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J Thorac Cardiovasc Surg 2010;139:732-740
© 2010 The American Association for Thoracic Surgery

Evolving Technology/Basic Science

The novel synthetic serine protease inhibitor CU-2010 dose-dependently reduces postoperative blood loss and improves postischemic recovery after cardiac surgery in a canine model

Gábor Szabó, MD, PhDa,*, Gábor Veres, MDb, Tamás Radovits, MDa, Humaira Haidera, Nelli Kriegera, Susanne Bährle, MDc, Silke Niklischd, Christiane Miesel-Gröschela, Andreas van de Locht, PhDd, Matthias Karck, MDa

a Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
b Department of Cardiovascular Surgery, Semmelweis University Medical School, Budapest, Hungary
c Department of Cardiology, Angiology and Pulmonology, University of Heidelberg, Heidelberg, Germany
d The Medicine Company, München, Germany

Read at the Eighty-ninth Annual Meeting of The American Association for Thoracic Surgery, Boston, Massachusetts, May 9–13, 2009.

Received for publication May 4, 2009; revisions received October 4, 2009; accepted for publication October 31, 2009.

* Address for reprints: Gábor Szabó, MD, PhD, Department of Cardiac Surgery, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. (Email: Gabor.Szabo{at}urz.uni-heidelberg.de).

Background: Serine protease inhibitors such as aprotinin reduce perioperative blood loss and may improve postpump cardiac performance owing to their anti-inflammatory properties. After the "aprotinin era," we investigated the efficacy of the novel synthetic serine protease inhibitors CU-2010 with improved coagulatory and anti-inflammatory profile on blood loss and reperfusion injury in a canine model.

Methods: Thirty-six dogs were divided into 6 groups: control, aprotinin (n = 8; Hammersmith scheme), and CU-2010 (0.5, 0.83, 1.25, and 1.66 mg/kg). All animals underwent 90 minutes of cardiopulmonary bypass with 60 minutes of hypothermic cardioplegic arrest. End points were blood loss during the first 2 hours after application of protamine, as well as recovery of myocardial contractility (slope of the end-systolic pressure–volume relationship, coronary blood flow, and vascular reactivity.

Results: CU-2010 dose-dependently reduced blood loss to a degree comparable with that of aprotinin at lower doses and even further improved at higher doses (control/aprotinin/CU-2010 in increasing doses: 142 ± 13, 66 ± 17, 95 ± 16, 57 ± 17, 46 ± 3, and 13 ± 4 mL; P < .05). Whereas aprotinin did not influence myocardial function, CU-2010 improved the recovery of end-systolic pressure–volume relationship (control 60 ± 6 mg kg vs aprotinin 73 ± 7 mg/kg vs CU-2010 1.66 mg/kg; 102% ± 8%; P < .05). Coronary blood flow (52 ± 4 vs 88 ± 7 vs 96 ± 7; P < .05) and response to acetylcholine (44% ± 6% vs 77% ± 7% vs 81% ± 6%; P < .05) were improved by both aprotinin and CU-2010.

Conclusions: The novel serine protease inhibitor CU-2010 significantly reduced blood loss after cardiac surgery comparable with aprotinin. Furthermore, an additionally improved anti-inflammatory profile led to a significantly improved postischemic recovery of myocardial and endothelial function.

Abbreviations and Acronyms ACT = activated clotting time; aPTT = partial thromboplastin time; CPB = cardiopulmonary bypass; dP/dt = left ventricular pressure development; ESPVR = end-systolic pressure–volume relationship; MCF = maximum clot strength; PRSW = preload recruitable stroke work; PT = prothrombin time




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