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PRECLINICAL STUDY

Borderzone Contractile Dysfunction Is Transiently Attenuated and Left Ventricular Structural Remodeling Is Markedly Reduced Following Reperfused Myocardial Infarction in Inducible Nitric Oxide Synthase Knockout Mice

Wesley D. Gilson, PhD^_*,, Frederick H. Epstein, PhD^_*,,, Zequan Yang, MD, PhD^_*,, Yaqin Xu, MD, PhD^_*, Konkal-Matt R. Prasad, PhD^_*, Marie-Claire Toufektsian, PhD^_*, Victor E. Laubach, PhD^, and Brent A. French, PhD^_*,,,_*

^_* Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia
Department of Radiology, University of Virginia, Charlottesville, Virginia
Department of Surgery, University of Virginia, Charlottesville, Virginia
Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia.

Manuscript received August 28, 2006; revised manuscript received June 22, 2007, accepted July 31, 2007.

^_* Reprint requests and correspondence: Dr. Brent A. French, Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville, Virginia 22903. (Email: bf4g{at}virginia.edu).

Objectives: We sought to determine the effect of inducible nitric oxide synthase (iNOS) expression on regional contractile function and left ventricular (LV) remodeling after reperfused myocardial infarction (MI).

Background: Inducible nitric oxide synthase is known to contribute to global LV dysfunction after a large MI, but the mechanisms underlying this dysfunction remain unclear.

Methods: We used immunohistochemistry to investigate the distribution of iNOS expression in wild-type (WT) and iNOS knockout (KO) mice early (day 1) and late (day 28) after reperfused MI. We also used serial cardiac magnetic resonance imaging at baseline and at 1, 7, and 28 days after MI to assess LV volumes, ejection fraction (EF), regional circumferential strain (E_cc), and day 1 infarct size.

Results: At baseline, LV volumes and EF were similar between groups. Day 1 infarct size was also similar between groups. Immunohistochemistry revealed that iNOS expression was abundant throughout the heart in WT mice on day 1 after MI, particularly near the infarct borderzone. On day 7 after MI, E_cc in KO mice was significantly improved in some borderzone sectors compared with WT. The LV volumes were significantly lower in KO mice at days 7 and 28 compared with WT. The EF on days 7 and 28 was significantly higher in KO mice compared with WT. The circumferential extent of wall thinning was also significantly reduced in KO versus WT mice at days 7 and 28.

Conclusions: Expression of iNOS contributes importantly to post-infarction contractile dysfunction and subsequent LV remodeling, suggesting new strategies to combat heart failure resulting from large MI.

Abbreviations and Acronyms   2D = two-dimensional   Bsl = baseline   Ecc = circumferential strain   ECG = electrocardiogram   EF = ejection fraction   iNOS = inducible nitric oxide synthase   KO = knockout   LV = left ventricle/ventricular   MI = myocardial infarction   MRI = magnetic resonance imaging   WT = wild-type

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