Mechanisms underlying hypothermia-induced cardiac contractile dysfunction

Rewarming patients after profound hypothermia may result in acute heart failure and high mortality (50-80%). However, the underlying pathophysiological mechanisms are largely unknown. We characterized cardiac contractile function in the temperature range of 15-30°C by measuring the intracellular Ca ²⁺ concentration ([Ca²⁺]_i) and twitch force in intact left ventricular rat papillary muscles. Muscle preparations were loaded with fura-2 AM and electrically stimulated during cooling at 15°C for 1.5 h before being rewarmed to the baseline temperature of 30°C. After hypothermia/rewarming, peak twitch force decreased by 30-40%, but [Ca ²⁺]_i was not significantly altered. In addition, we assessed the maximal Ca²⁺-activated force (F_max) and Ca²⁺ sensitivity of force in skinned papillary muscle fibers. F _max was decreased by ∼30%, whereas the pCa required for 50% of F_max was reduced by ∼0.14. In rewarmed papillary muscle, both total cardiac troponin I (cTnI) phosphorylation and PKA-mediated cTnI phosphorylation at Ser23/24 were significantly increased compared with controls. We conclude that after hypothermia/rewarming, myocardial contractility is significantly reduced, as evidenced by reduced twitch force and F_max. The reduced myocardial contractility is attributed to decreased Ca²⁺ sensitivity of force rather than [Ca²⁺]_i itself, resulting from increased cTnI phosphorylation.