Serum free thiols predict cardiovascular events and all-cause mortality in the general population: a prospective cohort study.

BACKGROUND: Serum free thiols (R-SH, sulfhydryl groups) reliably reflect systemic oxidative stress. Since serum free thiols are rapidly oxidized by reactive species, systemic oxidative stress is generally associated with reduced serum free thiol levels. Free thiols associate with favorable disease outcomes in many patient cohorts, and the current hypothesis is that oxidative stress might also play an important role in cardiovascular disease. In this study, we aimed to establish the role of serum free thiols in the general population by investigating their relationship with the risk of cardiovascular (CV) events and all-cause mortality. METHODS: Participants (n = 5955) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study from the general population were included. At baseline, serum levels of free thiols were quantified and adjusted to total protein levels. Protein-adjusted serum free thiol levels were studied for their associations with clinical and biochemical parameters, as well as with the risk of CV events and all-cause mortality. RESULTS: The mean protein-adjusted serum free thiol level was 5.05 ± 1.02 µmol/g of protein. Protein-adjusted serum free thiols significantly predicted the risk of CV events, even after adjustment for potential confounding factors (hazard ratio [HR] per doubling 0.68 [95% confidence interval [CI] 0.47-1.00], P = 0.048). Similarly, protein-adjusted serum free thiols were significantly predictive of the risk of all-cause mortality (HR per doubling 0.66 [95% CI 0.44-1.00], P = 0.050). Stratified analyses revealed lower HRs for subjects with a lower body mass index (BMI), without hypertension, and without diabetes. Conversely, HRs were lower in subjects with albuminuria. CONCLUSIONS: In this large population-based cohort study, serum free thiols significantly predicted the risk of CV events and all-cause mortality. Our results highlight the potential significance and clinical applicability of serum free thiols since they are amendable to therapeutic intervention.

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.

The fate of sulfate in chronic heart failure.

New leads to advance our understanding of heart failure (HF) pathophysiology are urgently needed. Previous studies have linked urinary sulfate excretion to a favorable cardiovascular risk profile. Sulfate is not only the end product of hydrogen sulfide metabolism but is also directly involved in various (patho)physiological processes, provoking scientific interest in its renal handling. This study investigates sulfate clearance in chronic HF (CHF) patients and healthy individuals and considers its relationship with disease outcome. Parameters related to renal sulfate handling were determined in and compared between 96 previously characterized CHF patients and sex-matched healthy individuals. Among patients, sulfate clearance was analyzed for associations with clinical and outcome parameters. In CHF patients, plasma sulfate concentrations are significantly higher, whereas 24-h urinary excretion, fractional excretion, and clearance of sulfate are significantly lower, compared with healthy individuals. Among patients, sulfate clearance is independently associated with diuretics use, creatinine clearance and 24-h urinary sodium excretion. Sulfate clearance is associated with favorable disease outcome [hazard ratio per SD increase 0.38 (95% confidence interval 0.23-0.63), P < 0.001]. Although significance was lost after adjustment for creatinine clearance, the decrease of sulfate clearance in patients is independent of this parameter, indicating that sulfate clearance is not merely a reflection of renal function. This exploratory study reveals aberrant sulfate clearance as a potential contributor to CHF pathophysiology, with reduced levels in patients and a positive association with favorable disease outcome. Further research is needed to unravel the nature of its involvement and to determine its potential as a biomarker and target for therapy.NEW & NOTEWORTHY Sulfate clearance is decreased in chronic heart failure patients compared with healthy individuals. Among patients, sulfate clearance is positively associated with favorable disease outcome, i.e., a decreased rehospitalization rate and increased patient survival. Hence, decreased sulfate clearance may be involved in the pathophysiology of heart failure.

Selecting heart failure patients for metabolic interventions.

INTRODUCTION: Heart failure (HF) has become the cardiovascular epidemic of the century and now imposes an immense burden on health care systems. While our understanding of the pathophysiology of HF has increased dramatically, the translation of knowledge into clinical practice has been disappointing. Metabolic dysfunction in HF has been studied for eight decades, but these efforts have not resulted in effective therapies. This paucity in clinical translation probably results from the variable contribution of metabolic dysfunction to the underlying heart disease. A major unmet need in cardiac drug development is therefore the ability to identify a homogeneous subset of patients in whom HF is driven by a specific mechanism that can be targeted. Areas covered: The available literature was evaluated to describe maladaptive metabolic perturbations that occur in failing hearts and may cause metabolic inflexibility, oxidative stress and cardiac energy depletion. Furthermore, the potential utility of various biomarkers and molecular imaging techniques to detect and quantify specific metabolic dysfunctions in HF were compared. Finally, the authors propose ways to utilize these techniques to select patients for specific metabolic interventions. Expert commentary: Metabolic dysfunction is among the most promising therapeutic targets in HF. Meticulous patient-selection with molecular imaging techniques and specific biomarkers appears indispensable for the effective translation of decades of scientific knowledge into clinical therapeutics.

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.

Hydrogen sulfide in renal physiology, disease and transplantation--the smell of renal protection.

Hydrogen sulfide (H2S), the third gasotransmitter, next to nitric oxide and carbon monoxide, is a key mediator in physiology and disease. It is involved in homeostatic functions, such as blood pressure control, electrolyte balance and apoptosis, and regulates pathological mechanisms, including oxidative stress and inflammation. Besides, it is believed to serve as an oxygen sensor under ischemic conditions. The kidney plays a decisive role in many of these processes, indicating an interplay between H2S and renal (patho)physiology. In this review we focus on the (protective) functions of H2S in the kidney. We first discuss endogenous renal H2S production and signaling and elaborate on its regulatory functions in renal physiology. Next, we present data on the role of aberrant H2S levels in the onset and progression of renal disease and suggest the use of H2S metabolites as biomarkers. Finally, we describe that exogenous H2S can protect the kidney against various forms of injury and conclude that modulation of renal H2S levels holds promise for renal patients in the future.

Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model.

PURPOSE: Earlier, we showed in acute myeloid leukemia (AML) patients that the microbiota changes dramatically during anticancer treatment, coinciding with gastrointestinal mucositis: The commensal anaerobic populations reduce in favor of potential pathogens. Therefore, interventions targeting the microbiota during mucositis might be interesting but can better be tested in animals than in vulnerable mucositis patients. Here, we aimed to study the potential microbial changes during methotrexate (MTX)-induced gastrointestinal mucositis in a well-established rat model and to study whether this model can be used for future microbial intervention studies. METHODS: After injection with MTX or saline (day 0), rats were sacrificed between days 2 and 11. Plasma citrulline level, jejunal histology, and the number and diversity of intestinal bacteria in feces (using fluorescence in situ hybridization (FISH)) were determined. RESULTS: Mucositis was most severe on day 4 when food intake, plasma citrulline, and villus length were the lowest, compared with controls (P < 0.0125). At the same time, MTX-treated rats showed an overall decrease (705-fold) in most bacteria (using a universal probe), compared with controls (P < 0.125). Reduced bacterial presence was related with the presence of diarrhea and a reduced villus length (rho = 0.38, P < 0.05). At day 4, there was an absolute and relative decrease of anaerobes (13-fold and -58 %, respectively) and streptococci (296-fold and -1 %, respectively) but a relative increase of Bacteroides (+49 %), compared with controls (P < 0.125). CONCLUSIONS: In the mucositis rat model, we found substantial decreases in the number and diversity of microbiota, resembling earlier findings in humans. The model therefore seems well suited to study the effects of different microbial interventions on mucositis, prior to performing human studies.

Sodium thiosulfate attenuates angiotensin II-induced hypertension, proteinuria and renal damage.

Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic interventions, the number of patients with end stage renal disease steadily increases. Hydrogen sulfide (H(2)S) is an endogenously produced gasotransmitter with vasodilatory, anti-inflammatory and antioxidant properties. These beneficial characteristics make H(2)S an attractive candidate for pharmacological use in hypertensive renal disease. We investigated the protective properties of H(2)S in angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with the H(2)S donor NaHS and major H(2)S metabolite sodium thiosulfate (STS) during three weeks of Ang II infusion reduced hypertension, proteinuria, oxidative stress and renal functional and structural deterioration. In an ex vivo isolated perfused kidney setup, NaHS, but not STS, reduced intrarenal pressure. The effect of NaHS could partially be explained by its activation of the ATP-sensitive potassium channels. In conclusion, treatment with H(2)S attenuates Ang II-associated functional and structural renal deterioration, suggesting that intervention in H(2)S production pathways has potential therapeutic benefit and might be a valuable addition to the already existing antihypertensive and renoprotective therapies.