Targeting Inflammation by Pioglitazone and its R-Enantiomer Mitigates Pathological Myocardial Remodeling in Murine Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is driven by sarcomeric mutations that cause energetic failure and secondary inflammation. This study demonstrates that targeting this metabolic-inflammatory axis with pioglitazone or its peroxisome proliferator-activated receptor gamma inactive enantiomer, R-pioglitazone, reverses disease progression in a murine HCM model. Both agents restored mitochondrial function (including Mitochondrial Pyruvate Carrier 1 [MPC1] levels) and resolved inflammation. Notably, R-pioglitazone showed superior efficacy, reducing interstitial fibrosis by >95% and hypertrophy by 33% without affecting healthy control hearts. These findings identify R-pioglitazone as a promising, mechanism-based candidate for disease-modifying therapy in HCM.