title: Endomyocardial nitric oxide synthase and left ventricular preload reserve in dilated cardiomyopathy.
abstract: BACKGROUND
  Patients with heart failure have modified myocardial expression of nitric oxide synthase (NOS), as is evident from induction of calcium-insensitive NOS isoforms. The functional significance of this modified NOS gene expression for left ventricular (LV) contractile performance was investigated in patients with dilated nonischemic cardiomyopathy.
  
  
  RESULTS
  In patients with dilated, nonischemic cardiomyopathy, invasive measures of LV contractile performance were derived from LV microtip pressure recordings and angiograms and correlated with intensity of gene expression of inducible (NOS2) and constitutive (NOS3) NOS isoforms in simultaneously procured LV endomyocardial biopsies (n=20). LV endomyocardial expression 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 endothelial release of NO) was infused intracoronarily (n=12). In patients with elevated LV end-diastolic pressure, an intracoronary infusion of substance P increased LV stroke volume from 72+/-13 to 91+/-16 mL (P=0.06) and LV stroke work from 67+/-11 to 90+/-15 g. m (P=0.03) and shifted the LV end-diastolic pressure-volume relation to the right.
  
  
  CONCLUSIONS
  In patients with dilated cardiomyopathy, an increase in endomyocardial NOS2 or NOS3 gene expression augments LV stroke volume and LV stroke work because of a NO-mediated rightward shift of the diastolic LV pressure-volume relation and a concomitant increase in LV preload reserve.
authors.affiliation: Cardiovascular Center, O.L.V. Ziekenhuis, Aalst, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Heymes
authors.forename: M
authors.initials: M
authors.lastname: Vanderheyden
authors.forename: J G
authors.initials: JG
authors.lastname: Bronzwaer
authors.forename: A M
authors.initials: AM
authors.lastname: Shah
authors.forename: W J
authors.initials: WJ
authors.lastname: Paulus
mesh_terms: D000328:Adult; D000368:Aged; D006328:Cardiac Catheterization; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*; D017023:Coronary Angiography; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013318:Stroke Volume / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D013373:Substance P; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III