Abstract 16622: Aberrant Calcium Handling Follows Conditional Knock Out of Cardiac Myosin Binding Protein C
Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and is the chief cause of sudden cardiac arrest (SCA) in young athletes. HCM results from mutations in sarcomeric proteins, of which cardiac myosin binding protein C (cMyBP-C) is highly prevalent. cMyBP-C is a myofilament accessory protein believed to act as a physiological brake on contractility. Its central role in cardiac function has been demonstrated in cMyBP-C null mice, which exhibit severe hypertrophy and impaired systolic and diastolic function. However, these studies have by necessity characterized the end-stage phenotype of HCM after extensive compensatory remodeling. Importantly, patients with HCM have an array of phenotypes, ranging from lack of symptoms to severe diastolic dysfunction, heart failure, and SCA. Further, many instances of SCA occur without hypertrophy and are reportedly Ca2+-triggered_thus, the pathophysiological changes underlying HCM may be much more complex than mere contractile dysfunction due to loss of cMyBP-C. To investigate acute changes after the loss of cMyBP-C, we used tamoxifen-inducible conditional cMyBP-C knockout mice (cMyBP-C-cKO), in which progressive knock-down of cMyBP-C occurs in parallel with worsening diastolic and systolic function, but without significant changes in cardiac structure or morphology. Using confocal microscopy, we show that cMyBP-C knock-down results in dysregulation of Ca2+ handling, characterized by ≥22% reduction in Ca2+ transient amplitude (e.g., fluorescence intensity ratios of 7.983 ± 0.537 in cMyBP-C-cKO cardiomyocytes [con-CMs] vs. 10.332 ± 0.502 in WT CMs), and ≥ two-fold prolongation of the tau of transient decay (mean 217.27 ± 18.052 msec for con-CMs vs. 107.44 ± 4.045 msec in WT CMs). Further, sarcoplasmic reticulum Ca2+ content is reduced in cKO-CMs (71% of control). Using qPCR, we show significant upregulation of ryanodine receptor and sodium-Ca2+ exchanger in cMyBP-C-cKO ventricular tissue vs. controls (58% and 40% increases, respectively), and downregulation of sodium-Ca2+ ATPase and phospholamban (37% and 22% decreases, respectively). Taken together, these data suggest that Ca2+ dysregulation precedes hypertrophic remodeling in HCM, and point to potential targets for therapeutic intervention.
- © 2012 by American Heart Association, Inc.