Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy

Throughout the past 40 years, a vast and sometimes contradictory literature has accumulated regarding hypertrophic cardiomyopathy (HCM), a genetic cardiac disease caused by a variety of mutations in genes encoding sarcomeric proteins and characterized by a broad and expanding clinical spectrum. To clarify and summarize the relevant clinical issues and to profile rapidly evolving concepts regarding HCM. Systematic analysis of the relevant HCM literature, accessed through MEDLINE (1966-2000), bibliographies, and interactions with investigators. Diverse information was assimilated into a rigorous and objective contemporary description of HCM, affording greatest weight to prospective, controlled, and evidence-based studies. Hypertrophic cardiomyopathy is a relatively common genetic cardiac disease (1:500 in the general population) that is heterogeneous with respect to disease-causing mutations, presentation, prognosis, and treatment strategies. Visibility attached to HCM relates largely to its recognition as the most common cause of sudden death in the young (including competitive athletes). Clinical diagnosis is by 2-dimensional echocardiographic identification of otherwise unexplained left ventricular wall thickening in the presence of a nondilated cavity. Overall, HCM confers an annual mortality rate of about 1% and in most patients is compatible with little or no disability and normal life expectancy. Subsets with higher mortality or morbidity are linked to the complications of sudden death, progressive heart failure, and atrial fibrillation with embolic stroke. Treatment strategies depend on appropriate patient selection, including drug treatment for exertional dyspnea (beta-blockers, verapamil, disopyramide) and the septal myotomy-myectomy operation, which is the standard of care for severe refractory symptoms associated with marked outflow obstruction; alcohol septal ablation and pacing are alternatives to surgery for selected patients. High-risk patients may be treated effectively for sudden death prevention with the implantable cardioverter-defibrillator. Substantial understanding has evolved regarding the epidemiology and clinical course of HCM, as well as novel treatment strategies that may alter its natural history. An appreciation that HCM, although an important cause of death and disability at all ages, does not invariably convey ominous prognosis and is compatible with normal longevity should dictate a large measure of reassurance for many patients.

Microvascular dysfunction, reflected by an inadequate increase in myocardial blood flow in response to dipyridamole infusion, is a recognized feature of hypertrophic cardiomyopathy. Its long-term effect on the prognosis is unknown. We prospectively evaluated a cohort of patients with hypertrophic cardiomyopathy after they had undergone quantitative assessment of myocardial blood flow by positron-emission tomography (PET). Fifty-one patients (New York Heart Association class I or II) were followed for a mean (+/-SD) of 8.1+/-2.1 years after PET. Twelve subjects with atypical chest pain served as controls. Measurement of flow was performed at base line and after the infusion of the coronary vasodilator dipyridamole, with the use of nitrogen-13-labeled ammonia. Patients were then divided into three equal groups with increasing values of myocardial blood flow. The response of myocardial blood flow to dipyridamole was severely blunted in the patients, as compared with the controls (1.50+/-0.69 vs. 2.71+/-0.94 ml per minute per gram of tissue, P<0.001). Sixteen patients (31 percent) had an unfavorable outcome (death from cardiovascular causes, progression to New York Heart Association class III or IV, or sustained ventricular arrhythmias requiring the implantation of a cardioverter-defibrillator) 2.2 to 9.1 years after PET. Reduced blood flow in response to dipyridamole was strongly associated with an unfavorable outcome. Multivariate analysis showed that among patients in the lowest of the three flow groups the age-adjusted relative hazard of death from cardiovascular causes was 9.6 (P=0.02) and the relative hazard of an unfavorable outcome (a combined end point) was 20.1 (P=0.003), as compared with patients in the two other flow groups. Specifically, all four patients who died from heart failure and three of five who died suddenly were in this subgroup. In patients with hypertrophic cardiomyopathy, the degree of microvascular dysfunction is a strong, independent predictor of clinical deterioration and death. Severe microvascular dysfunction is often present in patients with mild or no symptoms and may precede clinical deterioration by years. Copyright 2003 Massachusetts Medical Society

To make a quantitative assessment of the relation between disarray, fibrosis, and small vessel disease in hypertrophic cardiomyopathy. Detailed macroscopic and histological examination at 19 segments of the left and right ventricle and the left atrial free wall. 72 patients with hypertrophic cardiomyopathy who had suffered sudden death or progression to end stage cardiac failure (resulting in death or heart transplantation). The presence of scarring, atrial dilatation, and a mitral valve impact lesion were noted, and heart weight, wall thickness, per cent disarray, per cent fibrosis, and per cent small vessel disease quantitated for each heart. Within an individual heart the magnitude of hypertrophy correlated with the severity of fibrosis (p = 0.006) and disarray (p = 0.0002). Overall, however, total heart weight related weakly but significantly to fibrosis (r = 0.4, p = 0.0001) and small vessel disease (r = 0.3, p = 0.03), but not to disarray. Disarray was greater in hearts with mild left ventricular hypertrophy (maximum wall thickness < 20 mm) and preserved systolic function (60.9 (26)% v 43 (20.4)% respectively, p = 0.02) and hearts without a mitral valve impact lesion (26.3% v 18.9%, p = 0.04), but was uninfluenced by sex. Fibrosis was influenced by sex (7% in male patients and 4% in female, p = 0.04), but not by the presence of an impact lesion. No relation was found between disarray, fibrosis, and small vessel disease. Myocyte disarray is probably a direct response to functional or structural abnormalities of the mutated sarcomeric protein, while fibrosis and small vessel disease are secondary phenomena unrelated to disarray, but modified by factors such as left ventricular mass, sex, and perhaps local autocrine factors.