No: 1903

Influence of Carvedilol Therapy on Myocardial Expression of Inducible Nitric Oxide Synthase (NOS2) and the Contractile Response to Beta-Adrenergic Inotropic Stimulation in Patients with Dilated Cardiomyopathy

Keywords: Beta-adrenergic receptor blockers, Heart failure, Nitric oxide synthase, Cytokines, Hemodynamics

Author Block: W. H. Wilson Tang, Cleveland Clinic Foundation, Cleveland, OH; Fernando Lopez, Alamo Health Associates, San Antonio, TX; Sidney T Lo, University of New South Wales, Sydney, Australia; Yin-Gail Yee, Anne Mullin, Ying Zhang, Michael B Fowler; Stanford University, Stanford, CA


Background: Norepinephrine and inflammation can cause expression of inducible nitric oxide synthase (NOS2), which can depress myocardial contractility. Long-term carvedilol therapy consistently improves myocardial contractility in patients with dilated cardiomyopathy (DCM), but its impact on NOS2 expression and nitric oxide dependent beta-adrenergic inotropic responsiveness have not been previously examined in vivo. We hypothesized that recovery of myocardial contractility following chronic beta-blocker therapy is due to suppression of myocardial NOS2 expression.

Methods: To test this hypothesis, we measured NOS2 and IL-6 expression (TaqMan RT-PCR in ng/mg tissue) in endomyocardial RV biopsy samples from 43 patients with non-ischemic DCM (EF <45%, 20 with carvedilol >3 months, 23 without carvedilol). Sequential LV ejection fraction (EF) was determined over 6 months. A subgroup of 13 patients underwent a hemodynamic protocol to evaluate contractile response (measured by the peak rate of rise of LV pressure, +dP/dt) to dobutamine stimulation under temporary intravenous pacing with or without intracoronary L-NMMA (NOS2 inhibitor) infusion.

Results: We observed a trend towards lower gene expression of myocardial NOS2 (0.32 vs 0.52 ng, p=0.10) and IL-6 (0.071 vs 0.143 ng, p=0.01) following carvedilol(vs no carvedilol). Myocardial NOS2 expression correlated with IL-6 expression (r =0.67, p<0.01) and EF improvement following carvedilol (r =0.495, p=0.03, n=19). In the hemodynamic subgroup, although the baseline dP/dt were similar (883 vs 957 mmHg/s, p=0.33), patients treated with carvedilol demonstrate less relative augmentation in peak +dP/dt (+4% versus +40%, p=NS) following L-NMMA infusion when compared to that in the non-carvedilol group, a trend consistent with lower myocardial NOS2 expression.

Conclusion: In patients with DCM, carvedilol was associated with down-regulation in myocardial NOS2 and IL-6 expression, with a reduction in NOS2-dependent beta-adrenergic inotropic responsiveness. Long-term improvement in myocardial contractility following carvedilol therapy in DCM may be in part due to modulation of an inflammatory-mediated, nitric oxide-dependent contractile regulatory mechanism.