In heart failure patients, inflammation and norepinephrine can increase expression of myocardial inducible nitric oxide synthase (iNOS). This can depress myocardial contractility.

Myocardial contractility improves in patients with dilated cardiomyopathy who receive long-term therapy with the beta-blocker carvedilol. However, there have been no in vivo examinations of the impact of carvedilol on expression of iNOS, and no studies of nitric oxide-dependent beta-adrenergic inotropic responsiveness.

Dr. Tang and colleagues hypothesized that the suppression of myocardial iNOS expression is what leads to the recovery of myocardial contractility that occurs after patients start chronic beta-blocker therapy. To evaluate this, they measured myocardial iNOS mRNA gene expression, and augmentation of left ventricular contractility following dobutamine infusion during iNOS blockade.

The study included stable heart failure patients with left ventricular ejection fraction of less than 45% and NYHA functional class II-III. There were 20 carvedilol patients in this study. All underwent a biopsy protocol during right heart catheterization. Twelve of these patients also underwent a hemodynamic protocol to determine contractile response. Controls included stored biopsy specimens from 17 beta-blocker naïve patients. In addition, 5 beta-blocker naïve subjects underwent both biopsy and hemodynamic protocols.

Baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were slightly higher in the carvedilol group. The carvedilol group also had higher mean left ventricular ejection fraction. However, ejection fraction before carvedilol was similar to the control group.

Myocardial IL-6, BNP and mRNA gene expression of iNOS were all lower in the carvedilol group. However, the difference was statistically significant only for IL-6.

There was a direct correlation between myocardial iNOS and IL-6 mRNA expression. This suggested that there is an association between inflammation and myocardial iNOS expression in heart failure.

There were 18 patients in the study that had follow-up echocardiography 6 months after cardiac catheterization. In those patients, there was an association between higher myocardial iNOS levels and greater improvements in left ventricular contractility after initiation of carvedilol.

In the control patients, there was an augmentation of left ventricular contractility of about 40%. The mean augmentation was only 4% in the carvedilol patients. This suggests that carvedilol therapy is associated with less functional iNOS activity available to impair LV contractility

This study has several important limitations. Because of its case-control design, investigators cannot demonstrate causality. The small sample size limits the ability to confirm that differences are statistically significant. Finally, the determination of heart failure severity was subjective.

However, these data do suggest that carvedilol may modulate a contractile regulatory pathway that is inflammatory-mediated and iNOS-dependent. If so, carvedilol may act on specific targets in the pathway, or may modulate upstream processes, such as ischemia.

In a confirmatory study, Dr. Tang and co-investigators will measure sequential plasma levels of nitric oxide-dependent oxidant stress markers, such as nitrotyrosine. They will measure these stress markers in a larger group of patients, both before and after beta-blocker therapy.