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

Szabó, Gábor; Veres, Gábor; Radovits, Tamás; Haider, Humaira; Krieger, Nelli; Bährle, Susanne; Niklisch, Silke; Miesel-Gröschel, Christiane; van de Locht, Andreas; Karck, Matthias

doi:10.1016/j.jtcvs.2009.10.059

« Previous Next »The Journal of Thoracic and Cardiovascular Surgery
Volume 139, Issue 3 , Pages 732-740, March 2010

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

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

Gábor Szabó, MD, PhD
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
- Address for reprints: Gábor Szabó, MD, PhD, Department of Cardiac Surgery, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
Gábor Veres, MD
- Department of Cardiovascular Surgery, Semmelweis University Medical School, Budapest, Hungary
Tamás Radovits, MD
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
Humaira Haider
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
Nelli Krieger
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
Susanne Bährle, MD
- Department of Cardiology, Angiology and Pulmonology, University of Heidelberg, Heidelberg, Germany
Silke Niklisch
- The Medicine Company, München, Germany
Christiane Miesel-Gröschel
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
Andreas van de Locht, PhD
- The Medicine Company, München, Germany
Matthias Karck, MD
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany

Received 4 May 2009; received in revised form 4 October 2009; accepted 31 October 2009.

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.

CTSNet classification: 1, 25, 31, 37

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