Osteopontin as a novel prognostic marker in stable ischaemic heart disease: a 3-year follow-up study.

OBJECTIVES: Osteopontin (OPN) is a glycoprotein, which may play a major role in the regulation of biological phenomena. Increased levels of OPN have been linked to the presence and to the severity of atherosclerosis. This study was undertaken to assess the prognostic significance of plasma OPN levels in patients with stable ischaemic heart disease (IHD). METHODS: In 101 patients with stable IHD and angiographically documented significant coronary artery stenosis, plasma OPN levels were measured at baseline (time of coronary arteriography). Patients were prospectively followed for a median time of 3 years (minimum 2.25, maximum 3.9 years). The primary study endpoint was the composite of cardiovascular death, non-fatal myocardial infarction, need for revascularization and hospitalization for cardiovascular reasons. RESULTS: Baseline lnOPN levels were directly related to age (r = 0.27, P < 0.001) and inversely to left ventricular ejection fraction (r = -0.32, P < 0.01). Left ventricular ejection fraction was an independent predictor of plasma OPN levels after adjustment for age and gender (beta = -0.013, P = 0.02). Median OPN value was 55 ng mL(-1). In the univariate Cox-regression analysis, OPN levels > 55 ng mL(-1) (n = 50) were significantly related to adverse cardiac outcome (HR = 2.40, 95% CI: 1.11-5.23, P = 0.027). In multivariate model, OPN levels > 55 ng mL(-1) remained statistically significant independent predictor of adverse outcome after adjustment for age, gender, left ventricular ejection fraction and the number of diseased coronary arteries (HR = 2.88, 95% CI: 1.09-7.58, P = 0.032). CONCLUSION: OPN may provide significant prognostic information independent of other traditional prognostic markers in patients with stable IHD.

Design and synthesis of nitrate esters of aromatic heterocyclic compounds as pharmacological preconditioning agents.

Ischemic preconditioning (IPC) constitutes an endogenous protective mechanism in which one or more brief periods of myocardial ischemia and reperfusion render the myocardium resistant to a subsequent more-sustained ischemic insult. Pharmacological preconditioning represents an ideal alternative of IPC. We now describe the design and synthesis of indole, quinoline, and purine systems with an attached pharmacophoric nitrate ester group. The indole and quinoline derivatives 4 and 5 possess structural features of the nitrate containing K(ATP) channel openers. Purine analogues 11 and 12, substituted at the position 6 by a piperidine moiety and at position 9 by an alkyl nitrate, could combine the effects of the nitrate containing K(ATP) channel openers and those of adenosine. Compound 13 bears the nicotinamide moiety of nicorandil instead of nitrate ester. Compounds 4, 5, and 11 reduced infarction and the levels of malondialdehyde (MDA) at reperfusion in anesthetized rabbits. Compounds 12 and 13 did not significantly reduce the infarct size. Analogues 4 and 5 increased cGMP and MDA during ischemia, while combined analogue 4 and mitoK(ATP) blocker 5-hydroxydecanoic acid (5-HD) abrogated this benefit suggesting an action through mitoK(ATP) channel opening. Treatment with derivative 11 combined with 5-HD as well as treatment with 11 and adenosine receptor blocker 8-(p-sulfophenyl)theophylline (SPT) did not abrogate cardioprotection. Compound 11 is a lead molecule for the synthesis of novel analogues possessing a dual mode of action through cGMP-mitoK(ATP) channel opening-free radicals and through adenosine receptors.