733-4 Induction of Inducible Nitric Oxide Synthase (iNOS) mRNA and Protein in the Human Cardiac Allograft is Associated with Increased Myocardial cGMP Levels and Echocardiographic LV Dysfunction

Abstract

In humans the mechanisms underlying LV contractile dysfunction following cardiac transplantation remain poorly defined. iNOS is expressed in the rat heterotopic cardiac allograft during rejection; the resultant overproduction of nitric oxide (NO) might contribute to cardiac contractile dysfunction via cGMP-mediated negative inotropic actions, or by the cytotoxic actions of NO. We therefore prospectively studied 16 patients at surveillance endomyocardial biopsy during the first year posttransplant — a total of 123 biopsies (4–12 sequential per patient). iNOS mRNA was detected by reverse transcription PCR in biopsy allograft myocardium in every patient, and in 59/123 (48%) biopsies overall. iNOS mRNA expression was episodic and time dependent; expression was most frequent during the first 180 days posttransplant (p = 0.0006). iNOS expression was not related to the ISHLT histologic grade of rejection. iNOS protein was detected by immunofluorescence in the coronary microvasculature and in cardiac myocytes; expression was associated with increased myocardial cGMP levels (p = 0.01) and with systolic (p = 0.024) and diastolic (p = 0.006) left ventricular contractile dysfunction measured by echocardiography and Doppler. These data support a causal relationship between iNOS expression and myocardial contractile dysfunction in the human cardiac allograft.