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PRECLINICAL STUDY

Nitric Oxide Inhalation Improves Microvascular Flow and Decreases Infarction Size After Myocardial Ischemia and Reperfusion

Xiaoshun Liu, MD, PhD^_*, Yanming Huang, MD, PhD^_*, Peter Pokreisz, PhD, Pieter Vermeersch, MD, Glenn Marsboom, MSc, Marc Swinnen^_*, Eric Verbeken, MD, PhD, Jose Santos, MD^_*, Marijke Pellens, Hilde Gillijns, Frans Van de Werf, MD, PhD^_*, Kenneth D. Bloch, MD^,2 and Stefan Janssens, MD, PhD^_*,,1,2,_*

^_* Department of Cardiology, University of Leuven, Leuven, Belgium
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute of Biotechnology, University of Leuven, Leuven, Belgium
Department of Pathology, University of Leuven, Leuven, Belgium
Cardiovascular Research Center, Department of Medicine, and Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Manuscript received October 3, 2006; revised manuscript received April 2, 2007, accepted April 10, 2007.

^_* Reprint requests and correspondence: Dr. Stefan Janssens, Department of Cardiology and Center for Transgene Technology and Gene Therapy, University of Leuven, Belgium. (Email: stefan.janssens{at}uz.kuleuven.ac.be).

Objectives: The purpose of this study was to test if nitric oxide (NO) could improve microvascular perfusion and decrease tissue injury in a porcine model of myocardial ischemia and reperfusion (I/R).

Background: Inhaled NO is a selective pulmonary vasodilator with biologic effects in remote vascular beds.

Methods: In 37 pigs, the midportion of the left anterior descending coronary artery was occluded for 50 min followed by 4 h of reperfusion. Pigs were treated with a saline infusion (control; n = 14), intravenous nitroglycerin (IV-NTG) at 2 µg/kg/min (n = 11), or inhaled nitric oxide (iNO) at 80 parts per million (n = 12) beginning 10 min before balloon deflation and continuing throughout reperfusion.

Results: Total myocardial oxidized NO species in the infarct core was greater in the iNO pigs than in the control or IV-NTG pigs (0.60 ± 0.05 nmol/mg tissue vs. 0.40 ± 0.03 nmol/mg tissue and 0.40 ± 0.02 nmol/mg tissue, respectively; p < 0.01 for both). Infarct size, expressed as percentage of left ventricle area at risk (AAR), was smaller in the iNO pigs than in the control or IV-NTG pigs (31 ± 6% AAR vs. 58 ± 7% AAR and 46 ± 7% AAR, respectively; p < 0.05 for both) and was associated with less creatine phosphokinase-MB release. Inhaled NO improved endocardial and epicardial blood flow in the infarct zone, as measured using colored microspheres (p < 0.001 vs. control and IV-NTG). Moreover, NO inhalation reduced leukocyte infiltration, as reflected by decreased cardiac myeloperoxidase activity (0.8 ± 0.2 U/mg tissue vs. 2.3 ± 0.8 U/mg tissue in control and 1.4 ± 0.4 U/mg tissue in IV-NTG; p < 0.05 for both) and decreased cardiomyocyte apoptosis in the infarct border zone.

Conclusions: Inhalation of NO just before and during coronary reperfusion significantly improves microvascular perfusion, reduces infarct size, and may offer an attractive and novel treatment of myocardial infarction.

Abbreviations and Acronyms   AAR = area at risk   iNO = inhaled nitric oxide   LV = left ventricle/ventricular   MPO = myeloperoxidase   MVO = microvascular obstruction   NO = nitric oxide   NOx = oxidized nitric oxide species   NTG = nitroglycerin

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