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.
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Figure 1 Measurement of Circumferential Extent of Wall Thinning
Significant wall thinning was defined as left ventricular wall thickness <50% of the normal end-diastolic wall thickness of 1 mm (blue arrows). The circumferential extent was defined as the angle ( ) subtending the arc in which significant wall thinning occurred.
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Figure 2 Immunohistochemistry for Myoglobin, Neutrophils, and iNOS in Hearts From Mice at Day 1 and 28 After MI
(A, C) Low- and high-power (respectively) magnifications of a wild-type (WT) mouse heart on post-myocardial infarction (MI) day 1 double-immunostained for myoglobin (brown) and neutrophils (purple). (B, D) Low- and high-power (respectively) serial sections from the same mouse heart immunostained for inducible nitric oxide synthase (iNOS) (brown). The iNOS immunoreactivity in panel D is most abundant in the swath of cardiomyocytes located within the black oval. Comparison with panel C reveals that the same swath of cardiomyocytes contains little myoglobin and is largely nonviable. (E, F) Sections from WT mouse hearts on post-MI day 28 immunostained for iNOS. (E) iNOS in cardiomyocytes bordering scar tissue (arrows). (F) iNOS in cardiomyocytes bordering mature scar and in granulation tissue (arrows). (G) Graph of plasma nitrite/nitrate (NOx) concentrations over time after MI in WT and iNOS knockout (KO) mice. Significant elevations were observed at days 1 and 28 after MI in WT mice, whereas NOx levels were unchanged in iNOS KO mice. Error bars represent SEM. *p < 0.05 versus same group before MI.
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Figure 3 Bull’s-Eye Plots Showing Infarct as a Fraction of the Area in Each Sector
The outer circles correspond to the more basal slices, and inner circles correspond to more apical slices. Similar infarct distributions were observed in the WT and KO groups. 0 = no infarct; 1 = completely infarcted. Abbreviations as in Figure 2.
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Figure 4 Midventricular End-Systolic Magnetic Resonance Images of a WT Mouse Heart 1 Day After MI
(A) Black-blood cine image clearly delineates the left ventricular chamber at the endocardial border. (B) Delayed contrast-enhanced image highlights the transmurally infarcted myocardium extending from 10 to 5 o’clock. (C) Myocardial tagging reveals lack of tag deformation in contrast-enhanced zones (B) and preservation of contraction in remote myocardium. Abbreviations as in Figure 2.
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Figure 5 EDV, ESV, and EF During Left Ventricular Remodeling After MI
A significant difference in end-diastolic volume (EDV) and end-systolic volume (ESV) (A) and ejection fraction (EF) (B) is appreciated as early as 7 days after MI. These differences remained significant at day 28. Error bars represent SEM. *p < 0.05 versus WT. Abbreviations as in Figure 2.
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Figure 6 Mean Circumferential Extent of Wall Thinning
(A) Day 7 and (B) day 28 in WT and KO mice from the base, midventricle, and apex. The circumferential extent of wall thinning in KO mice is significantly reduced relative to WT mice at both days 7 and 28 after MI at all levels. Error bars represent SEM. *p < 0.05 versus WT. Abbreviations as in Figure 2.
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Figure 7 Plots of End-Systolic Ecc Over Time Reveal Differences in Some Borderzone and Remote Regions
(A) Recovery of function in the borderzone midventricular anterior septum is observed at day 7 in KO versus WT mice. (B) A similar result is seen in the apical anterior septum. (C) On day 7, hypercontractility is seen in the remote midventricular septum of KO mice that resolves by day 28 after infarction. Error bars represent SEM. *p < 0.05 versus WT. Ecc = circumferential strain; other abbreviations as in Figure 2.
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