Sarcolemmal Calcium Extrusion Defect in Patients with Diastolic Dysfunction

? DESCRIPTION (provided by applicant): Approximately one in five adults in the United States has hypertensive heart disease (HHD) with left ventricular hypertrophy (LVH). These individuals often have diastolic dysfunction (DD) that can progress to heart failure with preserved ejection fraction (HFpEF). Heart failure is the number 1 cause for hospital admissions and the epidemic growth of HHD is an important reason why the number of patients with HFpEF is rapidly increasing. The myocardial basis of this disease is poorly understood and there is no life-prolonging treatment. The focus of our work is cellular calcium, which governs cardiac contraction and relaxation, which has long believed to play an important role in HFpEF. In heart muscle samples from patients obtained during open heart surgery we have recently found that heart muscle tissue from patients with HHD and HFpEF cannot completely relax between heartbeats. This defect appears to be a primary result of intracellular calcium accumulation due to an insufficient cellular calcium extrusion. As a result the myocardium remains activated between heartbeats. This has unfavorable consequences especially at high heart rates. Incomplete relaxation that is more pronounced at high heart rates would translate in a loss of chamber size. We recently confirmed this in an analysis of echocardiograms in patients with HHD. The left ventricular main chamber in these patients is not able to maintain a normal size at increasing heart rates which directly impairs cardiac output reserve and exercise tolerance. We will quantify the detrimental mechanical and energetic consequences of this abnormality in patients. We expect that incomplete relaxation and diastolic cross bridge activation results in a disproportional increase in myocardial energy consumption at increasing heart rates. In parallel it is our goal to localize the underlying molecular defect in small heart samples obtained from patients with HHD and HFpEF. So far our results suggest a limitation in cellular calcium extrusion at increasing heart rates whereas intracellular calcium handling is increased. It is the overall aim of this translational study to quantify the mechanical and energetic consequences of incomplete cellar calcium extrusion, find the underlying defect and begin to test treatments.