Abstract 3466: Calpain Inhibition Attenuates Right Heart Failure and Prevents Talin Degradation During Acute Pressure Overload
Right heart failure from acute right ventricular pressure overload (RVPO) is an important cause of morbidity and mortality, and currently has no specific therapy. We previously showed that RV free wall contractile dysfunction develops during brief RVPO in the absence of RV ischemia, persists after normal loading conditions are restored, and is attenuated by inhibition of the calcium activated protease calpain. In this study, we tested the hypothesis that calpain inhibition preserves RV contractile function during sustained RVPO.
Methods: Anesthetized open chest pigs were treated with the calpain inhibitor MDL-28170 (MDL, n=20) or inactive vehicle (VEH, n=23) infused into the right coronary artery, then subjected to 4 hrs fixed constriction of the main pulmonary artery. Deterioration in RV function was assessed by decline in RV systolic pressure and RV stroke work, and development of systemic hypotension or RV pulsus alternans.
Results: At the onset of pulmonary artery constriction, RV systolic pressure increased to the same extent in VEH and MDL (62±1 vs 65±1 mmHg, respectively) and RV stroke work also increased to a similar extent in VEH and MDL (142±6% vs 147±4% of baseline, respectively). However, MDL attenuated progressive RV contractile dysfunction: after 4 hrs RVPO, RV systolic pressure was significantly lower in VEH vs MDL (44±4 vs 49±6 mmHg, respectively, p=.01) and RV stroke work was significantly lower in VEH vs MDL (72±5% vs 90±5% of baseline, respectively, p<.03). MDL significantly reduced the incidence of systemic hypotension (defined as SBP<85 mmHg, 19/23 VEH vs 9/20 MDL, p=.01) and RV pulsus alternans (8/23 VEH vs 2/20 MDL, p=.055). MDL preserved abundance of the focal adhesion protein talin (10% difference by Western blotting, p=.03); talin abundance correlated with maintenance of RV stroke work (r=0.4, p=.058).
Conclusions: Right heart failure from acute RV pressure overload is attenuated by calpain inhibition and is associated with reduced talin abundance.