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/

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).

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.

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.