Caffeic Acid Phenethyl Ester Improves Right Ventricular Function and Reduces Arrhythmogenesis by Attenuating Structural and Electromechanical Remodeling in Pulmonary Arterial Hypertensive Rats

Right heart failure is a major cause of mortality in patients with pulmonary arterial hypertension (PAH). This study aimed to evaluate the preventive anti-remodeling effect of a natural phenolic compound, caffeic acid phenethyl ester (CAPE), on pressure-overloaded right hearts. PAH was induced in Sprague-Dawley rats by intraperitoneal injection of monocrotaline (MCT; 60 mg/kg). The rats were randomly treated with CAPE (30 mg/kg/day, i.p.) or vehicle for 28 days. Right ventricular (RV) function was assessed, and remodeling was examined using both ex vivo and in vitro analyses. Chronic CAPE treatment in MCT rats attenuated right heart hypertrophy, fibrosis, and oxidative stress. CAPE improved RV function and normalized the elevated RV pressure and QTc interval in anesthetized animals. It also restored the prolonged QT interval and ventricular refractory period and reduced arrhythmia vulnerability in perfused hearts. CAPE normalized the prolonged action potential duration in right heart tissues. In RV myocytes, the delayed kinetics of Ca²⁺ transients and cell contraction were also corrected. Furthermore, CAPE reversed the PAH-induced downregulation of sarco(endo)plasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) and restored the densities of transient outward, steady-state outward, and inward rectifier K⁺ currents, along with the expression of their corresponding channel proteins. CAPE also significantly mitigated RV remodeling induced by PA banding, a model of fixed PA stenosis. These results indicate that CAPE ameliorates structural and electromechanical abnormalities in pressure-overloaded right hearts, likely through inhibition of oxidative stress. CAPE may represent a potential therapeutic candidate in PAH-related cardiac remodeling and dysfunction. Trial Registration: NCT03049046.