    Moderate patient -prosthesis mismatch after valve replacement for severe aortic stenosis has no impact on s.
    Heart. 2008.

    [2]. Ruel M, Al-Faleh H, Kulik A, Chan K, Mesana TG, Burwash IG.
    Prosthesis-patient mismatch after aortic valve replacement primarily affects patients with pre-existing left ventricular dysfunction: Impact on survival, freedom from heart failure, and left ventricular mass regression.
    J Thorac Cardiovasc Surg. 2006;131:1036-1044.

    [3]. Blais C, Dumesnil JG, Baillot R, Simard S, Doyle D, Pibarot P.
    Impact of prosthesis-patient mismatch on short-term mortality after aortic valve replacement.
    Circulation. 2003;108:983-988.

    [4]. Bleiziffer S, Eichinger WB, Hettich I, Guenzinger R, Ruzicka D, Bauernschmitt R, Lange R.
    Prediction of valve prosthesis-patient mismatch prior to aortic valve replacement: which is the best method?
    Heart. 2007;93:615-620.

    [5]. Dalmau MJ, Gonzalez-Santos JM, Lopez-Rodriguez J, Bueno M, Arribas A, Nieto F.
    One year hemodynamic performance of the Perimount Magna pericardial xenograft and the Medtronic Mosaic bioprosthesis in the aortic position: a prospective randomized study.
    ICVTS. 2007;6:345-349.

    [6]. Kunadian B, Vijayalakshmi K, Thornley AR, de Belder MA, Hunter S, Kendall S, Graham R, Stewart M, Thambyrajah J, Dunning J.
    Meta-analysis of valve hemodynamics and left ventricular mass regression for stentless versus stented aortic valves.
    Ann Thorac Surg. 2007;84:73-78.

    [7]. Mohty D, Malouf JF, Girard SE, Schaff HV, Grill DE, Enriquez- Sarano ME, Miller FA, Jr.
    Impact of prosthesis-patient mismatch on long- term survival in patients with small St. Jude medical mechanical prostheses in the aortic position.
    Circulation. 2006;113:420-426.

    [8]. Kohsaka S, Mohan S, Virani S, Lee VV, Contreras A, Reul GJ, Coulter SA.
    Prosthesis-patient mismatch affects long-term survival after mechanical valve replacement.
    J Thorac Cardiovasc Surg. 2008,135:1076-80.

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  17. Author's response

    Dear Editor,

    We appreciate the interest of Rosa et al in our study.[1] They raise 3 points with respect to our results.[2] The first queries whether we had left out the subjects dropped out during the course of the study, which might have overestimated the clinical effectiveness of the treatment arms. The second deals with the additional beneficial effects of irbesartan and ramipril beyond their blood pressure control. The third concerns the calculation of LV mass based on dimensions of the left ventricle at end- diastole.

    All our patients were analyzed on the basis of intention-to-treat, including all the cases up to their pre-defined follow-up at week 12, 24 or 52 before their withdrawal for various reasons as stated in the results section. The unequal randomization of patients into the three treatment arms that might have given Rosa et al a false impression of excluding drop -out cases for the analysis was due to our original intention of enrolling 400 patients with designated sequence of random allocation. The recruitment process was slow for reasons as mentioned in the limitations section. As the result, the sample of patients recruited for the three arms were unfortunately relatively small and, therefore, we were unable to detect any significant changes in terms of LV mass by 2-dimensional echocardiography. This issue warrants further study with a larger cohort of patients.[3]

    It is tantalizing to speculate that irbesartan with or without ramipril have additional beneficial effects on the myocardium and peripheral vascular endothelium beyond blood pressure control in patients suffering from heart failure with normal ejection fraction (HFNEF). For example, the relationship between arterial compliance and diastolic dysfunction is clearly important. [4]. However this interesting notion will require proof in HFNEF patients and deserves a further large-scale prospective randomized study, given the magnitude of this vexing clinical problem in Hong Kong and worldwide.[5,6]. Interestingly we found that cough was much less of a problem than predicted in an Asian population and our cough rate in the ramipril group (10%) is comparable to previous studies in the West.

    The comments on the effect of diuretics on left ventricular dimension are well taken and relevant but the formula we used is well established and widely used. Furthermore, all three patient groups received diuretics so the effect would have been similar. Future studies could use 3D- echocardiography or MRI for more accurate assessment of LV mass.

    References

    1. Rosa EM, Träsel HAV, Gravina LB.
    Interesting findings in The Hong Kong Heart Failure Study.
    Heart 2008 eLetters Online 24 May 2008

    2. Yip GW, Wang M, Wang T, et al.
    The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction.
    Heart. 2008;94:573-80.

    3. Carson P, Massie BM, McKelvie R, et al.
    The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design.
    J Cardiac Fail 2005;11:576–585.

    4. P M Mottram, B A Haluska, R Leano, S Carlier, C Case, and T H Marwick
    Relation of arterial stiffness to diastolic dysfunction in hypertensive heart disease
    Heart 2005; 91: 1551 - 1556.

    5. Yip GWK, Ho PPY, Woo KS, Sanderson JE
    Comparison of frequencies of left ventricular systolic and diastolic heart failure in Chinese living in Hong Kong.
    Am J Cardiol 1999;84:563-567.

    6. Sanderson JE.
    Heart failure with a normal ejection fraction.
    Heart. 2007;93:155-8.

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  18. Interesting findings in The Hong Kong Heart Failure Study

    Dear Editor,

    Patients with heart failure and a normal left ventricular systolic function correspond to almost half of all patients with congestive heart failure(1). However, the great majority of the data presented in the medical literature are related to studies that observe subjects with heart failure followed by systolic dysfunction. It is notable that Yip et al. (2) in their article assess the quality of life and global and regional ventricular function in heart failure with normal ejection fraction.

    After reading with interest The Hong Kong Heart Failure Study(2), we considered this study revealed important findings and, among those, three have caught our attention:

    1. The subjects who left the study due to adverse effects were not included in final analysis and, consequently, did not provide changes in final results. According to Fischer et al.(3), clinical effectiveness may be overestimated if an intention to treat analysis is not done.

    2. Both drugs Irbesartan and Ramipril do not play their roles like anti-hypertensive agents, as should be expected(4), neither do they present adverse events, like irritative coughs.

    3. Ventricular mass is inferred from a mathematical calculation, which depends on intraventricular diameter(5). The usage of diuretics decreases preload, consequently, there is a decrease in left ventricle internal diameter. Mathematically speaking, a reduction in ventricular mass occurs. This effect may not be reproduced if a direct anatomic analysis was conducted.

    References

    (1) Sanderson JE.
    Heart failure with a normal ejection fraction.
    Heart. 2007 Feb; 93(2):155-8.

    (2) Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, et al.
    The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction.
    Heart. 2008 May; 94(5):573-80.

    (3) Fisher L, Dixon D, Herson J, Frankowski R, Hearon M, Pearce K.
    Intention to treat in clinical trials. In: Pearce K, editor. Statistical issues in drug research and development.
    New York: Marcel Dekker; 1990: 331-50.

    (4) Franklin S, Lapuerta P, Cox D, Donovan M.
    Initial combination therapy with irbesartan/hydrochlorothiazide for hypertension: an analysis of the relationship between baseline blood pressure and the need for combination therapy.
    J Clin Hypertens (Greenwich). 2007 Dec; 9(12 Suppl 5):15-22.

    (5) Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al.
    Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.
    J Am Soc Echocardiogr. 2005 Dec; 18(12):1440-63.

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  19. Exercise Capacity in Diastolic Heart Failure

    Dear Editor,

    We read with great interest the article by Yip and colleagues, reporting the results of a randomised controlled trial of diuretics, irbesartan and ramipril in patients with heart failure and normal ejection fraction(1). The authors are to be commended for their contribution to the evidence base for the management of this condition. The PROBE design tested the hypothesis that addition of ramipril or irbesartan would be superior to diuretics alone and evaluated quality of life, exercise capacity, ventricular function and NT-pro-BNP levels in three groups of 50 patients. Quality of Life Score ( Minnesota Heart Failure Symptom Questionnaire) improved significantly and similarly in all three groups between baseline and 52 weeks. Exercise capacity assessed by 6 minute walk test at baseline and 24 weeks improved only slightly. The authors suggest that this may be because the test is not robust enough to identify effective treatment or that older patients have too many competing factors which influence mobility. Our experience differs from this. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) trial compared the effects of perindopril and placebo in 850 patients >70 years of age or older,( mean age 76) who had heart failure and echocardiographic markers suggesting diastolic heart failure(2). Perindopril reduced heart failure hospitalisations and improved symptoms at one year. There was also a statistically significant increase in 6 minute walk distance in patients assigned to perindopril over 1 year of follow up, with a mean difference in change of 14m (3 to 25, p<0.011)(3). A change of this magnitude is both statistically significant and clinically relevant.

    The baseline characteristics of patients in both studies were very similar, although patients in PEP-CHF were slightly older, had a higher prevalence of prior myocardial infarction and their baseline exercise capacity was poorer. Despite this, important benefits in function were seen in PEP-CHF with active treatment. The Hong Kong Study evaluated 6 minute walk distance after 24 weeks of treatment and it is possible that this was too short a time for effects on exercise capacity to be demonstrable.

    The 6 minute walk distance has previously been evaluated in frail, older patients with heart failure (4). O’Keefe’s study included frail patients with multiple comorbidity, median age 81 years (range 74-92 years) and showed that the 6 minute walk test was both reproducible and responsive.

    We agree entirely with the authors that, particularly for older patients, improvements in symptoms and exercise capacity are as important as mortality benefits, and would encourage clinicians to use the 6 minute walk test as a simple and meaningful outcome measure in heart failure.

    REFERENCES

    1. Yip GWK, Wang M, Wang T et al.
    The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction.
    Heart 2008;94:573-80.

    2.Cleland JGF, Tendera M, Adamus J et al
    Perindopril for elderly people with heart failure: the PEP-CHF Study.
    Eur J Heart Fail 2001;1:211-17

    3.Cleland JGF, Tendera M, Adamus J et al
    The perindopril in elderly people with chronic heart failure (PEP-CHF) study
    Eur Heart J 2006;27:2338-45

    4. O’Keeffe ST, Lye M, Donellan C et al.
    Reproducibility and responsiveness of quality of life assessment and six minute walk test in elderly heart failure patients.
    Heart 1998;80:377-382.

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  20. High-dose statin therapy, women and cancer

    Dear Editor,

    We read the interesting secondary analysis of the 4.9-year Treating to New Targets (TNT) study [1] reporting on the effects of aggressive low- density lipoprotein (LDL) cholesterol lowering in women (median age of 63.5 years) with stable coronary heart disease. Based on the reported data, we have serious concerns regarding the large excess in cancer mortality seen among the women randomized to high-dose atorvastatin (80 mg daily) therapy compared to the women randomized to low-dose (10 mg daily) atorvastatin therapy (p = 0.004). Alarmingly, annualized cancer mortality was 1 in 1000 patients in the low-dose atorvastatin group and 4 in a 1000 patients in the high-dose group. Unfortunately, there was a trend towards increased all-cause mortality in the high-dose compared to the low-dose atorvastatin group, neutralizing any benefit in cardiovascular mortality.

    A recent meta-analysis of large randomized statin trials has revealed a significant inverse relationship between achieved LDL-cholesterol levels and cancer incidence [2]. Statins have been shown to significantly increase peripheral regulatory T cell (Treg) concentration, in vivo, by inducing the transcription factor, forkhead box P3 [3]. An increase in Treg concentration may impair host anti-tumor response by suppressing tumor specific effector T cell responses leading to an increase in cancer [4]. Not surprisingly, in many solid tumors, an increased Treg concentration predicts a significant reduction in patient survival [5].

    Interestingly, estrogens also have been found to significantly increase Treg concentration [6]. Therefore, the combination of statins and estrogens may be particularly potent in raising Treg levels. This begs the question: Was the increase in cancer seen in the high-dose atorvastatin treated group, predominantly seen among those women whom were also taking estrogens? Perhaps, the investigators can provide that answer. This is important, since many women are treated with both statins and estrogens. Additionally, a synergism between statins and estrogen in raising Treg levels may explain why an increase in cancer mortality in the TNT trial was seen among women, but not among men randomized to the high-dose atorvastatin group [1]. Finally, we feel that high-dose atorvastatin therapy be avoided in women because of the increased risk of subsequent cancer death.

    References

    [1] Wenger NK, Lewis SJ, Welty FK, et al, on behalf of the TNT Steering Committee and Investigators.
    Beneficial effects of aggressive low-density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study.
    Heart 2008; 94: 434-439.

    [2] Alsheikh-Ali AA, Maddukuri PV, Han H, et al.
    Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized trials.
    J Am Coll Cardiol 2007; 50: 409-418.

    [3] Mausner-Fainberg K, Luboshits G, Mor A, et al.
    The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells.
    Atherosclerosis 2008; 197: 829-839.

    [4] Curiel TJ.
    Tregs and rethinking cancer immunotherapy.
    J Clin Invest 2007; 117: 1167-1174.

    [5] Yakirevich E, Resnick MB.
    Regulatory T lymphocytes: pivotal components of the host antitumor response.
    J Clin Oncol 2007; 25: 2506-2508.

    [6] Prieto GA, Rosenstein Y.
    Oestradiol potentiates the suppressive function of human CD4+CD25+ regulatory T cells by promoting their proliferation.
    Immunol 2006; 118: 58-65.

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  21. Multilevel analysis for OCT imaging

    Dear Editor,

    Chen et al., present the results of a non-randomised prospective study, in which individual struts in 28 stents implanted in 26 lesions in 24 patients were assessed by OCT. The authors report strut apposition and coverage as binary variables and pool strut-related observations to produce percentages of incompletely apposed/uncovered struts for stents types. It is evident that individual observations related strut coverage or strut-to-intima distance violate the fundamental assumption of independence of observations required for the application of classical statistical methods. Struts within lesions, in fact, share common characteristics, making them more similar to each other than to struts from different lesions. Ignoring this multilevel structure results in spuriously low estimated standard errors and p-values.

    Similarly, when assessing neontimal thickness (NIT), Chen et al. measure maximal and minimal NIT for each strut and produce summary statistics at stent level by compiling these values into means. Subsequently, they recompile the means to produce “means of means” and compare these between stent groups using standard statistical tools. The use of summary statistics ignores the variation at strut level and the precision of the cluster estimate. Moreover, this can only be used for data with a 2-level structure and, thus, not in cases such as the present study in which more than one lesion belong to the same patient (3-level structure: struts clustered within lesions clustered within patients).

    Optical coherence tomography (OCT) has revolutionised intracoronary imaging, providing a unique insight into all aspects of coronary stenting. Realisation of the multilevel structure of OCT data on coronary stenting is essential to the design, reporting and critical appraisal of all stent -related OCT research. To ignore this, could have disastrous effects on the validity of any statistical analysis and, eventually, on the credibility of the technique itself.

    REFERENCES

    (1) B X Chen, F Y Ma, W Luo, J H Ruan, W L Xie, X Z Zhao, S H Sun, X M Guo, F Wang, T Tian, and X W Chu
    Neointimal coverage of bare-metal and sirolimus-eluting stents evaluated with optical coherence tomography
    Heart 2008; 94: 566-570

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  22. Interesting findings in The Hong Kong Heart Failure Study

    Dear Editor,

    Patients with heart failure and a normal left ventricular systolic function correspond to almost half of all patients with congestive heart failure(1). However, the great majority of the data presented in medical literature are related to studies that observe subjects with heart failure followed by systolic disfunction. It is notable that Yip et al. (2) in your article assess the quality of life and global and regional ventricular function in heart failure with normal ejection fraction.

    After reading with interest The Hong Kong Heart Failure Study(2), we considered this study revealed important findings and, among those, three have caught our attention:

    1. The subjects who left the study due to adverse effects were not included in final analysis and, consequently, did not provide changes in final results. In according to Fischer et al.(3), clinical effectiveness may be overestimated if an intention to treat analysis is not done.

    2. Both drugs Irbesartan and Ramipril do not play their roles like anti-hypertensive agents, as should be expected(4-9), neither they present adverse events, like irritative coughs.

    3. Ventricular mass is inferred from a mathematical calculation, which depends on intraventricular diameter(10). The usage of diuretics decreases preload, consequently, there is a decrease in left ventricle intern diameter. Mathematically speaking, a reduction on ventricular mass occurs. This effect maybe would not be reproduced if a direct anatomic analysis was conducted.

    References

    (1) Sanderson JE.
    Heart failure with a normal ejection fraction.
    Heart. 2007 Feb;93(2):155-8.

    (2) Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, et al.
    The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction.
    Heart. 2008 May;94(5):573-80.

    (3) Fisher L, Dixon D, Herson J, Frankowski R, Hearon M, Pearce K.
    Intention to treat in clinical trials. In: Pearce K, editor. Statistical issues in drug research and development.
    New York: Marcel Dekker; 1990: 331-50.

    (4) Franklin S, Lapuerta P, Cox D, Donovan M.
    Initial combination therapy with irbesartan/hydrochlorothiazide for hypertension: an analysis of the relationship between baseline blood pressure and the need for combination therapy.
    J Clin Hypertens (Greenwich). 2007 Dec;9(12 Suppl 5):15-22.

    (5) Raskin P, Guthrie R, Flack J, Reeves R, Saini R.
    The long-term antihypertensive activity and tolerability of irbesartan with hydrochlorothiazide.
    J Hum Hypertens. 1999 Oct;13(10):683-7.

    (6) Lapuerta P.
    Irbesartan/HCTZ as initial treatment in patients with moderate hypertension.
    16th Meeting of the European Society of Hypertension; 2006; Madrid, Spain; 2006.

    (7) Neutel JM, Franklin SS, Lapuerta P, Bhaumik A, Ptaszynska A.
    A comparison of the efficacy and safety of irbesartan/HCTZ combination therapy with irbesartan and HCTZ monotherapy in the treatment of moderate hypertension.
    J Hum Hypertens. 2008 Apr;22(4):266-74.

    (8) Heidbreder D, Froer KL, Breitstadt A, Cairns V, Langley A, Bender N.
    Combination of ramipril and hydrochlorothiazide in the treatment of mild to moderate hypertension: Part 1--A double-blind, comparative, multicenter study in nonresponders to ramipril monotherapy.
    Clin Cardiol. 1992 Dec;15(12):904-10.

    (9) Genthon R.
    Study of the efficacy and safety of the combination ramipril 2.5 mg plus hydrochlorothiazide 12.5 mg in patients with mild-to-moderate hypertension. ATHES Study Group.
    Int J Clin Pharmacol Res. 1994;14(1):1-9.

    (10) Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al.
    Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.
    J Am Soc Echocardiogr. 2005 Dec;18(12):1440-63.

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  23. Elevation of BNP in Newborns with Hypertrophic Cardiomyopathy due to Pompe disease

    Dear Editor,

    Kaski et al. (1) recently reported that in children with hypertrophic cardiomyopathy (HC) the B-type natriuretic peptide (BNP) level correlated with maximal left ventricular (LV) wall thickness and could be a useful tool in assessing disease severity. In adult patients with HC, circulating plasma BNP has been related to the magnitude of heart failure and can be used to detect HC in patients when symptom evaluation is difficult (2). Here we further demonstrate the role of BNP in newborn babies affected by Pompe disease.

    We detect Pompe disease (acid alpha-glucosidase deficiency) in newborns though large-scale newborn screening (manuscript in press). We totally identified five patients at a median age of 0.75 months (range: 0.25-1 month) and none of them showed symptoms like feeding difficulty, dyspnea, or muscle weakness at the time of diagnosis. However, their median left ventricular mass index (LVMI) was 120.3 g/m2 (range: 108.9-186 g/m2; normal levels, 47.4 +/-6.2 g/m (3)), and mean BNP level was as high as 556.97 pg/mL (range: 420.37-1300 pg/mL, normal babies less than one month of age: median 28.61 pg/mL, 97.5th percentile 169.10 pg/mL, n=23). After receiving two infusions biweekly of human recombinant acid alpha- glucosiase (Myozyme, Genzyme), their median BNP level dropped to 16.35 pg/mL (range 0-77 pg/mL). We observed a positive correlation between BNP and LVMI (correlation coefficient=0.63) in the five babies detected by screening. We also examined BNP and LVMI in four older infants with Pompe disease who were diagnosed by clinical symptoms. In comparison with the newborn cases, those patients were discovered at a later age (median: 3.1 months, range: 1.8-4 months, p=0.016), tended to have higher LVMI (median: 189.1 g/m2, range: 151.6-307.5 g/m2, p=0.19), but lower median BNP level (412.6 pg/mL, range: 132.8-5190.5 pg/mL, p=0.556). However, the correlation between BNP and LVMI was very high (correlation coefficient=0.92). After 2 doses of Myozyme, their median BNP level dropped to 70.86 pg/mL (range: 12.45- 724.09 pg/mL), slightly higher than the babies detected by screening (p=0.016).

    Our observation suggests that in Newborns with Hypertrophic Cardiomyopathy due to Pompe disease, BNP is not only a good marker to monitor the treatment for HC, but also a very useful tool to make early diagnosis of Pompe disease, before the appearance of skeletal muscle weakness. Our current experience in treating early-diagnosed Pompe patients suggests that treatment initiated before the age of one month would be most fruitful (manuscript in preparation). Therefore, BNP will be indispensable in diagnosing HC among newborn babies affected by Pompe disease, probably as well as among babies affected by other congenital cardiomyopathies.

    Interestingly, the BNP levels in the Pompe newborns seem to be higher than the levels in the clinically-diagnosed cases that had more advanced disease and higher LVMI. BNP is synthesized and released by ventricular myocardial cells in response to myocyte stretch (4). It is possible that the hemodynamic abnormalities in newborn babies with Pompe disease are different from the older patients, which leads to the less correlation between BNP and LVMI. The higher pulmonary resistance in newborns may also exaggerate the ventricular wall stress in Pompe newborns. Further researches will be necessary to increase our knowledge about BNP and its applications.

    References

    1. Kaski JP, Tome-Esteban MT, Mead-Regan SJ, Pantazis A, Marek J, Deanfield JE, McKenna WJ, Elliott PM
    B-Type Natriuretic Peptide Predicts Disease Severity in Children With Hypertrophic Cardiomyopathy
    Heart 2007.

    2. Binder J, Ommen SR, Chen HH, Ackerman MJ, Tajik AJ, Jaffe AS
    Usefulness of brain natriuretic peptide levels in the clinical evaluation of patients with hypertrophic cardiomyopathy
    Am J Cardiol 2007; 100:712- 714.

    3. Joyce JJ, Dickson PI, Qi N, Noble JE, Raj JU, Baylen BG
    Normal right and left ventricular mass development during early infancy
    Am J Cardiol 2004; 93:797-801.

    4. de Lemos JA, McGuire DK, Drazner MH.
    B-type natriuretic peptide in cardiovascular disease
    Lancet 2003; 362:316-322.

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  24. QRISK - Limitations in Validation?

    Dear Editor,

    We have read with interest the recent article by Hippisley Cox et al on the validation of the new risk estimation function, QRISK. [1] QRISK demonstrated improved discrimination and calibration compared to Framingham in the independent British database, THIN. Previously, we wrote suggesting some methodological limitations in the derivation of the function. [2] Our main concerns were firstly, the use of data in which 70% had missing values for total cholesterol/HDL cholesterol ratio which were, su8bsequenrtly imputed and secondly, the use of data from persons on statin therapy. [3] We believed that the factors were contributing to the trivial and insignificant hazard ratio associated with TC/HDL ratio in the original function (0.001 per unit increase in ratio).

    Hippisley-Cox et al subsequently published a very satisfactory reply in which these concerns were confirmed. [4] A new version of the function excluding those on statin therapy and using an improved multiple imputation method was derived in which the TC/HDL ratio was a significant risk factor with a hazard ratio of 1.20 in men and 1.17 in women for CVD events. This was the version used in the recent validation exercise. In a further version of the function in which all those with missing data were excluded, the TC/HDL ratio assumed greater importance again, with hazard ratios of 1.25 in men and 1.20 in women. We suggest two possible limitations of the validation exercise. Firstly, again a large proportion of the dataset had missing data on lipid measurements (29%). In the case of missing data in the validation cohort mean values from the derivation cohort, QRESEARCH were substituted. The authors have not reported whether there were differences in outcomes in those with missing data. However, substantial differences can be assumed, given that in the previous cohort the mortality in those with missing data was substantially higher than that of individuals with complete data. (10.9% versus 4.9% respectively) Therefore, it is not reasonable to assume that this group would have the same risk factor levels as those with complete data in the QRESEARCH database. We suggest that validation of QRISK in a cohort with more complete data should be undertaken prior to widespread acceptance of the function.

    Secondly, the comparison to the performance of the Framingham function has been done using the function which was derived in 1991, using North American data with baselines between in the 1950s and 1970s. [5] Obviously, important secular trends have occurred during the intervening years. Therefore, the improvement in calibration of the QRISK function compared to Framingham may only reflect the use of more recent and local data, as opposed to an improvement related to the methods or variables used in QRISK. We suggest that a comparison to a version of Framingham or SCORE re-calibrated to a modern British population would be more appropriate. Additionally, while improve in the AUROC is a reasonable indication of superior discrimination of the model, the percentage of individuals correctly reclassified to a different risk category using the new function is particularly clinically relevant, since treatment decisions are often made based on risk categorisation [6] .

    References

    1. Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, Brindle P
    Performance of the QRISK cardiovascular risk prediction algorithm in an independent UK sample of patients from a general practice: a validation study
    Heart 2008; 94: 34-49

    2. Cooney MT, Dudina AL, Graham IM
    QRISK – Methodological limitations?
    www.bmj.com/cgi/eletters/335/7611/136#172411, accessed Oct 9th 2007

    3. Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, May M, Brindle P
    Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: prospective open cohort study.
    BMJ 2007; 335: 136-147

    4. Hippisley-Cox J, Coupland C, Vinogradova Y, May M, Brindle P
    QRISK – authors response
    www.bmj.com/cgi/eletters/335/7611/136#174181, accessed Oct 9th 2007

    5. Anderson KM, Odell PM, Wilson PW, Kannel WB
    Cardiovascular disease risk profiles
    Am Heart J 1991; 121: 293-8

    6. Pencina MJ, D' Agostino RB S, D' Agostino RB J, Vasan RS
    Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond.
    Stat Med 2008; 27: 207-12

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  25. Dear Editor,

    We would like to thank Jaarsma on highlighting an important topic regarding choosing appropriate outcomes in heart failure research. The COACH trial recently found that neither moderate or intensive disease management programmes by a nurse specialising in management of patients with heart failure reduced death or hospitalisation compared to standard treatment. (1) In contrast, our trial evaluated the effectiveness of improvements in prescribing of evidence based therapies for heart failure and the appropriate assessment in terms of echocardiography and quality of life. There are major differences between the two trials. The COACH trial enrolled patients with heart failure after hospitalisation (1). Most previously published studies of disease management programmes for patients with heart failure have recruited patients in a similar way (2). Our trial was one of the first large intervention trials to have recruited patients with both confirmed and presumed heart failure from the community. We chose our outcomes of process, intermediate outcomes of care and optimisation of diagnosis and medication management because despite the strong evidence base, patients are still inadequately diagnosed and managed in primary care (3) We also used an outcome of health related quality of life as these are important outcomes for patients and they have been recognised as important clinical indicators which predict use of health services and mortality in people with chronic heart failure. (4) Jaarsma mentions that the challenge is to find the most optimal heart failure management programme in both primary and secondary care. However, we believe that different models of care and assessment of outcomes will be required for management of patients who have been discharged after hospitalisation compared to those who are managed by primary care physicians. Jaarsma also highlights that the COACH trial used time to hospitalisation then questions whether this is a good endpoint. This was illustrated in our cost-effectiveness study when the disease management programme seemed to lead to increased use of outpatient and inpatient services. We therefore agree that time to hospitalisation may not be a good endpoint if appropriate care can lead to referrals for hospitalisation (5).

    References

    (1) Jaarsma T, van der Wal MH, Lesman-Leegte I, Luttik ML, Hogenhuis J, Veeger NJ et al.
    Effect of moderate or intensive disease management program on outcome in patients with heart failure: Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH).
    Arch Intern Med 2008; 168(3):316-324.

    (2) McAlister FA, Lawson FME, Teo KK, et al.
    Randomised trials of secondary prevention programmes in coronary heart disease: Systematic review.
    BMJ 2001; 323(7319):957-962.

    (3) Strum H, Haaijer-Ruskamp F, Veeger N, Balje-Volkers C, Swedberg K, van Gilst W.
    The relevance of comorbidities for heart failure treatment in primary care: A European survey.
    Eur J Heart Fail 2006;8:31-37.

    (4) Chin MH, Goldman L.
    Gender differences in 1-year survival and quality of life among patients admitted with congestive heart failure.
    Med Care 1998; 36(7):1033-1046.

    (5) Turner DA, Paul S, Stone M, Juarez-Garcia A, Squire I, Khunti K.
    The cost-effectiveness a disease management programme for secondary prevention of coronary heart disease and heart failure in primary care.
    Heart (in press)

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  26. Tissue Doppler Imaging Echocardiography – Technological advancement or retrograde development?

    Dear Editor,

    I read with great interest the article presenting tissue Doppler techniques as technological advances.[1] The authors conclude with the “limitations” of tissue Doppler stating “There is still a significant variability in TDI (tissue Doppler imaging) derived parameters because of differences in machine characteristics and lack of guidelines for standardization of sample positions and machine settings. Therefore it is still difficult to provide firm recommendations for clinical practice. More clinical trials are needed for establishing sensitive and effective parameters for diagnosing specific conditions or detecting abnormalities”. In which case is it technological advances?

    There are philosophical, methodical and application flaws in tissue Doppler.[2] The basic principles of measurement and Doppler are compromised in this technique. After you make a measurement as per established methods you could have “limitations”. But if you make a measurement paying scant regard to established norms it’s a “blunder”. So you cannot blame “differences in machine characteristics” nor “lack of guidelines for standardization of sample positions and machine settings”. It is like measuring the height of a patient without knowing the required alignment, making random measurements and calling the erroneous measurements as “limitations” of the scale (see figure)! This would be a case of right tool, wrongly used. You cannot sweep the basic flaws under the carpet by labeling them as “limitations”.

    The authors state “In practice, from the apical window, only longitudinal shortening can be obtained from every segment of the left and right ventricle. These longitudinal velocities reflect both active and passive myocardial motion, which forms the major limitation of the technique”. The problem here is much more than “active and passive myocardial motion”. Doppler will give consistent results only if there is a unique velocity or if the other conflicting velocity vectors are constant. In tissue motion there are several velocity vectors affecting the resultant longitudinal vector. Since we do not know the influence of these conflicting vectors we will consistently get variable results. Compare flow motion and tissue motion to understand this better.

    The authors also state that “The sample volume should be positioned in the centre of the region of interest. It is recommended to check the sample volume position before acquiring the still frames since the motion of the atrioventricular ring may differ around the basal myocardial segment”. Pray, where are the regions of interest and the points of interrogation? In case of flow Doppler these are unique points - the normal and abnormal orifices. Can we ever define a proper point of interrogation on tissue Doppler? That is also why the authors correctly state “normal values for longitudinal velocities depend on the position of the sample area within the wall”. This is also why, as the authors mention, there are “lack of guidelines for standardization of sample positions”.

    Doppler strain and E/E’ are incorrect because the foundation is wrong. Besides in the formula for strain calculation, the modulus of a vector quantity (velocity) is incorrectly substituted for a scalar quantity (length) in the original equation. E/E’ also goes against the scientific “principle of parsimony”.[3]

    When cardiac uses of Doppler were first studied, Doppler recordings were thought to come from the heart tissues and no signals were attributed to blood flow. Consequently the Doppler technique did not interest the cardiologists then! When considering developments in echocardiography, the developments should incrementally add to our knowledge and refine the data collection. In tissue Doppler it is a retrograde development. We use Doppler to study flow because we cannot image flow. When imaging flow becomes a reality, Doppler would be relegated to the background. When we can “see” the tissue there is no need for an indirect Doppler methodology. In this context the authors mention about 2D speckle tracking. They state “Local 2-dimensional tissue velocity vectors are derived from the spatial and temporal data of each speckle” This would be advancement in the right direction.

    Another problem is the high sensitivity of tissue Doppler compromising on the specificity. An akinetic segment correctly displayed on M-mode is never displayed as 0 velocity on tissue Doppler. This will also affect the temporal data. The authors correctly mention this albeit with a wrong explanation. “However, in patients with ischemic cardiomyopathy, TDI and realtime three-dimensional echocardiography show poor agreement for evaluating the magnitude of intraventricular dyssynchrony and the site of maximal mechanical delay. This may be explained by their respective assessment of longitudinal versus radial timing”.

    Tissue Doppler can never be a technological advancement. All advancements are built on strong foundations in basic sciences. Here the basic principles of measurement and Doppler are compromised. Making clinical judgments based on this faulty modality would be unacceptable to the scientific cardiologist.

    Figure 1
    Principles of measurement. We should know the alignment before we apply the measurement tool. In the case of measurement of height, the person has to be standing erect and the scale has to be applied in the AB direction. Any other measurement like XY would be invalid. Similarly you cannot measure the height correctly in a non-erect position. In tissue Doppler measurements we do not know the alignment of the significant velocity vector to apply the Doppler tool. Besides, myocardial motion is complex and cannot be studied with "line of sight" measurement tool like Doppler.

    References

    1. Van de Veire N, De Sutter J, Bax JJ, and Roelandt JR.
    Technological advances tissue doppler imaging echocardiography
    Heart Online First. January 29, 2008

    2. Thomas G.
    Tissue Doppler echocardiography – A case of right tool, wrong use.
    Cardiovascular Ultrasound 2004;2:12.
    Available at http://www.cardiovascularultrasound.com/content/2/1/12

    3. Thomas G.
    Is E/E’ really reliable? Comment on
    Cardiovascular Ultrasound 2007; 5:16.
    Available at http://www.cardiovascularultrasound.com/content/5/1/16/comments

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  27. Bubbles after scuba diving

    Dear Editor,

    With great interest I read the "Images in cardiology" article by Boussuges et al. (1) showing circulating bubbles in the right and the left cavities of a scuba diver's heart after diving. The authors stress the importance of a patent foramen ovale (PFO) as a possible right to left shunting mechanism. However, there are other mechanisms for right to left shunting of intravenous bubbles in scuba divers, e.g. exercise (2). Indeed, post-diving arterial bubbles have been detected in scuba divers who did not have a PFO (3). Thus, it should be emphasised that it is not the presence of the PFO per se that causes the problem but the level of venous circulating bubbles. Scuba divers in general should be cautioned to adhere to safe dive profiles in order to avoid any disastrous consequences of shunting bubbles.

    References

    1. Boussuges A, Blatteau JE, Pontier JM.
    Bubbles in the left cardiac cavities after diving.
    Heart 2008;94:445

    2. Eldridge MW, Dempsey JA, Haverkamp HC, Lovering AT, Hokanson JS.
    Exercise-induced intrapulmonary arteriovenous shunting in healthy humans.
    J Appl Physiol 2004;97:797-805

    3. Gerriets T, Tetzlaff K, Liceni T, Schafer C, Rosengarten B, Kopiske G, Algermissen C, Kaps M.
    Arteriovenous bubbles following cold water sport dives: relation to right-to-left shunting.
    Neurology 2000;55:1741-1743

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  28. How should paroxysmal atrial fibrillation be considered in CRT studies?

    Dear Editor,

    It is with great interest that we read the contribution by Kayvan and colleagues (1) on the long-term effects of cardiac resynchronization therapy (CRT) in patients with atrial fibrillation (AF), not treated with atrio-ventricular junction (AVJ) ablation. Somewhat surprising is the extremely high proportion of AF patients in this cohort : 86/295 patients (29%), probably the highest incidence ever reported in CRT. At a more careful analysis, it can be noted that 20/86 (23%) of AF patients presented only paroxysmal AF (PAF). PAF patients, even before CRT, spend more than 90% of the time in sinus rhythm (SR), and it is well known that CRT significantly reduces AF burden during follow-up (2). This means that PAF patients, after CRT, are paced in DDD modality for about 90-95% of the time. Would these 20 PAF patients be considered in the SR group, then the proportion of AF patients would approach that of other larger series (3, 4). Placing PAF patients as part of the AF group may have introduced 2 important biases in the Kayvan study: 1) patients with PAF, usually present higher mean biventricular pacing percentages (BVP%) compared to patients with permanent AF (explaining the 87% BVP% in this AF group); 2) PAF behave “clinically” like SR patients, and drag, within the AF group, the positive effects conferred by CRT in SR. Mixing these 20 “clinically”, SR-like patients into the AF group, may confound any outcome result. The high BVP% reported into the AF group is even more astonishing considering the low use of chronotropic-negative drugs and the lack of use of ventricular rate regularization (VRR) feature, extremely important to ensure biventricular capture in case of fast irregular rhythm. Conversely, in our experience (3), after 2 months of CRT, only 30% (48/162) of AF patients presented BVP% >85% despite implementation of a rigorous rate-control protocol (rate-lowering drugs plus VRR and trigger mode). Another explanation accounting for the high BVP% in the Kayvan series may be that several AF patients presented very low-rate AF at baseline, with a possible coexisting pacing indication, thus rendering futile recourse to AVJ ablation: unfortunately this hypothesis cannot be ruled out as mean baseline heart rate was not presented.

    References

    1) Kayvan K, Foley PW, Chalil S et al.
    Long-term effects of cardiac resynchronization therapy in patients with atrial fibrillation.
    Heart Online First, January 2008.

    2) Hugl B, Bruns HJ, Unterberger-Buchwald C et al.
    Atrial fibrillation burden during the post-implant period period after crt using device-based diagnostics.
    J Cardiovasc Electrophysiol 2006; 17: 813-7.

    3) Gasparini M, Auricchio A, Regoli F et al.
    Four-year efficacy of cardiac resynchronisation therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation.
    J Am Coll Cardiol. 2006 Aug 15;48(4):734-43.

    4) Auricchio A, Metra M, Gasparini M et al.
    Long-term survival of patients with heart failure and ventricular conduction delay treated with cardiac resynchronization therapy.
    Am J Cardiol. 2007;99:232-8.

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  29. 2002 mortality rate for coronary heart disease in Italy: a statistical outlier or a sentinel event?

    Dear Editor,

    The latest available, age-adjusted overall mortality rate for CHD in Italy refers to the year 2002 [1]. For the first time in the last twenty years, the 2002 rate (42.05 deaths per 100,000 inhabitants) showed a significant increase (+1.1%) over the previous year. The mortality rate for CHD grew by 0.8% in men and by 1.4% in women.

    Since 1980, the age-adjusted mortality rate for CHD declined by 47.8% in men and 49.1% in women, showing a progressive decline in the average annual reduction of mortality rate. The average annual mortality rate declined by 3.27% in men and 3.81% in women in the 1980s, decreasing to 2.84% and 2.61% in the 1990s.

    To better understand the complex dynamics of overall mortality rates, we examined the age-specific mortality data from CHD in 2002. Compared to the previous year, all age groups showed a significant decline in annual mortality rate, with the exception of the elderly population (over 75 years of age) showing a concerning 2.71% increase (1.91% in men and 3.16% in women). The increase in mortality rate seemed to be associated to ageing, growing by 0.16% in the 75-79 age group, by 1.92% in the 80-84 age group and by 6.42% in the population over 85 years. For this group, the 2002 mortality rate (2,316 per 100,000) was higher than the one registered in 1985 (2,199 deaths per 100,000).

    The 2002 dramatic change in CHD mortality rate affected the weakest cohort of the Italian society, raising concerns about the equality of the welfare system. Although it is too early to draw any sustainable conclusion, previous research demonstrated that the elderly represent the population subgroup most vulnerable to unequal income distribution [2]. In the past few years, the elderly living on inadequate social pensions found their disposable income progressively sliding well below the threshold of poverty [3]. 7.2% of them admitted they could not afford one complete meal every other day, while 9.6% did not have enough money to pay for heating, clothes or medicines [4].

    The 2002 “odd” mortality rate increase for CHD should provide the opportunity to better understand the difficult life conditions of the elderly and, hopefully, to take immediate social actions in favour of the most vulnerable cohort of citizens.

    References

    1. The cause of death was determined using the ICD-9 codes 410-414.
    Mortality data available at: http://www.iss.it/site/mortalita/Scripts/SelCause.asp

    2. Materia E, Cacciani L, Bugarini C et al (2005).
    Income inequality and mortality in Italy.
    European Journal of Public Health. Vol.15, No4:411 -417

    3. Istituto Nazionale di Statistica – ISTAT (2004).
    La povertá relativa in Italia. Anno 2003.
    Available at: http://www.istat.it/salastampa/comunicati/non_calendario/20041013_00/

    4. Istituto Nazionale di Statistica – ISTAT (2004).
    I consumi delle famiglie. Anno 2002.
    Available at: http://www.istat.it/dati/catalogo/20040330_00/

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  30. Cardiologists and cardiac surgeons

    Dear Editor,

    I would like to thank Mr Munsch for his enjoyable and informative article(1) in February’s journal, and think that it highlights an important issue.

    Multidisciplinary meetings are an integral part of cardiovascular practice and cardiologists and cardiac surgeons have long worked closely together, perhaps more so than other medical specialties with their respective surgical colleagues. This is primarily because of the overlap in care, particularly with regards to patients in need of coronary revascularisation.

    This collaboration appears to be set to continue, if not become even more pronounced. The advent of the percutaneous aortic valve replacement (trans- femoral and trans-apical) means cardiologist and cardiac surgeon work more closely than ever before, and it is important that the patients involved are not part of a turf war, but a combined discipline that puts them first, to ensure the best possible care.

    These types of combined procedure will surely become more common and may well appear in other specialties, and as a field cardiac care has the opportunity to set the standards for such practice. Teamwork is essential with a necessity for experienced practitioners in imaging, catheter intervention and surgery.

    Mr Munsch states that cardiology trainees would be welcomed with open arms into theatre and I believe many trainees would be very grateful for this opportunity, knowing that it would be a tremendous learning experience. However, it has to be said that this is difficult to incorporate into daily practice.

    It is also true that surgical trainees could learn from their medical colleagues, maybe spending some time in the catheter or echo labs. Trainees in each field surely have a lot to learn from the other discipline and perhaps some structured exposure to the complementary specialty during specialist training would help to build on current collaborations and facilitate effective ones in the future.

    References

    1. Munsch C.
    What cardiology trainees should know about coronary artery surgery--and coronary artery surgeons: ischaemic heart disease.
    Heart. 2008 Feb;94(2):230-6.

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  31. Left ventricular thrombus associated with apical ballooning: a rising clinical evidence ?

    Dear Editor,

    I read with great interest the report by Robles et al (1), recently published in the Journal, that describes the occurrence of left ventricular thrombus formation (LVTF) in a patient with apical ballooning (Takotsubo-like syndrome).

    This study likely provides further contribution to the knowledge on the various clinical aspects of this stress-related cardiac disease. In spite of the acute and often severe LV functional impairment in the majority of the patients, the complication described by Robles seems to be rare. Under a pathophysiological point of view, there are several reasons to theorize a common causal mechanism of TF between Takotsubo-like syndrome and ischemic (necrotic) apical dilatation. Apical blood flow stasis, together with the known abnormalities in the electrical charges of blood cells and endothelial or endocardial surface, and/or hyper- coagulation are time-honoured determinants of cardiovascular thrombosis. Therefore, it is conceivable that the occurrence of LVTF is not rigorously related to the hyper-adrenergic storm, which is typical of the apical ballooning, but to other pre-existing cofactor(s), as S- or C-protein, C- reactive protein, factor V Leiden, platelet aggregation, hormone levels, genetic factors, leukocyte adhesion molecules, fibrinogen, viscosity, etc., that may be accounted for such inter-individual differences as in patients with myocardial infarction. One of the most puzzling questions in the patients with ballooning concerns the discrepancy between the coronary bed (where thrombosis has never been described) and left ventricular cavity (where it has been). Recent working hypotheses have been addressed on adrenaline-induced switching from Gs-protein to Gi-protein signaling of the beta2- adrenoceptor that may make the apical myocardium more susceptible to (structural or functional) damage than other cardiac sites (2).

    However, though rare, LVTF has been already reported by at least 10 studies, including that one published in 2003 by Barrera-Ramirez et al (3) (from the same Institution of Robles et al ?). Thus, it is rather surprising that the Authors affirmed that "...a LV thrombus associated with Takotsubo-like ventricular dysfunction has not been demonstrated, although there have been reports regarding the embolic complications of this disorder", since the first description dates just back to that study (3).

    Based on the published reports, fortunately, embolic complications are not so frequent. About 20% of cadioembolic stroke, as the main clinical presentation, and another case of late renal infarct, but no fatal outcomes, have been reported in the patients with patent LVTF (4-6).

    On the other hand, we should also consider that over the last decade the diagnosis of Takotsubo-like disease was performed only by angiography, so that some LVTF might have been overlooked in the past. Contemporary techniques, such as high-resolution echocardiography or cardiac magnetic resonance, together with a rising clinical awareness about the syndrome, surely contribute to a better knowledge of its various aspects, even if lots of pathophysiological questions are still open.

    REFERENCES

    [1] Robles P, Jimenez JJ, Alonso M.
    Left ventricular thrombus associated with left ventricular apical ballooning.
    Heart 2007;93:861.

    [2]Lyon AR, SC Rees P, Prasad S, Poole-Wilson PA, Harding SE.
    Stress (Takotsubo) cardiomyopathy. A novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning.
    Nature 2008;5(1):22-9.

    [3]Barrera-Ramirez CF, Jimenez-Mazuecos JM, Alfonso F.
    Apical thrombus associated with left ventricular apical ballooning.
    Heart 2003;89:927.

    [4]Grabowski A, Kilian J, Strank C, Cieslinski G, Meyding-Lamad¨¦ U.
    Takotsubo cardiomyopathy. A rare cause of cardioembolic stroke.
    Cerebrovasc Dis 2007;24:146¨C8.

    [5]Nerella N, Lodha A, T¨ªu CT, Chandra PA, Rose M.
    Thromboembolism in Takotsubo syndrome: A case report.
    Int J Cardiol 2007;doi:10.1016/j.ijcard.2006.11.186.

    [6]de Gregorio C, Cento D, Di Bella G, Coglitore S.
    Minor stroke in a Takotsubo-like syndrome: a rare clinical presentation due to transient left ventricular thrombi.
    Int J Cardiol (in press).

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  32. Digitalis in atrial fibrillation: not the best friend nor the worst foe.

    Dear Editor,

    We have carefully read the article by Gjesdal et al [1] showing the result of an exploratory analysis pooling data from the SPORTIF III and V trials [2,3]. By means of a Cox proportional hazard analysis the authors concluded that the use of digitalis may increase mortality.
    Although we acknowledge the merit of this manuscript, in our opinion some points deserve further elucidation.
    In a previous publication [4] we showed that anticoagulation therapy was inversely associated while digoxin (digitalis) and antiarrhythmic drugs were directly associated with increased mortality after adjustment for other covariates in patients treated with a “rate control� approach compared to patients treated with a “rhythm control� approach. That conclusion did not apply to patients with advanced heart failure (HF) as the studies available for the meta-analysis did not include patients with NYHA class IV HF.
    Gjesdal et al suggested that the possible ominous effect of the digitalis may be concealed in patients with HF. However, no data are available about the possible progression to the end stage disease nor any mention about concomitant drug therapy, severity of symptoms, mechanism of HF and indication for digitalis use. They also reported a percentage of digoxin users up to 10% with levels in the range of toxicity, but they conclude that “there is little reason� to think that this is a serious problem as it was not clinically relevant.
    Moreover, in a previous independent non–funded publication we showed that long-term ximelgatran therapy was associated with a significantly reduced risk of major life-threatening bleeding in the prevention of atrial fibrillation-related stroke (OR 0.71 [0.55-0.92], p=0.009, p for H=0.83, I2 0%) [5].
    How did the authors address this point?
    Of note, the authors did not mention the hepatotoxicity related to ximelagatran prolonged administration but they include ximelagatran therapy in the multivariate analysis. We showed that ximelagratan treatment > 3 months was associated with an odds ratio for hepatotoxicity of 6.73 (95% confidence interval: 5.01-9.05) compared to warfarin (p<0.001). In absolute terms, for prolonged treatments, the incidence of hepatotoxicity rose from 1.1% to 7.1%, with a number needed to harm of 17 [5-7]. This risk led the U.S. Food and Drug Administration to deny approval for ximelagratan in the USA, the European Agency for the Evaluation of Medicinal Products (EMEA) to allow only short term administration and the manufacturer (Astrazeneca), after a further fatality in a post-marketing study, to withdraw the drug [8-10]
    We wonder if this point has been adequately addressed.
    Although hepatic damage was clinically silent in most cases (even without discontinuation of therapy), 2 fatal cases of hepatic injury have been reported in the SPORTIF trials and no data are available about the long term hepatic function of enrolled patients. Although a possible pharmacodinamic/pharmacokynetic interaction between digoxin and ximelgatran has been not demonstrated as both metabolisms do not involve the liver cytochrome P-450 system [11], the “clinical interaction�, i.e. the impact of hepatotoxicity on mortality cannot be excluded. Thus, the “background noise� of hepatotoxicity should have been included in the analysis.
    In conclusion, we wonder if a multi-drug context in which one of the two “study drugs� has been definitely withdrawn because of its potential fatal effect is really the appropriate context to assess the potentially fatal effect of a third drug.

    Reference

    1. K Gjesdal, J Feyzi and S B Olsson.
    Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data.
    Heart 2008:94;191-196.

    2. Olsson SB, The Executive Steering Committee on behalf of the SPORTIF III Investigators.
    Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non- valvular atrial fibrillation (SPORTIF III): randomised controlled trial.
    Lancet 2003;362:1691–8.

    3. Albers GW, Diener HC, Frison L, et al.
    Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.
    JAMA 2005;293:690–8.

    4. Testa L, Biondi-Zoccai GG, Dello Russo A, Bellocci F, Andreotti F, Crea F.
    Rate-control vs. rhythm-control in patients with atrial fibrillation: a meta-analysis.
    Eur Heart J. 2005;26:2000-6.

    5. Testa L, Andreotti F, Trotta G, Biondi Zoccai GGL, Burzotta F, Bellocci F, Crea F.
    Ximelagatran/melagatran versus conventional anticoagulant therapy: meta-analysis of 13 randomised controlled trials enrolling 22639 patients. European Society of Cardiology/World congress of Cardiology 2007. Oral Presentation for the Young Investigator Award in Thrombosis.
    Published in Int J Cardiol. 2007 Nov 15;122(2):117-24.

    6. Testa L, Bhindi R, Agostoni P, Abbate A, Zoccai GG, van Gaal WJ.
    The direct thrombin inhibitor Ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile.
    Expert Opin Drug Saf. 2007;6:397-406.

    7. Testa L, Van Gaal W, Agostoni P, Abbate A, Trotta G, Biondi-Zoccai GG.
    Ximelagatran versus warfarin in the prevention of atrial fibrillation- related stroke: both sides of the story.
    Stroke. 2007 ;38(7):e57.

    8. AstraZeneca receives action letter from FDA for Exantaâ„¢ (ximelagatran).
    Available at http://fdaadvisorycommittee.com

    9. Successful outcome of the mutual recognition procedure for Exantaâ„¢ (ximelagatran) in Europe.
    Press release from European Agency for the Evaluation of Medicinal Products (EMEA).
    Available at http://www.emea.eu.int

    10. AstraZeneca Decides to Withdraw Exantaâ„¢ (ximelagatran).
    Press release from AstraZeneca international, February 14, 2006.
    (Accessed February 15, 2006, at http://www.astrazeneca.com/pressrelease).

    11. Gheorghiade M, Adams KF Jr, Colucci WS.
    Digoxin in the management of cardiovascular disorders.
    Circulation. 2004;109:2959-64.

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  33. ‘Shoot the renals’ - The evidence is actually round the corner!

    Dear Editor,

    It was with great interest that we read the recent articles by Dear et al[1] and Luft et al[2] in the December edition of Heart. The issue of when to investigate and treat a patient with suspected ARVD is one of considerable controversy at present. The AHA provide guidelines[3] that recommend performing simultaneous renal arteriography with coronary arteriography in order to facilitate pro-active treatment of renal arterial lesions with ‘drive-by’ angioplasty and stenting. However, the paucity of randomised controlled trials (RCTs) and large studies in ARVD is well known, thus leaving the guidelines open to criticism. In particular, ideal management in ARVD, and prediction of renal and blood pressure outcome following revascularization remains elusive. The complex relationship between the degree of renal artery stenosis (RAS), hypertension, intra-parenchymal damage[4 5], early atherosclerotic induced damage[6] and cardiovascular co-morbidity[7 8] make this a much more challenging condition. The articles by Dear et al[1] and Luft et al[2] acknowledge the lack of firm evidence to support the guidelines, and thus the frustration of screening ‘for an entity that has no sound basis for management’[2] can be understood.

    In order to best answer the perplexing questions surrounding revascularization as a management option, large scale prospective RCTs are required in order to determine the overall effects of intervention in RAS, and more specifically, help identify which sub-groups of patients might benefit from revascularization. Whilst the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial is underway, it should be noted that the main ASTRAL (Angioplasty and STent for Renal Artery Lesions) trial[9] completed recruitment in April 2007. ASTRAL is the largest trial in ARVD to date with nearly 8 times as many patients recruited than in the previous largest RCT[10]. 806 patients from 58 centres have been entered into ASTRAL, half allocated to receiving optimal medical treatment and half revascularization and medical therapy. The primary aim of ASTRAL is to determine whether renal endovascular revascularization procedures (angioplasty and/or stenting) impact upon renal functional outcome. Secondary outcome measures include mortality, clinic blood pressure and major vascular events. Preliminary results, which involve a minimum 6 months follow up for all enrolled patients, are due to be reported in March 2008.

    Due to the increasing awareness of the strong relationship between ARVD and cardiac dysfunction and structure, two cardiac substudies have also been undertaken. A previous pilot study at our centre showed a trend towards improvement of cardiac measurements post renal-revascularisation (left ventricular mass index, left ventricular fractional fibre shortening, left ventricular end systolic dimameter and left ventricular end diastolic diameter[11]. The ASTRAL cardiac substudies have been conducted in a randomized, prospective manner, with subjects being randomized to have either revascularizaion with medical therapy or medical therapy alone, as for the main trial. The first sub-study, based upon echocardiography, enrolled around 110 patients from 15 centres, and the cardiac magnetic resonance imaging (CMR) sub-study, 65 patients from 6 centres. The aim of these studies is to show whether beneficial changes in cardiac structure and function follow renal revascularization procedures. Positive results from these studies would provide a new dimension of opportunity to improve ARVD patient welfare which would engage the cardiological community further. Results of the sub-studies will be available in October 2008.

    We eagerly await the results of the ASTRAL trial and its cardiac sub- studies, as they provide an imminent chance to increase our understanding of the complex inter-relationship between cardiac and renal disease in ARVD.

    Constantina Chrysochou 1, Janet Hegarty 1, Paul R Kalra 2, Keith Wheatley 3, John Moss 4, Philip A Kalra 1

    1 Department of Renal Medicine, Salford Royal Hospitals NHS Foundation Trust, Stott Lane, Salford, Manchester
    2 Department of Cardiology, Portsmouth Hospitals NHS trust, Portsmouth
    3 Birmingham Clinical Trials Unit, University of Birmingham, Edgbaston, Birmingham
    4 Department of Vascular Radiology, Gartnavel Hospital, Glasgow

    References

    1 Dear JW, Padfield PL, Webb DJ.
    New guidelines for drive-by renal arteriography may lead to an unjustifiable increase in percutaneous intervention.
    Heart 2007 Dec;93(12):1528-32.

    2 Luft FC, Gross CM.
    Commentary: Shoot the renals!
    Heart 2007 Dec;93(12):1530-2.

    3 White CJ, Jaff MR, Haskal ZJ, et al.
    Indications for renal arteriography at the time of coronary arteriography: a science advisory from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology, and the Councils on Cardiovascular Radiology and Intervention and on Kidney in Cardiovascular Disease.
    Circulation 2006 Oct 24;114(17):1892-5.

    4 Makanjuola AD, Suresh M, Laboi P, et al.
    Proteinuria in atherosclerotic renovascular disease.
    QJM 1999 Sep;92(9):515-8.

    5 Wright JR, Shurrab AE, Cheung C, et al.
    A prospective study of the determinants of renal functional outcome and mortality in atherosclerotic renovascular disease.
    Am J Kidney Dis 2002 Jun;39(6):1153-61.

    6 Chade AR, Rodriguez-Porcel M, Grande JP, et al.
    Distinct renal injury in early atherosclerosis and renovascular disease.
    Circulation 2002 Aug 27;106(9):1165-71.

    7 Conlon PJ, Little MA, Pieper K, et al.
    Severity of renal vascular disease predicts mortality in patients undergoing coronary angiography.
    Kidney Int 2001 Oct;60(4):1490-7.

    8 Shurrab AE, MacDowall P, Wright J, et al.
    The importance of associated extra-renal vascular disease on the outcome of patients with atherosclerotic renovascular disease.
    Nephron Clin Pract 2003;93(2):C51-C57.

    9 Mistry S, Ives N, Harding J, et al.
    Angioplasty and STent for Renal Artery Lesions (ASTRAL trial): rationale, methods and results so far.
    J Hum Hypertens 2007 Jul;21(7):511-5.

    10 van Jaarsveld BC, Krijnen P, Pieterman H, et al.
    The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group.
    N Engl J Med 2000 Apr 6;342(14):1007-14.

    11 Hegarty J, Wright JR, Kalra PR, et al.
    The heart in renovascular disease--an association demanding further investigation.
    Int J Cardiol 2006 Aug 28;111(3):339-42.

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  34. When is a heart failure programme successful?

    Dear Editor,

    With great interest we read the article of Khunti and colleagues reporting on a cluster randomized controlled trial evaluating a nurse-led disease management programme for secondary prevention of coronary heart disease and heart failure in primary care (1). The authors should be commended for their large trial with 1316 patients from 20 primary care practices.
    The authors describe favourable results of the intervention for CHD patients, however, for patients with confirmed diagnoses of left ventricular dysfunction the intervention in this trial was less effective than they had expected with no effects with regard to optimized treatment or quality of life. This study confirms the difficulty of finding an optimal model which is still pragmatically feasible to be implemented for a primary care setting and at the same time is effective.
    The authors evaluated the effectiveness of their heart failure programme as improvement of prescribing an ACE –inhibitor, the confirmation of the diagnosis by echocardiogram and quality of life. Although the MAHLER study recently showed the importance of guideline adherence in heart failure (2), one might wonder if the chosen outcomes in the study of Khunti et al. were the most optimal indices to evaluate optimal heart failure disease management.
    We recently published the COACH trial in which we found that moderate or intensive education and counselling did not decrease the time to hospitalisation when compared to a control group without education and counselling (3). We even found a small, non significant increase in hospitalisations. We discussed that due to a lower threshold of patients to the heart failure nurses the increase of hospitalisations could be explained and questioned if in evaluating heart failure disease management programmes hospitalisation is a good enpoint, since timely hospitalisation is likely to relieve symptoms and result in better diagnosis and management. (4)
    To date the challenge is to find the most optimal heart failure management program in both primary and secondary care and at the same time find a realistic way to evaluate cost-effectiveness of these programmes.

    References

    1. Khunti K, Stone M, Paul S, et al.
    Disease management programme for secondary prevention of coronary heart disease and heart failure in primary care: a cluster randomised controlled trial.
    Heart 2007 93:1398- 405.

    2. Komajda M, Lapuerta P, Hermans N, et al.
    Adherence to guidelines is a predictor of outcome in chronic heart failure: the MAHLER survey.
    Eur Heart J 2005 26:1653-9.

    3. Jaarsma T, Wal MHL van der, Lesman-Leegte I, et al.
    Effects of moderate and intensive disease management program on outcome in patients with heart failure. The Coordinating Study evaluating Outcomes of Advising and Counselling in Heart Failure (COACH).
    Arch Intern Med. 2008; 168:316- 324.

    4. Cleland JG, Coletta AP, Clark AL.
    Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet.
    Eur J Heart Fail 2007; 9: 740-5.

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  35. Reader's response

    Left ventricular outflow tract gradient provoked by upright position or exercise in hypertrophic cardiomyopathy without obstruction at rest

    Dear Editor,

    In a recent study published in the Heart, Shah et al. [1] assess the inducibility of left ventricular outflow tract gradient by upright exercise (bicycle ergometer) in patients with hypertrophic cardiomyopathy (HCM) without obstruction at rest. Similarly to Maron et al. [2] they [1] documented frequent provocation of the gradient by exercise. Interestingly, in HCM the obstruction may increase also due to load reduction after change of position from supine to upright [1,3] or amyl nitrate. [4] Previous studies [1,2] were performed after drug discontinuation. To assess the efficacy of current pharmacotherapy we studied 37 HCM treated patients with left ventricular outflow tract (LVOT) gradient < 30 mmHg at rest in supine position. The patients were then placed in upright position and the gradient was re-examined. Since 8 patients developed LVOT gradient > 30 mmHg during this maneuver (values ranged from 32 to 141 mmHg), the remaining nonobstructive 29 patients performed moderate-intensity exercise on a treadmill (modified Bruce protocol) with continuous monitoring of LVOT gradient. The exercise was stopped at 8 minutes or earlier if patients were unable to continue exercise (dyspnea in 11 patients), 10 patients developed a significant gradient. For comparison with rest values we measured LVOT gradients at peak exercise, and as soon as possible after exercise (within the first 60 seconds of the recovery period in left lateral decubitus). The resting minimal distance between mitral valve and ventricular septum at systole was used to assess the degree of narrowing of LVOT and this parameter differentiated between provocable and non-provocable subgroups. Patients with provocable gradient (either by changing position or exercise) presented with lower values of this parameter than non-provacable subgroup (table 1). At recovery in supine position, this significant gradient disappeared in 6 of 10 patients despite only a short delay of measurement. Similarly to Cotrim et al. [3] we demonstrated that LVOT gradient assessed in the immediate recovery period (in re-supine position) does not accurately reflect what happens during effort.

    The simultaneous evaluation of the gradient with exercise can help us to better understand the pathophysiology of patients with HCM and to optimize treatment (currently several methods are available). Like in the study of Cotrim et al. [3] our patients exercised moderately in upright position on a treadmill which was selected as a more physiological (reflects physical exercise during everyday activity) assessment of dynamic changes of the gradient. A substantial proportion of our patients had limiting exercise symptoms; therefore, identification of latent, exercise-triggered obstruction not only defined the probable mechanism for such symptoms but in many cases also created important options for their relief. The intensification of pharmacotherapy or use of nonpharmacological methods may be needed to consider for a significant portion of patients regarded as nonobstructive but only at rest.

    The moderate workload exercise on a treadmill was well tolerated in almost all patients (only 2 patients – one with suboptimal echo image and one with orthopaedic disease were excluded from the study). Table 2 summarizes the methodological considerations. We agree with previous studies [1-3] that exercise is the only provocative manoeuvre that is truly physiologically based. Without exercise echocardiography, the capability of HCM patients to develop elevated LVOT gradient during normal physical activity would have remained undefined.

    References

    1. Shah JS, Tome Esteban MT, Thaman R, et al.
    Prevalence of Exercise Induced Left Ventricular Outflow Tract Obstruction in Symptomatic Patients with Non-obstructive Hypertrophic Cardiomyopathy.
    Heart. 2007 Nov 21; [Epub ahead of print]

    2. Maron MS, Olivotto I, Zenovich AG, et al.
    Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction.
    Circulation. 2006;114:2232-9.

    3. Cotrim C, Loureiro MJ, Simoes O, et al.
    Evaluation of hypertrophic obstructive cardiomyopathy by exercise stress echocardiography. New methodology.
    Rev Port Cardiol. 2005;24:1319-27.

    4. Marwick TH, Nakatani S, Haluska B, et al.
    Provocation of latent left ventricular outflow tract gradients with amyl nitrite and exercise in hypertrophic cardiomyopathy.
    Am J Cardiol. 1995;75:805-9.

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  36. Heart failure in the UK

    Dear Editor,

    We read with interest the report of Nicol and colleagues on heart failure admissions in England, Wales and Northern Ireland1, having published extensively on this problem in Scotland.2,3

    In Scotland 51% of patients hospitalized in 2003 with heart failure as the principal diagnosis were men, compared to 50% in the rest of the UK. The average age of men was 72 years and for women it was 77 years, compared to 75 and 80 years, respectively in the other UK countries (table). The median length of stay in Scotland was 5 days (IQR 2-10) for men and 5 days (2-11) for women, compared to 7 (4-14) and 8 (4-15) days respectively, in the rest of the UK. The in-patient unadjusted case fatality rate for men in Scotland was 8.4% and 9.5% in women, compared to 16 and 14% respectively in England, Wales and Northern Ireland (we think the case-fatality rates reported in the abstract by Nicol et al are unadjusted rather than adjusted, as stated). We reported considerable between-hospital variation in outcomes in Scotland.4 A similar analysis for the other UK countries would be of interest. Of more concern, however, is the apparently large discrepancy in outcomes between all the UK countries and elsewhere. For example, 30 day mortality in the USA and Australia is in the range of 8 to 9% and in Canada 12%.5-8 Reported in hospital mortality is as low as 4 to 5% in some countries, compared to the much higher rates reported in the UK countries. 7,8 It is important for all UK physicians with an interest in the management of heart failure (and for our patients) to understand and explain these apparent differences.

    REFERENCES

    1. Nicol ED, Fittall B, Roughton M, Cleland JG, Dargie H, Cowie MR. NHS heart failure survey: a survey of acute heart failure admissions in England, Wales and Northern Ireland. Heart 2008; 94:172-7.

    2. McMurray J, McDonagh T, Morrison CE, Dargie HJ. Trends in hospitalization for heart failure in Scotland 1980-1990. Eur Heart J 1993; 14: 1158-62.

    3. Stewart S, MacIntyre K, MacLeod MM, Bailey AE, Capewell S, McMurray JJ. Trends in hospitalization for heart failure in Scotland, 1990-1996. An epidemic that has reached its peak? Eur Heart J 2001; 22: 209-17.

    4. Stewart S, Demers C, Murdoch DR, McIntyre K, MacLeod ME, Kendrick S, Capewell S, McMurray JJ. Substantial between-hospital variation in outcome following first emergency admission for heart failure. Eur Heart J 2002; 23: 650-7.

    5. Lee DS, Johansen H, Gong Y, Hall RE, Tu JV, Cox JL; Canadian Cardiovascular Outcomes Research Team. Regional outcomes of heart failure in Canada. Can J Cardiol 2004; 20: 599-607.

    6. Najafi F, Dobson AJ, Jamrozik K. Recent changes in heart failure hospitalisations in Australia. Eur J Heart Fail 2007; 9: 228-33.

    7. Baker DW, Einstadter D, Thomas C, Cebul RD. Mortality trends for 23,505 Medicare patients hospitalized with heart failure in Northeast Ohio, 1991 to 1997. Am Heart J 2003; 146: 258-64.

    8. Goldberg RJ, Spencer FA, Farmer C, Meyer TE, Pezzella S. Incidence and hospital death rates associated with heart failure: a community-wide perspective. Am J Med 2005; 118: 728-34.

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  37. Authors' Response

    Dear Editor,

    We thank Drs Mieczkowska and Mosiewicz for their interest in our research on socioeconomic status (SES), pathogen burden and cardiovascular disease risk. They rightly highlight the strong social gradient in cardiovascular disease that is present in many European countries and is increasingly apparent world wide.1 Our study used employment grade as the indicator of SES, and it is interesting that similar patterns emerge in Poland with level of education as the marker of social position. The social gradient is not fixed, since there was a positive association between SES and cardiovascular disease in the UK before the 2nd World War, shifting to an inverse gradient in the post war era.2 Drs Mieczkowska and Mosiewicz also point out the important role of adverse lifestyle factors such as smoking and obesity in maintaining the SES gradient.

    Our data on pathogens relate to cardiovascular risk factors such as adiposity, blood pressure and diabetes. However, we have recently had the opportunity to study a more direct measure of vascular pathophysiology in this population, namely arterial stiffness. Carotid arterial stiffness was measured using ultrasonography in conjunction with the Vascular Physiology Unit at the Institute of Child Health, University College London. The distensibility coefficient was calculated from the distension of the common carotid artery 1 cm proximal to the carotid bifurcation and simultaneous blood pressure data using standard formulae,3 with larger distensibility coefficients indicating lower arterial stiffness. Half the participants (50.8%) were seropositive for cytomegalovirus (CMV), and they had significantly lower distensibility coefficients than the remainder of the sample, with average levels of 14.77 (SD 4.2) 10-3kPa-1 compared with 15.71 (SD 5.2) 10-3kPa-1 after adjustment for age, gender, body mass index, waist/hip ratio, smoking, blood pressure and high density lipoprotein-cholesterol (p = 0.041). This indicates that carotid stiffness is greater among individuals with a history of CMV infection. CMV seropositivity was also more common among individuals of lower SES (indexed by grade of employment).4 But interestingly, when SES was included as a covariate in the analysis, the association between CMV seropositivity and arterial stiffness remained significant (p = 0.050), endorsing the conclusion of our article that the risks associated with infection history and lower SES are somewhat independent of one another.

    REFERENCES

    1. Avendano M, Kunst AE, Huisman M, et al.
    Socioeconomic status and ischaemic heart disease mortality in 10 western European populations during the 1990s.
    Heart 2006;92:461-7.

    2. Marmot MG, Adelstein AM, Robinson N, Rose GA.
    Changing social class distribution of heart disease.
    Br Med J 1978;ii:1109-1112.

    3. Dijk JM, Algra A, van der Graaf Y, Grobbee DE, Bots ML.
    Carotid stiffness and the risk of new vascular events in patients with manifest cardiovascular disease. The SMART study.
    Eur Heart J 2005;26:1213-20.

    4. Steptoe A, Shamaei-Tousi A, Gylfe A, Henderson B, Bergstrom S, Marmot M.
    Socioeconomic status, pathogen burden and cardiovascular disease risk.
    Heart 2007;93:1567-70.

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  38. Exercise echocardiography

    Dear Editor,

    The recent study by Ha et al (1) illustrates the potential benefit of using exercise stress for detection of early myocardial disease in diabetic patients. With modern advances in cardiac imaging the detection and management sub-clinical disease in patients at high cardiovascular risk is likely to become increasingly relevant. The use of exercise stress and its application outside the conventional application of coronary disease highlights an area of underutilisation in echocardiographic practice.

    The concept of applying a stress modality to assess cardiac status has long been one of the basic principles of our assessment of patients with known or suspected coronary disease and forms a large part of what we do in routine clinical practice. It allows us to better understand the nature of symptoms that develop during physical exertion and can detect asymptomatic disease in at risk individuals. Stress testing also has a lot to offer in other patient groups. As with coronary problems many patients with significant disease have abnormal findings exclusively during stress, resting abnormalities only being manifested in the advanced stages of the process. For example, echocardiography is often performed in the resting state in patients with exertional breathlessness. It frequently reveals normal appearances or only subtle pathology such as early diastolic relaxation abnormalities of uncertain significance. In these circumstances it is plausible that supplementary haemodynamic information could be added by a stress assessment.

    In mobile patients exercise echocardiography is a highly feasible and well-validated technique. It may be preferable to pharmacological stress testing. In the setting of coronary disease incorporation of functional treadmill variables into clinical decision-making adds useful information to echocardiographic data (2). Previous studies have demonstrated the value of exercise echocardiography in populations with valvular (3) and myocardial (4) disease as well as pulmonary hypertension (5). Other applications are developing with implications for diagnosis, therapy and possibly prognosis.

    Stress echocardiography is not just about using a pharmacological agent to look for ischaemia and viability. An exercise protocol can be used in a large proportion of patients and has applicability across a range of clinical problems in cardiology where it supplements information gained at rest.

    REFERENCES

    1. Ha JW, Lee HC, Kang ES et al.
    Abnormal left ventricular longitudinal functional reserve in patients with diabetes mellitus: implication for detecting subclinical myocardial dysfunction using exercise tissue Doppler echocardiography.
    Heart. 2007;93:1571-6.

    2. Marwick T, Case C, Vasey C, Allen S, Short L, Thomas J.
    Prediction of mortality by exercise echocardiography: a strategy for combination with the Duke treadmill score.
    Circulation 2001;103:2566–71.

    3. Lee R, Haluska B, Leung DY, Case C, Mundy J, Marwick TH.
    Functional and prognostic implications of left ventricular contractile reserve in patients with asymptomatic severe mitral regurgitation.
    Heart 2005; 91: 1383-4.

    4. Burgess MI, Jenkins C, Sharman JE, Marwick TH.
    Diastolic stress echocardiography: hemodynamic validation and clinical significance of estimation of ventricular filling pressure with exercise.
    J Am Coll Cardiol. 2006 May 2;47:1891-900.

    5. Collins, N, Bastian B, Quiqueree L, Jones C, Morgan R, Reeves G.
    Abnormal pulmonary vascular responses in patients registered with a systemic autoimmunity database: Pulmonary Hypertension Assessment and Screening Evaluation using stress echocardiography (PHASE-I).
    Eur J Echocardiogr 2006; 7: 439-46.

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  39. Chagas Disease: a neglected cardiomyopathy

    Dear Editor,

    Recently, Yacoub et al,[1] reviewed for the section Education in Heart of the journal Heart, different clinical but also epidemiological, diagnostic, therapeutic and other aspects of Chagas disease, “a neglected tropical cardiomyopathy”. Although it should be acknowledge the importance of such reviews, particularly in a topic that has been neglected in many aspects, including research as well international education, some aspects needs further comments and discussion.

    As Yacoub et al stated Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, its transmission (more than the spread) is due to different species of hematophagous reduviidae bugs, that include Triatoma infestans, but also Rhodnius prolixus, Triatoma dimidiata, and Panstrongylus megistus, among others.[2] About the geographical distribution is important to state that currently Chagas disease is endemic in Latin America, ranging from Argentina to Mexico, but in North America is present in also southern states of USA, including Texas,[3] Oklahoma,[4] Alabama,[5] and more recently in Louisiana due to Triatoma sanguisuga,[6] but also in western states such as Arizona,[7] New Mexico,[8] California.[9]

    Secondly, although the latin American immigration of patients with Chagas disease to north America is one of the most important, recently this phenomena has been increasingly relevant in other countries in Europe, particularly to Spain,[10] but also France,[11] Germany,[12] Switzerland,[13] among others. Even in the United Kingdom a patient from this country returned from Argentina with Chagas disease.[14] In Australia, Chagas disease in immigrants has been also reported.[10] In the case of USA, although up to year 2000 just five cases were reported, the diagnose of these cases included PCR,[15] and in 2007, when the autochthonous transmission of T. cruzi occurred in Louisiana, the patient had positive test results from 2 serologic tests and hemoculture at the Centers for Disease Control, Atlanta, Georgia, and the Triatoma sanguisuga (18) collected were positive for T. cruzi by PCR in 56%.[6] Then, Chagas disease could be an emergent disease in the United States.

    About the life cycle of the parasite, this involves many morphologically distinct stages – more than described for any other genus in the Family Trypanosomatidae. In the mammalian host, intracellularly multiplying amastigotes develop via epi- and promastigote intermediate stages to nonreplicative blood trypomastigotes. These trypomastigotes are ingested by the insect vectors and transform in the lumen of the digestive tract into dividing and nonreplicative amastigotes and spheromastigotes and dividing epimastigotes. Later, nonreplicative infective trypomastigotes develop. If the main intermediate stages are also considered, more than 18 different forms can be classified in the vector.[16]

    Clinically, an area of inflammation at the site of inoculation, called chagoma, when involves conjunctival inoculation could lead to the triad of conjunctivitis, periorbital edema, and preauricular satellite lymphadenopathy; and this is what is known as the Romaña sign.[17]

    Regard to the pathology we consider that those developments recently achieved in demonstrating that T. cruzi could be found in the myocardium during the chronic phase of Chagas disease, should be acknowledged citing some of them.[18, 19]

    Finally, in the XXI century when HIV/AIDS pandemics is affecting the human being worldwide, the interaction between T. cruzi and this retrovirus, should be also considered, because produce a different clinical spectrum. Chagas disease has been well recognized as an opportunistic infection associated with AIDS.[20, 21] To date, the cases reported largely represent reactivation of chronic infection, which is expected because of the differing patterns of epidemiological risk for these infections; T. cruzi infection occurs primarily in rural regions, and HIV infection occurs primarily in urban regions, but this pattern is changing and less rural and more urban pattern is now observed in different countries allowing the geographical overlapping between both entities.[22, 23] Clinical reactivation generally occurs in persons with CD4+ T cell counts <200 cells/mm3 and most commonly involves the CNS. Lesions are often multiple, with preferential involvement of the white matter. Hemorrhagic foci can produce mass effects simulating brain tumors. Histologically, brain lesions exhibit necrosis, hemorrhage, and inflammatory infiltrates. Amastigote forms of the parasite are abundant in glial cells and macrophages. Myocarditis is a common autopsy finding in persons who have died of meningoencephalitis. Such myocarditis is often clinically silent. When present, clinical manifestations include arrhythmias and congestive heart failure.[20]

    Cardiac manifestations previously seen only in resource-constrained countries, including certain parasitic infections such as Chagas disease, can be currently diagnosed anywhere in the globe. These epidemiologic transitions have been favored by multiple factors: growing travel and immigration, worldwide spread of HIV/AIDS epidemic, and growing number of organ transplantation, increased use of immunosuppressive agents, and blood transfusions.[23] Clinicians anywhere in the globe need to be aware of the potential cardiac manifestations of parasitic diseases, such as the American Trypanosomiasis, but also those related to other neglected diseases.

    References

    1. Yacoub S, Mocumbi AO, Yacoub MH.
    Neglected tropical cardiomyopathies: I. Chagas disease: myocardial disease.
    Heart (British Cardiac Society) 2008;94:244-8.

    2. Moncayo A.
    Chagas disease: current epidemiological trends after the interruption of vectorial and transfusional transmission in the Southern Cone countries.
    Memorias do Instituto Oswaldo Cruz 2003;98:577-91.

    3. Hanford EJ, Zhan FB, Lu Y, et al.
    Chagas disease in Texas: recognizing the significance and implications of evidence in the literature.
    Social science and medicine (1982) 2007;65:60-79.

    4. Bradley KK.
    American trypanosomiasis: Chagas disease an emerging zoonotic threat in Oklahoma?
    The Journal of the Oklahoma State Medical Association 1997;90:253-5.

    5. Olsen PF, Shoemaker JP, Turner HF, et al.
    Incidence of Trypanosoma cruzi (Chagas) in Wild Vectors and Reservoirs in East-Central Alabama.
    The Journal of parasitology 1964;50:599-603.

    6. Dorn PL, Perniciaro L, Yabsley MJ, et al.
    Autochthonous transmission of Trypanosoma cruzi, Louisiana.
    Emerging infectious diseases 2007;13:605-7.

    7. Pfeiler E, Bitler BG, Ramsey JM, et al.
    Genetic variation, population structure, and phylogenetic relationships of Triatoma rubida and T. recurva (Hemiptera: Reduviidae: Triatominae) from the Sonoran Desert, insect vectors of the Chagas' disease parasite Trypanosoma cruzi.
    Molecular phylogenetics and evolution 2006;41:209-21.

    8. Wood SF, Wood FD.
    Observations on vectors of Chagas' disease in the United States. III. New Mexico.
    The American journal of tropical medicine and hygiene 1961;10:155-65.

    9. Navin TR, Roberto RR, Juranek DD, et al.
    Human and sylvatic Trypanosoma cruzi infection in California.
    American journal of public health 1985;75:366-9.

    10. Schmunis GA.
    Epidemiology of Chagas disease in non endemic countries: the role of international migration.
    Mem Inst Oswaldo Cruz 2007.

    11. Brisseau JM, Cebron JP, Petit T, et al.
    Chagas' myocarditis imported into France.
    Lancet 1988;1:1046.

    12. Frank M, Hegenscheid B, Janitschke K, et al.
    Prevalence and epidemiological significance of Trypanosoma cruzi infection among Latin American immigrants in Berlin, Germany.
    Infection 1997;25:355-8.

    13. Sztajzel J, Cox J, Pache JC, et al.
    Chagas' disease may also be encountered in Europe.
    European heart journal 1996;17:1289.

    14. Todd IP, Porter NH, Morson BC, et al.
    Chagas disease of the colon and rectum.
    Gut 1969;10:1009-14.

    15. Herwaldt BL, Grijalva MJ, Newsome AL, et al.
    Use of polymerase chain reaction to diagnose the fifth reported US case of autochthonous transmission of Trypanosoma cruzi, in Tennessee, 1998.
    The Journal of infectious diseases 2000;181:395-9.

    16. Kollien AH, Schaub GA.
    The development of Trypanosoma cruzi in triatominae.
    Parasitology today, Personal ed 2000;16:381-7.

    17. Prata A.
    Clinical and epidemiological aspects of Chagas disease.
    The Lancet infectious diseases 2001;1:92-100.

    18. Anez N, Carrasco H, Parada H, et al.
    Myocardial parasite persistence in chronic chagasic patients.
    The American journal of tropical medicine and hygiene 1999;60:726-32.

    19. Schijman AG, Vigliano CA, Viotti RJ, et al.
    Trypanosoma cruzi DNA in cardiac lesions of Argentinean patients with end-stage chronic chagas heart disease.
    The American journal of tropical medicine and hygiene 2004;70:210-20.

    20. Karp CL, Auwaerter PG.
    Coinfection with HIV and tropical infectious diseases. I. Protozoal pathogens.
    Clin Infect Dis 2007;45:1208-13.

    21. Vaidian AK, Weiss LM, Tanowitz HB.
    Chagas' disease and AIDS.
    Kinetoplastid Biol Dis 2004;3:2.

    22. Guzman-Tapia Y, Ramirez-Sierra MJ, Dumonteil E.
    Urban Infestation by Triatoma dimidiata in the City of Merida, Yucatan, Mexico.
    Vector borne and zoonotic diseases (Larchmont, NY 2007;7:597-606.

    23. Franco-Paredes C, Rouphael N, Mendez J, et al.
    Cardiac manifestations of parasitic infections part 1: overview and immunopathogenesis.
    Clinical cardiology 2007;30:195-9.

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  40. Left ventricular thrombus associated with apical ballooning: a rising clinical evidence ?

    Dear Editor,

    I read with great interest the report by Robles et al (1), recently published in the Journal, that describes the occurrence of left ventricular thrombus formation (LVTF) in a patient with apical ballooning (Takotsubo-like syndrome).

    This study likely provides further contribution to the knowledge on the various clinical aspects of this stress-related cardiac disease. In spite of the acute and often severe LV functional impairment in the majority of the patients, the complication described by Robles seems to be rare. Under a pathophysiological point of view, there are several reasons to theorize a common causal mechanism of TF between Takotsubo-like syndrome and ischemic (necrotic) apical dilatation. Apical blood flow stasis, together with the known abnormalities in the electrical charges of blood cells and endothelial or endocardial surface, and/or hyper- coagulation are time-honoured determinants of cardiovascular thrombosis. Therefore, it is conceivable that the occurrence of LVTF is not rigorously related to the hyper-adrenergic storm, which is typical of the apical ballooning, but to other pre-existing cofactor(s), as S- or C-protein, C- reactive protein, factor V Leiden, platelet aggregation, hormone levels, genetic factors, leukocyte adhesion molecules, fibrinogen, viscosity, etc., that may be accounted for such inter-individual differences as in patients with myocardial infarction. One of the most puzzling questions in the patients with ballooning concerns the discrepancy between the coronary bed (where thrombosis has never been described) and left ventricular cavity (where it has been). Recent working hypotheses have been addressed on adrenaline-induced switching from Gs-protein to Gi-protein signaling of the beta2- adrenoceptor that may make the apical myocardium more susceptible to (structural or functional) damage than other cardiac sites (2).

    However, though rare, LVTF has been already reported by at least 10 studies, including that one published in 2003 by Barrera-Ramirez et al (3) (from the same Institution of Robles et al ?). Thus, it is rather surprising that the Authors affirmed that "...a LV thrombus associated with Takotsubo-like ventricular dysfunction has not been demonstrated, although there have been reports regarding the embolic complications of this disorder", since the first description dates just back to that study (3).

    Based on the published reports, fortunately, embolic complications are not so frequent. About 20% of cadioembolic stroke, as the main clinical presentation, and another case of late renal infarct, but no fatal outcomes, have been reported in the patients with patent LVTF (4-6).

    On the other hand, we should also consider that over the last decade the diagnosis of Takotsubo-like disease was performed only by angiography, so that some LVTF might have been overlooked in the past. Contemporary techniques, such as high-resolution echocardiography or cardiac magnetic resonance, together with a rising clinical awareness about the syndrome, surely contribute to a better knowledge of its various aspects, even if lots of pathophysiological questions are still open.

    REFERENCES

    1. Robles P, Jimenez JJ, Alonso M.
    Left ventricular thrombus associated with left ventricular apical ballooning.
    Heart 2007;93:861.

    2. Lyon AR, SC Rees P, Prasad S, Poole-Wilson PA, Harding SE.
    Stress (Takotsubo) cardiomyopathy. A novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning.
    Nature 2008;5(1):22-9.

    3. Barrera-Ramirez CF, Jimenez-Mazuecos JM, Alfonso F.
    Apical thrombus associated with left ventricular apical ballooning.
    Heart 2003;89:927.

    4. Grabowski A, Kilian J, Strank C, Cieslinski G, Meyding-Lamad¨¦ U.
    Takotsubo cardiomyopathy. A rare cause of cardioembolic stroke.
    Cerebrovasc Dis 2007;24:146¨C8.

    5. Nerella N, Lodha A, T¨ªu CT, Chandra PA, Rose M.
    Thromboembolism in Takotsubo syndrome: A case report.
    Int J Cardiol 2007;doi:10.1016/j.ijcard.2006.11.186.

    6. de Gregorio C, Cento D, Di Bella G, Coglitore S.
    Minor stroke in a Takotsubo-like syndrome: a rare clinical presentation due to transient left ventricular thrombi.
    Int J Cardiol (in press).

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  41. Atrial Septal Defect in Pulmonary Arterial Hypertension: to close or not to close?

    Dear Editor,

    With great interest we read the article of Balint and coworkers (1), in which they report the results of catheter-closure of an atrial septal defect (ASD) in 54 patients with associated pulmonary arterial hypertension (PAH). The authors describe successful closure and a decrease in pulmonary artery pressure and NYHA functional class at one year follow up in the majority of patients. On the other hand, more than half of the patients had persistent PAH (moderate or severe) after closure and two patients died during follow up. The interpretation of the authors of these data is that catheter-closure of ASD in patients with PAH is successful and has a good outcome. In our opinion, however, this conclusion is not justified and we feel that it is important to add some considerations on PAH associated with congenital pulmonary-to-systemic shunts, in order to put the interpretation of the data, as presented by the authors, in a broader perspective.

    PAH in congenital heart defects associated with a systemic-to- pulmonary shunt, including atrial septal defect, is a progressive pulmonary vascular disease. Its progressive course is characterized by a reversible phase early in the disease versus a progressive, irreversible phase in the advanced stage of the disease (2). When the heart defect is adequately corrected in the early, reversible phase of the pulmonary vascular disease (either surgically or by catheter intervention), the PAH will disappear and remodeled pulmonary arteries will normalize (1,2). However, when the heart defect is corrected late, in the advanced stage of the pulmonary vascular disease, and characteristic vascular lesions have developed, including concentric laminar intimal fibrosis and plexiform lesions, the pulmonary vascular disease will be not only irreversible, but will progress in time despite closure of the shunt (2,3). In this latter scenario, closure of the heart defect will eventually lead to deterioration of the clinical condition and a decreased survival in these patients. This is because the defect is no longer able to serve, in case of right ventricular failure, as an escape to maintain cardiac output at the cost of cyanosis as is the case in Eisenmenger’s syndrome.(3,4)

    The considerations above lead to two important comments with respect to the data presented by Balint and coworkers and to the interpretation of these data by the authors. The first question that should be asked in a patient with ASD and PAH, before attempting to close the defect is: How far is the progression of the pulmonary vascular disease in this individual patient? The authors provide no data regarding assessment of the progression of the pulmonary vascular disease in the patients studied. Determination of the acute response to pulmonary vasodilator testing, with nitric oxide, oxygen or other agents, has been generally used to assess this progression in patients with CHD and to assess the possibility to close the defect. (3) Although it is recognized that there is a grey area in which it may be difficult to distinguish between reversible and irreversible disease, most patients with advanced pulmonary vascular disease can be identified, in whom closure of the defect will have a detrimental effect in time (3). The second comment addresses the suggestion by the paper that a decrease in pulmonary artery pressure early after closure of the ASD is reassuring and can be regarded as a successful outcome of the procedure for the patient. In our opinion this is absolutely not the case. If an increased pulmonary blood flow is diminished by closure of a heart defect, the pulmonary artery pressure will always decrease, independent from pulmonary vascular resistance. This will also occur in patients with advanced, progressive, pulmonary vascular disease. In these latter patients, however, PAP will gradually increase again parallel with the progression of the vascular disease, and eventually outcome will be worse than that with an unclosed defect (4).

    In the current paper, Balint and co-workers report that PAH was still present after one year in more than half of their patients. In the lights of the conceptual considerations as described above, one could argue if the conclusion of the authors, “Transcatheter closure in patients with secundum ASD and PAH …is associated with good outcomes…” is justified. We think it is not: concerns are in place regarding the outcome of these patients at long term follow up (which is more than one year) compared to similar patients in whom the ASD is not closed. We absolutely do agree with the authors that follow up studies in this respect are needed.

    References

    1) Balint OH, Samman A, Haberer K, Tobe L, Mc Laughlin P, Siu SC, Horlick E, Granton J, Silversides CK.
    Outcomes in Patients with Significant Pulmonary Hypertension Undergoing Percutaneous Atrial Septal Defect Closure.
    Heart. 2007; doi:10.1136/hrt.2006.114660

    2) Wagenvoort CA.
    Morphological substrate for the reversibility and irreversibility of pulmonary hypertension.
    Eur Heart J. 1988; Suppl J:7-12.

    3) Berger RMF.
    Possibilities and impossibilities in the evaluation of pulmonary vascular disease in congenital heart defects.
    Eur Heart J. 2000;1:17-27

    4) Law MA, Grifka RG, Mullins CE, Nihill MR.
    Atrial septostomy improves survival in select patients with pulmonary hypertension.
    Am Heart J. 2007;153:779-84.

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  42. LEFT VENTRICULAR VOLUMES AS OUTCOME DETERMINANTS IN CARDIAC RESYNCHRONIZATION THERAPY (CRT)

    Dear Editor,

    An accurate selection and optimal timing in addressing patients to CRT is important in order to optimize the treatment. Consequently the identification of outcome predictors is critical.

    For these reasons we greatly appreciated the paper by Gradaus et al. entitled and stating that “diastolic filling pattern and left ventricular diameter predict response and prognosis after cardiac resynchronization therapy” that adds, on a larger scale, further evidence to the recently “in extenso” reported RESYNC results (Gimelli et al, 2007) about the relevance of the pre-CRT left ventricular dimensions (both systolic and diastolic) on functional response after CRT in patients with chronic heart failure (CHF) and left bundle branch block (LBBB).

    Particularly, an indexed left ventricular end-diastolic volume (iLVEDV), i.e. LVEDV/body surface area, upper than 142 ml/square meter at myocardial gated single photon emission computed tomography has been found (Valle et al, 2005) and has been emphasised (Cuocolo et al, 2006) to be a reliable predictor of functional recovery after CRT.

    RESYNC study survival branch is still ongoing, however the data already collected agree with those by Gradaus et al. about the critical role of left ventricular dimensions not only on functional outcome but also on the frequency of heart-related fatalities after CRT.

    In our opinion, according to Gradaus et al., left ventricular dimensions are critical prognostic parameters and should be carefully taken into account in view of a CRT. Moreover all these data probably justify an earlier recourse to CRT in managing patients with CHF and LBBB.

    REFERENCES

    1. Cuocolo A. et al.
    Eur. J. Nucl. Med. Mol. Imaging 2006; 33: 360-381

    2. Gimelli A. et al.
    J. Cardiovasc. Med. 2007; 8: 575-581

    3. Valle G. et al.
    Eur. J. Nucl. Med. Mol. Imaging 2005; 32 (Suppl.1):S165

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  43. Not only after myocardial infarction

    Dear Editor,

    We read with interest the study by Norhammar et al (1) describing the treatment and myocardial infarction survival rates according to the presence of diabetes. In this study, one-year mortality rates decreased from 1995 to 2002 from 16.6 to 12.1% in patients without diabetes and from 29.7 to 19.7%, respectively, in those with diabetes. Despite improved pre-admission and in-hospital treatment, diabetic patients were less often offered acute reperfusion therapy, acute revascularisation or revascularisation within 14 days, aspirin and lipid-lowering treatment at discharge.

    Although it is important the acute management in the treatment of patients with myocardial infarction, it is also crucial the secondary prevention of this population, especially of those at higher risk such as diabetics. In a study recently performed in Spanish clinical practice setting, in 2,024 hypertensive patients with chronic ischemic heart disease, the influence of diabetes on the diagnosis and therapeutic approach was analysed (2,3).

    Accordingly to the paper of Norhammar et al, the presence of other risk factors and cardiovascular comorbidities was also more frequent in diabetics. Overall, diabetic patients were taking more medication (96.9% of diabetics vs 85.4% of no-diabetics were treated with ≥4 drugs, p<0.001). With regard to antihypertensive agents, calcium channel blockers (49.1 vs 42.2%), diuretics (45.1 vs 30.4%) and renin-angiotensin system inhibitors (83.6 vs 72.9%) were more commonly prescribed in diabetics (all of them p <0.01), while beta blockers were used more frequently in no diabetics (63.8 vs 68.7% p=0.01). BP control rates (<130/80 mmHg) were higher in no diabetics (19.7% vs 26.4% p=0.001). Concerning lipid lowering drugs, they were more frequently prescribed in diabetics (77.8 vs 73.9%, p=0.036), nevertheless there were no differences in LDL-cholesterol control rates in both groups. Notably, patients with diabetes were surprisingly taking less antiplatelet agents than no diabetics (85.2 vs 89.7%, p=0.003). Finally, with regard to diagnostic procedures, no differences were found in the performance of stress test (84.5 vs 86.9%) or coronary angiography (60.9 vs 58.1%).

    In agreement with Norhammar et al, although in the last years the management of diabetics with coronary heart disease is improving, our data also confirm there is still a lack of application of evidence-based treatment.

    References

    1. Norhammar A, Lindbäck J, Rydén L, Wallentin L, Stenestrand U.
    Improved but still high short- and long-term mortality rates after myocardial infarction in patients with diabetes mellitus: a time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission.
    Heart 2007;93:1577-83.

    2. Escobar C, Barrios V, de Pablo C, Bertomeu V, Murga N, Calderon A, et al.
    Associated cardiovascular risk factors control in the hypertensive population with chronic ischemic heart disease attended by cardiologists in Spain. Data from the CINHTIA study.
    Eur Heart J 2007;28(Abst Suppl):684-85.

    3. Barrios V, Escobar C, Bertomeu V, de Pablo C, Murga N, Calderon A, et al.
    Blood pressure control in the hypertensive population with chronic ischemic heart disease attended by cardiologists in Spain.
    Eur Heart J 2007;28(Abst Suppl):867.

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  44. Pulmonary artery stiffness in arterial switch patients

    Dear Editor,

    The recent study by Grotenhuis and colleagues demonstrated the increased peak flow velocity across the pulmonary trunk, right ventricular hypertrophy and right ventricular relaxation abnormalities in patients after the arterial switch operation (1). The authors argued that one of the possible causes of the increased peak flow velocity was local scar tissue with loss of pulmonary artery distensibility.

    I recognize the soundness of the report. We previously analyzed an input impedance spectrum of pulmonary artery in patients after the arterial switch procedure, and reported the increased pulmonary artery stiffness of them (2). Concerning systemic circulation, many reports have demonstrated that the augmented aortic stiffness, which increases left ventricular pulsatile work, induces left ventricular hypertrophy (3). As for pulmonary circulation, it has reported that the increased pulmonary artery stiffness enhances right ventricular load (4). Therefore, the increased stiffness of pulmonary artery in arterial switch patients would cause right ventricular hypertrophy. I agree with Grotenhuis and colleagues in thinking that careful observation about right ventricular function (and arrhythmia) is needed in follow-up of the patients after the arterial switch procedure.

    References

    1. Grotenhuis HB, Kroft LM, van Elderen SGC, et al.
    Right ventricular hypertrophy and diastolic dysfunction in arterial switch patients without pulmonary artery stenosis.
    Heart. 2007;93:1604-1608

    2. Murakami T, Nakanishi T, Nakazawa M, et al.
    The spectrum of pulmonary input impedance in children with complete transposition after the arterial switch procedure.
    Cardiol Young. 1998;8:180-186

    3. Ou P, Celermajer DS, Jolivet O, et al.
    Increased central aortic stiffness and left ventricular mass in normotensive young subjects after successful coarctation repair.
    Am Heart J. 2008;155:187-193

    4. Hunter KS, Lee P, Lanning CJ, et al.
    Pulmonary vascular input impedance is a combined measure of pulmonary vascular resistance and stiffness and predicts clinical outcomes better than pulmonary vascular resistance alone in pediatric patients with pulmonary hypertension.
    Am Heart J. 2008;155:166-174

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  45. Socioecomonic status and cardiovascular disease risk

    Dear Editor,

    We congratulate Dr A Steptoe and associates on their extensive epidemiological research concerning the cardiovascular risk and its association with the pathogen burden depending on the socio-economic status (1). Since the middle of the 20th century, the cardiovascular risk in the populations of Europe and the United States has shown a reverse dependence on the economic and professional status. Many researchers including the authors of this study have attempted to find the causes of this tendency (2). The study referred to provides a lot of epidemiological information about the role played in vasculitis and the pathogenesis of atherosclerosis by the universally appearing infectious factors. The idea of associating the infectious factors initiating inflammatory changes in vessels influencing the development of atheroclerosis with the socio-economic status is inventive and interesting.

    Examinations were conducted on 1201 patients aged 40-60 selected from the population of Lublin (Poland), (3). Obesity and overweight were the most frequent cardiovascular risk factors. The most frequent occurrence of this disease was noted among patients with primary education, the fewest among those with higher education. Similarly, it was proved that the lower the patients' level of education, the greater and more severe the cigarette smoking habit. Hence the cardiovascular risk factors regarded as the indicators of social stress (obesity, smoking) occurred more frequently among the least educated patients. Moreover, the social stress is believed to belong to the obesity and smoking causes in the final phase. Having assessed the total cardiovascular risk, we observed the existence of higher level coronary artery disease risk in patients with vocational education as compared to people with higher education.

    Our findings accord with those recorded and currently observed in many European countries, where researchers have noticed a reverse dependence of the coronary artery disease on high standard of living. Consequently, there are more cases of the disease among lower social classes. Identifying the causes of this tendency will allow for designing better therapy and prevention strategies. My presentation and discussion of dr A Steptoe's research aims at finding the underlying cause of this tendency.

    References

    1. Steptoe A, Shamaei-Tousi A, Gylfe A et. al.
    Socioeconomic status, pathogen burden and cardiovascular disease risk.
    Heart. 2007; 93:1567-70.

    2. Bunde J Suls J.
    A quantitative analysis of the relationship between the Cook-Medley Hostility Scale and traditional coronary artery disease risk factors.
    Health Psychol Psychoz 2006;25:493-500.

    3. Mieczkowska J, Baraniak J, Kozak-Szkopek E.
    The influence of education on the cardiovascular risk.
    Annales Universitatis Mariae Curie-Sk³odowska Sectio D-Medicina 2006; 61(1): 290-295,

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  46. Management includes primary prevention

    Dear Editor,

    Though the mandate of Karthikeyan et al’s article is the management of manifest coronary disease, primary prevention at the population level should not be ignored. India is rapidly urbanising, and urban India shows marked increases in both coronary heart disease prevalence and risk factors when compared with rural settings. (1)Though coronary risk factors tend to be concentrated in those of higher social classes, (2) the poor in India are also increasingly affected whilst continuing to suffer from diseases of the age of pestilence and famine. Prevalence of cardiovascular risk factors such as smoking, high blood pressure and overweight are also higher than might have been expected in rural settings. (3) More than 70% of India still lives outside cities, and these data provide an early indication of the burden of heart disease that will occur in rural India in the coming years.

    Geoffrey Rose presented two approaches to prevention of disease—one based on the individual and the other on populations. In the individual strategy, high-risk individuals are sought and offered individual protection. In contrast, the ‘population strategy’ seeks to control the determinants of incidence in the population as a whole. (4) Rose argued that though the ‘high-risk’ strategy was the traditional medical approach to prevention and though this approach allowed the doctor to identify appropriate interventions for their patient in clinic, it was palliative and temporary in that it did not seek to alter the underlying causes of the disease but to identify individuals who were particularly susceptible to those causes.

    The population approach to primary prevention seeks to achieve leftward shift in the normal distribution of cardiovascular risk. The decline in coronary heart disease deaths in the developed world has been mostly attributed to primary prevention. (5)

    The Seven Countries Study initially led to the concept that cardiovascular disease prevention should be implemented at the population level. Though both individual and population approaches to disease prevention are needed, implementation and evaluation of the population approach is difficult whereas proof of efficacy is easier in the high-risk approach. (6)

    The policies for the primary prevention of cardiovascular diseases in most developed countries thus emphasise high-risk rather than population strategies. (7) However, to create an environment in which individual behavioural initiatives can succeed, major shifts in population behaviour through public health policy are necessary. The wider environment impacts on the health of an individual in addition to individual behavioural and biological influences. In developing countries such as India, any increase expenditure on 'healthcare' should not be used to imitate the western model of high-risk and secondary prevention but focus more on primary prevention at the population level. Without this approach, inequities in care - especially in urban poor and rural communities - are bound to worsen.

    References

    1. Ganesan Karthikeyan, Denis Xavier, Doriaraj Prabhakaran, and Prem Pais
    Perspectives on the management of coronary artery disease in India
    Heart 2007; 93: 1334-1338

    2. Gupta R, Gupta VP
    Meta-analysis of coronary heart disease prevalence in India
    Indian Heart J, vol. 48, no. 3, pp. 241-245.

    3. Singh RB, Beegom R, Mehta AS, Niaz MA, De AK, Mitra RK, Haque M, Verma SP, Dube GK, Siddiqui HM
    Social class, coronary risk factors and undernutrition, a double burden of diseases, in women during transition, in five Indian cities
    International Journal of Cardiology, vol. 69, no. 2, pp. 139-147.

    4. Chow C, Cardona M, Raju PK, Iyengar S, Sukumar A, Raju R, Colman S, Madhav P, Raju R, Srinath RK, Celermajer D, Neal B
    Cardiovascular disease and risk factors among 345 adults in rural India-the Andhra Pradesh Rural Health Initiative
    Int.J.Cardiol

    5. ROSE GEOF.
    Sick Individuals and Sick Populations
    International Journal of Epidemiology, vol. 14, no. 1, pp. 32-38

    6. Unal B, Critchley JA, Capewell S
    Modelling the decline in coronary heart disease deaths in England and Wales, 1981-2000: comparing contributions from primary prevention and secondary prevention
    BMJ, vol. 331, no. 7517, p. 614

    7. Emberson J, Whincup P, Morris R, Walker M, Ebrahim S
    Evaluating the impact of population and high-risk strategies for the primary prevention of cardiovascular disease
    European Heart Journal, vol. 25, no. 6, pp. 484-491

    8. Department of Health
    National Service Framework for coronary heart disease: modern standards and service models

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  47. Author's Response

    Dear Editor,

    Thank you for forwarding us the leter of Dr Rochefort and his kind comments on the paper. He has made a good point, and of course he is right about the increased mobilization of the MSC in experimental hypoxia, which he confirmed in an elegant experiment. Table 3 contains an typing error, which we are sorry to have missed during proofreading. The correct meaning of the sentence is "Increase of bone marrow-dependent mesenchymal stem cells (rats)".

    Again I apologize for the mistake.

    Sincerely, Wojciech Wojakowski MD on behalf of the authors

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  48. Hypoxia-induced Mesenchymal Stem Cells mobilization

    Dear Editor,

    I read with great interest the review by Wojakowski et al about the mobilization of bone marrow-derived stem/progenitor cells during acute coronary syndromes.1 The contribution of such cells, including hematopoietic stem cells, mesenchymal stem cells (MSCs), endothelial progenitor cells and other poorly defined progenitors, is well in coronary heart diseases. I agree this review discusses and summarizes information regarding mechanisms of mobilization, homing and engraftment of stem/progenitor cells that may take part in cardiac repair after ischaemic injury.

    Among all factors that can modulate the number of circulating stem/progenitor cells, authors stated that “hypoxia induced a decrease of (circulating) bone marrow-derived MSCs” (table 3)1; however, the quoted references, authored by Rochefort et al, clearly demonstrated the opposite.2 In fact, Rochefort et al evidenced that firstly MSCs were regularly observed in the rat circulating blood and that secondly MSCs were consistently and dramatically mobilized into the bloodstream after chronic hypoxia.2 Although, mechanisms inducing such a mobilization during chronic hypoxia remain unclear, this hypoxia-induced mobilization model represents a great tool to study the in vivo effect of factors in the MSC mobilization process.

    To conclude, even if this specific point about the hypoxia-induced mobilization was incorrect, data reported in the review by Wojakowski et al were not affected and this excellent review is to be applauded.

    References

    1. Wojakowski W, Kucia M, Kazmierski M, et al.
    Circulating progenitor cells in stable coronary heart disease and acute coronary syndromes: relevant reparatory mechanism?
    Heart 2008 94: 27-33

    2. Rochefort G, Delorme B, Lopez A, et al.
    Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia.
    Stem Cells 2006; 24: 2202–8.

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  49. Care with Single Coil AICD leads

    Dear Editor,

    Adamson and Nelson-Piercy give a thorough overview of arrhythmias in pregnancy1. However they mention that the presence of an automated implantable cardio-defibrillator (AICD) poses no risk to the fetus as, even after device therapy, ‘the electrical field to which the fetus is exposed is minimal’.

    We recently cared for a 23 year old patient with hypertrophic cardiomyopathy who had an AICD implanted at the age of 14 with a single coil lead and abdominal box. The box was therefore acting as an active can and any device therapy would involve a shock between the box and the single coil on the lead. During pregnancy the box came to lie directly over the uterus and any therapy would have resulted in a significant shock to the fetus. The AICD was disabled throughout pregnancy and the patient successfully delivered a healthy infant vaginally with no complications.

    It is not uncommon for patients to have had single coil defibrillator leads with abdominal generators implanted in childhood. The risks of device therapy to the fetus should be considered when these patients are assessed at cardiac pregnancy clinics.

    References

    1. Adamson DL, Nelson-Piercy C.
    Managing palpitations and arrhythmias during pregnancy.
    Heart 2007;93:1630-1636.

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  50. Authors Response

    Dear Editor,

    We thank Drs Mclaren et al. for their interest in our study.

    Firstly, we chose Vancomycin as we wished to use an antistaphylococcal drug that had been studied in cardiac surgical patients. Additional rifampicin was used in an attempt to prevent resistance developing. Clearly the strategy was successful as we did not see any increase in resistant organisms during, or for the 2 years after, the study. We are interested in their statement of a change in their antibiotic prophylaxis with no difference. This statement was unpublished and is not publicly available. They have chosen to retain a unique combination of cephazolin and rifampicin as their prophylaxis. They continue to use an additional antistaphylococcal agent and their choice of rifampicin as a sole agent is unusual, with very little prior experience. Even so, we would suggest that a randomised controlled prospective study is more relevant than the observational data that is quoted.

    Secondly, they have criticised our use of vancomycin timed at induction of anaesthesia. This is frequently how vancomycin for antibiotic prophylaxis is given in many surgical centres, is seen in the study they quote (Vuorisalo) and in other studies that compare vancomycin with cephalosporins, which we have referred to. Others1 have shown that administration more than 60 mins before surgical incision surprisingly may reduce efficacy. Furthermore, our strategy was effective and a more efficacious administration regime could only make this more effective if it had any further effect at all.

    Thirdly, they advocate an even higher dose of cefuroxime but such a dose has not been published in any guideline or used by any other study. We are confident in our dosage and formulation of cefuroxime, as the incidence of infection in the low risk patients ( where cefuroxime was used) operated at the same time, as referred to in our paper and not part of our study, was extremely low.

    Fourthly, Mclaren has questioned the security of blinding in our study with the use of Rifampicin. We clearly acknowledge this limitation in our paper, but the very significant results in further infection surgical procedures, deep SSI and readmission to hospital is unlikely to be accounted for by the possibility of noticing orange colouration of the urine at the time of surgery. Lastly, we used the term ‘longer’ , referring to our 48 hr regime, as increasingly guidelines on surgical prophylaxis are limiting prophylaxis to 24hrs, with little real evidence. The 2 articles quoted in support of their criticism (Habarth & Kato) use ‘48 hours ‘as their definition of short/long term and therefore do not contradict our study.

    To reiterate, in our cohort of patients at high risk of SSI, i.e. obese, diabetic or undergoing bilateral LITA, we showed that longer and broader antibiotic prophylaxis, reduced SSI with clinical, economic and statistical significance.

    References

    1. Kevin W. Garey, Thanh Dao, Hua Chen, et al.
    Timing of vancomycin prophylaxis for cardiac surgery patients and the risk of surgical site infections.
    Journal of Antimicrobial Chemotherapy (2006) 58, 645*650

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  51. Authors Response

    Dear Editor,

    We thank Dr. Ballo and colleagues for their interesting comments on our article. In agreement with our study, Ballo et al show a nonlinear association between circumferential midwall and longitudinal LV systolic function in patients with hypertension [1]. It is particularly noteworthy that this nonlinear association is apparent in two different study populations. The patients in our study were suffering from idiopathic heart failure (mean LVEF 44±17% and AVPD 6.9±2.7 mm) whereas the patients in Ballo´s study had a less severe diagnosis (arterial hypertension, mean LVEF 62 ±9.7% and AVPD 12.5±2.5 mm). Longitudinal function is dependent on subendocardial muscle fibres that are extremely sensitive to ischemia and increases in wall stress, and consequently capable of detecting small ventricular changes[2-4].

    REFERENCES

    [1] Ballo P, Quatrini I, Giacomin E, Motto A, Mondillo S.
    Circumferential versus longitudinal systolic function in patients with hypertension: a nonlinear relation.
    J Am Soc Echocardiogr. 2007;20:298-306.

    [2] Nikitin NP, Loh PH, Silva R, et al.
    Prognostic value of systolic mitral annular velocity measured with Doppler tissue imaging in patients with chronic heart failure caused by left ventricular systolic dysfunction.
    Heart. 2006;92:775-9.

    [3] Gruner Svealv B, Fritzon G, Andersson B.
    Gender and age related differences in left ventricular function and geometry with focus on the long axis.
    Eur J Echocardiogr. 2006;7:298-307.

    [4] Gruner Svealv B, Tang MS, Waagstein F, Andersson B.
    Pronounced improvement in systolic and diastolic ventricular long axis function after treatment with metoprolol.
    Eur J Heart Fail. 2007.

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  52. Antibiotic prophylaxis in cardiac surgery

    Dear Editor,

    The recent study by Dhadwal et al. (1) has a number of weaknesses which merit discussion. The study appears to have been initiated by a “perceived increase in crude infection rates” but the organisms responsible for this increase were not presented. Unless there was a high incidence of infection with resistant organisms such as methicillin- resistant Staphylococcus aureus (MRSA) prior to study commencement, the routine use of vancomycin in a multi-drug regimen is hard to justify (2, 3). The authors stated that their antibiotic regimen was based, at least in part, on Spelman et al. (4). However, it is worth noting that the prevalence of MRSA at this author’s institution fell significantly following an intensive infection control programme, prompting a return to cephazolin and rifampicin as prophylaxis against cardiac surgical-site infection (SSI). No significant increase in the incidence of SSI has been observed since the change (unpublished data).

    Dhadwal et al. (1) administered vancomycin after induction of anaesthesia. This approach is not recommended by the Centres for Disease Control and Prevention, as it does not provide adequate tissue levels of antibiotic at the time of surgical incision (2). Nonetheless, the authors documented a decrease in SSI. One explanation for this that appears not to have been considered was that the cefuroxime regimen used in the control arm was suboptimal. Other studies of cefuroxime in cardiac surgery have used considerably higher doses and a 1.5g load may be inadequate (5, 6). Moreover, a recent report highlighted significant problems with some formulations of cefuroxime (7). Dhadwal et al. (1) did not state which formulation they used.

    Blinding in the study was suboptimal both due to the orange discolouration of urine seen in patients given rifampicin and because the study required antibiotics to be given at different times and for different durations, potentially unmasking patient assignment.

    The authors concluded that longer duration of antibiotic prophylaxis reduces the incidence of SSI. However, this was not a study comparing two identical antibiotic regimens with different durations. We believe that this conclusion is both misleading and unjustified. There is substantial evidence that prolonged duration of prophylactic antibiotic therapy is detrimental to patients (8-10).

    References:

    1. Dhadwal K., Al-Ruzzeh S., Athanasiou T., et al.
    Comparison of clinical and economic outcomes of two antibiotic prophylaxis regimens for sternal wound infection in high-risk patients following coronary artery bypass grafting surgery: a prospective randomised double-blind trial.
    Heart 2007:93:1126-1133

    2. Mangram AJ., Horan TC., Pearson ML., Silver LC., Jarvis WR.
    Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee
    Infect Control Hosp Epidemiol 1999:20:250-278

    3. Vuorisalo S., Pokela R., Syrjala H.
    Comparison of vancomycin and cefuroxime for infection prophylaxis in coronary artery bypass surgery.
    Infect Control Hosp Epidemiol 1998:19:234-239

    4. Spelman D., Harrington G., Russo P., Wesselingh S.
    Clinical, microbiological, and economic benefit of a change in antibiotic prophylaxis for cardiac surgery.
    Infect Control Hosp Epidemiol 2002:23:402 -404

    5. Mandak J., Pojar M., Malakova J., et al.
    Tissue and plasma concentrations of cephuroxime during cardiac surgery in cardiopulmonary bypass- a microdialysis study.
    Perfusion 2007:22:129-136

    6. Nascimento JW., Carmona MJ., Strabelli TM., Auler JO Jr., Santos SR.
    Systemic availability of prophylactic cefuroxime in patients submitted to coronary artery bypass grafting with cardiopulmonary bypass.
    J Hosp Infect 2005:59:299-303

    7. Mastoraki E., Michalopoulos A., Kriaras I., et al.
    Incidence of postoperative infections in patients undergoing coronary artery bypass grafting surgery receiving antimicrobial prophylaxis with original and generic cefuroxime.
    J Infect 2007: Epub ahead of print.

    8. Harbarth S., Samore MH., Lichtenberg D., Carmeli Y.
    Prolonged antibiotic prophylaxis after cardiovascular surgery and its effect on surgical site infections and antimicrobial resistance.
    Circulation 2000:101:2916-2921

    9. Kato Y., Shime N., Hashimoto S., et al.
    Effects of controlled perioperative antimicrobial prophylaxis on infectious outcomes in pediatric cardiac surgery.
    Crit Care Med 2007:35:1763-1768

    10. Edwards FH., Engelman RM., Houck P., Shahian DM., Bridges CR.
    The Society of Thoracic Surgeons Practice Guideline Series: Antibiotic Prophylaxis in Cardiac Surgery, Part I: Duration.
    Ann Thorac Surg 2006:81:397-404

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  53. Prognostic value of left ventricular long-axis versus short-axis systolic function in heart failure

    Dear Editor,

    Grüner Sveälv et al.(1) recently found that left ventricular (LV) long-axis atrioventricular plane displacement (AVPD) in heart failure (HF) patients was linearly correlated with short-axis fractional shortening (LVFS) in the lower range of AVPD, but not in the higher range of AVPD. They also observed that decreasing AVPD quartiles showed a stepwise association with worsening prognosis. Notably, a similar gradual association with outcome was less evident for LVFS, as no differences in outcome were found between the third and fourth LVFS quartiles.

    These interesting results agree with our recent finding that the relation between longitudinal and circumferential systolic performance is nonlinear, as a depression in longitudinal indices such as AVPD and mitral annulus peak systolic velocity precedes that in endocardial or midwall circumferential function(2). Therefore, when plotting a long-axis versus a short-axis index (e.g., AVPD on the X-axis and LVFS on the Y-axis), the resulting relation tends to be horizontal in the higher range of indices, reflecting isolated long-axis impairment in the early stages of systolic dysfunction. Conversely, the slope of the relation rapidly increases in the lower range of indices, reflecting simultaneous deterioration in longitudinal and circumferential function in more advanced stages of HF. This explains the presence of linear correlation between AVPD and LVFS only in the lower range of AVPD.

    Intriguingly, the more gradual association with prognosis observed for AVPD than LVFS may represent the clinical correlate of their nonlinear relation. Based on currently recommended cut-offs for normal LVFS (>25% in males and >27% in women)(3), most patients in the two highest LVFS quartiles (23-31% and >31%, respectively; overall, 72% males) had preserved short-axis function. These subjects fall in the horizontal portion of the AVPD-LVFS curve, where circumferential indices cannot identify patients at heightened risk due to subtle systolic dysfunction. In contrast, because longitudinal systolic impairment is an early and progressive event in the natural history of HF, and considering that it represents a powerful prognostic predictor in HF patients(4), decreasing AVPD values may be expected to reflect the effective stage of LV dysfunction and to parallel the corresponding increase in cardiovascular risk better than circumferential indices.

    References

    1. Grüner Sveälv N, Olofsson EL, Andersson B.
    Ventricular long axis function is of major importance for long-term survival in heart failure patients.
    Heart 2007 Jun 17; [Epub ahead of print].

    2. Ballo P, Quatrini I, Giacomin E, Motto A, Mondillo S.
    Circumferential versus longitudinal systolic function in subjects with hypertension: a nonlinear relation.
    J Am Soc Echocardiogr 2007;20:298-306.

    3. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology.
    J Am Soc Echocardiogr 2005;18:1440-1463.

    4. Nikitin NP, Loh PH, Silva R, Ghosh J, Khaleva OY, Goode K, Rigby AS, Alamgir F, Clark AL, Cleland JG.
    Prognostic value of systolic mitral annular velocity measured with Doppler tissue imaging in patients with chronic heart failure caused by left ventricular systolic dysfunction.
    Heart 2006;92:775-9.

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  54. Low EF: the best marker of poor prognosis in patients affected by non compaction

    Dear Editor,

    McMahon et al reported in a recent article a reduction of TD velocities in children with noncompaction of the left ventricle, compared with normal controls. The authors concluded their work saying that the reduction of lateral mitral Ea velocity helps to predict children with LVNC who are at risk of adverse clinical outcomes including death and need for cardiac transplantation. In a precedent report our group reported a strong correlation between pathological tissue Doppler and reduction of ejection fraction. In our report the tissue Doppler analysis was performed segment by segment, and a correlation had been ob served only in patients with a low EF.

    Noncompaction of the ventricular myocardium (LVNC) is a rare congenital cardiomyopathy resulting from an arrest in normal endomyocardial embryogenesis; it is characterized by a thin compacted epicardial and an extremely thickened endocardial layer with prominent trabeculations and deep intertrabecular recesses (1-6). In this rare cardiomyopathy clinical presentation and outcome is variable, but heart failure, arrhythmias and sudden cardiac death are described like common clinical findings (1-6). Unfortunately the pathophysiological mechanisms are unknown. In 2002 Jenni et al. (7) reported a microvascular dysfunction in 12 patients affected by non compaction: areas of restricted myocardial perfusion have been documented by scintigraphy, suggesting a reduction of Coronary flow reserve (CFR). The decreased of CFR is not confined to noncompacted segments, but extends to most segments with wall motion abnormalities, thus global coronary microcirculatory dysfunction could be associated with IVNC (7-12). McMahon et al (1) reported in a recent article a reduction of TD velocities in children with noncompaction of the left ventricle, compared with normal controls. In a precedent report our group reported a strong correlation between pathological tissue Doppler and reduction of ejection fraction. In this study we performed a Tissue Doppler analysis, segment by segment, in a series of 15 children affected by non-compaction. The bidimensional echocardiogram showed a strong correlation between systolic function and diastolic dysfunction (2). Alterations of the diastolic function compared in 7 (49%) patients: in 2 cases, a reduction of the Ea wave was present in all segments. In 3 patients the diastolic dysfunction was limited to apical and lateral segments. In the last 2 children a reduction of the Ea wave interested only the apical segments. Every patient with diastolic dysfunction also presented a severe reduction of the systolic function (less then 40%). In our opinion the late enhancement can be depend on a CFR, and is the determinant of the tissue Doppler alterations. So the TD alteration is associated with EF, and is an indirect index of poor clinical outcome, like EF (1-12). McMahon et al (1) concluded their work saying that the reduction of lateral mitral Ea velocity helps to predict children with LVNC who are at risk of adverse clinical outcomes including death and need for cardiac transplantation. In our opinion, more then the Em, the EF at the admission can help to predict the mortality in these patients.

    References

    1)McMahon CJ, Pignatelli RH, Nagueh SF, Lee VV, Vaughn W, Valdes SO, Kovalchin JP, Jefferies JL, Dreyer WJ, Denfield SW, Clunie S, Towbin JA, Eidem BW
    Left ventricular non-compaction cardiomyopathy in children: characterisation of clinical status using tissue Doppler-derived indices of left ventricular diastolic relaxation
    Heart. 2007; 93:676-81.

    2)Fazio G, Pipitone S, Iacona MA, Marchì S, Mongiovì M, Zito R, Sutera L, Novo G, Novo S
    Evaluation of diastolic function by the Tissue doppler in children affected by non-compaction
    Int J Cardiol. 2007;116:e60-2.

    3)Fazio G, Sutera L, Corrado G, Novo S
    The chronic heart failure is not so frequent in non-compaction
    Eur Heart J. 2007; 28:1269.

    4) Fazio G, Corrado G, Pizzuto C, Zachara E, Rapezzi C, Sulafa AK, Sutera L, Stollberger C, Sormani L, Finsterer J, Benatar A, Di Gesaro G, Novo G, Cavusoglu Y, Baumhakel M, Drago F, Carerj S, Pipitone S, Novo S.
    Supraventricular arrhythmias in noncompaction of left ventricle: Is this a frequent complication?
    Int J Cardiol. 2007; [Epub ahead of print]

    5)Fazio G, Corrado G, Zachara E, Rapezzi C, Sulafa AK, Sutera L, Pizzuto C, Stollberger C, Sormani L, Finsterer J, Benatar A, Di Gesaro G, Cascio C, Cangemi D, Cavusoglu Y, Baumhakel M, Drago F, Carerj S, Pipitone S, Novo S.
    Ventricular tachycardia in non-compaction of left ventricle: is this a frequent complication?
    Pacing Clin Electrophysiol. 2007; 30:544-6

    6) Fazio G, Sutera L, Vernuccio F, Fazio M, Vernuccio D, Pizzuto C, Di Gesaro G, Cascio C, Novo S
    Heart failure and cardiomyopathies: a case report
    G Ital Cardiol. 2007; 8:129-32

    7) Jenni R, Wyss CA, Oechslin EN, Kaufmann PA
    Isolated ventricular noncompaction is associated with coronary microcirculatory dysfunction.
    J Am Coll Cardiol. 2002; 39:450-4

    8) Hamamichi Y, Ichida F, Hashimoto I, Uese KH, Miyawaki T, Tsukano S, Ono Y, Echigo S, Kamiya T
    Isolated noncompaction of the ventricular myocardium: ultrafast computed tomography and magnetic resonance imaging.
    Int J Cardiovasc Imaging. 2001;17:305-14

    9) Sato Y, Matsumoto N, Matsuo S, Kunimasa T, Yoda S, Tani S, Kasamaki Y, Kunimoto S, Saito S.
    Myocardial perfusion abnormality and necrosis in a patient with isolated noncompaction of the ventricular myocardium: Evaluation by myocardial perfusion SPECT and magnetic resonance imaging.
    Int J Cardiol. 2007; [Epub ahead of print]

    10) Jassal DS, Nomura CH, Neilan TG, Holmvang G, Fatima U, Januzzi J, Brady TJ, Cury RC.
    Delayed enhancement cardiac MR imaging in noncompaction of left ventricular myocardium.
    J Cardiovasc Magn Reson. 2006;8:489-91

    11) Korcyk D, Edwards CC, Armstrong G, Christiansen JP, Howitt L, Sinclair T, Bargeois M, Hart H, Patel H, Scott T
    Contrast-enhanced cardiac magnetic resonance in a patient with familial isolated ventricular non-compaction.
    J Cardiovasc Magn Reson. 2004;6:569-76

    12) Soler R, Rodríguez E, Monserrat L, Alvarez N
    MRI of subendocardial perfusion deficits in isolated left ventricular noncompaction.
    J Comput Assist Tomogr. 2002; 26:373-5

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  55. Instead of compression by haematoma, occlusion by a thrombus can be the complicating factor

    Dear Editor,

    In the context of involvement of the right pulmonary artery by aortic dissection, instead of being caused by extrinsic compression attributable to a haematoma(1)(2)(3), obstruction of the right pulmonary artery might be attributable to thrombosis, with associated extrinsic compression by a massively dilated aorta, as shown in the instance of a 69 year old man who initially presented with stigmata of pulmonary embolism including chest pain, dyspnoea, severe hypotension, and raised levels of D-dimer. In addition, through the medium of pulmonary artery digital subtration angiography, there was documentation of right pulmonary artery thrombosis with total peripheral avascularity. In view of his poor haemodynamic status thoracotomy was undertaken with a view to performing surgical thrombectomy. At operation, however, he was found to have, not only a large thrombus in the right pulmonary artery, but also an acute dissection of the ascending aorta. Extrinsic compression of the right pulmonary artery had also occured, immediately distal to its origin, but this was attributable to the massively dilated ascending aorta. Evidence of associated pulmonary embolism(PE) was obtained post-operatively when a ventilation/perfusion scan showed multiple mismatched ventilation/perfusion defects in the right lung, compatible with residual obstruction of distal branches of the right pulmonary artery(4). The occasional co-existence of PE and aortic dissection is also exemplified by a 74 year old man who presented with dyspnoea, and in whom spiral computed tomography demonstrated PE involving the right pulmonary artery, as well as thrombosed dissection of the abdominal aorta.

    Comment:-
    The irony of the overlap between stigmata of PE and those of aortic dissection, and the occasional co-existence of the two disorders is that, with the exception of exploratory thoracotomy(4), their therapeutic stategies are mutually incompatible. No wonder it was the considered opinion of Sir William Osler that "There is no disease more conducive to clinical humility than aneurysms of the aorta"(4)

    References

    1) Stougiannos PN., Mytas DZ., Pyrgakis VN
    The changing faces of aortic dissection: an unusual presentation mimicking pulmonary embolism
    Heart 2007:93:1324

    2) Nasrallah A., Goussous Y., El-Said G., Garcia E., Hall RJ
    Pulmonary artery compression due to acute dissecting aortic aneurysm: a clinical and angiographic diagnosis
    Chest 1975:67:228-230

    3) Charnsangavej C
    Occlusion of the right pulmonary artery by acute dissecting aortic aneurysm
    American Journal of Roentgenology 1979:132:274-6

    4) Neri E., Toscano T., Civelli L et al
    Acute dissecting aneurysm of the ascending thoracic aorta causing obstruction and thrombosis of the right pulmonary artery
    Texas Heart Institute Journal 2001:28:149-151

    5) Gupta R., Uhrbrock D., Burnbaum Y
    Images in cardiology: Coexisting pulmonary embolism and abdominal aortic dissection
    Clinical Cardiology 2003:26:395

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  56. Is this the first case ?

    Dear Editor,

    I would like to draw your attention to the statement"As far as we know, this is the first reported case of all three coronaries originating from a single ostium from the aorta." in the above article.

    There are mulitiple papers on single coronary artery, there are classifications for single coronary artery (e.g Smiths'), people have done treadmill testing in patients with single coronary artery.

    There are so many case reports on angioplasty and bypass surgery in single coronary artery.

    in order to highlight this issue, I am attaching articles from HEART itself on this issue.

    E. S. J. King
    A SINGLE CORONARY ARTERY
    Heart, Apr 1940; 2: 79 – 84

    Peter Swann and Margaret Fitzpatrick
    SINGLE CORONARY ARTERY
    Heart, Oct 1954; 16: 457 - 459.

    S J Leslie and I R Starkey
    Embolism of thrombus in the right coronary artery to the left anterior descending artery in a woman with a single coronary artery
    Heart, May 2004; 90: 562

    P O Lim
    Single coronary artery: circumflex/right coronary circle
    Heart, Nov 2007; 93: 1472.

    D A H Neil, R S Bonser, and J N Townend
    Coronary arteries from a single coronary ostium in the right coronary sinus: a previously unreported anatomy
    Heart, May 2000; 83: e9.

    Marc Hartmann, Patrick M J Verhorst, and Clemens von Birgelen
    Isolated "superdominant" single coronary artery: a particularly rare coronary anomaly
    Heart, Jun 2007; 93: 687.

    P G Horan, G Murtagh, and P P McKeown
    Single coronary artery: a familial clustering
    Heart, Dec 2003; 89: e27.

    H Guven, J Billadello, and M Beardslee
    An isolated single coronary artery supplying the entire myocardium in a patient with congenitally corrected transposition of the great vessels
    Heart, Dec 2004; 90: 1410.

    S MIKETIC, J CARLSSON, and U TEBBE
    An isolated single coronary artery
    Heart, May 1998; 79: 515.

    P. J. D. Snow
    A CASE OF SINGLE CORONARY ARTERY WITH STEREOGRAPHIC DEMONSTRATION OF THE ARTERIAL DISTRIBUTION
    Heart, Apr 1953; 15: 261 - 263.

    I Porto and A P Banning
    Unstable angina in a patient with single coronary artery
    Heart, Aug 2004; 90: 858.

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  57. Cardiovascular mortality in the Glasgow Cohort: from the Great War to the United Nations

    Dear Editor,

    Yu-Kang Tu brilliant work investigated the complex emerging field of microbial risk factors and cardiovascular disease. The paper concluded that tooth loss (used as an index for poor oral health) is related to CVD mortality. However, a clear link between both conditions is missing in the study. This publication raised in our group many reflections. The related editorial published in the same issue of Heart only partially cover our questions.
    A crucial point to reduce potential confounders in similar experiences deals with the socioeconomic status of the enrolled population.
    Race/ethnicity, education, and socioeconomic environment are important for periodontal health. Poverty and residence in a disadvantaged environment are associated with higher risk of periodontitis as well. Moreover low socioeconomic status seems associated with progression of atherosclerosis.
    Consistent data demonstrated also the association between adverse socioeconomic circumstances in childhood and both adult dental diseases and atherosclerosis. Children who grew up in low socioeconomic status families have poorer dental health including dental caries, plaque scores, gingival bleeding and periodontal diseases compared with those from high socioeconomic backgrounds.
    This study offers a unique, at our knowledge, chance to understand the relationship between social aspects and oral disease leading to higher vascular risk.
    We can’t forget how the birth time interval of the Glasgow Alumni study started right when the Great War came to an end until the United Nations headquarters officially open in New York City. This is a timeline of great changes in the western societies, where also UK specific socioeconomical features may have played a big role in the study.
    British economic growth between 1950 and 1955, as measured by an average annual increase in gross national product of 2.9 per cent , has been the slowest: less than one-third that of Germany (9.8), half of Austria (6.9), and Italy (5.9), lower than France (4.2), Belgium (3.1), the Netherlands (4.9) or Norway (3.5). And this trend was similar according to the United Nation reports in the following years.
    Postwar British society grew slowly until 1973 placed in comparison with international context. According to the British Nutrition Foundation the weekly intake of sugar in England and Wales in the decade 1942-1952 was below 300g, raising above 500g per week in 1962. Food rationing in UK ended around 1954. We can easily speculate on the large effect of sugar rationing measures, taken by British authorities, may have on the oral pathology of the study population. No comparable measures were taken in other western countries during postwar period.
    Adverse socioeconomic circumstances in childhood confer a greater risk for adult-life vascular diseases. We should also take into account how the 1918-19 influenza epidemic killed at least 40 million people worldwide and 675,000 people in the United States, exceeding the US combat deaths in the two World Wars combined.
    The first cases of the influenza epidemic in Britain appeared right in Glasgow in May, 1918. It soon spread to other towns and cities and during the next few months the virus killed 228,000 people in Britain. This was the highest mortality rate for any epidemic since the outbreak of cholera in 1849.
    In UK desperate methods were used to prevent the spread of the disease. However, despite attempts, all treatments devised to cope with this new strain of influenza were completely ineffectual.
    Besides its extraordinary virulence, the 1918-19 epidemic was also unique in that enormous number of its victims were men and women aged 15 and 44, giving the age profile of mortality a distinct ‘W’ shape rather than the customary ‘U’ shape, and leading to extremely high death rates in the working ages.
    Infants and young children are traditionally a more vulnerable group, both to influenza and other forms of infectious disease, and their relative mortality was also increased dramatically. The dependence of the very young on their parents, particularly their mothers, however, suggests that high adult illness and mortality is likely to have an impact on infants and children, and this makes discussion on the effects of a similar infants selection on the Glasgow Alumni study population. Another possible confounder is connected to the possible variation in attributes of coronary heart disease cases suggesting a change in the primary source- subpopulation of cases over time. It was proposed that an early 20th- century expansion of a coronary heart disease–prone subpopulation, characterized by high serum-cholesterol phenotype and high case-fatality which contributed to most of the coronary heart disease cases and deaths during the 1960s may be a late result of the 1918 pandemia. The same abnormal immune response to infection that in 1918 killed mostly men, whites, and born from 1880 to 1900 (20–40 years old) may have “primed” survivors of those birth cohorts to late vascular mortality. The extinction of such birth cohorts would result in a relative increase in cases coming from a 2nd subpopulation, which was characterized by insulin resistance and chronic expression of low-grade inflammation markers and was comparatively less vulnerable to die acutely from coronary heart disease.
    In conclusion the Glasgow Alumni experience may be biased by some global and local confounder that include: (i) a birth cohort selection bias: influenza survivors less vulnerable to vascular diseases; (ii) the study took place in a time span when UK may not represent the general socioeconomic trends in western countries and continental Europe: resulting in lower caloric and nutritional standards leading to peculiar patterns of dental status; (iii) no clear data regarding the familial income, and hygienic standards in the study population are available.

    References

    1. Tu YK, Galobardes B, Smith GD, McCarron P, Jeffreys M, Gilthorpe MS.
    Associations between tooth loss and mortality patterns in the Glasgow Alumni Cohort.
    Heart. 2007 Sep;93(9):1098-103. Epub 2006 Dec 12.

    2. Samuel P. Perry, Jr
    Economic Survey of Europe in 1956 by United Nations Economic Commission for Europe Annals of the American Academy of Political and Social Science
    Vol. 313, (Sep., 1957), pp. 190-191

    3. Abbas MA, Galantucci S, Parnetti L, Corea F.
    Atherosclerosis assessment confounders in the Rancho Bernardo study.
    Am J Cardiol. 2007 Mar 15;99(6):876.

    4. Corea F, Kwan J, Abbas MA.
    Predisposition to carotid atherosclerosis in ICARAS dental substudy.
    Stroke. 2007 Jan;38(1):12; author reply 13. Epub 2006 Nov 16.

    5. Abbas M, Sessa M, Corea F.
    Asymptomatic carotid lesions: traditional vs. emerging risk factors.
    Arch Med Res. 2006 Jul;37(5):687-8.

    6. Abbas M, Bignamini V, Corea F.
    Effects of chronic microbial infection on atherosclerosis.
    Atherosclerosis. 2006 Aug;187(2):439-40.

    7. Data downloaded from www.nutrition.org.uk on 30 August 2007

    8. Madjid M, Naghavi M, Litovsky S, Casscells SW
    Influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies.
    Circulation. 2003 Dec 2;108(22):2730-6. Epub 2003 Nov 10

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  58. Impact of blood pressure change and hypertension on aortic stenosis

    Dear Editor,

    I read with great interest the study by Little et al. (1) investigating the effect of acute blood pressure change on hemodynamic parameters of aortic stenosis (AS). Their implication that "differences in haemodynamics should be considered as a potential explanation for a change in AS severity independent of disease progression" should be stressed not only in clinical practice, but as well in prospective studies assessing the effect of medical treatment of AS. I would like to call attention to the coincidence of chronic blood pressure change in essential arterial hypertension with calcific AS, which may be much more frequent than previously reported. According to our data (2), hypertension was found in more than two thirds of 225 patients with nonrheumatic severe AS at the time of evaluation for surgery. Such a high percentage, however, should not be a surprise, as it is similar to the prevalence in the general population of corresponding age and gender (3). Within last decade, vasodilators have become common part of antihypertensive medication in clinical practice (2, 4), though their good tolerance in patients with AS has been demonstrated prospectively only recently (5). To conclude, in patients with AS arterial hypertension is frequent, should be actively sought after, and carefully controlled.

    References

    1. Little SH, Chan KL, Burwash IG.
    Impact of blood pressure on the Doppler echocardiographic assessment of severity of aortic stenosis.
    Heart 2007;93:848-855.

    2. Linhartová K, Filipovský J, Èerbák R, et al.
    Severe aortic stenosis and its association with hypertension: analysis of clinical and echocardiographic parameters.
    Blood Pressure 2007;16:122-128.

    3. Hajjar I, Kotchen A.
    Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000.
    JAMA 2003;290:199-206.

    4. Rosenhek R, Rader F, Loho N, et al.
    Statins but not angiotensin- converting enzyme inhibitors delay progression of aortic stenosis.
    Circulation, 2004;110:1291-1295.

    5. Jimenez-Candil J, Bermejo J, Yotti R, et al.
    Effects of angiotensin converting enzyme inhibitors in hypertensive patients in aortic stenosis: a drug withdrawal study.
    Heart 2005;91:1311-8.

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  59. QRS and prognosis in heart failure.

    Dear Editor,

    Breidthardt et al. (1) found that acute decompensated heart failure (HF) patients presenting to their Emergency Department with prolonged QRS interval (>=120 ms) showed higher long-term mortality. This is a pathophysiologically plausible finding: after initially representing a marker of diseased myocardium, prolonged QRS may itself subsequently contribute to disease progression. (2) Nevertheless, we cannot totally agree with the clinical implication the authors make regarding use of this particular ECG measure for clinical management of acute HF. The concept that QRS measurement could help guide rapid intensive care modalities is very attractive. However, patients with prolonged QRS interval at the time of admission to the Emergency Department did not show significant differences in 30-day mortality (P=0.27) or length of hospital stay (P=0.32). Therefore, the present study provides little direct evidence that prolonged QRS interval at presentation affects outcome in the acute phase of HF, and further studies will be needed to address this question. Patients presenting with prolonged QRS did show remarkably higher 2-year mortality (59% vs. 37%, P=0.004). However, attribution of part or all of this excess risk to the acute phase may imply some overinterpretation. We do not know how much of this excess risk can be attributed to acute phase occurrences, and how much may result from subsequent effects of QRS prolongation on progression of chronic HF. This consideration implicitly raises the question of whether QRS prolongation could help guide management of the chronic phase of HF (of note, admission ECGs would not be an appropriate measure to address this question since QRS duration can vary significantly during hospitalization, particularly after achievement of a compensated euvolemic state(3). In this regard, we previously reported that time-related changes in QRS duration during chronic HF seems to provide incremental independent prognostic information as compared with single measurements. (4, 5) To better interpret the findings of the present study, it would be interesting to know if prolonged QRS interval at the time of hospital discharge also appeared to be associated with worse long- term outcome.

    References

    1. Breidthardt T, Christ M, Matti M, et al.
    QRS and QTc interval prolongation in the prediction of long-term mortality of patients with acute destabilised heart failure.
    Heart (British Cardiac Society) 2007;93(9):1093-7.

    2. Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF.
    Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony.
    Circulation 1989;79(4):845-53.

    3. Aranda JM, Carlson ER, Pauly DF, et al.
    QRS duration variability in patients with heart failure.
    The American journal of cardiology 2002;90(3):335-7.

    4. Grigioni F, Boriani G, Magelli C, Branzi A.
    QRS interval time- related changes and prognosis in heart failure.
    The American journal of cardiology 2003;91(4):514.

    5. Grigioni F, Carinci V, Boriani G, et al.
    Accelerated QRS widening as an independent predictor of cardiac death or of the need for heart transplantation in patients with congestive heart failure.
    J Heart Lung Transplant 2002;21(8):899-902.

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  60. CRT Upgrade and Occurrence of Ventricular Arrhythmia

    Dear Editor,

    Lin et al. report an observational study in 52 patients investigating whether upgrading an ICD, implanted predominantly for secondary prevention to CRT-D, can reduce arrhythmias.[1] They failed to detect an effect of CRT on arrhythmias during a mean follow up of 14 months. The CARE-HF extension study suggested that reduction in sudden death with CRT might be a late phenomenon occurring only after one or more year of therapy and after extensive left ventricular remodelling.[2] There are number of disturbing aspects to this report. Pharmacological therapy at baseline was far from optimal and appeared to deteriorate after device upgrade suggesting that the investigators had focussed on device therapy to the detriment of pharmacological care. Many of the patients selected were in NYHA stage II. Currently, it is not known if such patients benefit from CRT; the results of the REVERSE, RAFT and MADIT-CRT trials are awaited.[3]
    Almost two-thirds of patients were in AF, a group of patients in whom the evidence of benefit for CRT is not clear.

    Although the mean ejection fraction increased in Lin’s study, LV dimension was unchanged, suggesting that reverse remodelling had not taken place, perhaps due to the selection of patients unable to benefit and neglect of pharmacological therapy. In turn, this may have been responsible for the lack of an observed effect on ventricular tachyarrhythmias.

    Finally, this was not a randomised controlled trial. It is not unlikely that arrhythmias worsen with longer duration of follow-up as heart disease progresses and therefore the apparent lack of effect of CRT may be deceptive. In conclusion, this was not a fair test of the hypothesis that guideline-indicated CRT associated with high quality pharmacological care reduces arrhythmias in patients with heart failure.

    References

    1. Lin G, Rea RF, Hammill SC, et al.
    Effect of cardiac resynchronisation therapy on occurence of ventricular arrhythmia in patients with implantable cardioverter defibrillators undergoing upgrade to cardiac resynchronisation therapy devices.
    Heart, 2007. doi:10.1136/hrt.2007.118372.

    2. Cleland JGF, Daubert JC, Erdmann E, at al. on behalf of The Cardiac Resynchronisation-Heart Failure (CARE-HF) Study Investigators.
    Longer-term effects of cardiac resynchronisation therapy on mortality in heart failure [the CArdiac REsynchronisation-Heart Failure (CARE-HF) trial extension phase].
    European Heart Journal, 2006. 27: p. 1928-1932.

    3. Cleland JGF, Nasir M, Tageldien A.
    Cardiac resynchronization therapy or atrio-biventricular pacing—what should it be called?
    Nature Clinical Practice Cardiovascular Medicine, 2007. 4: p. 90-101.

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  61. PFO Closure should be performed with ultrasound guidance

    Dear Editor,

    Dr. Wahl and colleagues studied the short and long- term safety and efficacy of percutaneous closure of patent foramen ovale (PFO) for prevention of paradoxical embolization using fluoroscopic guidance only (1). While we command their technical skills, we disagree that using fluoroscopy only is the safest and most efficient approach to percutaneous PFO closure. The authors correctly note that to date there are no randomized controlled trials that have shown improvement in hard clinical endpoints with PFO closure. This is an elective procedure that is frequently performed in young patients (mean age in their study 51) that have little to no co-morbidities. Therefore, any imaging guidance that minimizes the risk associated with this procedure should be utilized. The authors state “none of these complications could have been avoided by additional echocardiographic guidance”; however, they never had a ultrasound guided comparison group. Additionally, they did not use balloon inflation prior to closure, which provides information not only about the size but also of the shape and quality of septal tissue. They report embolization of devices in 1% (5 patients), upsizing of the device in 5%, and residual shunt in 27% of patients with larger devices. Furthermore, 14 patients (3%) underwent repeat intervention and 2 patients had erosions.

    Although the complication rates are small they are substantial considering the relatively healthy population that undergoes this procedure. The authors are very experienced; however, we believe that advocating closure of PFOs by only fluoroscopic guidance is dangerous and to some extent irresponsible. Specially, when the rate of complications by ultrasound guided approach as reported by Du et al and Bruch et al has been 0% with 100% closure at 6 months (2,3).

    Transesophageal echocardiography has certain limitations in the catheterization laboratory, intracardiac echocardiography (ICE) was introduced in 2000, it is easy to use, and its safety and efficacy has been validated in multiple studies (4). During the procedure, ICE can evaluate adequate device sizing and positioning in relation to septum primum, secundum and aorta (Figure 1); as well as the mechanism of residual shunt (e.g. multiple holes, Figure 2). It is also very useful in the infrequent situation where transseptal puncture for a tunneled PFO is necessary. Therefore, given the minimum associated risk and the preponderance of the information that is provided by intraprocedural ICE we feel that this modality should be an integral part of percutaneous PFO closure.

    References

    1. Wahl A, Kunz M, Moschovitis A, et al.
    Long-Term Results after Fluoroscopy Guided Closure of Patent Foramen Ovale for Secondary Prevention of Paradoxical Embolism. Heart 2007.

    2. Bruch L, Parsi A, Grad MO, et al.
    Transcatheter closure of interatrial communications for secondary prevention of paradoxical embolism: single- center experience.
    Circulation 2002;105(24):2845-8.

    3. Du ZD, Cao QL, Joseph A, et al.
    Transcatheter closure of patent foramen ovale in patients with paradoxical embolism: intermediate-term risk of recurrent neurological events.
    Catheter Cardiovasc Interv 2002;55(2):189- 94.

    4. Brochet E, Aubry P, Juliard JM, et al.
    [Intracardiac echography].
    Arch Mal Coeur Vaiss 2007;100(1):52-60.

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  62. Antibiotic Prophylaxis to Prevent Infective Endocarditis should be given to Patients with...

    Antibiotic Prophylaxis to Prevent Infective Endocarditis should be given to Patients with Valvular or Structural Heart Disease Prior to Dental Treatment: Results of a National Survey Amongst UK Cardiologists and Cardiac Surgeons

    Dear Editor,

    Recently published guidelines suggesting that antibiotic prophylaxis (ABP) should not be given prior to dental treatment to patients with valvular or structural heart disease who are considered to be at risk of infective endocarditis (IE)1,2 have been firmly opposed by ourselves3-6 on the grounds that such a change of policy is not evidenced-based, that it is contrary to the view of cardiologists and cardiac surgeons in Europe7,8 and because ABP is safe and cost-effective.

    Our reasons for advocating ABP are based on an understanding of the pathogenesis of IE, animal experimentation, case reports and the vast experience of clinical practice over the last 50 years worldwide rather than on specific randomised, controlled clinical trial data. Moreover, experience of the destructive cardiac complications and the devastating embolic and vasculitic complications of IE, the need for prolonged in- hospital (and often prolonged ITU) care and the requirement for high doses of parenteral antibiotics, a high morbidity and mortality and the not infrequent need for cardiac surgery, demand that clinicians do everything in their power to prevent the development of IE.

    However, there are some medical personnel who demand hard, clinical trial evidence of benefit of ABP before holding to what is currently considered to be standard practice and they dismiss case reports and case series as unacceptable evidence for supporting the case for continued ABP. In our view this is unreasonable. Although it was our personal opinion that only a minority of cardiac specialists within the UK held the “no ABP” stance, we performed a national survey amongst UK cardiologists and cardiac surgeons in order to firmly establish their views on the subject and on the importance of case reports associating IE with invasive procedures and bacteraemia.

    Between February – April 2007, 830 cardiologists and cardiac surgeons practising in the UK were sent a questionnaire by e-mail and/or post.

    Table 1 shows the 4 questions that were asked. 523 replies were received.

    Table 2 shows the responses to the questions.

    Of the questions that were answered:

    Q1.
    94.2% of the cardiac specialists felt that patients with valvular, congenital or other structural heart disease and considered to be at moderate risk of IE should receive ABP prior to dental treatment.

    Q2.
    83.3% took the view that case reports of IE following invasive procedures constituted “evidence” of an association between the two events, sufficient enough to warrant ABP prior to these procedures for those individuals considered to be at risk because of their heart disease.

    Q3.
    74.6% of respondents felt that evidence of bacteraemia following invasive diagnostic or interventional procedures constituted sufficient evidence to highlight these procedures for ABP in patients considered at moderate risk for IE.

    Q4.
    Finally, 95.8% of cardiac specialists were of the opinion that it was unsafe to recommend that patients with valvular, congenital or other structural heart disease and considered to be at moderate risk of IE should not receive ABP prior to dental treatment.

    All physicians and surgeons, general practitioners and dentists who have clinical responsibility for patients who have a previous history of IE, structural cardiac abnormalities or a prosthetic heart valve that puts them at increased risk of developing IE as a result of a procedure that gives rise to bacteraemia should take note of the results of this survey and offer such patients ABP in an attempt to prevent IE. This practice should continue until there is incontrovertible evidence that it is totally ineffective or harmful to our patients. Dentists and other colleagues are likely to find themselves unsupported by cardiologists and cardiac surgeons if their patient develops IE as a result of the wilful omission of ABP.

    Following the publication of the BSAC guidelines and the editorial by Martin in the British Dental Journal,9 some medical and dental practitioners have claimed to be unsure as to “what to do”. The National Institute for Clinical Excellence is planning to develop and publish NICE Guidelines on the “ABP for IE” issue. In the light of this survey, that the overwhelming consensus amongst cardiologists and cardiac surgeons in the UK is in favour of continuing to offer ABP to cardiac patients “at- risk”, it is unthinkable that any alternative advice will be proposed.

    Yours faithfully,

    David R Ramsdale BSc MB ChB MD FRCP, Consultant Cardiologist.

    Mohaned Egred BSc MD MRCP, Specialist Registrar Cardiology.

    Nick D Palmer MB BS MD MRCP, Consultant Cardiologist.

    John A C Chalmers BSc MB ChB FRCS, Consultant Cardiac Surgeon.

    The Cardiothoracic Centre,
    Thomas Drive,
    Liverpool, UK
    L14 3PE

    REFERENCES

    1. Gould FK, Elliott TSJ, Foweraker J et al.
    Guidelines for the prevention of endocarditis: report of the Working Party of the British Society for Antimicrobial Chemotherapy.
    J Antimicrob Chemother 2006;57:1035-42.

    2. Wilson W, Taubert KA, Gewitz M et al.
    Prevention of Infective Endocarditis. Guidelines from The American Heart Association.
    Circulation 2007 Apr 19; [Epub ahead of print].

    3. Ramsdale DR and Palmer ND.
    Antimicrobial prophylaxis for endocarditis: emotion or science?
    Heart Online. 7th February 2007.

    4. Chalmers JAC and Pullan DM.
    Antimicrobial prophylaxis for endocarditis: emotion or science?
    Heart Online. 7th February 2007.

    5. Ramsdale DR, Morrison L, Palmer ND and Fabri BF.
    Lethal consequences.
    Br Dent J 2006;201:187.

    6.Ramsdale DR, Egred M, Palmer ND and Chalmers JAC.
    Prevention of Infective Endocarditis. Guidelines from The American Heart Association 2007. Criticism of Guidelines and Writing Group’s response.
    http://www.americanheart.org/presenter.jhtml?identifier=3044644

    7. Ramsdale DR and Turner-Stokes L on behalf of the Advisory Group of the British Cardiac Society Clinical Practice Committee and the RCP Clinical Effectiveness and Evaluation Unit (2004).
    Prophylaxis and treatment of infective endocarditis in adults: a concise guide.
    Clin Med 2004;4:545-50.

    8. The Task Force on Infective Endocarditis of the European Society of Cardiology.
    Guidelines on Prevention, Diagnosis and Treatment of Infective Endocarditis. Executive Summary.
    Eur Heart J 2004;25:267-276.

    9. Martin M. A victory for science and common sense.
    The new guidelines on antimicrobial prophylaxis for infective endocarditis.
    Br Dent J 2006;200:471.

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  63. Saving lives means spending NHS resources effectively

    Dear Editor,

    O'Flaherty and colleagues (1) have identified a worrying change in the hitherto improving CHD mortality data in England and Wales that has occurred despite record spending on coronary revascularisation. They correctly propose that the health intervention measures, as recommended by Wanless (2) and supported by the National Heart Forum (3) and NICE (4), should be urgently implemented in an attempt to prevent premature death especially in young socially disadvantaged adults.

    What 0'Flaherty and colleagues fail to address is the funding issue. As Wanless hints in his report, the most logical and theoretically least challenging way to fund the expansion of effective preventative interventions is to redeploy resources from wasteful and expensive practices that are unproven or whose cost/benefit balance cannot be justified.

    PCT commissioners have a duty to optimise the effectiveness of NHS resources and should urgently review their blank cheque approach to palliative percutaneous coronary intervention (PCI). The Courage trial (5) confirmed that PCI does not improve prognosis and is only marginally superior to optimal drug treatment in ameliorating symptoms in low-risk stable angina patients. Griffin et al., (6) confirmed the suspicions first raised following the RITA-2 study (7), that the high cost of PCI cannot be justified. These data, coupled with concerns over late drug eluting stent (DES) thrombosis and the controversy around the inappropriate implantation of DES in unlicensed situations have combined to change practice in the US where manufacturers have recently reported a more than 40% slump in DES sales.

    When the QALY cost of preventative measures (£20-£400) (4) are compared to PCI (£47,000) (6) the case for redeploying resources becomes overwhelming, especially when the effectiveness of preventative measures take account of their ability to reduce the need for expensive revascularisation procedures.

    References

    1. O'Flaherty M E, Ford E S, Allender S, Scarborough P, Capewell S.
    Coronary heart disease trends in England and Wales from 1984 to 2004: concealed leveling of mortality rates among young adults
    Heart published online 19 Jul 2007; doi:10.1136/hrt.2007.118323

    2. Wanless report.
    http://www.hm- treasury.gov.uk/consultations_and_legislation/wanless/consult_wanless_final.cfm

    3. The National Heart Forum And The UKPHA Submission To: HM Treasury
    Review: Securing Good Health for the Whole Population by Derek Wanless.
    December 2003. LS\WANLESS\7791

    4. NICE Public Health Intervention Guidance no.2
    http://www.nice.org.uk/page.aspx?o=PhysicalActivityandEnv

    5. Boden et al.
    Optimal Medical Therapy with or without PCI for Stable Coronary Disease.
    N Engl J Med 2007; 356:1503-1516

    6. Griffin et al.
    Cost effectiveness of clinically appropriate decisions on alternative treatments for angina pectoris: prospective observational study.
    BMJ 2007;334:624(24 March)

    7. Sculpher MJ, Smith DH, Clayton T, Henderson R, Buxton MJ, Pocock SJ, et al.
    Coronary angioplasty versus medical therapy for angina.
    Eur Heart J 2002;23:1291-300

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  64. Low EF: the best marker of poor prognosis in patients affected by non compaction

    Dear Editor,

    McMahon et al reported in a recent article a reduction of TD velocities in children with noncompaction of the left ventricle, compared with normal controls. The authors concluded their work saying that the reduction of lateral mitral Ea velocity helps to predict children with LVNC who are at risk of adverse clinical outcomes including death and need for cardiac transplantation. In a precedent report our group reported a strong correlation between pathological tissue Doppler and reduction of ejection fraction. In our report the tissue Doppler analysis was performed segment by segment, and a correlation had been ob served only in patients with a low EF.

    Key Words:Noncompaction, tissue Doppler, diastolic dysfunction

    Noncompaction of the ventricular myocardium (LVNC) is a rare congenital cardiomyopathy resulting from an arrest in normal endomyocardial embryogenesis; it is characterized by a thin compacted epicardial and an extremely thickened endocardial layer with prominent trabeculations and deep intertrabecular recesses (1-6). In this rare cardiomyopathy clinical presentation and outcome is variable, but heart failure, arrhythmias and sudden cardiac death are described like common clinical findings (1-6). Unfortunately the pathophysiological mechanisms are unknown. In 2002 Jenni et al. (7) reported a microvascular dysfunction in 12 patients affected by non compaction: areas of restricted myocardial perfusion have been documented by scintigraphy, suggesting a reduction of Coronary flow reserve (CFR). The decreased of CFR is not confined to noncompacted segments, but extends to most segments with wall motion abnormalities, thus global coronary microcirculatory dysfunction could be associated with IVNC (7-12). McMahon et al (1) reported in a recent article a reduction of TD velocities in children with noncompaction of the left ventricle, compared with normal controls. In a precedent report our group reported a strong correlation between pathological tissue Doppler and reduction of ejection fraction. In this study we performed a Tissue Doppler analysis, segment by segment, in a series of 15 children affected by non-compaction. The bidimensional echocardiogram showed a strong correlation between systolic function and diastolic dysfunction (2). Alterations of the diastolic function compared in 7 (49%) patients: in 2 cases, a reduction of the Ea wave was present in all segments. In 3 patients the diastolic dysfunction was limited to apical and lateral segments. In the last 2 children a reduction of the Ea wave interested only the apical segments. Every patient with diastolic dysfunction also presented a severe reduction of the systolic function (less then 40%). In our opinion the late enhancement can be depend on a CFR, and is the determinant of the tissue Doppler alterations. So the TD alteration is associated with EF, and is an indirect index of poor clinical outcome, like EF (1-12). McMahon et al (1) concluded their work saying that the reduction of lateral mitral Ea velocity helps to predict children with LVNC who are at risk of adverse clinical outcomes including death and need for cardiac transplantation. In our opinion, more then the Em, the EF at the admission can help to predict the mortality in these patients.

    References:

    1)McMahon CJ, Pignatelli RH, Nagueh SF, Lee VV, Vaughn W, Valdes SO, Kovalchin JP, Jefferies JL, Dreyer WJ, Denfield SW, Clunie S, Towbin JA, Eidem BW
    Left ventricular non-compaction cardiomyopathy in children: characterisation of clinical status using tissue Doppler-derived indices of left ventricular diastolic relaxation
    Heart. 2007; 93:676-81.

    2)Fazio G, Pipitone S, Iacona MA, Marchì S, Mongiovì M, Zito R, Sutera L, Novo G, Novo S
    Evaluation of diastolic function by the Tissue doppler in children affected by non-compaction
    Int J Cardiol. 2007;116:e60-2.

    3)Fazio G, Sutera L, Corrado G, Novo S
    The chronic heart failure is not so frequent in non-compaction
    Eur Heart J. 2007; 28:1269.

    4) Fazio G, Corrado G, Pizzuto C, Zachara E, Rapezzi C, Sulafa AK, Sutera L, Stollberger C, Sormani L, Finsterer J, Benatar A, Di Gesaro G, Novo G, Cavusoglu Y, Baumhakel M, Drago F, Carerj S, Pipitone S, Novo S.
    Supraventricular arrhythmias in noncompaction of left ventricle: Is this a frequent complication?
    Int J Cardiol. 2007; [Epub ahead of print]

    5)Fazio G, Corrado G, Zachara E, Rapezzi C, Sulafa AK, Sutera L, Pizzuto C, Stollberger C, Sormani L, Finsterer J, Benatar A, Di Gesaro G, Cascio C, Cangemi D, Cavusoglu Y, Baumhakel M, Drago F, Carerj S, Pipitone S, Novo S.
    Ventricular tachycardia in non-compaction of left ventricle: is this a frequent complication?
    Pacing Clin Electrophysiol. 2007; 30:544-6

    6) Fazio G, Sutera L, Vernuccio F, Fazio M, Vernuccio D, Pizzuto C, Di Gesaro G, Cascio C, Novo S
    Heart failure and cardiomyopathies: a case report
    G Ital Cardiol. 2007; 8:129-32

    7) Jenni R, Wyss CA, Oechslin EN, Kaufmann PA
    Isolated ventricular noncompaction is associated with coronary microcirculatory dysfunction.
    J Am Coll Cardiol. 2002; 39:450-4

    8) Hamamichi Y, Ichida F, Hashimoto I, Uese KH, Miyawaki T, Tsukano S, Ono Y, Echigo S, Kamiya T
    Isolated noncompaction of the ventricular myocardium: ultrafast computed tomography and magnetic resonance imaging.
    Int J Cardiovasc Imaging. 2001;17:305-14

    9) Sato Y, Matsumoto N, Matsuo S, Kunimasa T, Yoda S, Tani S, Kasamaki Y, Kunimoto S, Saito S.
    Myocardial perfusion abnormality and necrosis in a patient with isolated noncompaction of the ventricular myocardium: Evaluation by myocardial perfusion SPECT and magnetic resonance imaging.
    Int J Cardiol. 2007; [Epub ahead of print]

    10) Jassal DS, Nomura CH, Neilan TG, Holmvang G, Fatima U, Januzzi J, Brady TJ, Cury RC.
    Delayed enhancement cardiac MR imaging in noncompaction of left ventricular myocardium.
    J Cardiovasc Magn Reson. 2006;8:489-91

    11) Korcyk D, Edwards CC, Armstrong G, Christiansen JP, Howitt L, Sinclair T, Bargeois M, Hart H, Patel H, Scott T
    Contrast-enhanced cardiac magnetic resonance in a patient with familial isolated ventricular non- compaction.
    J Cardiovasc Magn Reson. 2004;6:569-76

    12) Soler R, Rodríguez E, Monserrat L, Alvarez N
    MRI of subendocardial perfusion deficits in isolated left ventricular noncompaction.
    J Comput Assist Tomogr. 2002; 26:373-5

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  65. Rheumatoid factor and heart disease: supporting evidence regarding increased risk of mortality

    Dear Editor,

    A recent study in Heart by Edwards and colleagues found an interesting association between rheumatoid factor (RF) and ischaemic heart disease [1]. We examined independently the related issue of the role of systemic inflammation in relation to clinical outcome in a forthcoming study [2]. This subsequent study reports an association between systemic inflammation, as measured by C-reactive protein (CRP), and all cause mortality (n = 22,982). We also found a weak association with heart disease but the study was, we believe, statistically underpowered to properly evaluate this outcome. In light of the findings reported by Edwards and colleagues, here we report supplementary data from a sub-group of subjects from the CRP [2] study where data were available characterising RF (n = 3,588). The objective of this report was to characterise survival over a four year period from first CRP observation in this sub-groups of subjects where RF data were also available.

    Details of the data source and the general methods were published elsewhere [2]. In brief, data were routine data from hospital, record- linked sources in Cardiff and the Vale of Glamorgan. A Cox proportional hazards model (CPHM) was developed using SPSS for Windows v14. We evaluated a number of potential model covariates including age, sex, prior disease (cancer, diabetes, vascular disease), general morbidity at baseline (total days in hospital in year prior to first CRP observation), and CRP itself. RF was measured in IU/ml and included in the model as a continuous variable following logarithmic transformation.

    The mean age of the 3,588 evaluable subjects was 62 years and 33% were female. The CPHM of survival determined a strong association between RF and survival (hazard ratio [HR] for log RF = 1.229; p = 0.008). Furthermore, CRP (log transformed), was also included simultaneously in this statistical model (HR = 1.495; p < 0.001) in preference to other factors such as a history of diabetes and cancer. As expected, age and being male also increased risk of death in the CPHM. The association between RF and all cause mortality is illustrated in figure 1.

    Data from this study supports findings from the study by Edwards and colleagues, and shows that RF not only predicts the likelihood of ischaemic heart disease but it also predicts the likelihood of all cause mortality. Furthermore, data from this subgroup of subjects showed that CRP and RF were independent risk factors for all cause mortality. Thus, they are likely to represent distinct inflammatory processes that increase the risk of adverse outcome.

    Yours sincerely,

    Craig J. Currie Department of Medicine, School of Medicine, Cardiff University, Cardiff UK currie@cardiff.ac.uk

    Pete Conway Health Economics, Wyeth Europa Limited, Maidenhead, UK

    Chris D. Poole 360° Research Limited, Penarth, UK

    Acknowledgement: This study was funded by Wyeth Europa. PC is a full time employee of Wyeth Europa.

    Figure 1 Four-year risk of death as a function of increasing rheumatoid factor following standardisation for age, sex and C-reactive protein level.

    References

    1. Edwards CJ, Syddall H, Goswami R, Goswami P, Dennison EM, Arden NK, Cooper C, on behalf of the Hertfordshire Cohort Study Group.
    The autoantibody rheumatoid factor may be an independent risk factor for ischaemic heart disease in men.
    Heart 2007;0:1–5. doi: 10.1136/hrt.2006.097816

    2. Poole CD, Conway P, Currie CJ.
    An evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality.
    Heart 2007 (under final review)

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  66. Yet Again Primary Percutaneous Coronary Intervention (PPCI) is the winner

    Dear Editor,

    I read with interest, the recent original article by Nallamothu et al. The authors report higher 6-month mortality in both fibrinolysis and PPCI patients (p < 0.001 for both cohorts) with long treatment delays. For patients who received fibrinolytic therapy, 6-month mortality increased by 0.30% per 10-min delay in door-to-needle time between 30 and 60 min compared with 0.18% per 10-min delay in door-to-balloon time between 90 and 150 min for patients undergoing PPCI(1).Boersma E reported on behalf of the ‘The Primary Coronary Angioplasty vs. Thrombolysis Group’that PPCI was associated with significant 37% lower 30-day mortality relative to fibrinolysis[adjusted OR, 0.63; 95% CI (0.42-0.84)], regardless of treatment delay(2).These data convey two important messages.
    1. Reiteriates a familiar adage ‘Time is myocardium’ in patients presenting with ST segment Elevation Myocardial Infarction (3).
    2. In case of time delay, PPCI yields favorable outcome results than fibrinolysis.
    No doubt the preferred treatment of choice for STEMI in the 21st century is PPCI provided when it is delivered rapidly, in high volume centres and by experienced teams(4).However at present the feasibility of ‘PPCI-for- all’ is constrained by logical, economic and organizational constraints.
    Unfortunately in the real world experience time delay is unavoidable due to multiple reasons.STEMI patients are very high risk patients and every effort should be made to deliver the best possible care quickly and effectively in order to minimize the long term morbidity and to reduce short and long term mortality. A coordinated regional emergency response model as shown by Gross B et al may be the way forward (5).

    References

    1.Nallamothu B, Fox KA, Kennelly BM,et al.
    Relationship of treatment delays and mortality in patients undergoing fibrinolysis and primary percutaneous coronary intervention. The Global Registry of Acute Coronary Events.
    Heart 2007; 0: hrt.2006.112847v1

    2.Boersma E.
    The Primary Coronary Angioplasty vs.Thrombolysis Group. Does time matter? .A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients.
    Eur Heart J. 2006 Apr;27(7):761-3.

    3.Gibson CM.
    Time is myocardium and time is outcomes.
    Circulation. 2001 Nov 27;104(22):2632-4.

    4.Keeley EC, Boura JA, Grines CL.
    Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction:a quantitative review of 23 randomised trials.
    Lancet. 2003 Jan 4;361(9351):13-20.

    5.Gross BW, Dauterman KW, Moran MG, et al.
    An approach to shorten time to infarct artery patency in patients with ST-segment elevation myocardial infarction.
    Am J Cardiol. 2007 May 15;99(10):1360-3. Epub 2007 Apr.

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  67. Myocardial reduction of Gb3 content in Anderson-Fabry disease

    Dear Editor,

    We read with interest the study by Hughes et al (1) that for the first time showed a reduction of Gb3 content in endomyocardial biopsy tissue of patients with Fabry cardiomyopathy after six months agalsidase alfa treatment.

    However, it should be point out that this study doesn’t demonstrate the efficacy of enzyme replacement therapy in clearing the Gb3 deposits from the cardiomyocytes, that is a focal issue in the treatment of Fabry disease cardiomyopathy. In fact, it has been recently shown in an experimental model of Fabry disease that after intravenous injection of agalsidase alfa the enzyme is detectable in myocardial capillaries but not in cardiomyocytes (2). In this setting the reduction in Gb3 content in the heart could be interpreted as the result of clearance from other cell types, particularly endothelial cells. In addition blood contamination could be the source of Gb3 changes, since the plasma Gb3 levels decreased of 45% after treatment (1).

    In this context, the reduction in myocardial mass could be related to a progression of the disease with increased fibrosis and reduction in myocardial thickness.

    Probably, an immunohistochemical demonstration in endomyocardial biopsy tissue of Gb3 cellular distribution and changes after six months of treatment could have been useful in a better understanding of the study results and it’s desirable in future follow-up studies.

    References

    1. Hughes DA, Elliott PM, Shah J, Zuckerman J, Coughlan G, Brookes J, Mehta AB.
    Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomized, double-blind, placebo-controlled clinical trial of agalsidase-alfa.
    Heart 2007 May 4; [Epub ahead of print].

    2. Murray GJ, Anver MR, Kennedy MA, Quirk JM, Schiffmann R.
    Cellular and tissue distribution of intravenously administered agalsidase alfa.
    Mol Genet Metab. 2007;90:307-12.

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  68. Rheumatoid Factor-? Is it a biomarker of inflammation or an independent risk factor for IHD

    Dear Editor,

    I read with interest the original article by Christopher J Edwards et al about the possibility of Rheumatoid factor being an independent risk factor for Ischaemic Heart Disease (1).The contribution of inflammation to the initiation and progression of coronary atherosclerosis is well established.I agree this study adds support to the importance of inflammation in atherosclerosis. The concept of autoimmunity and the direct role of RF in the pathogenesis of atherosclerotic disease process are fascinating and will act as a basis to future research.

    The key unanswered question is whether RA is a marker of inflammation or an indedependant risk factor for IHD.As acknowledged by the authors it may be difficult to draw a firm conclusion from this cross sectional study. It may have been useful if the authors correlated RA to well established markers of inflammation such as C-reactive protein (2).Screening patients using RF is probably not justified at present until further research.

    References

    1) Christopher J Edwards, Holly Syddall, Rajee Goswami, Priya Goswami, Elaine Dennison, Nigel Arden, and Cyrus Cooper
    Rheumatoid Factor may be an Independent Risk Factor for Ischaemic Heart Disease
    Heart 2007; 0:hrt.2006.097816v1

    2) G.J.Blake and P.M Ridker
    Novel clinical markers of vascular wall inflammation
    Circ Res 89(2001),pp.763-771.

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  69. Percutaneous Coronary Interventions without on-site cardiac surgery standby: a word of caution

    Dear Editor,

    We congratulate the work by Dr. Carlsson et al. about the safety of percutaneous coronary interventions(PCI) in an hospital with or without on-site cardiac surgery standby, albeit their study raises several concerns.

    First, the majority of patients(nearly 80%) had 1 or 2 vessels disease and as depicted in Table 2 only around 15% of patients had 2 or vessels treated. Arguably, no fundamental data as the type of culprit vessels (whether LAD or PDA or a minor diagonal branch) and also the baseline ejection fraction were provided in the study.

    The data regarding the deaths following emergent CABG in the 2 groups are quite confusing as reported by the authors in last paragraph of the Results section; moreover, there is no clear specification about the percentage of patients undergoing emergency CABG with a myocardial infarction <24 hrs., as this fundamental factor may yield an almost doubled predicted operative mortality(16% vs 6%) in such specific group of patients, as previously reported by other authors.[2] According to the higher rate of pts. with STEMI in centers with on-site cardiac surgeons, it is more likely that this high-risk pts. underwent CABG.

    Finally, it is questionable the statement in the Discussion “…The presented data of contemporary practice could not show significant differences with respect to adjusted outcome variables…”, since the authors themselves in Table 3 and in Figure 2 (Kaplan-Meier long term mortality) depict that their results are non-adjusted.

    In conclusion, we believe that the study by Dr. Carlsson et al. do not fairly represent the general clinical scenario of all patients undergoing PCI and the conclusions of the manuscript should be carefully used only in a selected subset of patients and not so quickly adopted as a reference for the PCI guidelines as in the authors’ view.

    References

    [1] Carlsson J, James SN, Stahle E, Hofer S, Lagerqvist B.
    Outcome of percutaneous coronary intervention in hospitals with and without on-site cardiac surgery standby.
    Heart. 2007;93:335-8.

    [2] Haan CK, O'Brien S, Edwards FH, Peterson ED, Ferguson TB.
    Trends in emergency coronary artery bypass grafting after percutaneous coronary intervention, 1994-2003.
    Ann Thorac Surg. 2006;81:1658-65

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  70. IIb/IIIa inhibition in the elderly: do they have a role after pre-treatment with clopidogrel?

    Dear Editor,

    PRISM: ASA + heparin, ASA + tirofiban

    PRISM-PLUS: ASA + heparin, ASA + heparin + tirofiban

    PARAGON: ASA + heparin + lamifiban, ASA + lamifiban, ASA + heparin

    PURSUIT: ASA + heparin, ASA + heparin + eptifibatide

    GUSTO-IV ACS: ASA + heparin, ASA + heparin + abciximab

    PARAGON-B: ASA + heparin, ASA + heparin + lamifiban

    A meta-analysis by Hernandez et al (1) revealed that the reduction of death or non-fatal myocardial infarction achieved with IIb/IIIa inhibitors in patients with an acute coronary syndrome was independent of patient age. Although older patients had the largest absolute increases in bleeding from IIb/IIIa inhibitors, they also had the largest absolute reductions of death or myocardial infarction.

    An important point to remember about the trials included in this meta-analysis, however, is that they were all performed in an era prior to the widespread administration of clopidogrel to patients with an ACS (and undergoing PCI) patients. Clopidogrel has been shown to be beneficial in patients with an ACS (2), and indeed, is listed as a class I recommendation in such patients, whether or not an invasive approach is planned (3). The administration of GP IIb/IIIa inhibitors is a class I indication in patients with planned coronary interventions in the absence of clopidogrel, but carries a class IIa indication in patients already receiving clopidogrel (3). The weaker recommendation carries with it an implication that IIb/IIIa inhibitors may be less beneficial among patients treated with clopidogrel. Indeed, in 4 ISAR trials (ISAR-REACT, ISAR-SWEET, ISAR SMART 2, and ISAR-REACT 2) (4-7), IIb/IIIa inhibitors did not reduce death and myocardial infarction at 30 days in patients who were troponin-negative on study entry. Only troponin-positive patients in ISAR-REACT 2 benefited at 30 days. While these were all PCI trials, PCI is often a litmus test, an indicator of what benefits one might expect to see from a medication among patients with an ACS.

    Indeed, an analysis of the 38,691 patients enrolled in the National Registry of Myocardial Infarction 4 raised the concern that a strategy of adding clopidogrel and a GP IIb/IIIa to patients with a non–ST-elevation acute coronary syndrome who are on clopidogrel might not be justified, especially in patients who do not undergo PCI (8). And virtually all studies indicate that elderly patients are more likely to bleed than younger patients; bleeding has been shown to be an independent predictor of mortality in both ACS and PCI patients (9, 10).

    In an analysis of the ISAR-REACT 2 trial, a striking age-dependent difference in the efficacy of abciximab was found among PCI patients with a non–ST-segment elevation ACS who had been treated with clopidogrel (7).
    Abciximab did not reduce the 30-day incidence of death or any other component of MACE in older patients; in fact, it appeared to be harmful.
    We are currently analyzing the relationship between age and outcome in the other ISAR studies cited above.

    In conclusion while we applaud the excellent analysis of the authors, we caution that the results of their meta-analysis may not be generalizable to ACS or PCI patients and particularly the elderly who have been pre-treated with clopidogrel.

    References

    1) Adrián V Hernández, Cynthia M Westerhout, Ewout W Steyerberg et al.
    Effects of platelet glycoprotein IIb/IIIa receptor blockers in non-ST segment elevation acute coronary syndromes: benefit and harm in different age subgroups.
    Heart 2007; 93: 450-455 (http://heart.bmj.com/cgi/content/full/93/4/450)

    2) The CURE Investigators (2001)
    Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST segment elevation.
    N Engl J Med 345:494–502.

    3) E. Braunwald, E.M. Antman, J.W. Beasley, R.M. Califf, M.D. Cheitlin, J.S. Hochman, R.H. Jones, D. Kereiakes, J. Kupersmith, T.N. Levin et al. and American College of Cardiology; American Heart Association, Committee on the Management of Patients With Unstable Angina
    ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)
    Circulation 106 (2002), pp. 1893–1900.

    4) Kastrati A, Mehilli J, Schulhen H, Dirschinger J, Dotzer FJ, Bollwein H, Volmer C, Gawaz M, Berger PB, Schomig A, for the Intracoronary Stenting and Antithrombotic Regimen
    Rapid Early Action for Coronary Treatment (ISAR-REACT) Study Investigators. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel.
    N Engl J Med 2004;350:232-8.

    5) Mehilli J, Kastrati A, Schühlen H, Dibra A, Dotzer F, von Beckerath N, Bollwein H, Pache J, Dirschinger J, Berger PB, Schömig A; for the Intracoronary Stenting and Antithrombotic Regimen
    Is abciximab a superior way to eliminate elevated thrombotic risk in diabetics (ISAR-SWEET) Study Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel.
    Circulation 2004;110:3627-3635.

    6) Hausleiter J, Kastrati A, Mehilli J, Schuhlen H , Pache1 J, Dotzer F, Glatthor C, Siebert S, Dirschinger J, Schomig A for the ISAR-SMART-2 Investigators.
    A randomized trial comparing phosphorylcholine-coated stenting with balloon angioplasty as well as abciximab with placebo for restenosis reduction in small coronary arteries.
    Journal of Internal Medicine 2004; 256: 388–397.

    7) Kastrati A, Mehilli J, Neumann FJ, Dotzer F, Berg J, Bollwein H, Graf I, Ibrahim M, Pache J, Seyfarth M, Schuhlen H, Dirschinger J, Berger PB, Schomig A, for the Intracoronary Stenting and Antithrombotic Regimen Rapid Early Action for Coronary Treatment (ISAR-REACT 2) Trial Investigators.
    A randomized, double-blind, placebo-controlled trial of glycoprotein IIb/IIIa inhibition with abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment.
    JAMA 2006;295:1531-1538.

    8) Bromberg-Marin G, Marin-Neto JA, Parsons LS, Canto JG, Rogers WJ
    National Registry of Myocardial Infarction-4. Effectiveness and safety of glycoprotein IIb/IIIa inhibitors and clopidogrel alone and in combination in non-ST-segment elevation myocardial infarction (from the National Registry of Myocardial Infarction-4).
    Am J Cardiol. 2006 Nov 1;98(9):1125-31. Epub 2006 Aug 31.

    9) Manoukian SV, Feit F, Mehran R, Voeltz MD, Ebrahimi R, Hamon M, Dangas GD, Lincoff AM, White HD, Moses JW, King SB 3rd, Ohman EM, Stone GW.
    Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial.
    J Am Coll Cardiol. 2007 Mar 27;49(12):1362-8.

    10) Kinnaird TD. Stabile E. Mintz GS. Lee CW. Canos DA. Gevorkian N. Pinnow EE. Kent KM. Pichard AD. Satler LF. Weissman NJ. Lindsay J. Fuchs S.
    Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions.
    American Journal of Cardiology. 92(8):930-5, 2003 Oct 15.

    11) Ndrepepa G, Kastrati A, Mehilli J, Neumann F-J, ten Berg J, Bruskina O, Dotzer F, Seyfarth M, Pache J, Dirschinger J, Ulm K, Berger PB, Schömig A.
    Age-dependent effect of abciximab in patients with acute coronary syndromes treated with percutaneous coronary intervention.
    Circulation. 2006; 114: 2040–2046.

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  71. Re: Intravenous magnesium in rhythm control of atrial fibrillation

    Dear Editor,

    Thank you for the interest of Dr. Srikanth Vallurupalli on our meta- analysis. In response to his comments on rhythm conversion by intravenous magnesium, I would like to clarify the results of our meta-analysis to avoid misunderstanding.
    In the analysis of the efficacy of magnesium in converting atrial fibrillation to sinus rhythm, magnesium was compared to a placebo-control group when magnesium was added to either digoxin or ibutilide in five studies in our meta-analysis, as discussed in the results on page 6 and illustrated by the first stratum of the trials in figure 2. This stratum of trials showed that intravenous magnesium was not effective in converting atrial fibrillation to sinus rhythm (25.3 vs 19.3%, odds ratio 1.22, 95% confidence interval 0.56-2.65, p=0.61). There was only a small heterogeneity in the results of these five studies (chi-square =6.74, I- square = 25.8%). Furthermore, the overall average rhythm conversion rate of adding magnesium to either digoxin or ibutilide was only 25.3%. This conversion rate was far below the spontaneous conversion rate of recent onset atrial fibrillation reported in the literature (1,2). If the overall efficacy of magnesium in converting atrial fibrillation is only very modest and in a range similar to 25% as reported in our meta-analysis, a very large randomised controlled study (>1000 patients) will be needed to show this degree of efficacy. Nevertheless, we must interpret the role of intravenous magnesium in the correct context of the studies pooled in this meta-analysis. Most patients included in the studies of this meta- analysis had a normal serum magnesium concentration, and as such, we cannot generalise our results to patients with significant hypomagnesaemia. Previous studies have showed that intravenous magnesium may be more effective in converting atrial fibrillation to sinus rhythm in patients with hypomagnesaemia (3).

    Reference

    1) Danias PG, Caulfield TA, Weigner MJ, Silverman DI, Manning WJ.
    Likelihood of spontaneous conversion of atrial fibrillation to sinus rhythm.
    J Am Coll Cardiol 1998; 31:588-592.

    2) Cotter G, Blatt A, Kaluski E, Metzkor-Cotter E, Koren M, Litinski I, Simantov R, Moshkovitz Y, Zaidenstein R, Peleg E, Vered Z, Golik A.
    Conversion of recent onset paroxysmal atrial fibrillation to normal sinus rhythm: the effect of no treatment and high-dose amiodarone. A randomized,placebo-controlled study.
    Eur Heart J 1999; 20:1833-1842.

    3) Kiziltepe U, Eyileten ZB, Sirlak M, Tasoz R, Aral A, Eren NT, Uysalel A, Akalin H.
    Antiarrhythmic effect of magnesium sulfate after open heart surgery: effect of blood levels.
    Int J Cardiol 2003; 89:153-158.

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  72. When Quality Hurts

    Dear Editor,

    The article by Bridgewater et al “Has publication of cardiac surgery outcome data been associated with changes in practice in Northwest England? An analysis of 25,730 patients undergoing CABG surgery under 30 surgeons over 8 years.” (1) has received significant international attention with headlines around the world. However before the quality junkies lapse into a swoon of self congratulation over the great leap forward that they have accomplished with scrutiny of outcomes, its time to take a reality check. Despite the fact that the Euroscore is one of the most widely-used measures of expected outcomes in Cardiothoracic modern practice, superceding the out-dated Parsonnet score (2), it is not an accurate reflection of real operative risk in the twenty-first century. Real risk is probably about half of that (3) (4) – even the original developers of the Euroscore admit that (5). The disparity between actual and predicted outcomes (by Euroscore) probably relates to the fact that surgeons now more fastidiously look for, and have a lower threshold for assignation for, all the components of the risk score. This underscores one of the main problems with such studies of quality – all independent predictors of outcomes are adjudicated and data collected and maintained by the surgeons themselves. Public scrutiny of outcomes creates such a powerful conflict of interest in data collection for the surgeons that the data is at best questionable and at worst purely a smokescreen. Similar grave concerns for the accuracy and ascertainment bias inherent in any self-reported data were raised after comparisons of outcome data after multi-vessel stenting and CABG in New York State (6). Raw data showed a survival benefit for stenting in most subgroups but after ‘adjustment’ for patient co-morbidity data routinely collected by surgeons (but not by interventionalists) the study reported the exact opposite finding. This occurred because the surgically treated patients were assigned a far greater number of co-morbid conditions than those treated percutaneously. The counter-intuitive nature of this finding (in general patients with serious co-morbidities are treated percutaneously or medically), can be well explained by the fact that in New York State there is also mandatory reporting of outcomes, and co-morbidities are required for surgical reporting but not for interventional reporting. The study investigators were sufficiently aware of the problem to report both the raw and the adjusted data, so it was quite obvious that this was statistical error due to ascertainment bias (7). However, the magnitude of the resulting bias was astounding and a warning to any other investigators that dependence on self-reported quality data portends wildly erroneous conclusions which directly contradict randomised trial data. The conclusion in the article by Bridgewater et al that mandatory reporting and public scrutiny have not resulted in risk averse behaviour but rather have improved the surgeons performance is thus simply wishful thinking not supported by data from other quality-driven states such as New York(8). A far more likely explanation for their findings is that public scrutiny increased the pressure to assign higher Euroscores, so despite the fact that they did lower risk cases (as evidenced by the lower mortality) the predicted mortality was higher. Clearly, a better marker of whether risk averse behaviour is occurring would be to measure the operative risk of the patients that the surgeons are turning down – or as a bare minimum have Euroscores objectively assessed by an independent third party. In addition, in this age of politically driven lies damned lies and statistics, it is becoming increasingly important to document the proportion of patients who have adverse outcomes because of system failures – whether that be surgery denied because of quality-induced risk averse behaviour or because of too long waiting lists with resource scarcity. These data are unfortunately not available but would be a far more sensitive and publicly meaningful measure of whether risk averse behaviour is occurring. Quite apart from the deterioration in outcomes that may be induced by risk averse behaviour, such public airing of outcome data also inevitably has a profound effect on training of new surgeons. Consultants are far less likely to allow trainees to attempt difficult procedures when adverse outcomes will be very publicly and wholly attributed to the consultant. The consequence of this is that new consultants will have to perform procedures that they have never done before or rapid deskilling of the workforce will occur. In the current hostile ‘quality’ driven environment, most new consultants would be likely to opt out of high risk cases even more, and of course never be able to teach the necessary skills to the trainees under their tutelage. With increasing pressure from our politically-driven masters to feign public accountability with outcome smokescreens, we should take care not to believe our own publicity, lest it damage the core assets of the profession – our skills and our altruism for patients rather than administrators.

    REFERENCES

    1. Bridgewater B, Grayson A, Brooks N, et al.
    Has the publication of cardiac surgery outcome data been associated with changes in practice in Northwest England? An analysis of 25,730 patients undergoing CABG surgery under 30 surgeons over 8 years.
    Heart 2007.

    2. Wynne-Jones K, Jackson M, Grotte G, Bridgewater B.
    Limitations of the Parsonnet score for measuring risk stratified mortality in the north west of England. The North West Regional Cardiac Surgery Audit Steering Group.
    Heart 2000;84(1):71-8.

    3. Yap CH, Reid C, Yii M, et al.
    Validation of the EuroSCORE model in Australia.
    Eur J Cardiothorac Surg 2006;29(4):441-6.

    4. Bhatti F, Grayson AD, Grotte G, et al.
    The logistic EuroSCORE in cardiac surgery: how well does it predict operative risk?
    Heart 2006;92(12):1817-20.

    5. Nashef S.
    Validation of the EuroSCORE model in Australia (editorial comment).
    Eur J Cardiothorac Surg 2006;29(4):446.

    6. Hannan EL, Racz MJ, Walford G, et al.
    Long-term outcomes of coronary-artery bypass grafting versus stent implantation.
    N Engl J Med 2005;352(21):2174-83.

    7. Flaherty J, Davidson C.
    Coronary Artery Bypass Grafting versus stent implantation.
    N Engl J Med 2005;353:735.

    8. Moscucci M, Eagle KA, Share D, et al.
    Public reporting and case selection for percutaneous coronary interventions: an analysis from two large multicenter percutaneous coronary intervention databases.
    J Am Coll Cardiol 2005;45(11):1759-65.

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  73. Intravenous magnesium in rhythm control of atrial fibrillation

    Dear Editor,

    I read with interest the meta analysis by Ho et al on the use of intravenous magnesium to treat acute onset atrial fibrillation.

    In their analysis of the efficacy of magnesium in the conversion of atrial fibrillation to sinus rhythm, magnesium was compared to a control group which consists of both calcium channel antagonists and amiodarone. Calcium channel antagonists and beta blockers are considered rate controlling drugs with no inherent rhythm control properties. In large clinical trials and official guidelines, only Vaughn-Williams class I and III agents have been considered rhythm controlling medications. Thus comparing magnesium to a group that contains pharmacologically diverse agents may not lead to a scientifically rigorous analysis. A control group in meta analysis should be constituted with the same rigor as one in a randomized control trial. In addition, as the authors pointed out, the five studies included in the analysis are not similar in any respect (dose of drug given, duration of follow-up). I would thus argue that no conclusions can be drawn regarding the rhythm control properties of magnesium based on this meta analysis.

    The effect of intravenous magnesium on cardiac atrial tissue independent of its AV nodal blocking properties has also been studied. Animal studies demonstrate inhibition of rapid inward rectifying potassium channels and the L and T type calcium channels in the atria in a dose dependent fashion (1,2). In humans, administration of intravenous magnesium increases atrial conduction time and refractoriness(3). Evidence suggests that magnesium may actually enhance the efficacy of ibutilide in the conversion of atrial fibrillation(4). The clinical relevance of these properties is however uncertain due to the quality of studies done so far.

    Ho’s study illustrates how the results of a meta analysis are heavily dependent on the quality of the studies included. Before it is deemed ineffective, intravenous magnesium deserves a well conducted randomized controlled trial designed to study its efficacy (either alone or in combination with other agents) for rhythm control of atrial fibrillation.

    References

    1. Wu JY, Lipsius SL.
    Effects of extracellular Mg++ on T- and L-type Ca++ currents in single atrial myocytes.
    Am J Physiol 1990;259(6 pt 2):H1842-50

    2. Duchatelle-Gourdon I, Hartzell HC, Lagrutta AA.
    Modulation of the delayed rectifier potassium current in frog cardiomyocytes by b-adrenergic agonists and magnesium
    J Physiol 1989;415:251-74.

    3. Rasmussen HS, Thomsen PEB.
    The electrophysiologic effects of intravenous magnesium on human sinus node, atrioventricular node, atrium, and ventricle.
    Clin Cardiol 1989;12:85-90

    4. Kalus JS, Spencer AP, Tsikouris JP, Chung JO, Kenyon KW, Ziska M, Kluger J, White CM.
    Impact of prophylactic i.v. magnesium on the efficacy of ibutilide for conversion of atrial fibrillation or flutter.
    Am J Health Syst Pharm. 2003 Nov 15;60(22):2308-12

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  74. Iron Reduction and Cardiovascular Outcomes

    Dear Editor,

    The “Heartline Online” description (Heart 2007;93:773-774) of the results of our iron reduction study (JAMA 2007;297:603-610) is only partially correct. Indeed, analysis of the entire cohort showed no difference in outcomes for the primary endpoint, all cause mortality, and the secondary endpoint, combined endpoint of death plus non-fatal myocardial infarction and stroke. However, analysis according to randomization variables at entry showed potentially important interactions between iron reduction and several of these variables, notably age. Figure 3 showed a graded effect of age for both the primary and secondary endpoints that was statistically significant (p for interaction = 0.0038) for the secondary endpoint. Age analyzed as a continuous variable was significantly related to outcome for both the primary (p = 0.04) and secondary (p = 0.001) endpoints (figure 4). Analysis of the youngest age quartile showed that iron reduction significantly reduced the primary (p=0.02) and secondary (p=0.001) endpoints. We concluded that “iron reduction appeared to improve outcome to a significantly greater extent in younger compared to older patients,” an effect that likely represented benefit in earlier disease.

    Partial disclosure of these data, as in “Heartline Online”, has the effect of stifling future investigation into what may be an effective and low-cost strategy for disease prevention.

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  75. Author Response

    Dear Dr. Groves, Dr. Chester, and Editor,

    Thank you for the positive response to our paper on spinal cord stimulation for treatment of patients with refractory angina pectoris.(1)

    At the time when we performed the study and wrote the report, we were not aware of your scientific letter dealing with heart rate variability and spinal cord stimulation.(2) Otherwise we would certainly have discussed it in our paper.

    Your study supports our findings in showing that “LF spectral components were significantly diminished in the absence of perceived paraesthesia with SCS.” We are pleased to learn that there is additional data supporting the hypothesis that spinal cord stimulation, even at a level below the sensory threshold, elicits positive effects in patients with refractory angina pectoris.

    Sincerely,

    Heinz Theres, MD
    Stephan Eddicks, MD

    References

    1. Eddicks S, Maier-Hauff K, Schenk M et al.
    Thoracic spinal cord stimulation improves functional status and relieves symptoms in patients with refractory angina pectoris: the first placebo-controlled randomised study.
    Heart. 2007;93:585-590.

    2. Moore R, Groves D, Nolan J et al.
    Altered short term heart rate variability with spinal cord stimulation in chronic refractory angina: evidence for the presence of procedure related cardiac sympathetic blockade.
    Heart. 2004;90:211-212.

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  76. It's good to talk

    Dear Editor,

    In his editorial on ‘Alternative treatments for angina,’ Dr Lanza makes no mention of the value of rehabilitation, especially patient and carer education, in improving quality of life. Given the central role of patient education in [refractory] angina management, this requires comment.

    Damaging misconceptions are common in angina sufferers and their carers, and education is a potent and critically important intervention that can have profound effects on understanding, behaviour and quality of life (1,2). It is for this reason that both the ESC and the AHA/ACC/ACIP/ASM stable angina management guidelines recommend a continuous process of identifying and clarifying misconceptions throughout care (3,4). Similarly it is why the ESC Refractory Angina Study Group came to the same conclusion (5). It is perhaps because rehabilitation and patient education is not regarded as ‘treatment’ that this most important aspect of good clinical care is so often neglected.
    It is of great concern that this oversight seems to characterise each point of the patient’s journey. The AHA/ACC guidance has observed that, “…healthcare providers tend to focus on diagnostic and therapeutic interventions, often overlooking critically important aspects of high- quality care. Chief among these neglected areas is the education of patients.”(4)
    This point was vividly illustrated in an editorial on the British Cardiac Intervention Society website in 2001, when it was observed that, “The under-provision of cardiologists, out-patient facilities, hospital beds, cardiac catheterisation laboratories, and importantly, IT personnel and hardware in the average UK intervention centre frequently results in the patient arriving on the day of the procedure, having never been seen previously, and in many cases, not having met the interventional cardiologist before arriving in the catheterisation laboratory.”(6)

    It may be that clinicians do not put much store in clinical guidelines, however authoritative, but what is intriguing about this failure to educate patients is that it is not simply a minor clinical governance issue. Education is a decisive intervention for patients with angina and has the force of law. The requirement to ensure that patients are fully informed has been a necessary element of valid consent for decades but as recently as 2001, the BMA consent working party was able to conclude that “current awareness of the relevant ethical and legal principles relating to consent among the medical profession is largely inadequate” (7). In order to clarify the guidance on consent, the Parliamentary Ombudsman and the President of the Society of Cardiac Surgeons produced a joint recommendation on consent practice which emphasises the need to ensure full disclosure of facts (8). The joint statement reflects the trend away from the notion that doctors can decide what it is necessary for the patient to know, towards the North American standard of disclosing what a ‘prudent patient’ would wish to take into account in making a decision about treatment. More recently the GMC’s update of ‘Good Medical Practice’ makes explicit the requirement to ensure that patients fully understand their condition to enable them to be full and active participants in the decision-making process (9).

    In our experience many of the problems encountered by refractory angina patients and their carers are iatrogenic, arising from a deficient ‘education’ process, often involving many different healthcare professionals over many years. The perceived referral criterion for specialist refractory angina management is when no further intervention is possible, and this point in the patient’s career marks a significant moment when patients views about their condition can be adversely influenced by poorly communicated information.
    We frequently meet patients who, having been told that further revascularisation is not feasible, erroneously believe that their lives are threatened by their stable angina. The terms in which this message is delivered to patients often involve such colourful phrases as: ‘I am sorry but your narrowings are just too far gone and there is nothing more that can be done’; ‘he’s a walking time bomb’; ‘you must take things very easy’; 'the artery is hanging by a thread.’

    Much of our work involves treating the damaging consequences of cardiac misconceptions with individually targeted education. Careful dissection of angina patients’ beliefs and misconceptions about their condition is rewarding for health professionals and benefits patients in terms of quality of life, frequency and duration of hospital admissions and frequency and severity of pain. The alternative to patient education raises for doctors the risk that they may be open to challenge for having given treatment to patients who have given consent on the basis of fundamental misconceptions about the nature of their condition.

    References

    1. Health related quality of life of patients with refractory angina before and one year after enrolment onto a refractory angina program.
    Moore RK et al.
    Eur J Pain. 2005 Jun;9(3):305-10

    2. A Brief Cognitive-Behavioral Intervention Reduces Hospital Admissions in Refractory Angina Patients.
    Moore RK et al.
    J Pain Symptom Manage. 2007 Mar;33(3):310-316

    3. www.escardio.org/knowledge/guidelines/Guidelines_list.htm?hit=quick (2006 update)

    4. www.americanheart.org/presenter.jhtml?identifier=3006769 (2002 update)

    5. The problem of chronic refractory angina Report from the ESC Joint Study Group on the Treatment of Refractory Angina
    Mannheimer al.
    European Heart Journal (2002) 23, 355–370

    6. www.bcis.org.uk/news/News1588 (last accessed 23.04.07)

    7. www.bma.org.uk/ap.nsf/Content/Reportoftheconsentworkingparty

    8. Parliamentary and Health Service Ombudsman, and the President of the Society of Cardiothoracic Surgeons of Great Britain and Ireland a joint report. ‘Consent in cardiac surgery: a good practice guide to agreeing and recording consent’
    May 2005
    www.ombudsman.org.uk/improving_services/best_practice/cardiac05/index.html

    9. www.gmc-uk.org

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  77. Stimulating the memory

    Dear Editor,

    Eddicks and colleagues’ placebo controlled study of spinal cord stimulation in refractory angina is important and interesting work which shows for the first time that patient appreciation of the sensation of spinal cord stimulation is not necessary to achieve clinical benefit.

    The article gives the impression that no previous work had been carried out investigating sub-sensory threshold Spinal Cord Stimulation (SCS) applied clinically to refractory angina patients and that, before their work, the possibility of therapeutic effect of SCS applied at sub-sensory threshold levels could only be deduced from animal studies. This requires clarification.

    In 2004, we published the findings of a study in Heart in which we evaluated the effect of full therapeutic, half therapeutic (sub sensory threshold) and zero (placebo) voltages of spinal cord stimulation in refractory angina patients who, like the patients in Eddicks’ study, had all benefited from spinal cord stimulation (1).

    Our study showed that full (sensory) therapeutic voltage and half (sub-sensory) therapeutic voltage SCS both brought about a significant reduction in cardiac sympathetic drive (as measured by low frequency heart rate variability) compared to that brought about by zero(placebo) voltage SCS. From this we deduced that analgesia in refractory angina patients is brought about at least in part by SCS producing cardiac sympathetic blockade. We postulated that, “prolonged stimulation at this lower level could offer lessening in the total ischaemic burden and possibly altered arrhythmia thresholds for this patient group.”

    References

    1. Altered short term heart rate variability with spinal cord stimulation in chronic refractory angina: evidence for the presence of procedure related cardiac sympathetic blockade.
    R Moore, D Groves, J Nolan, D Scutt, J Pumprla, MR Chester
    Heart 2004;90:211-212

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  78. Papillary Fibroelastoma and Cardiac Conduction Defects

    Dear Editor,

    I read with interest the case report of a papillary fibroelastoma with heavily calcified bicuspid aortic valve, coronary artery disease and 2nd degree heart block. The authors mention this is the first case of a papillary fibroelastoma presenting with conduction block. While this may be true, it is evident that heavy calcification of a bicuspid aortic valve is a much more common and likely cause of conduction block in this patient, as is the possibility of AV nodal ischaemia in the setting of proven coronary artery disease. Hence the papillary fibroelastoma is likely to only be a coincidental finding in this case report.

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  79. Linear insertion of the AV valves without defect exists and was already described and published

    Dear Editor,

    In the article “Can atrioventricular septal defects exist with intact structures?”, the authors seem not to know that a similar case was described on a fetus and published in 2002[1].

    This case was diagnosed through the prenatal ultrasound screening of a supposed partial AVSD which led to the discovery of a Down Syndrome (DS). The parents asked for a termination of pregnancy and a fetal pathological examination. The standardized examination of the heart[2] showed no defect (neither atrial nor ventricular) and a normal mitral left atrioventricular valve. The pathologist, who also practised fetal ultrasonography (US), thought of sectioning this heart in the plane of the US four chamber view. There, instead of the normal offsetting, the septal leaflets of the atrioventricular valves were found to be at the same level of the crux of the heart. This we called: the Linear insertion of the atrioventricular valves (LIAVV) without defect[1].

    This case became the index case of an anatomical series of 52 hearts of DS fetuses. 23 out of 41 examinable hearts were “supposed normal” because without any associated defect. After a standardized complementary four chamber view section[3], 16 out of these 23 DS fetal hearts (70%) showed a LIAVV. This result was highly significant (p<10-6) compared with the controls showing a 100% normal offsetting.

    A further anatomical series of 213 fetal hearts confirmed these data[4]. 63% LIAVV without defect were found among 113 “supposed normal” DS hearts None of our “supposed normal”DS hearts ever showed any trileaflet left atrioventricular valve, unlike the 4 DS postnatal cases described in the article. Moreover, we noticed[4] some ballooning of the septal tricuspid leaflet and/or a particular aspect of the membranous septum. This one was more often losangic than triangular, and in a few cases, it was so thin that it looked like a spontaneously prenatally closed VSD.

    We previously defined the apex and the two inferior pulmonary veins as the most reliable hallmarks of an “optimal” fetal four chamber view through echo-anatomical correlations. These hallmarks are reproducible in the Fetal pathology complementary section[3] and in the routine US screening as well[4]. The histological study enabled us to find the best US incidence and settings able to emphasize the crux of the heart in order to search for LIAVV without defect cases[4,5].

    Further studies were required to establish the feasibility of the US screening of this marker and its diagnostic value for the detection of DS. So, we induced a prospective ultrasonographic study. Previously trained physicians studied the crux of the heart in all the routine 2nd and 3rd trimester prenatal screening they practised on low risk pregnancies. Reliable results will be soon submitted for publication.

    References

    1. Fredouille C, Piercecchi-Marti M-D, Liprandi A et al.
    Linear insertion of atrioventricular valves without septal defect; a new anatomical landmark for Down’s syndrome?
    Fetal Diagn Ther 2002 ; 17 : 188-92. Erratum in: Fetal Diagn Ther. 2002 ;17(5):292.

    2. Fredouille C.
    Diagnosis of a fetal cardiac malformation. Fetal heart.
    Ann Pathol.1997. Sep; 17(4):300-5.

    3. Fredouille C, Morice JE, Delbecque K, et al.
    New foetopathological section of the heart. Correlated to the ultrasonographic 4 Chamber view in fetuses.
    Ann Pathol. 2006 Feb;26(1):60-5.

    4. Fredouille C, Baschet N, Morice JE, et al.
    Linear insertion of the atrioventricular valves without defect
    Arch Mal Coeur Vaiss. 2005 May;98(5):549-55.

    5. Develay-Morice J-E.
    Settings in Fredouille C, Develay-Morice J-E. Fetal Heart Ultrasound. How Why and When.
    Elsevier-Churchill Livingstone 2007 page 77 in print

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  80. Echocardiographic Assessment of Epicardial Adipose Tissue

    Dear Editor,

    We read with great interest Kessels et. al's article on magnetic resonance imaging (MRI) of epicardial adipose tissue (EAT), a well established cardiovascular risk factor [1].

    EAT in vivo is shown in Fig. 1.

    Though MRI is the gold standard for viewing EAT, echocardiography is a more cost-effective and routinely conducted method that can also be used to view EAT (Fig. 2) [2].

    EAT assessed by echocardiography is reliable [2]. EAT is associated with anthropometric and clinical parameters of the metabolic syndrome [3], atrial dilation and diastolic function [4] in morbidly obese patients, and with insulin insensitivity and left ventricular mass in uncomplicated obesity [5].

    References

    1. Kessels K, Cramer MJ, Velthuis B.
    Epicardial adipose tissue imaged by magnetic resonance imaging: an important risk marker of cardiovascular disease.
    Heart. 2006; 92: 962.

    2. Iacobellis G, Assael F, Ribaudo MC, Zappaterreno A, Alessi G, Di Mario U, Leonetti F.
    Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction.
    Obes Res. 2003; 11: 304-10.

    3. Iacobellis G, Ribaudo MC, Assael F, Vecci E, Tiberti C, Zappaterreno A, Di Mario U, Leonetti F.
    Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk.
    2003; 88: 5163-8.

    4. Iacobellis G, Leonetti F, Singh N, Sharma AM.
    Relationship of epicardial adipose tissue with atrial dimensions and diastolic function in morbidly obese subjects.
    Int J Cardiol. 2007 115:272-3

    5. Iacobellis G, Ribaudo MC, Zappaterreno A, Vecci E, Tiberti C, Di Mario U, Leonetti F.
    Relationship of insulin sensitivity and left ventricular mass in uncomplicated obesity.
    Obes Res. 2003; 11:518-24.

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