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Increased Plasma S-Nitrosothiol Concentrations Predict Cardiovascular Outcomes among Patients with End-Stage Renal Disease: A Prospective Study

Ziad A. Massy^*,, Christine Fumeron, Didier Borderie, Philippe Tuppin^||, Thao Nguyen-Khoa^*,¶, Marie-Odile Benoit^#, Christian Jacquot^**, Claude Buisson, Tilman B. Drüeke^*, Ohvanesse G. Ekindjian, Bernard Lacour^¶ and Marie-Christine Iliou

*INSERM U507, Necker Hospital, Paris, France; Divisions of Clinical Pharmacology and Nephrology, Faculty of Pharmacy, University of Picardie and Centre Hospitalier Universitaire Amiens, Amiens, France; Hemodialysis Unit, Association pour L’Utilisation du Rein Artificiel, Paris, France; Biochemistry Laboratory A, Cochin Hospital, Paris, France; ^||French Transplantation Agency, Paris, France; ^¶Biochemistry Laboratory A, Necker Hospital, Paris, France; ^#Biochemistry Laboratory and **Division of Nephrology, Hopita Européen - Goerges Pompidou, Paris, France; and Cardiac Rehabilitation Centre, Broussais Hospital, Paris, France.

Correspondence to Dr. Ziad A. Massy, INSERM U507, Necker Hospital, 161, rue de Sèvres, 75015, Paris, France. Phone: +33-1-4449-5234; Fax: +33-1-4566-5133; E-mail: massy{at}necker.fr

ABSTRACT. The plasma concentrations of S-nitrosothiols, which are circulating nitric oxide metabolites with potential biologic activity, are increased among patients undergoing chronic hemodialysis (HD). However, the ability of S-nitrosothiols to release nitric oxide at physiologically relevant sites may be reduced among HD patients, because of impaired availability and/or activity of factors involved in S-nitrosothiol breakdown. The resultant lack of S-nitrosothiol bioavailability could contribute to the high cardiovascular risk for such patients. A possible relationship between plasma S-nitrosothiol levels and cardiac outcomes, as well as all-cause mortality rates, was investigated in a cohort of 250 chronic HD patients and who were undergoing regular dialysis three times per week were monitored for 1 yr. During that follow-up period, major cardiac events and all-cause deaths were prospectively recorded. At baseline, high plasma S-nitrosothiol levels (>2 µM, corresponding to the top quartile of all measured values) were independently associated with pulse pressure in an adjusted multivariate analysis (odds ratio, 1.03; 95% confidence interval, 1.01 to 1.05; P = 0.007). During the follow-up period, 36 patients died (16 as a result of cardiac causes) and 33 patients experienced major adverse cardiac events. In an adjusted Cox proportional-hazards model, high plasma S-nitrosothiol concentrations (i.e., the top quartile versus the three other quartiles) were an independent predictor of cardiac events (hazard ratio, 3.30; 95% confidence interval, 1.61 to 6.76; P = 0.001) but not of all-cause death. Therefore, among chronic HD patients, markedly elevated plasma S-nitrosothiol levels are associated with pulse pressure and predict cardiovascular outcomes. These findings support the hypothesis that impaired S-nitrosothiol bioavailability in uremia is an important factor for the excessive cardiovascular risk among HD patients.

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