The Role of Atrio-Ventricular Coupling in Exercise Tolerance in Non-Obstructive Hypertrophic Cardiomyopathy

Primary hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease characterized by thickening (hypertrophy) of the left ventricular (LV) wall, dyspnea and/or fatigue in the setting of a normal or supra-normal LV ejection fraction. The specific mechanisms underlying heart failure-related symptomatology in non-obstructive HCM are poorly defined, but as the vast majority of HCM patients with heart failure have apparently preserved LV contractile function, their symptoms of dyspnea and fatigue are presumed due to perturbations of the relaxation/filling phase (diastole) of the cardiac cycle, which has been termed "diastolic dysfunction". In fact, diastole is mechanistically complex and involves LV pressure decay (relaxation), chamber compliance and atrial contractile function. LV end-diastolic volume, which represents fiber stretch, governs LV contractile function and stroke volume via the Frank-Starling mechanism. End-diastolic fiber stretch is, in turn, dependent on late diastolic filling due to atrial ejection. This atrial "booster pump" is load-dependent and also responsive to inotropic effect. The interaction of atrial inotropic reserve, LV end-diastolic pressure (atrial afterload) and LV compliance (which mediates LV end-diastolic pressure and volume) may be generically considered as "atrio-ventricular coupling" which, in theory, should be at least partially responsible for modulations in exercise-induced augmentation of cardiac output related to enhancement of LV end-diastolic volume or "preload reserve". Previous studies have suggested that limitations of preload reserve may explain exercise-associated symptoms of congestive heart failure. The potential ability of new technologies to accurately assess atrio-ventricular coupling as it relates to preload reserve present opportunities for investigation into mechanisms of heart failure operative in patients with stiff left ventricles with intact systolic function. Elucidation of these previously unapproachable mechanisms may be important in targeting therapy and the design and analysis of future interventional trials. In this pilot study, we hypothesize that exercise intolerance in HCM patients is due to limited LV preload-reserve which, in turn, is mediated by disequilibrium of atrio-ventricular coupling and, possibly, limitations in atrial inotropic reserve. We will test novel analytic tools, including measures of LV compliance and load-independent atrial systolic fuction (atrial systolic elastance), in attempts to dissect out the components of atrio-ventricular coupling which underly HCM-associated symptoms and reduced preload reserve. Further, we will assess serum and cardiac MRI markers of myocardial fibrosis to determine the effect of collagen remodeling on LV relaxation, compliance and atrial afterload. Finally, we will examine the effects of short-term cardiac glycoside (inotropic) therapy on atrial systolic elastance, preload reserve and exercise tolerance. The results of this investigation will be implemented in the design of subsequent interventional protocols targeted towards mechanisms of the stiff heart syndrome.