MRI in HCM Left ventricular (LV) Mass: Accurate measurement of LV mass (LV wall thickness) is essential to diagnosis of HCM. LV mass is difficult to estimate by echocardiography due to distortions of LV shape. We have demonstrated that MRI provides an accurate and reproducible estimation of maximum LV wall thickness and LV mass in HCM. This finding has allowed us to develop protocols to study the phenotype of novel genetic causes of HCM, and to evaluate potential ability of several genes and drugs to modify the cardiac phenotype. Stress MRI studies also provided valuable information about LV function and myocardial perfusion. Spiral HCM: Cine fast gradient echo cardiac MRI in about a hundred HCM patients has identified a new variant of HCM: ?spiral HCM is characterized by rotation of the maximum LV wall thickness by 90 degrees around the short axis from base to apex. Spiral HCM is associated with generation of LV outflow obstruction and a more complete systolic ejection during exercise. Stress Perfusion MRI: Identification of myocardial ischemia has important prognostic and therapeutic implications in HCM patients. We performed dipyramidole stress gadpentetate dimeglumine perfusion MRI in 16 patients with non- obstructive HCM and normal coronary arteries. MRI detected perfusion defect in 12 patients with an average of 6+/- segments per patient. All defects involved the subendocardium. Most of the defects were in regions of LV hypertrophy. The remaining defects were in areas with normal LV wall thickness. Exercise thallium scintigraphy in 7 patients. The findings suggest that apparent cavity dilatation observed during nuclear studies is the result of subendocardial ischemia involving hypertrophic regions.Modifying Factors HCM may be caused by mutations in sarcomeric genes, and the associated cardiac hypertrophy may be a maladaptive response to impaired function of contractile proteins. However, the molecular mechanisms whereby the sarcomeric mutations lead to the increased cardiac mass are unknown. Notably, the associated cardiac hypertrophy varies significantly in HCM, even in affected individuals with the identical mutation. To explain the phenotypic variability we are assessing the potential role of several genes that may modify clinical expression of HCM caused by sarcomeric gene mutations. Our studies include assessing therapeutic strategies that may cause reversal of the disease phenotype. Renin-Angiotensin System: The severity of LV hypertrophy may be related to inheritance of a deletion (D) polymorphism of the ACE gene and plasma ACE levels. We are conducting a double-blind placebo-controlled study of enalapril (ACE inhibitor) and losartan (AT1 receptor inhibitor) either singly or in combination to cause regression of LV hypertrophy and to improve myocardial perfusion and LV diastolic function in non-obstructive HCM. The study also evaluates the electrophysiologic properties of these drugs and their ability to attenuate cardiac pain sensation. Calcineurin System: We studied the potential role of calcium sensitive phosphatase calcineurin as HCM has been associated with elevated intracellular calcium, and in animal models calcineurin has been implicated in the development of cardiac hypertrophy, leading to cardiac failure. We quantified myocardial activated calcineurin levels by calmodulin co-precipitation followed by Western blotting. To control for variability in the immunoprecipitation procedure and to normalize calcineurin levels, the same blot was probed with calmodulin antibody. Cardiac tissue was studied from 10 adult patients with HCM caused by sarcomeric gene mutations, as well as from 6 normal controls. Calcineurin levels were significantly higher in HCM patients: 356?169 per cent; range, 127 to 626 per cent greater than controls, p<0.001, (>250 per cent higher than controls in 8/10 HCM patients). Myocardial calcineurin enzymatic activity in 4 of the HCM patients was compared with 4 normal controls. The calcineurin activity was significantly greater in the HCM patients. Hence, activated calcineurin may be involved in mediating cardiac hypertrophy in HCM. Further studies are indicated to confirm the role of the calcineurin regulatory pathway in HCM and to investigate the therapeutic potential of calcineurin antagonists. Double-Blind Placebo-Controlled Study of Cyclosporin A in Patients with LV Hypertrophy Caused by Sarcomeric Gene Mutations: HCM is characterized by marked increase in cardiac mass caused by proliferation/hypertrophy of several cell types (myocytes, fibroblasts, smooth muscle cells, and endothelial cells). There is often associated LV diastolic dysfunction and myocardial ischemia. The severity of the LV hypertrophy, diastolic dysfunction, and myocardial ischemia are important determinants of clinical course. In several animal models of LV hypertrophy, calcineurin has been implicated in the development of myocardial hypertrophy, leading to cardiac dilatation and failure. Inhibitors of calcineurin (Cyclosporin A and FK506) have been shown to prevent the development of cardiac hypertrophy in these animal models, where cardiac hypertrophy is related to sarcomeric dysfunction. A study is ongoing to study the ability of Cyclosporin A (CsA) to reduce LV mass, and to improve symptoms, LV diastolic function, and myocardial perfusion in HCM caused by sarcomeric gene mutations.
