We previously described increased levels of growth and differentiation factor 15 (GDF-15) in skeletal muscle and serum of patients with mitochondrial diseases. Here we evaluated GDF-15 as a biomarker for mitochondrial diseases affecting children and compared it to fibroblast-growth factor 21 (FGF-21). To investigate the mechanism of GDF-15 induction in these pathologies we measured its expression and secretion in response to mitochondrial dysfunction. We analysed 59 serum samples from 48 children with mitochondrial disease, 19 samples from children with other neuromuscular diseases and 33 samples from aged-matched healthy children. GDF-15 and FGF-21 circulating levels were determined by ELISA. Our results showed that in children with mitochondrial diseases GDF-15 levels were on average increased by 11-fold (mean 4046pg/ml, 1492 SEM) relative to healthy (350, 21) and myopathic (350, 32) controls. The area under the curve for the receiver-operating-characteristic curve for GDF-15 was 0.82 indicating that it has a good discriminatory power. The overall sensitivity and specificity of GDF-15 for a cut-off value of 550pg/mL was 67.8% (54.4%-79.4%) and 92.3% (81.5%-97.9%), respectively. We found that elevated levels of GDF-15 and or FGF-21 correctly identified a larger proportion of patients than elevated levels of GDF-15 or FGF-21 alone. GDF-15, as well as FGF-21, mRNA expression and protein secretion, were significantly induced after treatment of myotubes with oligomycin and that levels of expression of both factors significantly correlated. Our data indicate that GDF-15 is a valuable serum quantitative biomarker for the diagnosis of mitochondrial diseases in children and that measurement of both GDF-15 and FGF-21 improves the disease detection ability of either factor separately. Finally, we demonstrate for the first time that GDF-15 is produced by skeletal muscle cells in response to mitochondrial dysfunction and that its levels correlate in vitro with FGF-21 levels.

Diurnal rhythms influence cardiovascular physiology, i.e. heart rate and blood pressure, and they appear to also modulate the incidence of serious adverse cardiac events. Diurnal variations occur also at the molecular level including changes in gene expression in the heart and blood vessels. Moreover, the risk/benefit ratio of some therapeutic strategies and the concentration of circulating cardiovascular system biomarkers may also vary across the 24‐hr light/dark cycle. Synchrony between external and internal diurnal rhythms and harmony among molecular rhythms within the cell are essential for normal organ biology. Diurnal variations in the responsiveness of the cardiovascular system to environmental stimuli are mediated by a complex interplay between extracellular (i.e. neurohumoral factors) and intracellular (i.e. specific genes that are differentially light/dark regulated) mechanisms. Neurohormones, which are particularly relevant to the cardiovascular system, such as melatonin, exhibit a diurnal variation and may play a role in the synchronization of molecular circadian clocks in the peripheral tissue and the suprachiasmatic nucleus. Moreover, mounting evidence reveals that the blood melatonin rhythm has a crucial role in several cardiovascular functions, including daily variations in blood pressure. Melatonin has antioxidant, anti‐inflammatory, chronobiotic and, possibly, epigenetic regulatory functions. This article reviews current knowledge related to the biological role of melatonin and its circadian rhythm in cardiovascular disease.

Current guideline recommendations for the use of beta-blockers after myocardial infarction without reduced ejection fraction are based on trials conducted before routine reperfusion, invasive care, complete revascularization, and contemporary pharmacologic therapies became standard practice. We conducted an open-label, randomized trial in Spain and Italy to evaluate the effect of beta-blocker therapy, as compared with no beta-blocker therapy, in patients with acute myocardial infarction (with or without ST-segment elevation) and a left ventricular ejection fraction above 40%. The primary outcome was a composite of death from any cause, reinfarction, or hospitalization for heart failure. In total, 4243 patients were randomly assigned to receive beta-blocker therapy and 4262 to receive no beta-blocker therapy; after exclusions, 8438 patients were included in the main analysis. During a median follow-up of 3.7 years, a primary-outcome event occurred in 316 patients (22.5 events per 1000 patient-years) in the beta-blocker group and in 307 patients (21.7 events per 1000 patient-years) in the no-beta-blocker group (hazard ratio, 1.04; 95% confidence interval [CI], 0.89 to 1.22; P = 0.63). Death from any cause occurred in 161 patients and 153 patients, respectively (11.2 vs. 10.5 events per 1000 patient-years; hazard ratio, 1.06; 95% CI, 0.85 to 1.33); reinfarction in 143 patients and 143 patients (10.2 vs. 10.1 events per 1000 patient-years; hazard ratio, 1.01; 95% CI, 0.80 to 1.27); and hospitalization for heart failure in 39 patients and 44 patients (2.7 vs. 3.0 events per 1000 patient-years; hazard ratio, 0.89; 95% CI, 0.58 to 1.38). No apparent between-group differences in safety outcomes were noted. Among patients discharged after invasive care for a myocardial infarction with a left ventricular ejection fraction above 40%, beta-blocker therapy appeared to have no effect on the incidence of death from any cause, reinfarction, or hospitalization for heart failure. (Funded by Centro Nacional de Investigaciones Cardiovasculares Carlos III and others; ClinicalTrials.gov number, NCT03596385; EudraCT number, 2017-002485-40.).

Introduction: There is a hyperoxidative state in sepsis. The objective of this study was to determine serum malondialdehyde (MDA) levels during the first week of follow up, whether such levels are associated with severity during the first week and whether non-surviving patients showed higher MDA levels than survivors during the first week. Methods: We performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in 328 patients (215 survivors and 113 non-survivors) with severe sepsis at days one, four and eight of diagnosis, and in 100 healthy controls. The primary endpoint was 30-day mortality and the secondary endpoint was six -month mortality. The association between continuous variables was carried out using Spearman’s rank correlation coefficient. Cox regression analysis was applied to determine the independent contribution of serum MDA levels on the prediction of 30-day and 6-month mortality. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated as measures of the clinical impact of the predictor variables. Results: We found higher serum MDA in septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001) of diagnosis than in healthy controls. Serum MDA was lower in surviving than non-surviving septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001). Serum MDA levels were positively correlated with lactic acid and SOFA during the first week. Finally, serum MDA levels were associated with 30-day mortality (HR = 1.05; 95% CI = 1.02-1.09; p = 0.005) and six-month mortality (hazard ratio (HR) = 1.05; 95% CI = 1.02-1.09; p = 0.003) after controlling for lactic acid levels, acute physiology and chronic health evaluation (APACHE)-II, diabetes mellitus, bloodstream infection and chronic renal failure. Conclusions: To our knowledge, this is the largest series providing data on the oxidative state in septic patients to date. The novel finding is that high serum MDA levels sustained throughout the first week of follow up were associated with severity and mortality in septic patients.