Extracellular matrix instability and chronic inflammation underlie maladaptive right ventricular pressure overload remodeling and failure in male mice

Abstract

Right ventricular dysfunction (RVD) portends increased death risk for heart failure (HF) and pulmonary arterial hypertension (PAH) patients, regardless of left ventricular function or disease etiology. In both, RVD arises from chronic RV pressure overload and represents advanced cardiopulmonary disease. RV remodeling responses and survival rates of patients, however, differ by sex. Men develop more severe RVD and die at younger ages than women do. Mechanistic details of this sexual dimorphism in RV pressure overload remodeling are incompletely understood. We sought to elucidate the cardiac histologic and molecular pathophysiology underlying the sex-specific RV remodeling phenotypes, maladaptive [decompensated RVD with RV failure (RVF)] versus adaptive (compensated RVD). We subjected male (M-) and female (F-) adult mice to moderate pulmonary artery banding (PAB) for 9 wk. Mice underwent serial echocardiography, cardiac MRI, RV pressure-volume loop recordings, and histologic and molecular analyses. M-PAB developed severe RVD with RV failure (RVF), increased RV collagen deposition and degradation, extracellular matrix (ECM) instability, and recruitment and activation of macrophages. Despite equal severity and chronicity of RV pressure overload, F-PAB had more stable ECM, lacked chronic inflammation, and developed mild RVD without RVF. ECM destabilization and chronic activation of recruited macrophages are associated with maladaptive RV remodeling and RVF in M-PAB. These two RV remodeling phenotypes suggest that adverse ECM remodeling and chronic inflammation are also sex-dependent, thereby contributing to the sexual dimorphism of RV pressure overload remodeling. Further mechanistic studies are needed to assess their pathogenic roles and potential as targets for RVD therapy and RVF prevention.NEW & NOTEWORTHY We compared pressure overload-induced RV remodeling in adult male versus female mice subjected to PAB. This study discovered an association between severe RVD, RVF, ECM instability, and chronic inflammation in pressure-overloaded RV of male PAB mice. These features distinguished maladaptive RV remodeling in male from adaptive RV remodeling in female PAB mice. In male patients with RV pressure overload due to HF or PAH, enhancing ECM stability and countering the recruitment of macrophages may help preserve RV function such that RVF could be prevented or delayed.

Keywords: fibrosis; pressure-overload; right ventricular dysfunction; right ventricular remodeling; sex differences.