Abstract

While cardioplegic arrest is a common requirement for cardiac surgery, transient left ventricular (LV) dysfunction can occur following reperfusion and rewarming. The overall goal of this project is to define basic mechanisms responsible for LV dysfunction following cardioplegic arrest and to identify unique strategies at the cellular and molecular level which will protect the fundamental contractile unit of the heart, the myocyte, during cardioplegic arrest. Past studies have demonstrated that myocardial preconditioning protects the myocardium from a subsequent prolonged ischemic insult. Potential mechanisms for preconditioning include opening of the ATP sensitive potassium (Katp) channels and activation of the myocyte adenosine receptor system. Recent reports have identified a link between the adenosine receptor and the Katp channel; activation of protein kinase C (PKC). Based on these findings and preliminary results from our laboratory, the following hypotheses will be tested: (1) Katp activation will improve myocyte contractile processes following cardioplegic arrest and that a contributory mechanism for this effect is improved ionic homeostasis, (2) Adenosine receptor activation followed by cardioplegic arrest will improve myocyte contractile processes and the intracellular mechanisms for this effect are similar to that of Katp activation and cardioplegic arrest, (3) The specific intracellular trigger for myocyte protection during cardioplegic arrest is PKC stimulation, which in turn activates the Katp channel, (4) Katp opening or adenosine treatment with cardioplegic arrest provide particular beneficial effects in the setting of pre-existing LV dysfunction. Using LV myocytes isolated from normal and heart failure pigs, and an isolated myocyte system developed by this laboratory, the effects and mechanisms for each treatment will be defined. In order to facilitate the transfer of the findings from this project to clinical applications, this project will isolate LV myocytes from patients undergoing cardiac surgery in order to develop a predictive model which will identify the patients which will benefit from these treatment strategies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056603-04
Application #
6183460
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1997-04-01
Project End
2001-11-30
Budget Start
2000-04-01
Budget End
2001-11-30
Support Year
4
Fiscal Year
2000
Total Cost
$254,160
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425

  Publications

Mohsin, Sadia; Wu, Joseph C; Sussman, Mark A (2014) Predicting the future with stem cells. Circulation 129:136-8
Ford, Rachael L; Mains, Ira M; Hilton, Ebony J et al. (2008) Endothelin-A receptor inhibition after cardiopulmonary bypass: cytokines and receptor activation. Ann Thorac Surg 86:1576-83
Dorman, Bruce H; Stroud, Robert E; Wyckoff, Michael M et al. (2008) Differential effects of epsilon-aminocaproic acid and aprotinin on matrix metalloproteinase release in patients following cardiopulmonary bypass. J Cardiovasc Pharmacol 51:418-23
Ikonomidis, John S; Hilton, Ebony J; Payne, Kimberly et al. (2007) Selective endothelin-A receptor inhibition after cardiac surgery: a safety and feasibility study. Ann Thorac Surg 83:2153-60;discussion 2161
Apple, Kimberly A; McLean, Julie E; Squires, Christina E et al. (2006) Differential effects of protein kinase C isoform activation in endothelin-mediated myocyte contractile dysfunction with cardioplegic arrest and reperfusion. Ann Thorac Surg 82:664-71
Clark, Leslie L; Ikonomidis, John S; Crawford Jr, Fred A et al. (2006) Preoperative statin treatment is associated with reduced postoperative mortality and morbidity in patients undergoing cardiac surgery: an 8-year retrospective cohort study. J Thorac Cardiovasc Surg 131:679-85
Yarbrough, William M; Mukherjee, Rupak; Squires, Christina E et al. (2004) Caspase inhibition attenuates contractile dysfunction following cardioplegic arrest and rewarming in the setting of left ventricular failure. J Cardiovasc Pharmacol 44:645-50
Schneider, Susan; Gunasinghe, Himali; Sistino, Joseph et al. (2003) Effects of leukocyte depletion filters on matrix metalloproteinase activation in an extracorporeal circulation circuit. J Extra Corpor Technol 35:139-42
Ergul, A; Joffs, C; Walker, A C et al. (2001) Potential role of endothelin receptor antagonists in the setting of cardiopulmonary bypass: relevance to myocardial performance. Heart Fail Rev 6:287-94
Joffs, C; Walker, C A; Hendrick, J W et al. (2001) Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass. J Thorac Cardiovasc Surg 122:365-70

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