Submitted on January 30, 2007
Accepted on July 23, 2007
Moderate hypothermia (30°C) maintains myocardial integrity and modifies the response of cell survival proteins after reperfusion
Xue-Han Ning1*, Emil Y Chi2, Norman E. Buroker3, Shi-Han Chen4, Cheng-Su Xu5, Ying-Tzang Tien2, Outi M. Hyyti5, Ming Ge3, and Michael A. Portman6
1 Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, Washington, United States; Cardiology, Children's Hospital and Regional Medical Center, Seattle, Washington, United States
2 Department of Pathology, University of Washington, Seattle, Washington, United States
3 Cardiology, Children's Hospital and Regional Medical Center, Seattle, Washington, United States
4 Division of Genetics and Development, Department of Pediatrics, University of Washington, Seattle, Washington, United States
5 Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, Washington, United States
6 Division of Cardiology, Department of Pediatrics, University of Washington, Seattle, Washington, United States; Cardiology, Children's Hospital and Regional Medical Center, 4800 Sandpoint Way NE, Seattle, Washington, 98105, United States
* To whom correspondence should be addressed. E-mail: xh{at}u.washington.edu.
Hypothermia preserves myocardial function, promotes signaling for cell survival, and inhibits apoptotic pathways during forty-five minutes of reperfusion. We tested the hypothesis that signaling at the transcriptional level is followed by corresponding proteomic response and maintenance of structural integrity following 3-hours of reperfusion. Isolated hearts were perfused with the Langendorff method and exposed to mild (group I, n = 6, 34°C) or moderate (group H, n = 6, 30°C) hypothermia during 120 minutes of total ischemia with cardioplegic arrest, and 180 minutes of 37°C reperfusion. Moderate hypothermia suppressed anaerobic metabolism during ischemia and significantly diminished LVEDP at the end of ischemia from 52.7±3.3 mmHg in I to 1.8±0.9 mmHg in H. Unlike group I, which showed poor cardiac function and high left ventricular pressure. Moderate hypothermia suppressed anaerobic metabolism during ischemia. Unlike group I, which showed poor cardiac function, H showed preservation of myocardial function, coronary flow, and oxygen consumption. Compared to normal control hearts without ischemia (n = 5), histological staining in group I showed marked disarray and fragmentation of collagen network (Score 4-5), while H showed preserved collagen integrity (score 0-1). The apoptosis linked, tumor suppressor protein, p53 was expressed throughout I only (Score 4-5). Group H produced elevated expression for hypoxia inducible factor 1
and heme oxygenase 1, though minimally affected vascular endothelial growth factor (VEGF) expression. Group H also elevated expression for survival proteins peroxisomal proliferator activated receptor 
and Akt-1. These results show in a constant left ventricular volume modelthat moderate hypothermia at 30°C decreases myocardial energy utilization during ischemia and subsequently promotes expression of proteins involved in cell survival, while inhibiting induction of the p53 protein. These data also show that 34°C proffers minimal cardiac protection and produces poor functional recovery (P<0.05) and loss of myocardial integrity.
