Cysteine protease inhibition attenuates acute right heart failure

Abstract

Acute right ventricular pressure overload (RVPO) causes RV failure, morbidity, and mortality in patients, and currently has no direct treatment. We previously showed that 90 min RVPO without ischemia causes RV free wall (RVFW) dysfunction (RVD) that persists following relief of RVPO. We tested the hypothesis that cysteine protease (CP) activation contributes to, and therefore that CP inhibition would attenuate, RVD during RVPO. Methods Under open-chest, anesthetized conditions, 32 pigs were subjected to 4 hrs RVPO by constriction of the pulmonary artery. Prior to initiation of RVPO, pigs were randomized to treatment with MDL-28170 (INH), a membrane permeable CP inhibitor, or inactive vehicle (VEH). Investigators were blinded to treatment assignment until all analyses were completed. Results Neither INH nor VEH had any hemodynamic effects prior to RVPO. Beginning RV systolic pressure was similar in both groups, but INH significantly attenuated the decline in RV stroke work vs VEH during the ensuing 4 hrs (32±3% vs 49±5% decline, p<0.05). INH significantly attenuated degradation of the endogenous serine protease inhibitor α-1-antichymotrypsin by 51% (p<0.05) that otherwise occurs in RVFW during RVPO, but did not affect degradation of troponin, desmin, or spectrin, substrates of the cysteine protease calpain. Conclusions The CP inhibitor MDL-28170 attenuates RV dysfunction during sustained RVPO. The mechanism for the salutary effect may involve indirect or cross-class inhibition of endogenous serine proteases. Supported by Department of Veterans Affairs and NHLBI.