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(Circulation. 2006;114:I-257 – I-263.)
© 2006 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Indices of Apoptosis Activation After Blood Cardioplegia and Cardiopulmonary Bypass

Basel Ramlawi, MD; Jun Feng, MD, PhD; Shigetoshi Mieno, MD; Csaba Szabo, MD, PhD; Zsuzsanna Zsengeller, PhD; Richard Clements, PhD; Neel Sodha, MD; Munir Boodhwani, MD; Cesario Bianchi, MD, PhD; Frank W. Sellke, MD

From the Division of Cardiothoracic Surgery (B.R., J.F., S.M., R.C., N.S., M.B., C.B., F.W.S.), Department of Surgery, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass; Department of Human Physiology and Experimental Research (C.S.), Semmelweis University Medical School, Budapest, Hungary and Department of Surgery, University of Medicine and Dentistry of New Jersey, Newark, NJ; Perlmutter Laboratory (Z.Z.), Children’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Frank W. Sellke, Division of Cardiothoracic Surgery, BIDMC, LMOB 2A, 110 Francis St, Boston, MA 02215. E-mail fsellke{at}caregroup.harvard.edu

Background— Cardioplegic arrest (CA) using cold blood cardioplegia (CBC) has been reported to reduce ischemia-reperfusion (IR)-induced myocardial injury via apoptosis. We studied key apoptotic mediators via the caspase-dependent and intrinsic pathways as well as poly(ADP)-ribosylating protein (PARP) activity in myocardial and peripheral tissues after CA and cardiopulmonary bypass (CBP).

Methods and Results— Right atrial (RA) and skeletal muscle(SM) was harvested from cardiac surgical patients with similar baseline characteristics (N =6) before and after CPB and CBC. Total and modified caspase-3, Bcl-2, Bad, apoptosis-inducing factor (AIF), and PARP were quantified by immunoblotting. Terminal caspase-3 activity was assessed and immunohistochemistry was performed for PARP and AIF. TUNEL staining was used for identification of apoptotic cells. Microarray gene expression analysis was performed using Affymetrix U95 GeneChip. In RA tissue, CA with CBC significantly increased phosphorylation of Bcl-2 (Ser⁷⁰), Bad (Ser¹¹²) (2.63±0.4 and 1.77±0.3-fold respectively; P<0.05), and cleavage of the downstream caspase 3 (1.45±0.1-fold; P<0.05). There was no significant change in total protein levels. Also, there was an increase in mature AIF (57 kDa) levels (1.22±0.01-fold; P<0.05) and a trend toward nuclear translocation on histological staining. Caspase 3 activity was increased 1.5±0.14-fold (P<0.05). The number of apoptotic cells in atrial tissue increased after compared with before CPB/CA using TUNEL staining (1.55±0.66 versus 0.325±0.05%, respectively; P=0.03). In contrast, SM samples did not show any of the changes observed in RA tissue after CPB.

Conclusion— Despite optimal current surgical myocardial protection, we found that CA with CBC induced both programmed cell death and survival signaling in myocardial tissue.

Key Words: apoptosis • blood cardioplegia • extracorporeal circulation • ischemia reperfusion • myocardial protection • signal transduction

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