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Introduction: Differential expression of long non-coding RNAs (lncRNAs) is a hallmark of cardiovascular aging, cerebrovascular diseases, and neurodegenerative disorders. This research article investigates the association between a panel of lncRNAs and the risk of death and ischemic stroke in a cohort of non-institutionalized elderly subjects. Method: A total of 361 healthy individuals aged 75 years old, prospectively recruited in the Vienna Transdanube Aging (VITA) cohort, were included. Expression of lncRNAs at baseline was assessed using quantitative polymerase chain reaction PCR with pre-amplification reaction, using 18S for normalization. The primary endpoint was all-cause mortality; the secondary endpoint was the incidence of new ischemic brain lesions. Death was assessed over a 14-year follow-up, and ischemic brain lesions were evaluated by magnetic resonance imaging (MRI) over a 90-month follow-up. Ischemic brain lesions were divided into large brain infarcts (Ø≥ 1.5 cm) or lacunes (Ø< 1.5 cm) RESULTS: The primary endpoint occurred in 53.5 % of the study population. The incidence of the secondary endpoint was 16 %, with a 3.3 % being large brain infarcts, and a 12.7 % lacunes. After adjustment for potential confounders, the lncRNA H19 predicted the incidence of the primary endpoint (HR 1.194, 95 % C.I. 1.012-1.409, p = 0.036), whereas the lncRNA NKILA was associated with lacunar stroke (HR 0.571, 95 % C.I. 0.375-0.868, p = 0.006). Conclusion: In a prospective cohort of non-institutionalized elderly subjects, high levels of lncRNA H19 are associated with a higher risk of death, while low levels of lncRNA NKILA predict an increased risk of lacunar stroke.

IMPORTANCE The Global Registry of Acute Coronary Events (GRACE) risk score, a guideline-recommended risk stratification tool for patients presenting with acute coronary syndromes (ACS), does not consider the extent of myocardial injury. OBJECTIVE To assess the incremental predictive value of a modified GRACE score incorporating high-sensitivity cardiac troponin (hs-cTn) T at presentation, a surrogate of the extent of myocardial injury. DESIGN, SETTING, AND PARTICIPANTS This retrospectively designed longitudinal cohort study examined 3 independent cohorts of 9803 patients with ACS enrolled from September 2009 to December 2017; 2 ACS derivation cohorts (Heidelberg ACS cohort and Newcastle STEMI cohort) and an ACS validation cohort (SPUM-ACS study). The Heidelberg ACS cohort included 2535 and the SPUM-ACS study 4288 consecutive patients presenting with a working diagnosis of ACS. The Newcastle STEMI cohort included 2980 consecutive patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Data were analyzed from March to June 2023. EXPOSURES In-hospital, 30-day, and 1-year mortality risk estimates derived from an updated risk score that incorporates continuous hs-cTn T at presentation (modified GRACE). MAIN OUTCOMES AND MEASURES The predictive value of continuous hs-cTn T and modified GRACE risk score compared with the original GRACE risk score. Study end points were all-cause mortality during hospitalization and at 30 days and 1 year after the index event. RESULTS Of 9450 included patients, 7313 (77.4%) were male, and the mean (SD) age at presentation was 64.2 (12.6) years. Using continuous rather than binary hs-cTn T conferred improved discrimination and reclassification compared with the original GRACE score (in-hospital mortality: area under the receiver operating characteristic curve [AUC], 0.835 vs 0.741; continuous net reclassification improvement [NRI], 0.208; 30-day mortality: AUC, 0.828 vs 0.740; NRI, 0.312; 1-y

BACKGROUND Patients with acute coronary syndromes (ACS) remain at risk of cardiovascular disease (CVD) recurrences. Peripheral artery disease (PAD) may identify a very high risk (VHR) group who may derive greater benefit from intensified secondary prevention. METHODS Among ACS-patients enrolled in the prospective multi-center Special Program University Medicine (SPUM), we assessed the impact of PAD on major cardiovascular events (MACE: composite of myocardial infarction, stroke and all-cause death) and major bleeding. Multivariate analysis tested the relation of each significant variable with MACE, as well as biomarkers of inflammation and novel markers of atherogenesis. RESULTS Out of 4787 ACS patients, 6.0% (n = 285) had PAD. PAD-patients were older (p < 0.001), with established CVD and signs of increased persistent inflammation (hs-CRP; 23.6 ± 46.5 vs 10.4 ± 27.2 mg/l, p < 0.001 and sFlt-1; 1399.5 ± 1501.3 vs 1047.2 ± 1378.6 ng/l, p = 0.018). In-hospital-death (3.2% vs 1.4%, p = 0.022) and -MACE (5.6% vs 3.0%, p = 0.017) were higher in PAD-patients. MACE at 1 year (18.6% vs 7.9%,p < 0.001) remained increased even after adjustment for confounders (Adj. HR 1.53, 95% CI: 1.14-2.08, p = 0.005). Major bleeding did not differ between groups (Adj. HR 1.18; 95% CI 0.71-1.97, p = 0.512). Although PAD predicted MACE, PAD-patients were prescribed less frequently for secondary prevention at discharge. CONCLUSIONS In this real-world ACS patient cohort, concomitant PAD is a marker of VHR and is associated with increased and persistent inflammation, higher risk for MACE without an increased risk of major bleeding. Therefore, a history of PAD may be useful to identify those ACS patients at VHR who require more aggressive secondary prevention.

Aims Enhancing SIRT1 activity exerts beneficial cardiovascular effects. In diabetes, plasma SIRT1 levels are reduced. We aimed to investigate the therapeutic potential of chronic recombinant murine SIRT1 (rmSIRT1) supplementation to alleviate endothelial and vascular dysfunction in diabetic mice (db/db). Methods and results Left internal mammary arteries obtained from patients undergoing coronary artery bypass grafting with or without a diagnosis of diabetes were assayed for SIRT1 protein levels. Twelve-week-old male db/db mice and db/+ controls were treated with vehicle or rmSIRT1 intraperitoneally for 4 weeks, after which carotid artery pulse wave velocity (PWV) and energy expenditure/activity were assessed by ultrasound and metabolic cages, respectively. Aorta, carotid, and mesenteric arteries were isolated to determine endothelial and vascular function using the myograph system. Arteries obtained from diabetic patients had significantly lower levels of SIRT1 relative to non-diabetics. In line, aortic SIRT1 levels were reduced in db/db mice compared to db/+ mice, while rmSIRT1 supplementation restored SIRT1 levels. Mice receiving rmSIRT1 supplementation displayed increased physical activity and improved vascular compliance as reflected by reduced PWV and attenuated collagen deposition. Aorta of rmSIRT1-treated mice exhibited increased endothelial nitric oxide (eNOS) activity, while endothelium-dependent contractions of their carotid arteries were significantly decreased, with mesenteric resistance arteries showing preserved hyperpolarization. Ex vivo incubation with reactive oxygen species (ROS) scavenger Tiron and NADPH oxidase inhibitor apocynin revealed that rmSIRT1 leads to preserved vascular function by suppressing NADPH oxidase (NOX)-related ROS synthesis. Chronic rmSIRT1 treatment resulted in reduced expression of both NOX1 and NOX4, in line with a reduction in aortic protein carbonylation and plasma nitrotyrosine levels. Conclusions In diabetic conditions

Background Patients with ST-segment elevation typically feature total coronary occlusion (TCO) of the infarct-related artery (IRA) on angiography, which may result in worse outcomes. Yet, relying solely on electrocardiogram (ECG) findings may be misleading and those presenting with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) may have TCO as well. Herein, we aimed to delineate clinical characteristics and outcomes of patients with ACS stratified by IRA location. Methods A total of 4787 ACS patients were prospectively recruited between 2009 and 2017 in SPUM-ACS (ClinicalTrials.gov Identifier: NCT01000701). The primary endpoint was major adverse cardiovascular events (MACEs), a composite of all-cause death, non-fatal myocardial infarction and non-fatal stroke at 1 year. Multivariable-adjusted survival models were fitted using backward selection. Results A total of 4412 ACS patients were included in this analysis, 56.0% (n = 2469) ST-elevation myocardial infarction (STEMI) and 44.0% (n = 1943) NSTE-ACS. The IRA was the right coronary artery (RCA) in 33.9% (n = 1494), the left-anterior descending coronary artery (LAD) in 45.6% (n = 2013), and the left circumflex (LCx) in 20.5% (n = 905) patients. In STEMI patients, TCO (defined as TIMI 0 flow at angiography) was observed in 55% of cases with LAD, in 63% with RCA, and in 55% with LCx. In those presenting with NSTE-ACS, TCO was more frequent in those with LCx and RCA as compared to the LAD (27 and 24%, respectively, vs. 9%, P < 0.001). Among patients with NSTE-ACS, occlusion of the LCx was associated with an increased risk of MACE during 1 year after the index ACS (fully adjusted hazard ratio 1.68, 95% confidence interval 1.10–2.59, P = 0.02; reference: RCA and LAD). Features of patients with NSTE-ACS associated with TCO of the IRA included elevated lymphocyte and neutrophil counts, higher levels of high-sensitivity C reactive protein (hs-CRP) and high-sensitivity cardiac troponin T, lower eGFR, and no

Background Patients with cancer are at increased risk of venous thromboembolism (VTE) and arterial thromboembolic/thrombotic events (ATEs). Growth differentiation factor-15 (GDF-15) improves cardiovascular risk assessment, but its predictive utility in patients with cancer remains undefined. Objectives To investigate the association of GDF-15 with the risks of VTE, ATE, and mortality in patients with cancer and its predictive utility alongside established models. Methods The Vienna Cancer and Thrombosis Study (CATS)—a prospective, observational cohort study of patients with newly diagnosed or recurrent cancer—which was followed for 2 years, served as the study framework. Serum GDF-15 levels at study inclusion were measured, and any association with VTE, ATE, and death was determined using competing risk (VTE/ATE) or Cox regression (death) modeling. The added value of GDF-15 to established VTE risk prediction models was assessed using the Khorana and Vienna CATScore. Results Among 1531 included patients with cancer (median age, 62 years; 53% men), median GDF-15 levels were 1004 ng/L (IQR, 654-1750). Increasing levels of GDF-15 were associated with the increased risks of VTE, ATE, and all-cause death ([subdistribution] hazard ratio per doubling, 1.16 [95% CI, 1.03-1.32], 1.30 [95% CI, 1.11-1.53], and 1.57 [95% CI, 1.46-1.69], respectively). After adjustment for clinically relevant covariates, the association only prevailed for all-cause death (hazard ratio, 1.21; 95% CI, 1.10-1.33) and GDF-15 did not improve the performance of the Khorana or Vienna CATScore. Conclusion GDF-15 is strongly associated with survival in patients with cancer, independent of the established risk factors. While an association with ATE and VTE was identified in univariable analysis, GDF-15 was not independently associated with these outcomes and failed to improve established VTE prediction models.

Background and aims Low-density lipoprotein (LDL)-cholesterol (LDL-C) promotes atherosclerotic cardiovascular disease (ASCVD), with changes in LDL electronegativity modulating its pro-atherogenic/pro-thrombotic effects. Whether such alterations associate with adverse outcomes in patients with acute coronary syndromes (ACS), a patient population at particularly high cardiovascular risk, remains unknown. Methods This is a case-cohort study using data from a subset of 2619 ACS patients prospectively recruited at four university hospitals in Switzerland. Isolated LDL was chromatographically separated into LDL particles with increasing electronegativity (L1-L5), with the L1-L5 ratio serving as a proxy of overall LDL electronegativity. Untargeted lipidomics revealed lipid species enriched in L1 (least) vs. L5 (most electronegative subfraction). Patients were followed at 30 days and 1 year. The mortality endpoint was reviewed by an independent clinical endpoint adjudication committee. Multivariable-adjusted hazard ratios (aHR) were calculated using weighted Cox regression models. Results Changes in LDL electronegativity were associated with all-cause mortality at 30 days (aHR, 2.13, 95% CI, 1.07–4.23 per 1 SD increment in L1/L5; p=.03) and 1 year (1.84, 1.03–3.29; p=.04), with a notable association with cardiovascular mortality (2.29; 1.21–4.35; p=.01; and 1.88; 1.08–3.28; p=.03). LDL electronegativity superseded several risk factors for the prediction of 1-year death, including LDL-C, and conferred improved discrimination when added to the updated GRACE score (area under the receiver operating characteristic curve 0.74 vs. 0.79, p=.03). Top 10 lipid species enriched in L1 vs. L5 were: cholesterol ester (CE) (18:2), CE (20:4), free fatty acid (FA) (20:4), phosphatidyl-choline (PC) (36:3), PC (34:2), PC (38:5), PC (36:4), PC (34:1), triacylglycerol (TG) (54:3), and PC (38:6) (all p < .001), with CE (18:2), CE (20:4), PC (36:3), PC (34:2), PC (38:5), PC (36:4), TG (54:3), an