Associations of systemic oxidative stress with functional outcomes after ST-segment elevation myocardial infarction

BackgroundIschemia-reperfusion is accompanied by oxidative stress. Serum free thiols (FTs; sulfhydryl groups) reliably reflect systemic oxidative stress. This study evaluates longitudinal changes in FTs and their associations with outcomes after ST-segment elevation myocardial infarction (STEMI).MethodsFTs were detected in archived serum samples from 378 participants of a neutral randomized trial on metformin therapy after STEMI. FT levels were determined at presentation with STEMI and at 24 h, 2 weeks, 4 months and 1 year thereafter. Outcomes included infarct size and left ventricular ejection fraction (LVEF), both determined with cardiac magnetic resonance imaging after 4 months, and 5-year major adverse cardiovascular events (MACE).ResultsSerum FT concentrations at presentation and at 24 h were 356 ± 91 and 353 ± 76 μmol/L, respectively. The change in FTs between presentation and 24 h (ΔFTs) was associated with outcomes in age- and sex-adjusted analysis (per 100 μmol/L FT increase, β = −0.87 for infarct size, 95%-confidence interval (CI): −1.75 to −0.001, P = 0.050; β = 1.31, 95%-CI: 0.37 to 2.25 for LVEF, P = 0.007). Associations between ΔFTs and LVEF were markedly stronger in patients with Thrombolysis in Myocardial Infarction flow of 0 or 1 before percutaneous coronary intervention (PCI)(β = 2.73, 95%-CI: 0.68 to 4.77, P = 0.009). Declining FTs during the first 24 h might be associated with higher incidence of 5-year MACE (P = 0.09).ConclusionsChanges in oxidative stress early post-PCI may predict functional outcomes after STEMI. Our findings warrant validation in larger cohorts, and then may be used as rationale for development of thiol-targeted therapy in ischemic heart disease

Associations of systemic oxidative stress with functional outcomes after ST-segment elevation myocardial infarction

BackgroundIschemia-reperfusion is accompanied by oxidative stress. Serum free thiols (FTs; sulfhydryl groups) reliably reflect systemic oxidative stress. This study evaluates longitudinal changes in FTs and their associations with outcomes after ST-segment elevation myocardial infarction (STEMI).MethodsFTs were detected in archived serum samples from 378 participants of a neutral randomized trial on metformin therapy after STEMI. FT levels were determined at presentation with STEMI and at 24 h, 2 weeks, 4 months and 1 year thereafter. Outcomes included infarct size and left ventricular ejection fraction (LVEF), both determined with cardiac magnetic resonance imaging after 4 months, and 5-year major adverse cardiovascular events (MACE).ResultsSerum FT concentrations at presentation and at 24 h were 356 ± 91 and 353 ± 76 μmol/L, respectively. The change in FTs between presentation and 24 h (ΔFTs) was associated with outcomes in age- and sex-adjusted analysis (per 100 μmol/L FT increase, β = −0.87 for infarct size, 95%-confidence interval (CI): −1.75 to −0.001, P = 0.050; β = 1.31, 95%-CI: 0.37 to 2.25 for LVEF, P = 0.007). Associations between ΔFTs and LVEF were markedly stronger in patients with Thrombolysis in Myocardial Infarction flow of 0 or 1 before percutaneous coronary intervention (PCI)(β = 2.73, 95%-CI: 0.68 to 4.77, P = 0.009). Declining FTs during the first 24 h might be associated with higher incidence of 5-year MACE (P = 0.09).ConclusionsChanges in oxidative stress early post-PCI may predict functional outcomes after STEMI. Our findings warrant validation in larger cohorts, and then may be used as rationale for development of thiol-targeted therapy in ischemic heart disease

Associations of systemic oxidative stress with functional outcomes after ST-segment elevation myocardial infarction

BackgroundIschemia-reperfusion is accompanied by oxidative stress. Serum free thiols (FTs; sulfhydryl groups) reliably reflect systemic oxidative stress. This study evaluates longitudinal changes in FTs and their associations with outcomes after ST-segment elevation myocardial infarction (STEMI).MethodsFTs were detected in archived serum samples from 378 participants of a neutral randomized trial on metformin therapy after STEMI. FT levels were determined at presentation with STEMI and at 24 h, 2 weeks, 4 months and 1 year thereafter. Outcomes included infarct size and left ventricular ejection fraction (LVEF), both determined with cardiac magnetic resonance imaging after 4 months, and 5-year major adverse cardiovascular events (MACE).ResultsSerum FT concentrations at presentation and at 24 h were 356 ± 91 and 353 ± 76 μmol/L, respectively. The change in FTs between presentation and 24 h (ΔFTs) was associated with outcomes in age- and sex-adjusted analysis (per 100 μmol/L FT increase, β = −0.87 for infarct size, 95%-confidence interval (CI): −1.75 to −0.001, P = 0.050; β = 1.31, 95%-CI: 0.37 to 2.25 for LVEF, P = 0.007). Associations between ΔFTs and LVEF were markedly stronger in patients with Thrombolysis in Myocardial Infarction flow of 0 or 1 before percutaneous coronary intervention (PCI)(β = 2.73, 95%-CI: 0.68 to 4.77, P = 0.009). Declining FTs during the first 24 h might be associated with higher incidence of 5-year MACE (P = 0.09).ConclusionsChanges in oxidative stress early post-PCI may predict functional outcomes after STEMI. Our findings warrant validation in larger cohorts, and then may be used as rationale for development of thiol-targeted therapy in ischemic heart disease

Safety and Tolerability of Sodium Thiosulfate in Patients with an Acute Coronary Syndrome Undergoing Coronary Angiography:A Dose-Escalation Safety Pilot Study (SAFE-ACS)

Background. In animal studies, hydrogen sulfide (H2S) has been shown to protect the heart from ischemia-reperfusion injury. This study evaluates the safety and tolerability of the H2S donor sodium thiosulfate (STS) in patients with acute coronary syndrome (ACS). Methods. Eighteen patients, undergoing coronary angiography for ACS, received STS intravenously immediately after arrival at the catheterization laboratory according to a “3 + 3 dose-escalation design” with fixed dosing endpoint (0, 2.5, 5, 10, 12.5, and 15 grams). This first dose STS was combined with verapamil and nitroglycerin required for transradial procedures. A second dose STS was administered 6 hours later. Primary endpoint was dose-limiting toxicity, defined as significant hemodynamic instability or death up to 24 hours or before discharge from the coronary care unit. Secondary outcomes included the occurrence of anaphylaxis, nausea, vomiting, and systolic blood pressure (SBP) course. Results. Sixteen patients received two dosages of STS and two patients one dosage. None of the patients reached the primary endpoint, nor experienced a serious adverse event. We observed a clinically well-tolerated decline in SBP 1 hour after administration of the first STS dose and concomitant verapamil/nitroglycerin. SBP for all patients together reduced 16.8 (8.1–25.5) mmHg (P=0.0008). No significant decline in SBP occurred after the second dose. Mild nausea was observed in one patient. Conclusion. This is the first report on sodium thiosulfate administration in patients with acute coronary syndromes. Our data suggest that sodium thiosulfate was well tolerated in this setting. The potential benefit of this intervention has to be examined in larger studies

Genetic Determinants of Serum Calcification Propensity and Cardiovascular Outcomes in the General Population

BACKGROUND: Serum calciprotein particle maturation time (T(50)), a measure of vascular calcification propensity, is associated with cardiovascular morbidity and mortality. We aimed to identify genetic loci associated with serum T(50) and study their association with cardiovascular disease and mortality. METHODS: We performed a genome-wide association study of serum T(50) in 2,739 individuals of European descent participating in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, followed by a two-sample Mendelian randomization (MR) study to examine causal effects of T(50) on cardiovascular outcomes. Finally, we examined associations between T(50) loci and cardiovascular outcomes in 8,566 community-dwelling participants in the Rotterdam study. RESULTS: We identified three independent genome-wide significant single nucleotide polymorphism (SNPs) in the AHSG gene encoding fetuin-A: rs4917 (p = 1.72 × 10(−101)), rs2077119 (p = 3.34 × 10(−18)), and rs9870756 (p = 3.10 × 10(−8)), together explaining 18.3% of variation in serum T(50). MR did not demonstrate a causal effect of T(50) on cardiovascular outcomes in the general population. Patient-level analyses revealed that the minor allele of rs9870756, which explained 9.1% of variation in T(50), was associated with a primary composite endpoint of all-cause mortality or cardiovascular disease [odds ratio (95% CI) 1.14 (1.01–1.28)] and all-cause mortality alone [1.14 (1.00–1.31)]. The other variants were not associated with clinical outcomes. In patients with type 2 diabetes or chronic kidney disease, the association between rs9870756 and the primary composite endpoint was stronger [OR 1.40 (1.06–1.84), relative excess risk due to interaction 0.54 (0.01–1.08)]. CONCLUSIONS: We identified three SNPs in the AHSG gene that explained 18.3% of variability in serum T(50) levels. Only one SNP was associated with cardiovascular outcomes, particularly in individuals with type 2 diabetes or chronic kidney disease

Evaluation of the 2021 ESC recommendations for family screening in hereditary transthyretin cardiac amyloidosis

AIMS: The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement.METHODS AND RESULTS: We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%.CONCLUSIONS: Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common.</p

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinant

Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk

Proteomic study uncovers molecular principles of single-cell-level phenotypic heterogeneity in lipid storage of Nannochloropsis oceanica

Abstract Background Nannochloropsis oceanica belongs to a large group of photoautotrophic eukaryotic organisms that play important roles in fixation and cycling of atmospheric CO2. Its capability of storing solar energy and carbon dioxide in the form of triacylglycerol (TAG) of up to 60% of total weight under nitrogen deprivation stress sparked interest in its use for biofuel production. Phenotypes varying in lipid accumulation among an N. oceanica population can be disclosed by single-cell analysis/sorting using fluorescence-activated cell sorting (FACS); yet the phenomenon of single cell heterogeneity in an algae population remains to be fully understood at the molecular level. In this study, combination of FACS and proteomics was used for identification, quantification and differentiation of these heterogeneities on the molecular level. Results For N. oceanica cultivated under nitrogen deplete (−N) and replete (+N) conditions, two groups differing in lipid content were distinguished. These differentiations could be recognized on the population as well as the single-cell levels; proteomics uncovered alterations in carbon fixation and flux, photosynthetic machinery, lipid storage and turnover in the populations. Although heterogeneity patterns have been affected by nitrogen supply and cultivation conditions of the N. oceanica populations, differentiation itself seems to be very robust against these factors: cultivation under +N, −N, in shaker bottles, and in a photo-bioreactor all split into two subpopulations. Intriguingly, population heterogeneity resumed after subpopulations were separately recultivated for a second round, refuting the possible development of genetic heterogeneity in the course of sorting and cultivation. Conclusions This work illustrates for the first time the feasibility of combining FACS and (prote)-omics for mechanistic understanding of phenotypic heterogeneity in lipid-producing microalgae. Such combinatorial method can facilitate molecular breeding and design of bioprocesses

Subsequent Event Risk in Individuals with Established Coronary Heart Disease:Design and Rationale of the GENIUS-CHD Consortium

BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators