The Role of Atrio-Ventricular Coupling in Exercise Tolerance in Non-Obstructive Hypertrophic Cardiomyopathy
Data Collection
Aortic Valve Disease+7
+ Aortic Stenosis, Subvalvular
+ Aortic Valve Stenosis
Summary
Study start date: December 1, 2003
Actual date on which the first participant was enrolled.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.
Protocol
This section provides details of the study plan, including how the study is designed and what the study is measuring.50 patients to be enrolled
Total number of participants that the clinical trial aims to recruit.Eligibility
Researchers look for people who fit a certain description, called eligibility criteria: person's general health condition or prior treatments.Any sex
Biological sex of participants that are eligible to enroll.Healthy volunteers not allowed
If individuals who are healthy and do not have the condition being studied can participate.Conditions
Pathology
Criteria
INCLUSION CRITERIA - HCM Patients: HCM defined as maximal LV wall thickness by echocardiography greater than 13mm in the absence of other causes of LVH or greater than 15mm asymmetrical LV wall thickness if there is a history of mild hypertension (defined as systolic less than 160mmHg and diastolic less than 100mHg) controlled for greater than 6 months Non-obstructive HCM Age greater than or equal to 21 years. Patients with LV obstruction treated by LV myotomy and myectomy or percutaneous septal alcohol ablation that meet inclusion criteria are eligible for this study. EXCLUSION CRITERIA - HCM Patients: LV outflow obstruction noted during Doppler echocardiography at rest or with Valsalva maneuver defined as instantaneous peak gradient greater than 30 mmHg Hemodynamically significant valvular disorders, history of significant coronary obstruction (greater than 50% in any single artery), angina symptoms, myocardial ischemia on an imaging stress test or evidence of prior myocardial infarction. Patients older than 40 years of age with effort induced anginal symptoms typical of coronary insufficiency and a coronary distribution of myocardial ischemia on an imaging stress test will be considered for the study if coronary angiography rules out significant obstructive coronary disease. Chronic atrial fibrillation Cardiac pacemaker or other metallic implant unsafe for MRI Uncontrolled hypertension Dependence on a beta blocker that cannot be withdrawn Dependence on a calcium blocker that cannot be withdrawn Current use of digoxin History of digitalis intolerance Renal failure Diabetes mellitus Pregnancy or lactation Failure to indicate effective method of birth control measures if female patient is of childbearing age. Inability to exercise or disease states likely to result in impaired exercise capacity (such as pulmonary, hematological and musculoskeletal disorders) Echocardiographic images of insufficient quality, even after administration of contrast agent, for volumetric analysis. Inability to provide informed consent
Study Centers
These are the hospitals, clinics, or research facilities where the trial is being conducted. You can find the location closest to you and its status.This study has 1 location