Acute and chronic remote ischemic conditioning attenuate septic cardiomyopathy, improve cardiac output, protect systemic organs, and improve mortality in a lipopolysaccharide-induced sepsis model

Abstract

Remote ischemic conditioning (RIC) is acutely cardioprotective in ischemia–reperfusion injury. We aimed to evaluate the effect of RIC on septic cardiomyopathy and associated multi-organ failure in a lipopolysaccharide (LPS)-induced sepsis mouse model. Balb/c mice were divided into sham, LPS, and LPS + RIC groups. LPS 10 mg/kg or saline control was injected intraperitoneally. RIC was performed by four cycles of 5 min ischemia and 5 min reperfusion of the left lower limb just before the LPS injection. Cardiac function on echocardiography, circulating mediators, blood biochemistry, and MAPK signalling was assessed. Survival 7 days after LPS injection was evaluated in sham-treated, RIC, and daily repeated RIC groups. An LPS-induced decrease in cardiac output was ameliorated by RIC with preserved left ventricular systolic function. LPS-induced increases in TNF-α, IL-1β, IL-6, and high-mobility group box 1 protein (HMGB1) were significantly suppressed by RIC. RIC also suppressed increases in plasma cardiac troponin I, aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine with suppressed ERK and JNK phosphorylation in heart, liver, and kidney tissue. RIC significantly improved survival rate (p = 0.0037). Survival rate in the daily repeated RIC group was 100%, and it was higher than that in the RIC group (p = 0.0088). In summary, RIC reduced circulating and myocardial inflammatory mediators associated with septic cardiomyopathy, and led to improved ventricular function, cardiac output, and survival. Our data also revealed that chronic RIC has additional benefit in terms of mortality in sepsis. While further studies are required, RIC may be a clinically useful tool to ameliorate sepsis-induced cardiomyopathy.