Hemodynamic effects of inducible nitric oxide synthase and nitrotyrosine generation in heart failure

Abstract 

Objectives

The hemodynamic effects of cardiac inducible nitric oxide synthase (iNOS) and of iNOS-mediated peroxynitrite in patients with left ventricular (LV) dysfunction are unclear. The present study investigates the incidence and functional significance of iNOS expression and nitrotyrosine formation in patients with heart failure.

Methods

LV endomyocardial biopsies obtained from 24 patients with heart failure due to idiopathic dilated cardiomyopathy (ejection fraction [EF] <45% and left ventricular end-diastolic volume index [LVEDVI] >102 ml/m²) were analyzed for iNOS and nitrotyrosine. LV contractile performance was assessed by left ventricular ejection fraction (LVEF) and stroke work normalized for end-diastolic pressure (SW/EDP). LV filling pattern was assessed by Doppler E/A wave ratio, deceleration time (DT) of early LV filling and indexed LV end-diastolic volume normalized for EDP as a marker of diastolic distensibility.

Results

iNOS immunostaining correlated significantly with nitrotyrosine formation (r = 0.86, p < 0.001). In the whole study group, patients expressing iNOS (n = 13) showed larger LV end-diastolic (173 ± 16 vs 128 ± 9 ml/m², p = 0.031) and end-systolic volume indices (110 ± 16 vs 61 ± 9 ml/m², p = 0.018) and similar LVEDP (18 ± 2 vs 21 ± 2 mm Hg, p = 0.227). In patients with advanced heart failure and reduced pre-load reserve (LVEDP > 16 mm Hg, n = 18), iNOS protein and nitrotyrosine formation correlated positively with LVSW/EDP (r = 0.65, p = 0.03 and r = 0.64, p = 0.04, respectively), DT (r = 0.96, p < 0.01 and r = 0.88, p < 0.01, respectively) and inversely with E/A (r = −0.82, p < 0.01 and r = −0.88, p < 0.01, respectively). In addition, nitrotyrosine formation correlated positively with LVEDVI/EDP (r = 0.64, p = 0.02). Advanced iNOS-positive heart failure patients had a higher LVEDVI/EDP compared with iNOS-negative patients (5.30 ± 0.64 vs 3.13 ± 0.34 ml/mm Hg · m², p = 0.02).

Conclusions

In heart failure, iNOS protein expression is associated with nitrotyrosine formation. Although iNOS-positive patients are generally characterized by larger LV volume and depressed function, the preserved NO generation appears to be associated with higher cardiac work due to the preserved Frank-Starling relationship in end-stage heart failure.