Resolution of Established Cardiac Hypertrophy and Fibrosis and Prevention of Systolic Dysfunction in a Transgenic Rabbit Model of Human Cardiomyopathy Through Thiol-Sensitive Mechanisms

Abstract

Background-Cardiac hypertrophy, the clinical hallmark of hypertrophic cardiomyopathy (HCM), is a major determinant of morbidity and mortality not only in HCM but also in a number of cardiovascular diseases. There is no effective therapy for HCM and generally for cardiac hypertrophy. Myocardial oxidative stress and thiol-sensitive signaling molecules are implicated in pathogenesis of hypertrophy and fibrosis. We posit that treatment with N-acetylcysteine, a precursor of glutathione, the largest intracellular thiol pool against oxidative stress, could reverse cardiac hypertrophy and fibrosis in HCM. Methods and Results-We treated 2-year-old ␤-myosin heavy-chain Q403 transgenic rabbits with established cardiac hypertrophy and preserved systolic function with N-acetylcysteine or a placebo for 12 months (nϭ10 per group). Transgenic rabbits in the placebo group had cardiac hypertrophy, fibrosis, systolic dysfunction, increased oxidized to total glutathione ratio, higher levels of activated thiol-sensitive active protein kinase G, dephosphorylated nuclear factor of activated T cells (NFATc1) and phospho-p38, and reduced levels of glutathiolated cardiac ␣-actin. Treatment with N-acetylcysteine restored oxidized to total glutathione ratio, normalized levels of glutathiolated cardiac ␣-actin, reversed cardiac and myocyte hypertrophy and interstitial fibrosis, reduced the propensity for ventricular arrhythmias, prevented cardiac dysfunction, restored myocardial levels of active protein kinase G, and dephosphorylated NFATc1 and phospho-p38. Conclusions-Treatment with N-acetylcysteine, a safe prodrug against oxidation, reversed established cardiac phenotype in a transgenic rabbit model of human HCM. Because there is no effective pharmacological therapy for HCM and given that hypertrophy, fibrosis, and cardiac dysfunction are common and major predictors of clinical outcomes, the findings could have implications in various cardiovascular disorders.

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

“…Compromised coronary flow due to hypertrophy, microvascular dysfunction (42), increased oxidative stress (43), and increased metabolic demands imposed by abnormal biophysical properties of mutant sarcomeres (7,8) are factors that contribute to premature myocyte death and the emergence of focal fibrosis in HCM. Far less is known about mechanisms that expand the extracellular matrix in HCM hearts.…”

Can markers of collagen turnover or other biomarkers contribute to the diagnostics of heart failure with normal left ventricular ejection fraction?

“…Our study extends these projects in the analysis of big endothelin (indicator of vascular function and neurohumoral activity) and of homocysteine, cysteine, cysteinylglycine, and glutathione (agents affecting primarily myocardial oxidative stress). These agents are likely to have an impact on the development of myocardial hypertrophy and/or fibrosis 36,37 , two important determinants of LV diastolic dysfunction, and could teoretically contribute to the HFNEF diagnostics. In our study, we demonstrated a significant association of big endothelin, PIIINP, and MMP-2 with the diagnosis of HFNEF.…”

Assessment of Myocardial Fibrosis in Hypertrophic Cardiomyopathy by Cardiac Magnetic Resonance: Modalities and Clinical Applications

“…The accumulation of collagen, increasing the rigidity of left ventricle, is responsible for passive diastolic dysfunction, that is the leading cause of dyspnea [7,8,10]. In animal models with genetic mutations responsible for human HCM, it has been shown that treatment with an AT1 receptor antagonist, [11] or with simvastatin, [11] or more recently with N-acetylcysteine, [12] a precursor of glutathione, reduces the hypertrophy, the fibrosis, disarray and improves diastolic function.…”