Diastolic calcium accumulation is a novel and so far unexplained defect in diastolic dysfunction (DD) in patients with hypertensive heart disease (HHD) and heart failure with preserved EF (HFpEF). The SR has an essential role in excitation-contraction coupling, by controlling cytosolic Ca2+ concentration which in turn activates the myofilaments in a concentration-dependent fashion. The SR has three basic functions: uptake of cytosolic Ca2+ in diastole to induce relaxation; SR Ca2+-storage; and SR Ca2+-release to induce systolic contraction. CASQ2 is highly conserved among different species and the only isoform expressed in neonates and during development. CASQ2 binds Ca2+ and plays part in the regulation of SR Ca2+ release. The biological function of CASQ2 in the development of HHD and HFpEF will be studied to further understand the myocardial Ca2+-overload and diastolic dysfunction in human HFpEF. It would provide a novel mechanism of diastolic dysfunction. The heart rate is a powerful regulator for SR activity. High heart rates are a predictor of adverse outcomes in heart failure and heart rate lowering is unequivocally beneficial in HFrEF. These researchers found this concern confirmed in a secondary analysis of the TOPCAT HFpEF trial and documented that beta-blocker withdrawal in HFpEF patients result in sustained and marked improvements of heart function. It is therefore important to acknowledge that the increase in diastolic Ca2+-levels at higher heart rates in HFpEF will likely not predict clinical outcomes.
This project has three specific aims:
- To determine the biological role of CASQ in cardiomyoctes. Overexpression constructs of CASQ2 in adenoviral and adeno-associated viral vectors will be used in cultured Human hiPSC-derived cardiomyocytes to determine the function of CASQ2.
- To study how heart rate affects Ca2+ uptake, storage and release in the cardiomyoctes with normal CASQ2 and high CASQ2 levels. Cardiac muscle strips will be prepared from CASQ2 overexpression rats mediated by AAV9-hCASQ2 injection to observe the Ca2+ handing under different heart rates. After AAV injection the cardiac papillary muscle strips will be collected from the animal and used for further muscle contractility analysis.
- To elucidate the role of CASQ2 during the development of HHD and HEpEF.