Sudden Death in Hypertrophic Cardiomyopathy
January 1, 2002 3 minutes read
Sudden Death in Hypertrophic Cardiomyopathy
Abstract & Commentary
Synopsis: Troponin T mutations result in severe myocardial disarray with only mild hypertrophy and fibrosis. These characteristics result in a high risk for sudden death at an early age.
Source: Varnava AM, et al. Circulation. 2001;104: 1380-1384.
Varnava and colleagues at st. george’s Hospital Medical School in London studied the relationship between myocyte disarray and sudden death in patients with mutations in the gene for cardiac troponin T. Troponin T is a protein that is part of the troponin-tropomyosin regulatory system for cardiac contractility. Varnava et al performed histopathologic studies and genetic analysis in 50 patients with a diagnosis of hypertrophic cardiomyopathy whose hearts were obtained at either autopsy or transplantation who also had blood available for analysis. Each heart underwent detailed histopathologic analysis. The degree of myocardial disarray was estimated from the number of sections showing disarray in 19 full-thickness blocks taken from the left and right ventricular free and septal walls at various levels. Fibrosis was quantified as the percentage of fibrous tissue replacing muscle present in each microscopic field. The severity of small-vessel disease was also estimated. Genetic screening was performed either on the patients or on family members. Findings in patients with mutations in the gene for troponin T were compared to those in other patients in the series.
Troponin T mutations were identified in 9 hearts. Eight of the 9 patients with troponin T mutations were sudden cardiac death victims. The other troponin T mutation patient had a history of arrhythmias, and his heart was obtained at the time of cardiac transplantation. Thus, all the patients with troponin T mutations had a history of life-threatening arrhythmias. In contrast, sudden death was observed in 19 of the 40 patients with hypertrophic cardiomyopathy not due to mutations in troponin T. Patients with troponin T mutations ranged in age from 6 to 37, with a mean of 21 years. This was considerably younger than the age of those without troponin T mutations in whom the mean was 39.1 years with a range of 14-72 years. Troponin T hearts had significantly lower heart weights, less fibrosis, and greater myocellular disarray than did the other patients with hypertrophic cardiomyopathy. These observations held true even when only the patients in both groups who died suddenly were compared.
Varnava et al conclude that troponin T mutations result in severe myocardial disarray with only mild hypertrophy and fibrosis. These characteristics result in a high risk for sudden death at an early age.
Comment by John P. DiMarco, MD, PhD
This study provides important information about the mechanism of death in high-risk patients with hypertrophic cardiomyopathy. It has been shown in previous studies that the clinical presentations of hypertrophic cardiomyopathy are dependent upon the specific genetic mutation in the patient. A family history has therefore been an important risk factor for sudden death. Other risk factors have been a history of syncope, the presence of nonsustained ventricular arrhythmias during ambulatory monitoring, and severe left ventricular hypertrophy. This study focused on autopsy data, and data concerning spontaneous arrhythmias or syncope prior to death are not reported. However, in patients with troponin T mutations, hypertrophy and fibrosis are not dramatically increased. Rather, myocyte disarray appears to be the major histopathologic finding. Why this results in the high risk for sudden death is uncertain. In patients with marked hypertrophy, it has been postulated that subendocardial ischemia and abnormal blood pressure response to exercise may trigger arrhythmias in fibrotic and/or hypertrophy myocytes. In patients with troponin T mutations, these same stimuli appear to interact with myocardial disarray, which is particularly arrhythmogenic.
The early age at which death occurred in these patients and the observation that for 6 of the 9 patients death was the initial clinical manifestation indicates that an aggressive approach in patients who are identified to have troponin T mutations and family members with a similar genotype is warranted. Since this disorder is relatively uncommon, it is unlikely that clinical trials will ever be performed. However, the use of implantable defibrillators in teenagers and adults, and therapy with amiodarone in younger children with this disorder, certainly appears to be justified.
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