Endomyocardial nitric oxide synthase and left ventricular preload reserve in dilated cardiomyopathy

Background-Patients with heart failure have modified myocardial expression of nitric oxide synthase (NOS), as is evident from induction of calcium-ins ensitive NOS isoforms. The functional significance of this modified NOS gen e expression for left ventricular (LV) contractile performance was investig ated in patients with dilated nonischemic cardiomyopathy. Methods and Results-In patients with dilated, nonischemic cardiomyopathy. i nvasive measures of LV contractile performance were derived from LV microti p pressure recordings and angiograms and correlated with intensity of gene expression of inducible (NOS2) and constitutive (NOS3) NOS isoforms in simu ltaneously procured LV endomyocardial biopsies (n=20). LV endomyocardial ex pression of NOS2 was linearly correlated with LV stroke Volume (P=0.001; r= 0.66), LV ejection fraction (P=0.007; r=0.58), and LV stroke work (P=0.003; r=0.62), In patients with elevated LV end-diastolic pressure (>16 mm Hg), a closer correlation was observed between endomyocardial expression of NOS2 and LV stroke volume (P=0.001; r=0.74), LV ejection fraction (P=0.0007; r= 0.77), and LV stroke work (r=0.82; P=0.0002). LV endomyocardial expression of NOS3 was linearly correlated with LV stroke Volume (P=0.01; r=0.53) and LV stroke work (P=0.01; r=0.52). To establish the role of nitric oxide (NO) as a mediator of the observed correlations, substance P (which causes endo thelial release of NO) was infused intracoronarily (n = 12). In patients wi th elevated LV end-diastolic pressure, an intracoronary infusion of substan ce P increased LV stroke volume from 72+/-13 to 91+/-16 mt (P=0.06) and LV stroke work from 67+/-11 to 90+/-15 g.m (P=0.03) and shifted the LV end-dia stolic pressure-volume relation to the right. Conclusions-In patients with dilated cardiomyopathy, an increase in endomyo cardial NOS2 or NOS3 gene expression augments LV stroke volume and LV strok e work because of a NO-mediated rightward shift of the diastolic LV pressur e-volume relation and a concomitant increase in LV preload reserve.