Genetically De-Sensitizing Myofilaments to Ca in a Mouse Model for Hypertrophic Cardiomyopathy Decreases Arrhythmia Incidence

Abstract

Increased myofilament Ca sensitivity, a common finding in hypertrophic cardiomyopathy (HCM), is associated with an increased susceptibility for arrhythmias. In isolated hearts expressing a Ca sensitizing troponin T (I79N) HCM mutation fast pacing induces reentry-type tachycardia (VT) in 60% of the hearts. We hypothesized that reducing myofilament Ca sensitivity will decrease arrhythmia incidence.Methods: We generated knock-in mice with a TnT-R141W (HET) mutation, which is associated with dilated cardiomyopathy and reduced myofilament Ca sensitivity, and crossed them with I79N mice (CROSS). We determined heart weight-to-body weight ratio (HW/BW), cell diameter and fibrosis content and we monitored arrhythmia incidence in isolated hearts.Results: The HW/BW ratio was 6.6±1.1 in the WT, with 5.6±0.9 lower in the I79N, with 7.6±1.0 higher in the HET and similar to I79N in the CROSS (5.8±1.0). In the CROSS cell diameter was smaller than in the HET and fibrosis content attenuated compared to I79N. Importantly, VT incidence in the CROSS was similar to control (23.5% vs 11.1% in WT).Conclusions: Correcting myofilament Ca sensitivity reduces arrhythmia incidence of I79N mice and attenuates pathological remodeling observed in mice expressing each mutation alone.View Large Image | View Hi-Res Image | Download PowerPoint Slide