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J Thorac Cardiovasc Surg 2009;137:1005-1011
© 2009 The American Association for Thoracic Surgery

Cardiopulmonary Support

Improved myocardial protection in the failing heart by selective endothelin-A receptor blockade

Karola Trescher, MDa,b, Michael Bauer, MDb, Wolfgang Dietl, MDb, Seth Hallström, PhDc, Nikolaus Wick, MDd, Margarita Wolfsberger, MDe, Robert Ullrich, PhDd, Günther Jürgens, PhDc, Ernst Wolner, MDb, Bruno K. Podesser, MDa,b,*

a Department of Cardiac Surgery, LK St Poelten, Austria
b Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna Medical University, Vienna, Austria
c Institute of Physiological Chemistry, Center of Physiological Medicine, Medical University Graz, Austria
d Department of Pathology, Vienna Medical University, Vienna, Austria
e Department of Pediatrics, Vienna Medical University, Vienna, Austria

Received for publication April 4, 2008; revisions received October 6, 2008; accepted for publication October 27, 2008.

* Address for reprints: Bruno K. Podesser, MD, Ludwig Boltzmann Cluster for Cardiovascular Research, C/O Core Unit for Biomedical Research, Medical University of Vienna, Vienna General Hospital, Währinger Gürtel 18-20, 1090 Vienna, Austria. (Email: bruno.podesser{at}meduniwien.ac.at).

Objective: Ischemia/reperfusion injury caused by cardioplegic arrest is still a major challenge in patients with reduced left ventricular function. We investigated the effect of chronic versus acute administration of the selective endothelin-A receptor antagonist (ERA) TBC-3214Na during ischemia/reperfusion in failing hearts.

Methods: Male Sprague–Dawley rats underwent coronary ligation. Three days after myocardial infarction (MI), 19 randomly assigned animals (ERA chronic) were administered TBC-3214Na continuously with their drinking water, 29 MI rats received placebo, and 3 rats died during the observation period. Six weeks after infarction, hearts were evaluated in a blood-perfused working heart model during 60 minutes of ischemia and 30 minutes of reperfusion. In 14 MI rats, TBC-3214Na (ERA acute) was added to the cardioplegic solution during ischemia. Thirteen MI rats served as control.

Results: At a similar infarct size, postischemic recovery of cardiac output (ERA chronic: 91% ± 10%, ERA acute: 86% ± 11% vs control: 52% ± 15%; P < .05) and external heart work (ERA chronic: 90% ± 10%, ERA acute: 85% ± 13% vs control: 51% ± 17%; P < .05) was significantly enhanced in both TBC-3214Na–treated groups whereas recovery of coronary flow was only improved in ERA acute rats (ERA acute: 121% ± 23% vs ERA chronic: 75% ± 13%; control: 64% ± 15%; P < .05). Blood gas measurements showed enhanced myocardial oxygen delivery and consumption with acute TBC-3214Na therapy. Additionally, high-energy phosphates (phosphocreatine) were significantly higher and transmission electron microscopy revealed less ultrastructural damage under acute TBC-3214Na administration.

Conclusion: Acute endothelin-A receptor blockade is superior to chronic blockade in attenuating ischemia/reperfusion injury in failing hearts. Therefore, acute endothelin-A receptor blockade might be an interesting option for patients with heart failure undergoing cardiac surgery.

Abbreviations and Acronyms ADP = adenosine diphosphate; AMP = adenosine monophosphate; ATP = adenosine triphosphate; CO = cardiac output; ERA = endothelin-A receptor antagonist; ET = endothelin; I/R = ischemia/reperfusion; LV = left ventricle; MDO2 = myocardial oxygen delivery; MI = myocardial infarction; MVO2 = myocardial oxygen consumption; PCr = phosphocreatine; WH = working heart mode; rWH = working heart mode during reperfusion






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