The majority of coronary artery bypass grafting (CABG) and valve repair surgeries use cardioplegia and cardiopulmonary bypass (CP/CPB) to respectively arrest the heart and systemically circulate oxygenated blood. Hypothermic cardioplegia solutions provide myocardial protection during prolonged surgicallyinduced global ischemia that would otherwise prove lethal. However, cardioplegic arrest of the heart during surgery results in reversible ischemic injury that manifests in impaired contractility of viable myocardium and reductions in cardiac function (a.k.a myocardial stunning). In the majority of patients, this temporary impairment resolves quickly, however ~ 10 % can develop an associated cardiac low output syndrome lasting hours to days that greatly enhances the risk of mortality. Following CP/CPB, HSP27 and cryAB are phosphorylated on multiple residues. Current data in the literature suggests that the presence of nonphosphorylated sHSP is beneficial for post ischemic contractile function, and that ischemic insults (including CP/CPB) that induce phosphorylation of HSP27 and cryAB, and subsequent depletion of the nonphosphorylated sHSP pool, may play a role in myocardial contractile deficits or stunning. These studies are designed around the central hypothesis that preservation of non-phosphorylated HSP27 and cryAB levels will reduce or block CP-induced deficits in myocardial contractility. These studies will be performed in Aim I - Determine the upstream signaling mechanism of CP/CPB-induced HSP27 and cryAB phosphorylation.
Aim II - Determine if overexpression of phospho-mutant sHSP's will reduce cardioplegia-induced contractile deficits in isolated myocytes.
Aim III - Determine specific cardiac contractile signaling mechanisms associated with ischemia-induced alterations in sHSP proteins. Experimental interventions (pharmacological and genetic approaches) will be performed using isolated rat cardiomyocytes and Langendorff perfused hearts. If these Aims are successful, these studies will enhance our understanding of CP-induced contractile deficits, and suggest treatment strategies that could greatly improve current myocardial protection and reduce complications associated with cardiac surgery

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Schwartz, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rhode Island Hospital
United States
Zip Code
Cordeiro, Brenda; Shinn, Connor; Sellke, Frank W et al. (2015) Rottlerin-induced BKCa channel activation impairs specific contractile responses and promotes vasodilation. Ann Thorac Surg 99:626-34
Clements, Richard T; Terentyev, Dmitry; Sellke, Frank W (2015) Ca(2+)-activated K(+) channels as therapeutic targets for myocardial and vascular protection. Circ J 79:455-62
Cordeiro, Brenda; Terentyev, Dmitry; Clements, Richard T (2015) BKCa channel activation increases cardiac contractile recovery following hypothermic ischemia/reperfusion. Am J Physiol Heart Circ Physiol 309:H625-33
Feng, Jun; Liu, Yuhong; Chu, Louis M et al. (2012) Changes in microvascular reactivity after cardiopulmonary bypass in patients with poorly controlled versus controlled diabetes. Circulation 126:S73-80
Clements, Richard T; Cordeiro, Brenda; Feng, Jun et al. (2011) Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts. Circulation 124:S55-61
Clements, Richard T; Feng, Jun; Cordeiro, Brenda et al. (2011) p38 MAPK-dependent small HSP27 and ýýB-crystallin phosphorylation in regulation of myocardial function following cardioplegic arrest. Am J Physiol Heart Circ Physiol 300:H1669-77