Role of superoxide ion formation in hypothermia/rewarming induced contractile dysfunction in cardiomyocytes

Abstract

Rewarming following accidental hypothermia is associated with circulatory collapse due primarily to impaired cardiac contractile (systolic) function. Previously, we found that reduced myofilament Ca sensitivity underlies hypothermia/rewarming (H/R)-induced cardiac contractile dysfunction. This reduced Ca sensitivity is associated with troponin I (cTnI) phosphorylation. We hypothesize that H/R induces reactive oxygen species (ROS) formation in cardiomyocytes, which leads to cTnI phosphorylation and reduced myofilament Ca sensitivity. To test this hypothesis, we exposed isolated rat cardiomyocytes to a 2-h period of severe hypothermia (15 °C) followed by rewarming (35 °C) with and without antioxidant (TEMPOL) treatment. Simultaneous measurements of cytosolic Ca ([Ca]) and contractile (sarcomere shortening) responses indicated that H/R-induced contractile dysfunction and reduced Ca sensitivity was prevented in cardiomyocytes treated with TEMPOL. In addition, TEMPOL treatment blunted H/R-induced cTnI phosphorylation. These results support our overall hypothesis and suggest that H/R disrupts excitation-contraction coupling of the myocardium through a cascade of event triggered by excessive ROS formation during hypothermia. Antioxidant treatment may improve successful rescue of accidental hypothermia victims.

Cooling to Hypothermic Circulatory Arrest by Immersion vs. Cardiopulmonary Bypass (CPB): Worse Outcome After Rewarming in Immersion Cooled Pigs

“…Thus, it does not appear that the decrease in contractility of cardiac myocytes (heart failure) after rewarming can be solely attributed to dysregulation of [Ca 2+ ] cyt release and reuptake. By the use of isolated, electrically stimulated myocytes cooled to 15°C, and rewarmed we have documented that the reduction in force generation, independent of [Ca 2+ ] cyt levels, is the effect of an increased phosphorylation of cardiac troponin I (cTnI) leading to reduced Ca 2+ sensitivity of the contractile response after rewarming ( Han et al, 2010 ; Schaible et al, 2016 , 2018 ). Further, with relevance to the group (CPBc) treated with a chemical cardioplegic solution during HCA in the present study; we observed both maintained cytosolic Ca 2+ levels and myofilament Ca 2+ sensitivity in myocytes, which were not electrically stimulated (cardioplegic) during cooling to 15°C and rewarming ( Han et al, 2018 ).…”

Effects of rewarming with extracorporeal membrane oxygenation to restore oxygen transport and organ blood flow after hypothermic cardiac arrest in a porcine model

“…We have previously documented hypothermia-rewarming induced cardiac dysfunction in both in vivo and in vitro models 23 – 28 . Underlying pathophysiologic mechanisms include derangement in metabolism and calcium homeostasis 23 – 25 , 29 , elevated protein kinase A levels with increased phosphorylation in myocardial contractile proteins 27 , 28 , 30 , and reactive oxygen species formation 31 . Likewise, after rewarming, we have documented derangements in renal 32 and nervous tissue morphology 33 .…”

Effects of Rewarming with Extracorporeal Membrane Oxygenation to Restore Oxygen Transport and Organ Blood Flow After Hypothermic Cardiac Arrest in a Porcine Model.

“…We previously have documented hypothermia-rewarming induced cardiac dysfunction in both in vivo and in vitro models [20,[27][28][29][30][31]. Underlying pathophysiologic mechanisms include derangement in metabolism and calcium homeostasis [20,27,28,32], elevated protein kinase A levels with increased phosphorylation in myocardial contractile proteins [30,31,33], and reactive oxygen species formation [34]. Likewise, after rewarming, we have documented derangements in renal [35] and nervous tissue morphology [36].…”