Endothelial nitric oxide synthase limits left ventricular remodeling aftermyocardial infarction in mice

Background-To investigate the role of endothelial nitric oxide synthase (NO S3) in left ventricular (LV) remodeling after myocardial infarction (MI), t he impact of left anterior descending coronary artery ligation on IV size a nd function was compared in 2- to 4-month-old wild-type (WT) and NOS3-defic ient mice (NOS3(-/-)). Methods and Results-Two days after MI, both strains of mice had a similar L V size, fractional shortening, and ejection fraction by echocardiography. T wenty-eight days after MI, both strains had dilated LVs with decreased frac tional shortening and lower ejection fractions. Although the infarcted frac tion of the LV was similar in both strains, LV end-diastolic internal diame ter, end-diastolic volume, and mass were greater, but fractional shortening , ejection fraction, and the maximum rate of developed LV pressure (dP/dt(m ax)) were lower in NOS3(-/-) than in WT mice. Impairment of diastolic funct ion, as measured by the time constant of isovolumic relaxation (tau) and th e maximum rate of LV pressure decay (dP/dt(min)), was more marked in NOS3(- /-) than in WT mice. Mortality after MI was greater in NOS3(-/-) than in WT mice. Long-term administration of hydralazine normalized blood pressure in NOS3(-/-) mice, but it did not prevent the IV dilatation, impaired systoli c and diastolic function, and increased LV mass that followed MI. In WT mic e, capillary density and myocyte width in the nonischemic portion of the IV did not differ before and 28 days after MI, whereas in NOS3(-/-) mice, cap illary density decreased and myocyte width increased after MI, whether or n ot hydralazine was administered. Conclusions-These results suggest that the presence of NOS3 limits LV dysfu nction and remodeling in a murine model of MI by an afterload-independent m echanism, in part by decreasing myocyte hypertrophy in the remote myocardiu m.