Urinary Excretion of Sulfur Metabolites and Risk of Cardiovascular Events and All-Cause Mortality in the General Population.

Aims: Thiosulfate and sulfate are metabolites of hydrogen sulfide (H2S), a gaseous signaling molecule with cardiovascular (CV) protective properties. Urinary thiosulfate excretion and sulfate excretion are associated with favorable disease outcome in high-risk patient groups. We investigated the relationship between urinary excretion of sulfur metabolites, and risk of CV events and all-cause mortality in the general population. Results: Subjects (n = 6839) of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study were followed prospectively. At baseline, 24-h urinary excretion of thiosulfate and sulfate was determined. Median urinary thiosulfate and sulfate excretion values were 1.27 (interquartile range [IQR] 0.89-2.37) µmol/24 h and 15.7 (IQR 12.0-20.3) mmol/24 h, respectively. Neither thiosulfate nor sulfate excretion showed an independent association with risk of CV events. Sulfate, but not thiosulfate, was inversely associated with risk of all-cause mortality, independent of potential confounders (hazard ratio 0.73 [95% confidence interval 0.63-0.84], p < 0.001). This association appeared most pronounced for normolipidemic subjects (pinteraction = 0.019). Innovation: The strong association between sulfate excretion and mortality in the general population emphasizes the (patho)physiological importance of sulfate or its precursor H2S. Conclusion: We hypothesize that urinary sulfate excretion, which is inversely associated with all-cause mortality in the general population, holds clinical relevance as a beneficial modulator in health and disease. Antioxid. Redox Signal. 30, 1999-2010.

Serum free thiols in chronic heart failure.

Oxidative stress is a key element of the pathophysiology of heart failure (HF). As free thiols are readily oxidized by reactive oxygen and sulfur species, their circulating level may directly reflect the systemic redox status. This study addresses the role of serum free thiols in chronic HF, which is of particular interest as free thiols are amenable to therapeutic modulation and thus are a potential target for therapy. Free thiols were measured in serum of 101 previously characterized stable chronic HF patients (93% male, age 63.7±10.0y, left ventricular ejection fraction 34.6±8.2%), adjusted for total serum protein, and subsequently analysed for associations with clinical and outcome parameters. The mean serum free thiol concentration was 3.6±0.5µM/g protein. Patients with above-average levels were younger, had better renal function, lower levels of NT-proBNP and PTH, and higher levels of cholesterol. Furthermore, above-average levels were associated with favourable disease outcome, i.e. a decreased rehospitalisation rate and increased patient survival (HR 0.27 (95% CI 0.11-0.62), P=0.002) independent of associated clinical parameters, age and PTH. After adjustment for cholesterol or established prognostic factors in HF, eGFR and NT-proBNP the association was no longer significant, suggesting involvement of these variables in a common pathophysiological pathway. This exploratory study demonstrates favourable associations of serum free thiols with markers of HF severity and prognosis as well as disease outcome, which should be further investigated in larger prospective studies. Restoring redox status by therapeutic modulation of free thiols may be a promising strategy to improve disease outcome in CHF.