Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic...

Area of Science:

• Cardiovascular Research
• Pharmacology
• Oxidative Stress Biology

Background:

• Cardiac hypertrophy is a key feature of hypertrophic cardiomyopathy (HCM) and a predictor of mortality in cardiovascular diseases.
• Current therapies for HCM and cardiac hypertrophy are limited, highlighting the need for novel treatments.
• Myocardial oxidative stress and thiol-sensitive signaling pathways are implicated in the development of cardiac hypertrophy and fibrosis.

Purpose of the Study:

• To investigate the potential of N-acetylcysteine (NAC), a glutathione precursor, to reverse cardiac hypertrophy and fibrosis in a rabbit model of HCM.
• To assess the impact of NAC on oxidative stress markers and signaling pathways involved in cardiac remodeling.

Main Methods:

• Transgenic rabbits with established cardiac hypertrophy were treated with N-acetylcysteine or placebo for 12 months.
• Evaluated cardiac phenotype, fibrosis, systolic function, ventricular arrhythmias, and key molecular markers of oxidative stress and signaling pathways.

Main Results:

• N-acetylcysteine treatment reversed cardiac and myocyte hypertrophy and interstitial fibrosis.
• NAC normalized glutathione redox balance, restored glutathiolated cardiac alpha-actin, and reduced pro-hypertrophic signaling (active protein kinase G, dephosphorylated NFATc1, phospho-p38).
• Treatment prevented cardiac dysfunction and reduced the incidence of ventricular arrhythmias.

Conclusions:

• N-acetylcysteine effectively reversed established cardiac hypertrophy and fibrosis in a preclinical model of HCM.
• As a safe antioxidant prodrug, NAC demonstrates potential therapeutic implications for HCM and other cardiovascular disorders characterized by hypertrophy and fibrosis.
• The findings suggest that targeting oxidative stress with NAC could be a viable strategy for managing cardiac remodeling and dysfunction.