Indian Pacing Electrophysiol. J.
Indian Pacing Electrophysiol. J. 2010;
Ventricular Arrhythmias in Hypertrophic Cardiomyopathy- Can We Ever Predict Them?
Download PDF 142 KBNarayanan Namboodiri1, Johnson Francis2
1 Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
2 Malabar Institute of Medical Sciences, Calicut, Kerala, India
Address for correspondence: Dr. K K Narayanan Namboodiri, MD, DM, Associate Professor, Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India 695 011. E-mail: kknnamboodiri/at/yahoo.co.in
Key Words: hypertrophic cardiomyopathy; ventricular arrhythmias
Hypertrophic cardiomyopathy (HCM) is characterized by gross cardiac and myocyte hypertrophy, myocyte disarray, and interstitial fibrosis. This condition is relatively common, with a prevalence of about 1:500 in the general population. Most patients with HCM are either asymptomatic or have only minimal symptoms. In general, HCM is a relatively benign disease with an annual mortality rate of slightly less than 1% in unselected HCM populations [1,2]. However, sudden cardiac death (SCD) may be the first manifestation of the disease. Approximately 60% to 70% of all patients with HCM die suddenly , and the fatal event is generally assumed, though not proven so far, due to ventricular arrhythmias.
The high arrhythmic propensity in HCM is contributed by a combination of many primary substrate abnormalities like hypertrophy, myocardial fibre disarray, interstitial fibrosis etc, and possible secondary triggers like ischemia, physical exercise, and excessive sympathetic stimulation. Marked heterogeneity in substrate and triggers would substantially reduce the predictive accuracy of any risk stratification model as known to occur in patients with many other cardiac arrhythmic conditions. To compound this, heterogeneity in the studied population, low event rate, effect of drug therapy etc would also limit the application of any predictive model.
However, a few revelations in the last decade have contributed to the better understanding of the fatal arrhythmia risk. Nonsustained ventricular tachycardia (NSVT) detected on Holter monitoring in younger (less than 30 years) patients have been identified to be associated with higher mortality rate . Unlike their older counterparts where myocyte loss and fibrosis contribute incrementally to arrhythmogenicity, the higher mortality risk in younger patients probably reflects a more potent arrhythmogenic substrate caused by myocyte disarray, myocardial ischemia, and abnormal autonomic function. No doubt, the association between SCD and NSVT in young patients is striking; however, the majority of SCDs, even in young patients, occurred in patients without NSVT. This clearly shows that Holter monitoring identifies only a subset of subjects at higher risk. Clearly we need to rule out other contributing risk factors before reassuring an individual patient based on this non-invasive modality only.
Is there any role for 12-lead electrocardiogram to predict arrhythmia risk in them? In a cohort of patients with HCM selected because of their high risk for SCD, none of the studied electrocardiographic features (markedly increased voltages, QRS duration, left or rightward QRS axis, abnormal Q waves, and QTc or QT dispersion) did not predict subsequent appropriate implantable defibrillator intervention for ventricular tachyarrhythmias and was not useful in risk stratification for SCD . Similarly, T wave alternans was also not useful to predict SCD in patients with HCM .
Another possible predictor could be exercise-induced arrhythmias. Though occurrence of ventricular arrhythmias during exercise is rare in HCM, its presence has long been identified to be associated with an increased SCD risk. In a recent study, the presence exercise-induced nonsustained VT or ventricular fibrillation was associated with a 3.73-fold increase in the risk of SCD or hemodynamically compromising sustained VT during follow-up .
Of late, a few studies with cardiac magnetic resonance (CMR) imaging in HCM also have shown some promising insights into risk stratification [8-12]. Delayed enhancement in CMR in HCM correlates with the histological finding of fibrosis and thus represents a likely substrate for ventricular tachyarrhythmias. In asymptomatic or mildly symptomatic HCM patients this finding in CMR had a significantly increased frequency of ventricular tachyarrhythmias on Holter monitoring compared with those without it. However, larger studies are required before establishing the role this non-invasive tool in the risk stratification in HCM.
Is there a role of genotype in deciding risk of SCD in these patients? Since the discovery of first causal gene and mutation for HCM in 1990, more than a dozen sarcomeric genes have been implicated in this disease . Of these, certain mutations are considered high risk - for example, most mutations in TNNT2, R719Q and R403Q in MYH7, and double-causal mutations. However, a myriad of genetic (modifier genes, microRNAs, post-translational modifications of proteins, epigenetic factors etc) and nongenetic factors interplay to result in the complex phenotype in HCM. So a predictive model to assess the global risk of SCD in HCM based on genotype alone is still far from reality.
In conclusion, despite being half a century down the initial detailed clinical description of the entity, the predictors of fatal arrhythmias in this disease still remain largely elusive. However, in future, more advanced research into the causal genes and genotype-phenotype correlation, and larger natural history studies may likely enable us to predict the arrhythmia risk in HCM in a better way.
1. Kofflard MJ, Waldstein DJ, Vos J, ten Cate FJ. Prognosis in hypertrophic cardiomyopathy observed in a large clinic population. Am J Cardiol 1993; 72:939-43.
2. Cannan CR, Reeder GS, Bailey KR, Melton LJ 3rd, Gersh BJ. Natural history of hypertrophic cardiomyopathy. A population- based study, 1976 through 1990. Circulation 1995;92:2488-95.
3. Maron BJ, Shen WK, Link MS, et al. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000; 342:365-73.
4. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol 2003; 42:873-9.
5. Sherrid MV, Cotiga D, Hart D, Ehlert F, Haas TS, Shen WK, Link MS, Estes NA 3rd, Epstein AE, Semsarian C, Daubert JP, Winters SL, Giudici MC, Maron BJ. Relation of 12-lead electrocardiogram patterns to implanted defibrillator-terminated ventricular tachyarrhythmias in hypertrophic cardiomyopathy. Am J Cardiol. 2009;104:1722.
6. Fuchs T, Torjman A. The usefulness of microvolt T-wave alternans in the risk stratification of patients with hypertrophic cardiomyopathy. Isr Med Assoc J. 2009; 11:606-10.
7. Gimeno JR, Tomé-Esteban M, Lofiego C, Hurtado J, Pantazis A, Mist B, Lambiase P, McKenna WJ, Elliott PM. Exercise-induced ventricular arrhythmias and risk of sudden cardiac death in patients with hypertrophic cardiomyopathy. Eur Heart J. 2009; 30:2599-605.
8. Petkow-Dimitrow P, Klimeczek P, Vliegenthart R, Pasowicz M, Miszalski-Jamka T, Oudkerk M, Podolec P, Dubiel JS, Tracz W. Late gadolinium enhancement in cardiovascular magnetic resonance in patients with hypertrophic cardiomyopathy complicated by life-threatening ventricular tachyarrhythmia. Kardiol Pol. 2009; 67:964-9.
9. Suk T, Edwards C, Hart H, Christiansen JP. Myocardial scar detected by contrast-enhanced cardiac magnetic resonance imaging is associated with ventricular tachycardia in hypertrophic cardiomyopathy patients. Heart Lung Circ. 2008; 17:370-4.
10. Leonardi S, Raineri C, De Ferrari GM, Ghio S, Scelsi L, Pasotti M, Tagliani M, Valentini A, Dore R, Raisaro A, Arbustini E. Usefulness of cardiac magnetic resonance in assessing the risk of ventricular arrhythmias and sudden death in patients with hypertrophic cardiomyopathy. Eur Heart J. 2009;30:2003-10.
11. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL, Gibson CM, Lesser JR, Hanna CA, Udelson JE, Manning WJ, Maron MS. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol. 2008; 51:1369-74.
12. Kwon DH, Setser RM, Popović ZB, Thamilarasan M, Sola S, Schoenhagen P, Garcia MJ, Flamm SD, Lever HM, Desai MY. Association of myocardial fibrosis, electrocardiography and ventricular tachyarrhythmia in hypertrophic cardiomyopathy: a delayed contrast enhanced MRI study. Int J Cardiovasc Imaging. 2008; 24:617-25.
13. Geisterfer-Lowrance AA, Kass S, Tanigawa G, Vosberg HP, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 1990; 62:999- 1006.