Targeting mitochondrial oxidants in a pediatric model of sepsis‐induced cardiomyopathy

Abstract

Multi‐organ failure is a frequent complication of infant sepsis. In fact, septic cardiomyopathy represents one of the major predictors of morbidity and mortality. Children have limited cardiac reserve as compared to adults, which could explain why 50% of children with septic shock present with low cardiac output and elevated systemic vascular resistance, referred to as “cold shock.” There are no effective therapies to treat sepsis and physicians must rely on supportive care. Reports suggest that sepsis can cause mitochondrial dysfunction in the heart, which may lead to cardiomyopathy. We developed a model of pediatric sepsis with “cold shock” using a clinically relevant cecal ligation and puncture (CLP) model in 17‐19 day‐old rat pups (developmentally comparable to a 5 to 6‐month‐old human infant). The goals of our study were to characterize the effects of sepsis on cardiac function using echocardiography and then evaluate the therapeutic potential of the mitochondria‐targeted antioxidant, MitoTEMPO. At 18 hours, stroke volume, cardiac output, ejection fraction, and fractional shortening were decreased by 36%, 37%, 20% and 30% respectively, in CLP (n = 5) versus Sham (n = 7; P < 0.05). When given at the time of CLP, MitoTEMPO (10 mg/kg, ip, n = 7) prevented the decrease in both ejection fraction and fractional shortening but not stroke volume or cardiac output. Still, survival at 18 hours was increased from 51% in CLP to 78% with MitoTEMPO, perhaps by reducing mitochondrial injury thereby preserving cardiac contractility. The data also suggest that MitoTEMPO should be evaluated in combination with agents that reduce systemic vascular resistance to improve cardiac output.