A body of work now exists to suggest that mitochondrial DNA defects occurring either through inherited or acquired pathways are associated with cardiovascular abnormalities. Previously, the investigator have shown that mitochondrial calcium ([Ca2+]mt) accumulation and mitochondrial gene expression are altered during surgically induced global ischemia and reperfusion and that these alterations are associated with decreased post-ischemic functional recovery in the aged but not the mature heart. They have also shown that increased [Ca2+]mt accumulation in the aged heart was associated with decreased mitochondrial gene expression and enzyme activity. These phenomena were shown to be related to decreased preservation and resynthesis of high energy phosphates during ischemia and reperfusion in the aged myocardium. In preliminary investigations using a novel polymerase chain reaction methodology, the PI showed that in the rabbit heart the prevalence of the mtDNA7, 436 deletion is increased during global ischemia and reperfusion and that these alterations are associated with decreased pot ischemic functional recovery in the aged but not the mature heart. In a parallel study using atrial appendage tissues from human patients undergoing cardiac surgery, similar results have been obtained indicated that ischemia-reperfusion increases the prevalence of the mtDNA, 436 deletion. The pathophysiology leading to these alterations in mtDNA and their relationship to myocardial dysfunction remain to be elucidated, however, preliminary investigation would suggest that AT-rich sequences flanking the mtDNA7,436 deletions in the rabbit and human heart may be of significance. The investigators plan to investigate the relevance of mtDNA deletions in a clinically relevant animal model and in human atrial tissue samples from cardiac surgery patients to determine the mechanisms leading to increased prevalence of mtDNA deletions during ischemia and/or reperfusion and to determine the identity and relative contribution of mtDNA deletions to post-ischemia functional recovery in the cardiac surgical patient. These studies will provide insight as to: the prevalence of mtDNA deletions in the cardiac patient; the effect of myocardial aging; and the effect of mtDNA deletions on surgical outcome. In addition, these investigation will provide information which will allow for the development of alternative myoprotective surgical procedures to optimize potential outcome in cardiac surgical patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059542-03
Application #
6184065
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1998-08-01
Project End
2001-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
3
Fiscal Year
2000
Total Cost
$178,632
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Black, Kendra M; Barnett, Reanne J; Bhasin, Monoj K et al. (2012) Microarray and proteomic analysis of the cardioprotective effects of cold blood cardioplegia in the mature and aged male and female. Physiol Genomics 44:1027-41
McCully, James D; Bhasin, Monoj K; Daly, Christian et al. (2009) Transcriptomic and proteomic analysis of global ischemia and cardioprotection in the rabbit heart. Physiol Genomics 38:125-37
McCully, James D; Cowan, Douglas B; Pacak, Christina A et al. (2009) Injection of isolated mitochondria during early reperfusion for cardioprotection. Am J Physiol Heart Circ Physiol 296:H94-H105
Levitsky, Sidney; Laurikka, Jari; Stewart, Robert D et al. (2003) Mitochondrial DNA deletions in coronary artery bypass grafting patients. Eur J Cardiothorac Surg 24:777-84
Wakiyama, Hidetaka; Cowan, Douglas B; Toyoda, Yoshiya et al. (2002) Selective opening of mitochondrial ATP-sensitive potassium channels during surgically induced myocardial ischemia decreases necrosis and apoptosis. Eur J Cardiothorac Surg 21:424-33
McCully, James D; Wakiyama, Hidetaka; Cowan, Douglas B et al. (2002) Diazoxide amelioration of myocardial injury and mitochondrial damage during cardiac surgery. Ann Thorac Surg 74:2138-45; discussion 2146
McCully, J D; Toyoda, Y; Uematsu, M et al. (2001) Adenosine-enhanced ischemic preconditioning: adenosine receptor involvement during ischemia and reperfusion. Am J Physiol Heart Circ Physiol 280:H591-602
Toyoda, Y; Levitsky, S; McCully, J D (2001) Opening of mitochondrial ATP-sensitive potassium channels enhances cardioplegic protection. Ann Thorac Surg 71:1281-8; discussion 1288-9
Toyoda, Y; Khan, S; Chen, W et al. (2001) Effects of NHE-1 inhibition on cardioprotection and impact on protection by K/Mg cardioplegia. Ann Thorac Surg 72:836-43; discussion 843-4

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