Nitric oxide in the pathogenesis of cardiac disease

Abstract

Endothelial dysfunction is characterized by a vasoconstrictive and prothrombotic state in the vasculature; it plays a role in all stages of cardiac disease and is a significant independent predictor of cardiovascular outcomes. Nitric oxide (NO) performs multiple biologic activities in the endothelium, including vasodilation and antithrombotic actions. Reduced NO bioactivity is a major component of endothelial dysfunction. Impaired NO bioactivity is an important factor in the pathogenesis of atherosclerosis and in the metabolic syndrome. The functions of NO bioactivity in the heart go well beyond those in the endothelium, as all 3 NO synthase (NOS) isoforms-endothelial NOS, neuronal NOS, and inducible NOS-are expressed in cardiac myocytes and mediate systolic, diastolic, and chronotropic cardiac functions. Impairment of NO bioactivity is a pathogenic factor in various forms of cardiac disease. Although these findings support the potential use of NO-targeted therapies for treatment of cardiac disease, the complexities of the biologic actions of NO in the vasculature and heart are such that development of therapies is still largely in the preliminary stages.

Figure 1

In a study of platelets isolated from 87 patients with coronary heart disease (37 with stable angina and 50 with unstable angina or a myocardial infarction within 2 weeks), activation of the platelets with 5 μmol/L adenosine diphosphate showed that nitric oxide (NO) production was significantly lower in the platelets of patients with acute coronary syndromes compared with those with stable angina. Reproduced with permission from Freedman et al. ²⁰

Figure 2

Two brothers (Patient 1 and Patient 2) who both sustained thrombotic cardiovascular events before the age of 2 years were found to have a genetic deficiency of the plasma isoform of glutathione peroxidase (GPx‐3), whose function is to protect nitric oxide (NO) from deactivation from the lipid peroxyl radicals that inactivate NO. Exogenous administration of GPx‐3 to the plasma of the 2 brothers allowed the NO donor S‐nitroso‐N‐acetyl‐l‐cysteine to suppress platelet aggregation, while administration of the NO donor without GPx‐3 resulted in a significantly greater rate of platelet aggregation in the 2 patients, demonstrating the effect of restored NO bioactivity. *P<.05. Reproduced with permission from Freedman et al. ³²