Abstract 16134: Rapid Progression of Pressure Overload-induced Cardiac Hypertrophy to Heart Failure in Mice with a Human RyR2R4496C+/− Mutation
Introduction and Hypothesis: Increased diastolic Ca2+ release (Ca2+ leak) from the sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodine receptor, RyR2) due to defective regulation of the RyR2 occurs during heart failure (HF) and causes contractile dysfunction and arrhythmias. However, whether an increased diastolic SR Ca2+ leak per se is causally involved in accelerated decompensation from cardiac hypertrophy to HF, remains unclear.
Material and Methods: Transverse aortic constriction (TAC) was performed in knock-in RyR2R4496C+/− mice carrying a human RyR2 mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). In vivo cardiac function was assessed by transthoracic echocardiography. Hearts and lungs were dissected, weighed and normalized to tibia length. Gross morphology and cardiac fibrosis were examined in paraffin-embedded slices from hearts stained with hematoxylin/eosin and picrosirius red, respectively. Investigators were blinded to the surgical intervention and/or genetic background of the animals.
Results: Gross morphology, fibrosis and cardiac function were comparable between WT and RyR2R4496C+/− sham hearts. However, whereas WT-TAC mice exhibited concentric left ventricular hypertrophy with preserved ejection fraction 1 week after TAC, RyR2R4496C+/−-TAC mice developed eccentric hypertrophy and significant deterioration of phenotypic changes associated with the transition to HF, such as chamber dilation and reduced ejection fraction. The HF phenotype in the RyR2R4496C+/−-TAC mice further aggravated 3 weeks after aortic banding, ultimately resulting in pulmonary congestion determined by relative lung weight increase and increased collagen fraction. Hypertrophy continued to increase 3 weeks after TAC in RyR2R4496C+/−-TAC mice, while it saturated in WT-TAC mice. RyR2R4496C+/−-TAC mice died spontaneously with only 38% alive after 4 weeks as compared to 85% alive for WT-TAC mice.
Conclusions: We conclude that increased spontaneous SR Ca2+ leak facilitates the progression from pressure overload-induced cardiac hypertrophy to HF in mice with CPVT. The data suggest that impaired SR Ca2+ homeostasis per se may be causally involved in the development and progression of HF.
- © 2010 by American Heart Association, Inc.