Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia

Abstract

Sarcomere protein gene mutations cause hypertrophic cardiomyopathy (HCM), a disease with distinctive histopathology and increased susceptibility to cardiac arrhythmias and risk for sudden death. Myocyte disarray (disorganized cell-cell contact) and cardiac fibrosis, the prototypic but protean features of HCM histopathology, are presumed triggers for ventricular arrhythmias that precipitate sudden death events. To assess relationships between arrhythmias and HCM pathology without confounding human variables, such as genetic heterogeneity of disease-causing mutations, background genotypes, and lifestyles, we studied cardiac electrophysiology, hypertrophy, and histopathology in mice engineered to carry an HCM mutation. Both genetically outbred and inbred HCM mice had variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of histopathology. Among inbred HCM mice, neither the extent nor location of myocyte disarray or cardiac fibrosis correlated with ex vivo signal conduction properties or in vivo electrophysiologically stimulated arrhythmias. In contrast, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. These data demonstrate that distinct somatic events contribute to variable HCM pathology and that cardiac hypertrophy, more than fibrosis or disarray, correlates with arrhythmic risk. We suggest that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in HCM.fibrosis ͉ somatic modifiers ͉ disarray ͉ electrophysiology ͉ left ventrical wall thickness

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

“…Periostin levels in extracts from prehypertrophic α-MHC 719/+ csa, WT, and WTcsa mice were low ( Figure 2A), but levels were markedly higher among age-matched hypertrophic α-MHC 719/+ csa mice. The amount of increase in periostin protein was variable among hypertrophic α-MHC 719/+ csa LV extracts, a finding that is consistent with our earlier evidence that fibrotic load differs among identical HCM mice (18).…”

“…Studies used male heterozygous α-MHC 403/+ or α-MHC 719/+ mice that are in the 129/SvJ background. α-MHC 403/+ mice have been extensively characterized (17,18). α-MHC 719/+ mice were generated by homologous recombination as previously described (17,62,63).…”

“…We used the previously described α-MHC 403/+ mice (17,18), and we produced what we believe to be a new model that carries the Arg719Trp mutation in the α-cardiac myosin heavy chain gene (α-MHC 719/+ mice), using homologous recombination technology (Supplemental Figure 1). Hearts from young (<20 weeks) α-MHC 719/+ mice, like those of juvenile α-MHC 403/+ mice, do not have LV hypertrophy or HCM histopathology and are designated prehypertrophic.…”

“…Echocardiograms were performed under 2.0% isoflurane anesthesia, using a Vevo 770 High-Resolution In Vivo Micro-Imaging System and RMV 707B Scanhead (VisualSonics Inc.), by 2 experienced researchers, without knowledge of mouse genotypes. Measurements of left parasternal long and short axes and M-mode (left parasternal short axis) images were obtained at a heart rate of 500-550 bpm, as described previously (18). LV end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), and wall thickness were measured from M-mode tracings, and the average of 3 consecutive cardiac cycles is reported.…”

“…These mice exhibit protean manifestations of HCM, including hypertrophy and focal fibrosis in adulthood (17,18). The hearts from young α-MHC 403/+ and α-MHC 719/+ mice, like human children with HCM mutations, have normal dimensions and histology throughout a period of clinical latency (denoted as prehypertrophic).…”