Improved myocardial protection in the failing heart by selective endothelin-A receptor blockade Karola Trescher, MD, Michael Bauer, MD, Wolfgang Dietl,

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Improved myocardial protection in the failing heart by selective endothelin-A receptor blockade Karola Trescher, MD, Michael Bauer, MD, Wolfgang Dietl, MD, Seth Hallström, PhD, Nikolaus Wick, MD, Margarita Wolfsberger, MD, Robert Ullrich, PhD, Günther Jürgens, PhD, Ernst Wolner, MD, Bruno K. Podesser, MD The Journal of Thoracic and Cardiovascular Surgery Volume 137, Issue 4, Pages 1005-1011.e1 (April 2009) DOI: 10.1016/j.jtcvs.2008.10.037 Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Time schedule of the perfusion protocol. LD, Langendorff mode; WH, Working heart mode; rLD, Langendorff mode during reperfusion; rWH, Working heart mode during reperfusion. Cardioplegic arrest was induced (I, induction) by cold blood cardioplegia according to Buckberg. Cardioplegia continued with two cold reinfusions (1. R, 2. R) and was finished by a “hot shot.” The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1005-1011.e1DOI: (10.1016/j.jtcvs.2008.10.037) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Ex vivo hemodynamic measurements. Data of the reperfusion period are presented as recovery values (percentage of baseline). A, Recovery of coronary flow (CF) ERA acute versus both ERA chronic and control groups, ∗P < .01 (BL, baseline). B, Recovery of cardiac output (LAF, left atrial flow) ERA acute versus control group, ∗P < .01; ERA chronic versus control group, #P < .01. C, Recovery of external heart work (EHW) (cardiac output × LV systolic pressure). ERA acute versus control group, ∗P < .01; ERA chronic versus control group; #P < .01. D, Recovery of diastolic left atrial pressure (LAP),∗P < .01 ERA acute versus control group. All data are presented as mean ± SEM. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1005-1011.e1DOI: (10.1016/j.jtcvs.2008.10.037) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Representative micrographs of transmission electron microscopy at the end of reperfusion. A, Control. B, ERA chronic. C, ERA acute. In A and B, swelling and disruption of mitochondrial cristae and myofilaments indicate severe ischemic injury. In C, the integrity of mitochondria and myofilaments are preserved by TBC-3214 treatment during I/R. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1005-1011.e1DOI: (10.1016/j.jtcvs.2008.10.037) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 High-energy phosphates in biopsy tissue of the LV in the treatment groups receiving ERA compared with the control group. Changes in phosphocreatine and adenine nucleotide levels (A) and energy charge (B) in ERA the chronic and acute groups versus the control group; ∗P < .01 versus control; #P < .05 versus control. PCr, Phosphocreatine; AMP, adenosine monophosphate; ADM, adenosine diphosphate; ATP, adenosine triphosphate. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1005-1011.e1DOI: (10.1016/j.jtcvs.2008.10.037) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Ex vivo hemodynamic measurements in absolute values Ex vivo hemodynamic measurements in absolute values. A: Coronary flow (CF). ERA acute versus both ERA chronic and control groups;∗P < .01. B, Cardiac output (left atrial flow, LAF). ERA acute versus control group, †P < .05; ERA chronic versus control group, #P < .01. C, External heart work (EHW) (cardiac output × LV systolic pressure). ERA acute versus control group, ∗P < .01; ERA chronic versus control group; #P < .01. D, Diastolic left atrial pressure (LAP dia).∗P < .01 ERA acute versus control group. All data are presented as mean ± SEM. BL, Baseline. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 1005-1011.e1DOI: (10.1016/j.jtcvs.2008.10.037) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions