Abstract P086: Serca1a Expression Exacerbates Cardiac Arrhythmia and Leads to Heart Failure and Early Mortality in a Mouse Model of Exercise-Induced Sudden Cardiac Death
Abnormal calcium (Ca2+) handling has been implicated in a range of cardiac diseases, including heart failure, a disease state characterized by compromised systolic and/or diastolic myocardial function and pathological remodeling. Excessive diastolic SR calcium release via the Ryanodine receptor (RyR2) has been suggested to deplete the SR Ca2+ store thereby reducing cardiac contractility. Although abnormal RyR2 activity and elevated SR Ca2+ leak are characteristic features of advanced heart failure (HF) in both humans and animal models, clear evidence is lacking whether altered RyR2 function plays a causal role in HF development. Indeed, while nearly 80 mutations in RyR2 have been identified and associated with SR Ca2+ leak, none of these mutations have been reliably linked to HF. One possible explanation for this is that the SR Ca2+ leak caused by the mutations is too small and/or compensated by other processes involved in Ca2+ homeostasis. In the present study we sought to generate a genetic model with chronically increased diastolic release by combining overexpression of the fast skeletal muscle isoform of SERCA, SERCA1a, with ablation of CASQ2. Strikingly, the new hybrid strain (CASQ2 null/1a) exhibit early mortality (avg dying age 39.30days) due to heart failure preceded by pathological remodeling including eccentric hypertrophy, significant dilation of the atrial and ventricular chambers, necrosis induced cell death and widespread fibrosis. Animals are susceptible to ventricular arrhythmias at baseline in the absence of adrenergic triggers and show significant systolic dysfunction. Similarly, cardiomyocytes display increased SR Ca2+ load along with significant disturbances in RyR2 mediated Ca2+ release at baseline and are increasingly prone to spontaneous calcium waves. Our results demonstrate that excessive Ca2+ leak via the RyR2 can lead to severe contractile dysfunction and heart failure. Since abnormal RyR2 activity has been implicated in human HF, our results suggest that up-regulation of SERCA activity as a therapy for HF must be advocated with extreme caution.
- © 2011 by American Heart Association, Inc.