Mechanisms underlying hypothermia-induced cardiac contractile dysfunction.

Area of Science:

• Cardiology
• Physiology
• Biochemistry

Background:

• Profound hypothermia rewarming is linked to high mortality from acute heart failure.
• The exact pathophysiological mechanisms behind this cardiac dysfunction remain largely unknown.

Purpose of the Study:

• To investigate the mechanisms of cardiac contractile dysfunction following hypothermia and rewarming.
• To characterize changes in intracellular calcium concentration and force generation in cardiac muscle.

Main Methods:

• Intact left ventricular rat papillary muscles were cooled to 15°C for 1.5 hours and then rewarmed to 30°C.
• Intracellular calcium concentration ([Ca(2+)](i)) and twitch force were measured using fura-2 AM.
• Maximal Ca(2+)-activated force (F(max)) and Ca(2+) sensitivity were assessed in skinned muscle fibers.

Main Results:

• Rewarming after hypothermia significantly reduced peak twitch force (30-40%) and F(max) (approx. 30%).
• Intracellular calcium concentration ([Ca(2+)](i)) was not significantly altered.
• Decreased Ca(2+) sensitivity of force was observed, indicated by a shift in pCa for 50% F(max).
• Total and PKA-mediated cardiac troponin I (cTnI) phosphorylation at Ser23/24 increased significantly after rewarming.

Conclusions:

• Hypothermia and rewarming significantly reduce myocardial contractility.
• This reduction is primarily due to decreased Ca(2+) sensitivity of force, not altered [Ca(2+)](i).
• Increased cTnI phosphorylation is identified as a key mechanism contributing to impaired cardiac contractility post-rewarming.