Dear Editor

We were interested to read the recent scientific letter from Pollard et al published in Heart.[1]

The authors evaluated the safety of a protocol for earlier sit up and mobilisation after routine transfemoral cardiac catheterisation in contemporary practice. Patients were randomised to be mobilised after 2½ hours or 4½ hours bed rest. The authors report that a significant reduction in the duration of bed rest was achieved in the early mobilisation protocol group with no adverse effect on vascular complications. They also report that early mobilisation was associated with a reduction in pain and discomfort, although this data is not presented. On this basis, the authors call into question the role of alternative arterial access sites for diagnostic cardiac catheterisation.

The published data does not support this viewpoint. Firstly, the early mobilisation protocol still required 2½ hours of bed rest. There is extensive published evidence that bed rest after medical procedures has few benefits and a wide range of adverse effects.[2] The combination of back pain related to bed rest and groin pain related to femoral puncture and pressure haemostasis delays mobilisation and return to normal activity after discharge in at least one third of patients.[3] Secondly, despite studying only a selected low risk group of patients (only some elective patients with chest pain undergoing diagnostic angiography were eligible for the study. Patients with a difficult femoral puncture, those undergoing percutaneous revascularisation, receiving adjunctive antithrombotic therapy or with previously treated peripheral vascular disease were excluded) haematomas re-bleeding and vaso-vagal reactions were common. Indeed this study suggests that these problems occur in 15- 20% of these low risk patients. In contrast to this, we have recently reported on a series of 1000 consecutive transradial cases, in which a third of the study subjects had major risk factors for vascular complications.[4] Patients undergoing diagnostic angiography or percutaneous intervention were mobilised immediately, removing the potential for adverse effects from bed rest. Avoiding a groin puncture will facilitate a rapid return to normal activity after discharge. In this high risk population the incidence of both major and minor vascular complications was less than 1%. The data from the North Staffordshire series is entirely compatible with other published case series and randomised trials, which consistently show that use of the transradial access site is associated with short mobilisation and discharge times, a reduction in procedure costs and vascular complications, and a consistent improvement in patient quality of life when compared to the femoral access site.[5-7]

In our view the data presented (a 2½ hour period of bed rest and 15- 20% incidence of access site problems) strengthens the case for selecting the radial artery (no bed rest and less than 1% incidence of access site problems) in the majority of patients undergoing routine diagnostic cardiac catheterisation.

References

(1) Pollard SD, Munks K, Wales C, Crossman DC, Cumberland DC, Oakley GDG, Gunn J. Position and mobilisation post-angiography study. (PAMAS): a comparison of 4.5 hours and 2.5 hours bed rest. Heart 2003;89:447-448.

(2) Allen C, Glasziou P, Del Mar C. Bed rest: a potentially harmful treatment needing more careful evaluation. Lancet 1999;354:1229-1233.

(3) Foulger V. Patients’ views of day-case cardiac catheterisation. Professional Nurse 1997;12:478-480.

(4) Eccleshall SC, Banks M, Carroll R, Jaumdally R, Fraser D, Nolan J. Implementation of a diagnostic and interventional transradial programme: resource and organisational implications. Heart 2003;89:561-562.

(5) Eccleshall S, Muthusamy T, Nolan J. The transradial access site for cardiac procedures: a clinical perspective. Stent 1999;2(3):74-9.

(6) Al-Allaf K, Eccleshall S, Kaba R, et al. Arterial access for cardiac procedures utilising the percutaneous transradial approach. Br J Cardiol 2000;7:548-52.

(7) Kiemeneij F, Laarman GJ, Odekerken D et al. A randomised comparison of percutaneous transluminal coronary angioplasty by the radial, brachial and femoral approaches: the Access study. J Am Coll Cardiol 1997;29(6):1269-75.

Dear Editor

We read the review paper by Tousoulis et al. with great interest. We applaud their thoroughness in describing the molecular and cellular mechanisms involved in the inflammatory mechanisms and haemostatic factors leading to coronary atherosclerosis. They also describe the role of chronic infection in this process.[1] However, they omit an important factor that is common to the majority of patients suffering from this condition – current or previous cigarette smoking.

We have undertaken an investigation into the relationship between smoking habit, notably quantitative measurement of nicotine intake and factors involved in the formation of the plaque and the inflammatory process. Due to ‘social desirability bias’ associated with smoking patients frequently under-report or deny their smoking habit. It would seem therefore that the greater the clinical impact of smoking the greater the patient guilt enhancing the likelihood of denial.

To improve the accuracy of information about smoking a 6-minute point -of-care test to detect nicotine metabolites (including cotinine), called SmokeScreen® was developed.[2] The easy to use colorimetric urine test can provide qualitative, semi-quantitative and quantitative measurements of nicotine intake. With this test we undertook an audit of smoking habits of 154 new patients attending a large inner-city hospital cardiology outpatient clinic, comparing the test identification of smoking with self- completed questionnaire of current smoking habit. The results identified 112 (72.7%) as non-smokers, 30 (19.5%) as confessed smokers and 12 (7.8%) as ‘smoking deceivers’. We followed this with another study of the same population (n=85, 33 smokers and 52 never-smokers) to examine the interaction of smoking with risk factors associated coronary artery disease, as assessed by a biochemical screen and a blood count. Interestingly, none of the parameters measured in the biochemical screen, such as cholesterol, HDL and triglycerides; urea and electrolytes and liver function tests were associated with smoking habit or quantitative assessment of nicotine intake. Whereas white blood cell count (WBC) was significantly higher in smokers (p=0.002), in particular neutrophils (p=0.01) and eosinophils (p=0.02). Lymphocytes, monocytes and basophiles were higher but failed to reach significance. Quantitative assessment of nicotine intake of the smokers further revealed a positive correlation with WBC (p<_0.0001 neutrophils="neutrophils" p0.001="p0.001" eosinophils="eosinophils" p0.004="p0.004" and="and" lymphocytes="lymphocytes" p0.02="p0.02" with="with" monocytes="monocytes" approaching="approaching" significance="significance" p="p"/> It would seem from this pilot study that smoking or the amount of tobacco consumed doesn’t influence the biochemical risk factors for coronary artery disease, such as cholesterol and HDL, but does increase many of the cellular factors which Tousoulis et al. identified as contributors to the inflammatory response and to the formation and instability of the atheromatous plaque.[1] We suggest that identification of smokers, feedback from the point-of-care test and subsequent advice on smoking cessation could have a significant impact on reducing many of the risk factors associated with coronary atherosclerosis and lower cardiovascular events and mortality.

References

(1) Tousoulis D, Davies G, Stefanadis, Toutouzas P, Ambrose JA. Inflammatory and thrombotic mechanisms in coronary atherosclerosis. Heart 2003;89:993-997.

(2) Cope GF, Nayyar P, Holder R, Gibbons J, Bunce R. A simple near-patient test for nicotine and its metabolites in urine to assess smoking habit. Clin Chim Acta 1996;256:135-149.

Dear Editor

In the report by Palka et al,[1] and in previous such reports [2,3] the phenotypic variation seen in supposedly genetically identical monozygotic (MZ) twins with hypertrophic cardiomyopathy (HCM) is interpreted as a measure of the importance of environmental influences. However, although environmental factors undoubtedly contribute to the phenotype in HCM, there is substantial evidence that discordance between MZ twins in fact has a genetic component. MZ twins develop from a separation of the embryonic cells at any point from the two-cell stage up until as late as day 8 when the primordial streak has already started to form.[4] The timing of the separation has consequences for the genetic composition of each twin, as the cells become more heterogeneous with time with respect to the mitochondria they carry [5] and the pattern of methylation, and hence potential gene expression, they display.[6]

Mitochondria are inherited through the maternal line only and contain their own genome which encodes a subset of mitochondrial proteins. During mitosis mitochondria can segregate unequally between the daughter cells. Where the oocyte contains a mixed population of mitochondrial DNA variants somatic mosaicism can arise, one consequence of which is that one MZ twin may inherit a different complement of mitochondrial DNA than the other. While such a difference in mitochondrial DNA is often of only theoretical relevance, it would be of particular importance in HCM. Not only do many of the mitochondrial DNA mutation syndromes display HCM-like features, but common variants in mtDNA are associated with susceptibility to cardiomyopathy [7] and co-inheritance of mitochondrial variants with sarcomeric mutations produces a much more extreme phenotype .[8] These findings can be explained by the recent recognition that perturbations of myocardial energetics play a central role in HCM pathogenesis.[9]

DNA methylation plays a recognised role in regulation of gene expression, and important changes in the methylation of genes occur during embryogenesis. In particular the male gametic genome is first demethylated [10] and then selectively re-methylated in a step wise fashion up to the stage of the blastocyst.[5] Hence, some of the observed discordance between MZ twins can also be due to separation of a heterogeneously methylated group of cells, with discordant patterns of gene expression.

It is through these epigenetic modifying phenomena that we may begin to explain the differences in phenotypic expression of HCM, not only in MZ twins but also that seen within and between pedigrees containing the same causal mutant gene.

References

(1) Palka P, A Lange, DJ Burstow. Different presentation of hypertrophic cardiomyopathy in monozygotic twins. Heart 2003;89(7):751.

(2) Reid JM, AB Houston, E Lundmark. Hypertrophic cardiomyopathy in identical twins. Br Heart J 1989;62(5):384-8.

(3) Ko YL et al. Idiopathic hypertrophic cardiomyopathy in identical twins. Morphological heterogeneity of the left ventricle. Chest1992;102(3):783-5.

(4) Gringras, P. and W. Chen, Mechanisms for differences in monozygous twins. Early Hum Dev 2001;64(2):105-17.

(5) Youssoufian H, RE Pyeritz. Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet 2002;3(10):748-58.

(6) Singh SM, B Murphy, R O'Reilly. Epigenetic contributors to the discordance of monozygotic twins. Clin Genet 2002;62(2):97-103.

(7) Khogali SS et al. A common mitochondrial DNA variant associated with susceptibility to dilated cardiomyopathy in two different populations. Lancet 2001;357(9264):1265-7.

(8) Arbustini E. et al. Coexistence of mitochondrial DNA and beta myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure. Heart 1998;80(6):548-58.

(9) Blair E. et al. Mutations in the gamma(2) subunit of AMP- activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet 2001;10(11):1215-20.

(10) Mayer W et al. Demethylation of the zygotic paternal genome. Nature 2000;403(6769):501-2.

Dear Editor

We read with great interest the article recently published in "Heart" on the current use of anticoagulation for non-valvar atrial fibrillation [1].

This article analyses the use of aspirin and anticoagulant treatment in 313 consecutive patients, presented with chronic atrial fibrillation of non-valvar etiology, in a single hospital in Northern Italy, from January 1 to June 30 2000. From this cohort, 168 patients with no contraindications to anticoagulation were identified. These patients were classified as being at high risk for embolic stroke, hence anticoagulation was indicated according to recent guidelines.[2] Bo et al. [1] reported appropriate use of warfarin therapy in only 75 (44%) of patients, with a substantial proportion (42%) receiving subtherapeutic dosage. Furthermore, the use of anticoagulation declined with increasing age, despite the greater net benefit of such use in older patients.

Our group has previously reported on 628 patients presenting with non -valvar atrial fibrillation in the region of North-Western Greece (representing mostly rural areas) from March 1 to November 1 1998.[3] We thought that the similarities in the patient population characteristics, as well as the inclusion and exclusion criteria, enable a useful comparison between the two studies.

In our patient population,[3] of the 628 patients, 188 (29.9%) were excluded from the analysis by criteria similar to those used by Bo et al [1]. Of the 440 remaining patients, 328 (74.5%) were classified as being at high risk for embolic stroke, and of them, 95 (29%) were on anticoagulant therapy, 133 (40.5%) on aspirin and 100 (30.5%) on neither treatment. In concert with the results reported by Bo et al,[1] a subtherapeutic dose was given in 50% of our patients, and the use of anticoagulation declined with increasing age. We attempted to compare the use of anticoagulation and aspirin in the two patient cohorts, using chi-square.

Chi square= 12.42, p<_0.01 p="p"/> This comparison reinforces the conclusions drawn by Bo et al.[1] Anticoagulation treatment for non-valvar atrial fibrillation is substantially underused, especially in older patients, with therapeutic doses being achieved in only approximately half of the patients. Furthermore, these limitations appear even more prominent in rural areas, most likely due to additional difficulties in monitoring international normalized ratio (INR) values, compared to urban areas.

References

(1) Bo S, Ciccone G, Scaglione L, Taliano C, Piobbici M, Mereletti F, Pagano G. Warfarin for non-valvar atrial fibrillation: still underused in the 21st century? Heart 2003;89:553-554.

(2) Scottish Intercollegiate Guidelines Network (SIGN). Antithrombotic therapy. A national guideline. Edinburgh: SIGN, 1999, SIGN publication number 36.

(3) Patsouras D, Vakalis I, Giogakas V, Kitsanou M, Sioros L, Oikonomidis K, Goudevenos J. Status of anticoagulation therapy for patients with atrial fibrillation in north-western Greece. Hellenic J Cardiol (Athens) 1998;39:237-245.