<div><h4>High-sensitivity troponins and mortality in the general population.</h4><i>McEvoy JW, Daya N, Tang O, Fang M, ... Christenson RH, Selvin E</i><br /><b>Aims</b><br />Cardiac troponin T and I can be measured using a number of high-sensitivity (hs) assays. This study aimed to characterize correlations between four such assays and test their comparative associations with mortality.<br /><b>Methods and results</b><br />Among adults without cardiovascular disease in the 1999-2004 National Health and Nutrition Examination Survey, hs-troponin T was measured using one assay (Roche) and hs-troponin I using three assays (Abbott, Siemens, and Ortho). Cox regression was used to estimate associations with all-cause and cardiovascular mortality. Pearson\'s correlation coefficients comparing concentrations from each assay ranged from 0.53 to 0.77. There were 2188 deaths (488 cardiovascular) among 9810 participants. Each hs-troponin assay [log-transformed, per 1 standard deviation (SD)] was independently associated with all-cause mortality: hazard ratio (HR) 1.20 [95% confidence interval (CI) 1.13-1.28] for Abbott hs-troponin I; HR 1.10 (95% CI 1.02-1.18) for Siemens hs-troponin I; HR 1.23 (95% CI 1.14-1.33) for Ortho hs-troponin I; and HR 1.31 (95% CI 1.21-1.42) for Roche hs-troponin T. Each hs-troponin assay was also independently associated with cardiovascular mortality (HR 1.44 to 1.65 per 1 SD). Associations of hs-troponin T and all-cause and cardiovascular mortality remained significant after adjusting for hs-troponin I. Furthermore, associations of hs-troponin I remained significant after mutually adjusting for hs-troponin I from the other individual assays: e.g. cardiovascular mortality HR 1.46 (95% CI 1.19-1.79) for Abbott after adjustment for the Siemens assay and HR 1.29 (95% CI 1.09-1.53) for Abbott after adjustment for the Ortho assay.<br /><b>Conclusion</b><br />This study demonstrates only modest correlations between hs-troponin T and three hs-troponin I assays and that hs-troponin I assays can provide distinct risk information for mortality in the general population.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 02 Jun 2023; epub ahead of print</small></div>

<div><h4>Short-duration head-up tilt test potentiated with sublingual nitroglycerin in suspected vasovagal syncope: the fast Italian protocol.</h4><i>Russo V, Parente E, Tomaino M, Comune A, ... Golino P, Brignole M</i><br /><b>Background</b><br />The traditional nitroglycerin (NTG) head-up tilt test (HUTT) is time-consuming and the test duration is a barrier to widespread utilization in clinical practice. It was hypothesized that a short-duration protocol is not inferior to the traditional protocol regarding the positivity rate and has a similar distribution of hemodynamic response.<br /><b>Methods and results</b><br />Patients undergoing HUTT were randomized 1:1 to a 10 min passive phase plus a 10 min 0.3 mg NTG if the passive phase was negative (Fast) or to a 20 min passive phase plus a 15 min 0.3 mg NTG if the passive phase was negative (Traditional). A sample size of 277 patients for each group achieved 80% power to detect an expected difference of 0% with a non-inferiority margin of -10% using a one-sided t-test and assuming a significant level alpha of 0.025. A total of 554 consecutive patients (mean age 46.6 ± 19.3 years, 47.6% males) undergoing HUTT for suspected vasovagal syncope were randomly assigned to the Fast (n = 277) or Traditional (n = 277) protocol. A positive response was defined as the induction of syncope in presence of hypotension/bradycardia, and was observed in 167 (60.3%) patients with Fast and in 162 (58.5%) patients with the Traditional protocol. There was a trend of lesser vasodepressor response (14.8% Fast vs. 20.6% Traditional) which was significant during the passive phase (P = 0.01).<br /><b>Conclusion</b><br />The diagnostic value of the Fast HUTT protocol is similar to that of the Traditional protocol and therefore the Fast protocol can be used instead of the Traditional protocol.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 02 Jun 2023; epub ahead of print</small></div>

<div><h4>Coronary steal: how many thieves are out there?</h4><i>Achim A, Johnson NP, Liblik K, Burckhardt A, Krivoshei L, Leibundgut G</i><br /><AbstractText>The colorful term \"coronary steal\" arose in 1967 to parallel \"subclavian steal\" coined in an anonymous 1961 editorial. In both instances, the word \"steal\" described flow reversal in the setting of an interconnected but abnormal vascular network-in one case a left subclavian stenosis proximal to the origin of the vertebral artery and in the other case a coronary fistula. Over time, the term has morphed to include a larger set of pathophysiology without explicit flow reversal but rather with a decrease in stress flow due to other mechanisms. This review aims to shed light on this phenomenon from a clinical and a pathophysiological perspective, detailing the anatomical and physiological conditions that allow so-called steal to appear and offering treatment options for six distinct scenarios.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 02 Jun 2023; epub ahead of print</small></div>

<div><h4>Red meat consumption, cardiovascular diseases, and diabetes: a systematic review and meta-analysis.</h4><i>Shi W, Huang X, Schooling CM, Zhao JV</i><br /><b>Aims</b><br />Observational studies show inconsistent associations of red meat consumption with cardiovascular disease (CVD) and diabetes. Moreover, red meat consumption varies by sex and setting, however, whether the associations vary by sex and setting remains unclear.<br /><b>Methods and results</b><br />This systematic review and meta-analysis was conducted to summarize the evidence concerning the associations of unprocessed and processed red meat consumption with CVD and its subtypes [coronary heart disease (CHD), stroke, and heart failure], type two diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM) and to assess differences by sex and setting (western vs. eastern, categorized based on dietary pattern and geographic region). Two researchers independently screened studies from PubMed, Web of Science, Embase, and the Cochrane Library for observational studies and randomized controlled trials (RCTs) published by 30 June 2022. Forty-three observational studies (N = 4 462 810, 61.7% women) for CVD and 27 observational studies (N = 1 760 774, 64.4% women) for diabetes were included. Red meat consumption was positively associated with CVD [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.05 to 1.16 for unprocessed red meat (per 100 g/day increment); 1.26, 95% CI 1.18 to 1.35 for processed red meat (per 50 g/day increment)], CVD subtypes, T2DM, and GDM. The associations with stroke and T2DM were higher in western settings, with no difference by sex.<br /><b>Conclusion</b><br />Unprocessed and processed red meat consumption are both associated with higher risk of CVD, CVD subtypes, and diabetes, with a stronger association in western settings but no sex difference. Better understanding of the mechanisms is needed to facilitate improving cardiometabolic and planetary health.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 02 Jun 2023; epub ahead of print</small></div>

<div><h4>COVID-19 vaccination-related myocarditis: a Korean nationwide study.</h4><i>Cho JY, Kim KH, Lee N, Cho SH, ... Jeong MH, Cho JG</i><br /><b>Aims</b><br />A comprehensive nationwide study on the incidence and outcomes of COVID-19 vaccination-related myocarditis (VRM) is in need.<br /><b>Methods and results</b><br />Among 44 276 704 individuals with at least 1 dose of COVID-19 vaccination, the incidence and clinical courses of VRM cases confirmed by the Expert Adjudication Committee of the Korea Disease Control and Prevention Agency were analyzed. COVID-19 VRM was confirmed in 480 cases (1.08 cases per 100 000 persons). Vaccination-related myocarditis incidence was significantly higher in men than in women (1.35 vs. 0.82 per 100 000 persons, P < 0.001) and in mRNA vaccines than in other vaccines (1.46 vs. 0.14 per 100 000 persons, P < 0.001). Vaccination-related myocarditis incidence was highest in males between the ages of 12 and 17 years (5.29 cases per 100 000 persons) and lowest in females over 70 years (0.16 cases per 100 000 persons). Severe VRM was identified in 95 cases (19.8% of total VRM, 0.22 per 100 000 vaccinated persons), 85 intensive care unit admission (17.7%), 36 fulminant myocarditis (7.5%), 21 extracorporeal membrane oxygenation therapy (4.4%), 21 deaths (4.4%), and 1 heart transplantation (0.2%). Eight out of 21 deaths were sudden cardiac death (SCD) attributable to VRM proved by an autopsy, and all cases of SCD attributable to VRM were aged under 45 years and received mRNA vaccines.<br /><b>Conclusion</b><br />Although COVID-19 VRM was rare and showed relatively favorable clinical courses, severe VRM was found in 19.8% of all VRM cases. Moreover, SCD should be closely monitored as a potentially fatal complication of COVID-19 vaccination.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 02 Jun 2023; epub ahead of print</small></div>

<div><h4>Sodium-glucose cotransporter 2 inhibitors vs. sitagliptin in heart failure and type 2 diabetes: an observational cohort study.</h4><i>Fu EL, Patorno E, Everett BM, Vaduganathan M, ... Schneeweiss S, Desai RJ</i><br /><b>Aims</b><br />The effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with heart failure (HF) in routine clinical practice is not extensively studied. This study aimed to evaluate the comparative effectiveness of SGLT2i vs. sitagliptin in older adults with HF and type 2 diabetes and to investigate whether there were any differences between agents within the SGLT2i class or for reduced and preserved ejection fraction.<br /><b>Methods and results</b><br />Using Medicare claims data (April 2013 to December 2019), 16 253 SGLT2i initiators vs. 43 352 initiators of sitagliptin aged ≥65 years with type 2 diabetes and HF were included. The primary outcome was a composite of all-cause mortality, hospitalization for HF or urgent visit requiring intravenous diuretics; secondary outcomes included its individual components. Propensity score fine stratification weighted Cox regression was used to adjust for 100 pre-exposure characteristics. Mean age was 74 years; 49.8% were women. Initiation of SGLT2i vs. sitagliptin was associated with a lower risk of the primary composite outcome [adjusted hazard ratio (HR) 0.72; 95% confidence interval 0.67-0.77]. The adjusted HRs were 0.70 (0.63-0.78) for all-cause mortality, 0.64 (0.58-0.70) for hospitalization for HF, and 0.77 (0.69-0.86) for urgent visit requiring intravenous diuretics. Similar associations with the primary composite outcome were observed for all three agents within the SGLT2i class, for reduced and preserved ejection fraction, and subgroups based on demographics, comorbidities, and other HF treatments. Bias-calibrated HRs for the primary endpoint using negative and positive control outcomes ranged between 0.81 and 0.89, suggesting that the observed benefit could not be fully explained by residual confounding.<br /><b>Conclusion</b><br />In routine US clinical practice, SGLT2i demonstrated robust clinical effectiveness in older adults with HF and type 2 diabetes compared with sitagliptin, with no evidence of heterogeneity across the SGLT2i class or across ejection fraction.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 01 Jun 2023; epub ahead of print</small></div>

<div><h4>SCORE2-Diabetes: 10-year cardiovascular risk estimation in type 2 diabetes in Europe.</h4><i>SCORE2-Diabetes Working Group and the ESC Cardiovascular Risk Collaboration </i><br /><b>Aims</b><br />To develop and validate a recalibrated prediction model (SCORE2-Diabetes) to estimate the 10-year risk of cardiovascular disease (CVD) in individuals with type 2 diabetes in Europe.<br /><b>Methods and results</b><br />SCORE2-Diabetes was developed by extending SCORE2 algorithms using individual-participant data from four large-scale datasets comprising 229 460 participants (43 706 CVD events) with type 2 diabetes and without previous CVD. Sex-specific competing risk-adjusted models were used including conventional risk factors (i.e. age, smoking, systolic blood pressure, total, and HDL-cholesterol), as well as diabetes-related variables (i.e. age at diabetes diagnosis, glycated haemoglobin [HbA1c] and creatinine-based estimated glomerular filtration rate [eGFR]). Models were recalibrated to CVD incidence in four European risk regions. External validation included 217 036 further individuals (38 602 CVD events), and showed good discrimination, and improvement over SCORE2 (C-index change from 0.009 to 0.031). Regional calibration was satisfactory. SCORE2-Diabetes risk predictions varied several-fold, depending on individuals\' levels of diabetes-related factors. For example, in the moderate-risk region, the estimated 10-year CVD risk was 11% for a 60-year-old man, non-smoker, with type 2 diabetes, average conventional risk factors, HbA1c of 50 mmol/mol, eGFR of 90 mL/min/1.73 m2, and age at diabetes diagnosis of 60 years. By contrast, the estimated risk was 17% in a similar man, with HbA1c of 70 mmol/mol, eGFR of 60 mL/min/1.73 m2, and age at diabetes diagnosis of 50 years. For a woman with the same characteristics, the risk was 8% and 13%, respectively.<br /><b>Conclusion</b><br />SCORE2-Diabetes, a new algorithm developed, calibrated, and validated to predict 10-year risk of CVD in individuals with type 2 diabetes, enhances identification of individuals at higher risk of developing CVD across Europe.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 29 May 2023; epub ahead of print</small></div>

<div><h4>Modifiable cardiovascular risk factors and genetics for targeted prevention of dementia.</h4><i>Juul Rasmussen I, Frikke-Schmidt R</i><br /><AbstractText>Dementia is a major global challenge for health and social care in the 21st century. A third of individuals >65 years of age die with dementia, and worldwide incidence numbers are projected to be higher than 150 million by 2050. Dementia is, however, not an inevitable consequence of old age; 40% of dementia may theoretically be preventable. Alzheimer\'s disease (AD) accounts for approximately two-thirds of dementia cases and the major pathological hallmark of AD is accumulation of amyloid-β. Nevertheless, the exact pathological mechanisms of AD remain unknown. Cardiovascular disease and dementia share several risk factors and dementia often coexists with cerebrovascular disease. In a public health perspective, prevention is crucial, and it is suggested that a 10% reduction in prevalence of cardiovascular risk factors could prevent more than nine million dementia cases worldwide by 2050. Yet this assumes causality between cardiovascular risk factors and dementia and adherence to the interventions over decades for a large number of individuals. Using genome-wide association studies, the entire genome can be scanned for disease/trait associated loci in a hypothesis-free manner, and the compiled genetic information is not only useful for pinpointing novel pathogenic pathways but also for risk assessments. This enables identification of individuals at high risk, who likely will benefit the most from a targeted intervention. Further optimization of the risk stratification can be done by adding cardiovascular risk factors. Additional studies are, however, highly needed to elucidate dementia pathogenesis and potential shared causal risk factors between cardiovascular disease and dementia.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 24 May 2023; epub ahead of print</small></div>

<div><h4>Vegetarian or vegan diets and blood lipids: a meta-analysis of randomized trials.</h4><i>Koch CA, Kjeldsen EW, Frikke-Schmidt R</i><br /><b>Aims</b><br />Due to growing environmental focus, plant-based diets are increasing steadily in popularity. Uncovering the effect on well-established risk factors for cardiovascular diseases, the leading cause of death worldwide, is thus highly relevant. Therefore, a systematic review and meta-analysis were conducted to estimate the effect of vegetarian and vegan diets on blood levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B.<br /><b>Methods and results</b><br />Studies published between 1980 and October 2022 were searched for using PubMed, Embase, and references of previous reviews. Included studies were randomized controlled trials that quantified the effect of vegetarian or vegan diets vs. an omnivorous diet on blood lipids and lipoprotein levels in adults over 18 years. Estimates were calculated using a random-effects model. Thirty trials were included in the study. Compared with the omnivorous group, the plant-based diets reduced total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B levels with mean differences of -0.34 mmol/L (95% confidence interval, -0.44, -0.23; P = 1 × 10-9), -0.30 mmol/L (-0.40, -0.19; P = 4 × 10-8), and -12.92 mg/dL (-22.63, -3.20; P = 0.01), respectively. The effect sizes were similar across age, continent, duration of study, health status, intervention diet, intervention program, and study design. No significant difference was observed for triglyceride levels.<br /><b>Conclusion</b><br />Vegetarian and vegan diets were associated with reduced concentrations of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B-effects that were consistent across various study and participant characteristics. Plant-based diets have the potential to lessen the atherosclerotic burden from atherogenic lipoproteins and thereby reduce the risk of cardiovascular disease.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 24 May 2023; epub ahead of print</small></div>

<div><h4>Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER.</h4><i>Butt JH, Kondo T, Yang M, Jhund PS, ... Solomon SD, McMurray JJV</i><br /><b>Aims</b><br />Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation.<br /><b>Methods and results</b><br />A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD.<br /><b>Conclusion</b><br />The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 23 May 2023; epub ahead of print</small></div>

<div><h4>Dapagliflozin and diuretic utilization in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial.</h4><i>Chatur S, Vaduganathan M, Claggett B, Vardeny O, ... McMurray JJV, Solomon SD</i><br /><b>Aims</b><br />Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated.<br /><b>Methods and results</b><br />In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001).<br /><b>Conclusion</b><br />In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 23 May 2023; epub ahead of print</small></div>

<div><h4>Telemonitoring for heart failure: a meta-analysis.</h4><i>Scholte NTB, Gürgöze MT, Aydin D, Theuns DAMJ, ... van der Boon RMA, Brugts JJ</i><br /><b>Aims</b><br />Telemonitoring modalities in heart failure (HF) have been proposed as being essential for future organization and transition of HF care, however, efficacy has not been proven. A comprehensive meta-analysis of studies on home telemonitoring systems (hTMS) in HF and the effect on clinical outcomes are provided.<br /><b>Methods and results</b><br />A systematic literature search was performed in four bibliographic databases, including randomized trials and observational studies that were published during January 1996-July 2022. A random-effects meta-analysis was carried out comparing hTMS with standard of care. All-cause mortality, first HF hospitalization, and total HF hospitalizations were evaluated as study endpoints. Sixty-five non-invasive hTMS studies and 27 invasive hTMS studies enrolled 36 549 HF patients, with a mean follow-up of 11.5 months. In patients using hTMS compared with standard of care, a significant 16% reduction in all-cause mortality was observed [pooled odds ratio (OR): 0.84, 95% confidence interval (CI): 0.77-0.93, I2: 24%], as well as a significant 19% reduction in first HF hospitalization (OR: 0.81, 95% CI 0.74-0.88, I2: 22%) and a 15% reduction in total HF hospitalizations (pooled incidence rate ratio: 0.85, 95% CI 0.76-0.96, I2: 70%).<br /><b>Conclusion</b><br />These results are an advocacy for the use of hTMS in HF patients to reduce all-cause mortality and HF-related hospitalizations. Still, the methods of hTMS remain diverse, so future research should strive to standardize modes of effective hTMS.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 22 May 2023; epub ahead of print</small></div>

<div><h4>NT-proBNP and high-intensity care for acute heart failure: the STRONG-HF trial.</h4><i>Adamo M, Pagnesi M, Mebazaa A, Davison B, ... Cotter G, Metra M</i><br /><b>Background:</b><br/>and aims</b><br />STRONG-HF showed that rapid up-titration of guideline-recommended medical therapy (GRMT), in a high intensity care (HIC) strategy, was associated with better outcomes compared to usual care (UC). The aim of this study was to assess the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and its changes early during up-titration.<br /><b>Methods</b><br />A total of 1077 patients hospitalized for acute heart failure (HF) and with a >10% NT-proBNP decrease from screening (i.e. admission) to randomization (i.e. pre-discharge), were included. Patients in HIC were stratified by further NT-proBNP changes from randomization to 1 week later as decreased (≥30% decrease), stable (<30% decrease to ≤10% increase) or increased (>10% increase). The primary endpoint was 180-day HF readmission or death.<br /><b>Results</b><br />The effect of HIC vs. UC was independent of baseline NT-proBNP. Patients in the HIC group with stable or increased NT-proBNP were older, with more severe acute HF and worse renal and liver function. Per protocol, patients with increased NT-proBNP received more diuretics and were up-titrated more slowly during the first weeks after discharge. However, by 6 months they reached 70.4% optimal GRMT doses, compared with 80.3% for those with NT-proBNP decrease. As a result, the primary endpoint at 60 and 90 days occurred in 8.3% and 11.1% of patients with increased NT-proBNP vs 2.2% and 4.0% in those with decreased NT-proBNP (p=0.039 and p=0.045, respectively). However, no difference in outcome was found at 180 days (13.5% vs. 13.2%; p=0.93).<br /><b>Conclusions</b><br />Among patients with acute HF enrolled in STRONG-HF, HIC reduced 180-day HF readmission or death regardless of baseline NT-proBNP. GRMT up-titration early post-discharge utilizing increased NT-proBNP as guidance to increase diuretic therapy and reduce the GRMT up-titration rate resulted in the same 180-day outcomes regardless of early post-discharge NT-proBNP change.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 22 May 2023; epub ahead of print</small></div>

<div><h4>Conventional heart failure therapy in cardiac ATTR amyloidosis.</h4><i>Ioannou A, Massa P, Patel RK, Razvi Y, ... Gillmore JD, Fontana M</i><br /><b>Background:</b><br/>and aims</b><br />The aims of this study were to assess prescription patterns, dosages, discontinuation rates and association with prognosis of conventional heart failure (HF) medications in patients with transthyretin cardiac amyloidosis (ATTR-CA).<br /><b>Methods</b><br />A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000-2022 identified 2371 patients with ATTR-CA.<br /><b>Results</b><br />Prescription of HF medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin-II receptor blockers (ARB) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (IQR 10.6-51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARB discontinued. In contrast, only 7.5% had MRAs discontinued. Propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population (HR 0.77 [95% CI 0.66-0.89], P<0.001) and in a pre-specified subgroup of patients with a left ventricular ejection fraction (LVEF) >40% (HR 0.75 [95% CI 0.63-0.90], P=0.002); and treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% (HR 0.61 [95% CI 0.45-0.83], P=0.002). No convincing differences were found for treatment with ACEi/ARBs.<br /><b>Conclusions</b><br />Conventional HF medications are currently not widely prescribed in ATTR-CA, and those that received medication had more severe cardiac disease. Beta-blockers and ACEi/ARBs were often discontinued, but low-dose beta-blockers were associated with reduced risk of mortality in patients with a LVEF ≤40%. In contrast, MRAs were rarely discontinued and were associated with reduced risk of mortality in the overall population; but these findings require confirmation in prospective randomized controlled trials.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 22 May 2023; epub ahead of print</small></div>

<div><h4>Dapagliflozin versus metolazone in heart failure resistant to loop diuretics.</h4><i>Ern Yeoh S, Osmanska J, Petrie MC, Brooksbank KJM, ... McMurray JJV, Campbell RT</i><br /><b>Background:</b><br/>and aims</b><br />To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide.<br /><b>Methods</b><br />A multi-centre, open-label, randomized, active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 hours). The primary endpoint was diuretic effect, assessed by change in weight (kg). Secondary endpoints included change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score.<br /><b>Results</b><br />61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 hours was 976 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 hours was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; p=0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) versus 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; p=0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments.<br /><b>Conclusion</b><br />In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone.<br /><b>Clinicaltrials.gov identifier</b><br />NCT04860011.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 21 May 2023; epub ahead of print</small></div>

<div><h4>Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF.</h4><i>Vaduganathan M, Mentz RJ, Claggett BL, Miao ZM, ... Braunwald E, Solomon SD</i><br /><b>Background:</b><br/>and aims</b><br />The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction.<br /><b>Methods</b><br />Both PARAGLIDE-HF and PARAGON-HF were multicenter, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a \'PARAGLIDE-like\' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death).<br /><b>Results</b><br />Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF (n=1,088; rate ratio [RR] 0.78; 95% confidence interval [CI] 0.61-0.99; P=0.042) and in the pooled analysis of all participants (n=5,262; RR 0.86; 95% CI: 0.75-0.98; P=0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by day 9 after randomization and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction=0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis (hazard ratio [HR] 0.67; 95% CI 0.43-1.05; P=0.080) and the pooled analysis of all participants (HR 0.60; 95% CI 0.44-0.83; P=0.002).<br /><b>Conclusions</b><br />In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 21 May 2023; epub ahead of print</small></div>

<div><h4>Efficacy of Pulmonary Artery Pressure Monitoring in Patients with Chronic Heart Failure: A Meta-Analysis of Three Randomized Controlled Trials.</h4><i>Clephas PRD, Radhoe SP, Boersma E, Gregson J, ... de Boer RA, Brugts JJ</i><br /><b>Background:</b><br/>and aims</b><br />Adjustment of treatment based on remote monitoring of pulmonary artery (PA) pressure may reduce the risk of hospital admission for heart failure (HF). We have conducted a meta-analysis of large randomized trials investigating this question.<br /><b>Methods</b><br />A systematic literature search was performed for randomized clinical trials (RCTs) with PA pressure monitoring devices in patients with HF. The primary outcome of interest was the total number of HF hospitalizations. Other outcomes assessed were urgent visits leading to treatment with intravenous diuretics, all-cause mortality, and composites. Treatment effects are expressed as hazard ratios, and pooled effect estimates were obtained applying random effects meta-analyses.<br /><b>Results</b><br />Three eligible RCTs were identified that included 1898 outpatients in New York Heart Association functional class II-IV, either hospitalized for HF in the prior 12 months or with elevated plasma NT-proBNP concentrations. Mean follow-up was 14.7 months, 67.8% of the patients were men, and 65.8% had an ejection fraction ≤40%. Compared to patients in the control group, the hazard ratio (95% confidence interval) for total HF hospitalizations in those randomized to PA pressure monitoring was 0.70 (0.58-0.86) (p=0.0005). The corresponding hazard ratio for the composite of total HF hospitalizations, urgent visits and all-cause mortality was 0.75 (0.61-0.91; p=0.0037) and for all-cause mortality 0.92 (0.73-1.16). Subgroup analyses, including ejection fraction phenotype, revealed no evidence of heterogeneity in the treatment effect.<br /><b>Conclusions</b><br />The use of remote PA pressure monitoring to guide treatment of patients with HF reduces episodes of worsening HF and subsequent hospitalizations.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 21 May 2023; epub ahead of print</small></div>

<div><h4>Novel mechanisms and therapeutic targets in atherosclerosis: inflammation and beyond.</h4><i>Weber C, Habenicht AJR, von Hundelshausen P</i><br /><AbstractText>This review based on the ESC William Harvey Lecture in Basic Science 2022 highlights recent experimental and translational progress on the therapeutic targeting of the inflammatory components in atherosclerosis, introducing novel strategies to limit side effects and to increase efficacy. Since the validation of the inflammatory paradigm in CANTOS and COLCOT, efforts to control the residual risk conferred by inflammation have centred on the NLRP3 inflammasome-driven IL-1β-IL6 axis. Interference with the co-stimulatory dyad CD40L-CD40 and selective targeting of tumour necrosis factor-receptor associated factors (TRAFs), namely the TRAF6-CD40 interaction in macrophages by small molecule inhibitors, harbour intriguing options to reduce established atherosclerosis and plaque instability without immune side effects. The chemokine system crucial for shaping immune cell recruitment and homoeostasis can be fine-tuned and modulated by its heterodimer interactome. Structure-function analysis enabled the design of cyclic, helical, or linked peptides specifically targeting or mimicking these interactions to limit atherosclerosis or thrombosis by blunting myeloid recruitment, boosting regulatory T cells, inhibiting platelet activity, or specifically blocking the atypical chemokine MIF without notable side effects. Finally, adventitial neuroimmune cardiovascular interfaces in advanced atherosclerosis show robust restructuring of innervation from perivascular ganglia and employ sensory neurons of dorsal root ganglia to enter the central nervous system and to establish an atherosclerosis-brain circuit sensor, while sympathetic and vagal efferents project to the celiac ganglion to create an atherosclerosis-brain circuit effector. Disrupting this circuitry by surgical or chemical sympathectomy limited disease progression and enhanced plaque stability, opening exciting perspectives for selective and tailored intervention beyond anti-inflammatory strategies.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 20 May 2023; epub ahead of print</small></div>

<div><h4>Management strategies for heavily calcified coronary stenoses: an EAPCI clinical consensus statement in collaboration with the EURO4C-PCR group.</h4><i>Barbato E, Gallinoro E, Abdel-Wahab M, Andreini D, ... Wijns W, Ribichini F</i><br /><AbstractText>Since the publication of the 2015 EAPCI consensus on rotational atherectomy, the number of percutaneous coronary interventions (PCI) performed in patients with severely calcified coronary artery disease has grown substantially. This has been prompted on one side by the clinical demand for the continuous increase in life expectancy, the sustained expansion of the primary PCI networks worldwide and the routine performance of revascularization procedures in elderly patients; on the other side, the availability of new and dedicated technologies such as orbital atherectomy and intravascular lithotripsy, as well as the optimization of the rotational atherectomy system, have increased operators\' confidence in attempting more challenging PCI. This current EAPCI clinical consensus statement prepared in collaboration with the EURO4C-PCR group describes the comprehensive management of patients with heavily calcified coronary stenoses, starting with how to use non-invasive and invasive imaging to assess calcium burden and inform procedural planning. Objective and practical guidance is provided on the selection of the optimal interventional tool and technique based on the specific calcium morphology and anatomic location. Finally, the specific clinical implications of treating these patients are considered, including the prevention and management of complications, and the importance of adequate training and education.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 19 May 2023; epub ahead of print</small></div>

<div><h4>Left main bifurcation stenting: impact of residual ischaemia on cardiovascular mortality.</h4><i>Wang HY, Zhang R, Dou K, Huang Y, ... Wijns W, Xu B</i><br /><b>Background:</b><br/>and aims</b><br />The present study sought to determine the rate and prognostic implications of post-procedural physiologically significant residual ischemia according to Murray law-based quantitative flow ratio (μQFR) after left main (LM) bifurcation percutaneous coronary intervention (PCI).<br /><b>Methods</b><br />Consecutive patients undergoing LM bifurcation stenting at a large tertiary care center between January 2014 and December 2016 with available post-PCI μQFR were included. Physiologically significant residual ischemia was defined by post-PCI μQFR values ≤0.80 in the left anterior descending (LAD) or circumflex artery (LCX). The primary outcome was 3-year cardiovascular death. The major secondary outcome was 3-year bifurcation oriented composite endpoint (BOCE).<br /><b>Results</b><br />Among 1,170 included patients with analyzable post-PCI μQFR, 155 (13.2%) had residual ischemia in either LAD or LCX. Patients with vs. those without residual ischemia had a higher risk of 3-year cardiovascular mortality (5.4% vs. 1.3%; adjusted hazard ratio [HR] 3.20, 95% confidence interval [CI]: 1.16-8.80). The 3-year risk of BOCE was significantly higher in the residual ischemia group (17.8% vs. 5.8%; adjusted HR 2.79, 95% CI: 1.68-4.64), driven by higher incidence of the composite of cardiovascular death and target bifurcation-related myocardial infarction (14.0% vs. 3.3%; adjusted HR 4.06, 95% CI: 2.22-7.42). A significant, inverse association was observed between continuous post-PCI μQFR and the risk of clinical outcomes (per 0.1 μQFR decrease, HR of cardiovascular death 1.27, 95% CI: 1.00-1.62; HR of BOCE 1.29, 95% CI: 1.14-1.47).<br /><b>Conclusion</b><br />After angiographically successful LM bifurcation PCI, residual ischemia assessed by μQFR was identified in 13.2% of patients and was associated with higher risk of 3-year cardiovascular death, indicating the superior prognostic value of post-PCI physiological assessment.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 16 May 2023; epub ahead of print</small></div>

<div><h4>Takotsubo syndrome is a coronary microvascular disease: experimental evidence.</h4><i>Dong F, Yin L, Sisakian H, Hakobyan T, ... Chilian WM, Ohanyan V</i><br /><b>Background:</b><br/>and aims</b><br />Takotsubo syndrome (TTS) is a conundrum without consensus about the cause. In a murine model of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion played a key role in the development of TTS.<br /><b>Methods and results</b><br />Vascular Kv1.5 channels connect coronary blood flow to myocardial metabolism and their deletion mimics the phenotype of CMD. To determine if TTS is related to CMD, wild-type (WT), Kv1.5-/-, and TgKv1.5-/- (Kv1.5-/- with smooth muscle-specific expression Kv1.5 channels) mice were studied following transaortic constriction (TAC). Measurements of left ventricular (LV) fractional shortening (FS) in base and apex, and myocardial blood flow (MBF) were completed with standard and contrast echocardiography. Ribonucleic Acid deep sequencing was performed on LV apex and base from WT and Kv1.5-/- (control and TAC). Changes in gene expression were confirmed by real-time-polymerase chain reaction. MBF was increased with chromonar or by smooth muscle expression of Kv1.5 channels in the TgKv1.5-/-. TAC-induced systolic apical ballooning in Kv1.5-/-, shown as negative FS (P < 0.05 vs. base), which was not observed in WT, Kv1.5-/- with chromonar, or TgKv1.5-/-. Following TAC in Kv1.5-/-, MBF was lower in LV apex than in base. Increasing MBF with either chromonar or in TgKv1.5-/- normalized perfusion and function between LV apex and base (P = NS). Some genetic changes during TTS were reversed by chromonar, suggesting these were independent of TAC and more related to TTS.<br /><b>Conclusion</b><br />Abnormalities in flow regulation between the LV apex and base cause TTS. When perfusion is normalized between the two regions, normal ventricular function is restored.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 12 May 2023; epub ahead of print</small></div>

<div><h4>Rapid, accurate publication and dissemination of clinical trial results: benefits and challenges.</h4><i>Zannad F, Crea F, Keaney J, Spencer S, ... Winslow R, Jessup M</i><br /><AbstractText>Large-scale clinical trials are essential in cardiology and require rapid, accurate publication, and dissemination. Whereas conference presentations, press releases, and social media disseminate information quickly and often receive considerable coverage by mainstream and healthcare media, they lack detail, may emphasize selected data, and can be open to misinterpretation. Preprint servers speed access to research manuscripts while awaiting acceptance for publication by a journal, but these articles are not formally peer-reviewed and sometimes overstate the findings. Publication of trial results in a major journal is very demanding but the use of existing checklists can help accelerate the process. In case of rejection, procedures such as easing formatting requirements and possibly carrying over peer-review to other journals could speed resubmission. Secondary publications can help maximize benefits from clinical trials; publications of secondary endpoints and subgroup analyses further define treatment effects and the patient populations most likely to benefit. These rely on data access, and although data sharing is becoming more common, many challenges remain. Beyond publication in medical journals, there is a need for wider knowledge dissemination to maximize impact on clinical practice. This might be facilitated through plain language summary publications. Social media, websites, mainstream news outlets, and other publications, although not peer-reviewed, are important sources of medical information for both the public and for clinicians. This underscores the importance of ensuring that the information is understandable, accessible, balanced, and trustworthy. This report is based on discussions held on December 2021, at the 18th Global Cardiovascular Clinical Trialists meeting, involving a panel of editors of some of the top medical journals, as well as members of the lay press, industry, and clinical trialists.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 11 May 2023; epub ahead of print</small></div>

<div><h4>Inverse association between apolipoprotein C-II and cardiovascular mortality: role of lipoprotein lipase activity modulation.</h4><i>Silbernagel G, Chen YQ, Rief M, Kleber ME, ... Scharnagl H, Konrad RJ</i><br /><b>Aims</b><br />Apolipoprotein C-II (ApoC-II) is thought to activate lipoprotein lipase (LPL) and is therefore a possible target for treating hypertriglyceridemia. Its relationship with cardiovascular risk has not been investigated in large-scale epidemiologic studies, particularly allowing for apolipoprotein C-III (ApoC-III), an LPL antagonist. Furthermore, the exact mechanism of ApoC-II-mediated LPL activation is unclear.<br /><b>Methods and results</b><br />ApoC-II was measured in 3141 LURIC participants of which 590 died from cardiovascular diseases during a median (inter-quartile range) follow-up of 9.9 (8.7-10.7) years. Apolipoprotein C-II-mediated activation of the glycosylphosphatidylinositol high-density lipoprotein binding protein 1 (GPIHBP1)-LPL complex was studied using enzymatic activity assays with fluorometric lipase and very low-density lipoprotein (VLDL) substrates. The mean ApoC-II concentration was 4.5 (2.4) mg/dL. The relationship of ApoC-II quintiles with cardiovascular mortality exhibited a trend toward an inverse J-shape, with the highest risk in the first (lowest) quintile and lowest risk in the middle quintile. Compared with the first quintile, all other quintiles were associated with decreased cardiovascular mortality after multivariate adjustments including ApoC-III as a covariate (all P < 0.05). In experiments using fluorometric substrate-based lipase assays, there was a bell-shaped relationship for the effect of ApoC-II on GPIHBP1-LPL activity when exogenous ApoC-II was added. In ApoC-II-containing VLDL substrate-based lipase assays, GPIHBP1-LPL enzymatic activity was almost completely blocked by a neutralizing anti-ApoC-II antibody.<br /><b>Conclusion</b><br />The present epidemiologic data suggest that increasing low circulating ApoC-II levels may reduce cardiovascular risk. This conclusion is supported by the observation that optimal ApoC-II concentrations are required for maximal GPIHBP1-LPL enzymatic activity.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 08 May 2023; epub ahead of print</small></div>

<div><h4>Pre-treatment bicarbonate levels and decongestion by acetazolamide: the ADVOR trial.</h4><i>Martens P, Verbrugge FH, Dauw J, Nijst P, ... Dupont M, Mullens W</i><br /><b>Aims</b><br />Acetazolamide inhibits proximal tubular sodium and bicarbonate re-absorption and improved decongestive response in acute heart failure in the ADVOR trial. It is unknown whether bicarbonate levels alter the decongestive response to acetazolamide.<br /><b>Methods and results</b><br />This is a sub-analysis of the randomized, double-blind, placebo-controlled ADVOR trial that randomized 519 patients with acute heart failure and volume overload in a 1:1 ratio to intravenous acetazolamide (500 mg/day) or matching placebo on top of standardized intravenous loop diuretics (dose equivalent of twice oral maintenance dose). The primary endpoint was complete decongestion after 3 days of treatment (morning of day 4). Impact of baseline HCO3 levels on the treatment effect of acetazolamide was assessed. : Of the 519 enrolled patients, 516 (99.4%) had a baseline HCO3 measurement. Continuous HCO3 modelling illustrated a higher proportional treatment effect for acetazolamide if baseline HCO3 ≥ 27 mmol/l. A total of 234 (45%) had a baseline HCO3 ≥ 27 mmol/l. Randomization towards acetazolamide improved decongestive response over the entire range of baseline HCO3- levels (P = 0.004); however, patients with elevated baseline HCO3 exhibited a significant higher response to acetazolamide [primary endpoint: no vs. elevated HCO3; OR 1.37 (0.79-2.37) vs. OR 2.39 (1.35-4.22), P-interaction = 0.065), with higher proportional diuretic and natriuretic response (both P-interaction < 0.001), greater reduction in congestion score on consecutive days (treatment × time by HCO3-interaction <0.001) and length of stay (P-interaction = 0.019). The larger proportional treatment effect was mainly explained by the development of diminished decongestive response in the placebo arm (loop diuretics only), both with regard to reaching the primary endpoint of decongestion as well as reduction in congestion score. Development of elevated HCO3 further worsened decongestive response in the placebo arm (P-interaction = 0.041). A loop diuretic only strategy was associated with an increase in the HCO3 during the treatment phase which was prevented by acetazolamide (day 3: placebo 74.8% vs. acetazolamide 41.3%, P < 0.001).<br /><b>Conclusion</b><br />Acetazolamide improves decongestive response over the entire range of HCO3- levels; however, the treatment response is magnified in patients with baseline or loop diuretic-induced elevated HCO3 (marker of proximal nephron NaHCO3 retention) by specifically counteracting this component of diuretic resistance.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 04 May 2023; epub ahead of print</small></div>

<div><h4>2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance.</h4><i>Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, ... Catapano AL, Ray KK</i><br /><AbstractText>This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 02 May 2023; epub ahead of print</small></div>

<div><h4>Big tau aggregation disrupts microtubule tyrosination and causes myocardial diastolic dysfunction: from discovery to therapy.</h4><i>Luciani M, Montalbano M, Troncone L, Bacchin C, ... Kayed R, Del Monte F</i><br /><b>Background</b><br />Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer\'s disease (AD) and other forms of dementia, are emerging as determinants of proteinopathies \'beyond the brain\'. This study aims to establish tau\'s putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in heart failure (HF).<br /><b>Methods and results</b><br />A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls was employed in this study. Tau protein expression was examined together with its distribution, and in vitro tau-related pathophysiological mechanisms were identified using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau is expressed in normal and diseased human hearts, in contradistinction to the current oft-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform is high-molecular-weight (HMW) tau (also known as big tau), and hyperphosphorylated tau segregates in aggregates in HF and AD hearts. As previously described for amyloid-beta, the tauopathy phenotype in human myocardium is of diastolic dysfunction. Perturbation in the tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy.<br /><b>Conclusion</b><br />The study presents new mechanistic evidence and potential treatment for the brain-heart tauopathy axis in myocardial and brain degenerative diseases and ageing.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 01 May 2023; 44:1560-1570</small></div>

<div><h4>Leveraging electronic health records to streamline the conduct of cardiovascular clinical trials.</h4><i>Khan MS, Usman MS, Talha KM, Van Spall HGC, ... Butler J, McGuire DK</i><br /><AbstractText>Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. Trial recruitment, participation, and data collection can burden participants and research personnel. In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication. Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. Importantly, the data collection infrastructure should be reusable to support multiple cardiovascular RCTs over time. Systems, processes, and policies will need to have sufficient flexibility to allow interoperability between different sources of data acquisition. Clinical research guidelines, ethics oversight, and regulatory requirements also need to evolve. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. There is a particular focus on methods to utilize routinely generated data for trials while complying with regional data protection laws. The discussion is supported with examples of cardiovascular outcome trials that have successfully leveraged the electronic health record, web-enabled devices or administrative databases to conduct randomized trials.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 26 Apr 2023; epub ahead of print</small></div>

<div><h4>Statin loading before coronary artery bypass grafting: a randomized trial.</h4><i>Liakopoulos OJ, Kuhn EW, Hellmich M, Schlömicher M, ... Wahlers T, StaRT-CABG Investigators</i><br /><b>Aims</b><br />Evidence suggests that a high-dose statin loading before a percutaneous coronary revascularization improves outcomes in patients receiving long-term statins. This study aimed to analyse the effects of such an additional statin therapy before surgical revascularization.<br /><b>Methods and results</b><br />This investigator-initiated, randomized, double-blind, and placebo-controlled trial was conducted from November 2012 to April 2019 at 14 centres in Germany. Adult patients (n = 2635) with a long-term statin treatment (≥30 days) who were scheduled for isolated coronary artery bypass grafting (CABG) were randomly assigned to receive a statin-loading therapy or placebo at 12 and 2 h prior to surgery using a web-based system. The primary outcome of major adverse cardiac and cerebrovascular events (MACCE) was a composite consisting of all-cause mortality, myocardial infarction (MI), and a cerebrovascular event occuring within 30 days after surgery. Key secondary endpoints included a composite of cardiac death and MI, myocardial injury, and death within 12 months. Non-statistically relevant differences were found in the modified intention-to-treat analysis (2406 patients; 1203 per group) between the statin (13.9%) and placebo groups (14.9%) for the primary outcome [odds ratio (OR) 0.93, 95% confidence interval (CI) 0.74-1.18; P = 0.562] or any of its individual components. Secondary endpoints including cardiac death and MI (12.1% vs. 13.5%; OR 0.88, 95% CI 0.69-1.12; P = 0.300), the area under the troponin T-release curve (median 0.398 vs. 0.394 ng/ml, P = 0.333), and death at 12 months (3.1% vs. 2.9%; P = 0.825) were comparable between treatment arms.<br /><b>Conclusion</b><br />Additional statin loading before CABG failed to reduce the rate of MACCE occuring within 30 days of surgery.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 22 Apr 2023; epub ahead of print</small></div>

<div><h4>Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium-glucose cotransporter 2 inhibitors.</h4><i>Packer M</i><br /><AbstractText>Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major heart failure events, an action that is statistically linked to enhanced erythropoiesis, suggesting that stimulation of erythropoietin and cardioprotection are related to a shared mechanism. Four hypotheses have been proposed to explain how these drugs increase erythropoietin production: (i) renal cortical reoxygenation with rejuvenation of erythropoietin-producing cells; (ii) counterregulatory distal sodium reabsorption leading to increased tubular workload and oxygen consumption, and thus, to localized hypoxia; (iii) increased iron mobilization as a stimulus of hypoxia-inducible factor-2α (HIF-2α)-mediated erythropoietin synthesis; and (iv) direct HIF-2α activation and enhanced erythropoietin gene transcription due to increased sirtuin-1 (SIRT1) signaling. The first two hypotheses assume that the source of increased erythropoietin is the interstitial fibroblast-like cells in the deep renal cortex. However, SGLT2 inhibitors do not alter regional tissue oxygen tension in the non-diabetic kidney, and renal erythropoietin synthesis is markedly impaired in patients with anemia due to chronic kidney disease, and yet, SGLT2 inhibitors produce an unattenuated erythrocytic response in these patients. This observation raises the possibility that the liver contributes to the production of erythropoietin during SGLT2 inhibition. Hypoxia-inducible factor-2α and erythropoietin are coexpressed not only in the kidney but also in hepatocytes; the liver is a major site of production when erythropoietin stimulation is maintained for prolonged periods. The ability of SGLT2 inhibitors to improve iron mobilization by derepressing hepcidin and ferritin would be expected to increase cytosolic ferrous iron, which might stimulate HIF-2α expression in both the kidney and liver through the action of iron regulatory protein 1. Alternatively, the established ability of SGLT2 inhibitors to enhance SIRT1 might be the mechanism of enhanced erythropoietin production with these drugs. In hepatic cell lines, SIRT1 can directly activate HIF-2α by deacetylation, and additionally, through an effect of SIRT in the liver, peroxisome proliferator-activated receptor-γ coactivator-1α binds to hepatic nuclear factor 4 to promote transcription of the erythropoietin gene and synthesis of erythropoietin. Since SIRT1 up-regulation exerts direct cytoprotective effects on the heart and stimulates erythropoietin, it is well-positioned to represent the shared mechanism that links erythropoiesis to cardioprotection during SGLT2 inhibition.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 22 Apr 2023; epub ahead of print</small></div>

<div><h4>Psychological therapies for depression and cardiovascular risk: evidence from national healthcare records in England.</h4><i>El Baou C, Desai R, Cooper C, Marchant NL, ... John A, Stott J</i><br /><b>Aims</b><br />People with depression are up to 72% more at risk to develop cardiovascular disease (CVD) in their lifetime. Evidence-based psychotherapies are first-line interventions for the treatment of depression and are delivered nationally in England through the National Health Service via the Improving Access to Psychological Therapy (IAPT) primary care programme. It is currently unknown whether positive therapy outcomes may be associated with cardiovascular risk reduction. This study aimed to examine the association between psychotherapy outcomes for depression and incident CVD.<br /><b>Methods and results</b><br />A cohort of 636 955 individuals who have completed a course of psychotherapy was built from linked electronic healthcare record databases of national coverage in England: the national IAPT database, the Hospital Episode Statistics (HES) database, and the HES-ONS (Office of National Statistics) mortality database. Multivariable Cox models adjusting for clinical and demographic covariates were run to estimate the association between reliable improvement from depression and the risk of subsequent incidence of cardiovascular events. After a median follow-up of 3.1 years, reliable improvement from depression symptoms was associated with a lower risk of new onset of any CVD [hazard ratio (HR): 0.88, 95% confidence interval (CI): 0.86, 0.89], coronary heart disease (HR: 0.89, 95% CI: 0.86, 0.92), stroke (HR: 0.88, 95% CI: 0.83, 0.94), and all-cause mortality (HR: 0.81, 95% CI: 0.78, 0.84). This association was stronger in the under 60 compared with the over 60 for all outcomes. Results were confirmed in sensitivity analyses.<br /><b>Conclusion</b><br />Management of depression through psychological interventions may be associated with reduced risk of CVD. More research is needed to understand the causality of these associations.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 18 Apr 2023; epub ahead of print</small></div>

<div><h4>Impact of Early Versus Delayed Atrial Fibrillation Catheter Ablation on Atrial Arrhythmia Recurrences.</h4><i>Kalman JM, Al-Kaisey AM, Parameswaran R, Hawson J, ... Sanders P, Kistler PM</i><br /><b>Background</b><br />Catheter ablation is an effective strategy in atrial fibrillation (AF). However, its timing in the course of management remains unclear. The aim of this study was to determine if an early versus delayed AF ablation strategy is associated with differences in arrhythmia outcomes during 12-month follow-up.<br /><b>Methods and results</b><br />One hundred patients with symptomatic AF referred to a tertiary centre for management were randomised in a 1:1 ratio to either an early ablation strategy (within 1 month of recruitment) or a delayed ablation strategy (optimised medical therapy followed by catheter ablation at 12 months post recruitment). The primary endpoint was atrial arrhythmia free survival at 12 months post ablation. Secondary outcomes included: (i) AF burden, (ii) AF burden by AF phenotype, and (iii) antiarrhythmic drug (AAD) use at 12 months. Overall, 89 patients completed the study protocol (Early vs Delayed: 48 vs 41). Mean age was 59 ± 12.9 years (29% women). Pulmonary vein isolation was achieved in 100% of patients. At 12 months, 56.3% of patients in the early ablation group were free from recurrent arrhythmia, compared with 58.6% in the delayed ablation group (HR 1.12, 95% CI 0.59-2.13, P = 0.7). All secondary outcomes showed no significant difference including median AF burden (Early vs Delayed: 0% [IQR 3.2] vs 0% [5], p= 0.66), median AF burden amongst paroxysmal AF patients (0% [IQR 1.1] vs 0% [4.5], p= 0.78), or persistent AF patients (0% [IQR 22.8] vs 0% [5.6], p=0.45) or AAD use (33% vs 37%, p = 0.8).<br /><b>Conclusion</b><br />Compared to an early ablation strategy, delaying AF ablation by 12 months for AAD management did not result in reduced ablation efficacy.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>A worldwide survey on incidence, management and prognosis of oesophageal fistula formation following atrial fibrillation catheter ablation: The POTTER-AF study.</h4><i>Tilz RR, Schmidt V, Pürerfellner H, Maury P, ... Keelani A, Heeger CH</i><br /><b>Aims</b><br />Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management and outcome are sparse.<br /><b>Methods and results</b><br />This international multicenter registry investigates the characteristics of oesophageal fistulae after treatment of atrial fibrillation by catheter ablation. A total of 553,729 catheter ablation procedures (radiofrequency: 62.9%, cryoballoon: 36.2%, other modalities: 0.9%) were performed at 214 centers in 35 countries. In 78 centers 138 patients (0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (p<0.0001)) were diagnosed with an oesophageal fistula. Periprocedural data were available for 118 patients (85.5%). Following catheter ablation, the median time to symptoms and the median time to diagnosis were 18 (7.75, 25; range: 0-60) days and 21 (15, 29.5; range: 2-63) days, respectively. The median time from symptom onset to oesophageal fistula diagnosis was 3 (1, 9; range: 0-42) days. The most common initial symptom was fever (59.3%). The diagnosis was established by chest computed tomography in 80.2% of patients. Oesophageal surgery was performed in 47.4% and direct endoscopic treatment in 19.8%, and conservative treatment in 32.8% of patients. The overall mortality was 65.8%. Mortality following surgical (51.9%) or endoscopic treatment (56.5%) was significantly lower as compared to conservative management (89.5%) (odds ratio 7.463 (2.414, 23.072) p<0.001).<br /><b>Conclusions</b><br />Oesophageal fistula after catheter ablation of atrial fibrillation is rare and occurs mostly with the use of radiofrequency energy rather than cryoenergy. Mortality without surgical or endoscopic intervention is exceedingly high.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>Importance of cystatin C in estimating glomerular filtration rate: the PARADIGM-HF trial.</h4><i>Tolomeo P, Butt JH, Kondo T, Campo G, ... Packer M, McMurray JJV</i><br /><b>Aims</b><br />The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation combining creatinine and cystatin C provides a better estimation of glomerular filtration rate (GFR) compared to the creatinine-only equation.<br /><b>Methods and results</b><br />CKD-EPI creatinine-cystatin C equation (creatinine-cystatin) was compared to creatinine-only (creatinine) equation in a subpopulation of Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF). Patients were categorized according to difference in eGFR using the two equations: Group 1 (<-10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min lower than creatinine), Group 2 (>-10 and <10 mL/min/1.73 m2), and Group 3 (>10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min higher than creatinine). Cystatin C and creatinine were available in 1966 patients at randomization. Median (interquartile range) eGFR difference was -0.7 (-6.4-4.8) mL/min/1.73 m2. Compared to creatinine, creatinine-cystatin led to a substantial reclassification of chronic kidney disease stages. Overall, 212 (11%) and 355 (18%) patients were reallocated to a better and worse eGFR category, respectively. Compared to patients in Group 2, those in Group 1 (lower eGFR with creatinine-cystatin) had higher mortality and those in Group 3 (higher eGFR with creatinine-cystatin) had lower mortality. Increasing difference in eGFR (due to lower eGFR with creatinine-cystatin compared to creatinine) was associated with increasing elevation of biomarkers (including N-terminal pro-B-type natriuretic peptide and troponin) and worsening Kansas City Cardiomyopathy Questionnaire clinical summary score. The reason why the equations diverged with increasing severity of heart failure was that creatinine did not rise as steeply as cystatin C.<br /><b>Conclusion</b><br />The CKD-EPI creatinine-only equation may overestimate GFR in sicker patients.<br /><b>Clinical trial registration</b><br />URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01035255.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 13 Apr 2023; epub ahead of print</small></div>

<div><h4>Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.</h4><i>Chen HY, Dina C, Small AM, Shaffer CM, ... Engert JC, Thanassoulis G</i><br /><b>Aims</b><br />Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS.<br /><b>Methods and results</b><br />A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS.<br /><b>Conclusion</b><br />Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 11 Apr 2023; epub ahead of print</small></div>

<div><h4>Outcomes of patients with atrial fibrillation and ischemic stroke while on oral anticoagulation.</h4><i>Benz AP, Hohnloser SH, Eikelboom JW, Carnicelli AP, ... Yi Q, Connolly SJ</i><br /><b>Aims</b><br />The prognosis of patients with atrial fibrillation (AF) and ischemic stroke while taking oral anticoagulation is poorly understood. This study aimed to characterize the outcomes of patients following a stroke event while on oral anticoagulation.<br /><b>Methods and results</b><br />Individual participant data from five pivotal randomized trials of antithrombotic therapy in AF were used to assess the outcomes of patients with a post-randomization ischemic stroke while on study medication (warfarin, standard-, or lower-dose direct oral anticoagulant regimen) during trial follow-up. The primary outcome was recurrent ischemic stroke after the first post-randomization ischemic stroke. The primary analysis included 1163 patients with a first post-randomization ischemic stroke while on study medication (median age 73 years, 39.3% female, 35.4% history of stroke before trial enrollment). During a median continued follow-up of 337 days, 74 patients had a recurrent ischemic stroke [cumulative incidence at 1 year: 7.0%, 95% confidence interval (CI) 5.2%-8.7%]. The cumulative incidence of mortality at 3 months after stroke was 12.4% (95% CI 10.5%-14.4%). Consistent results for the incidence of recurrent ischemic stroke at 1 year were obtained in an analysis accounting for the competing risk of death (6.2%, 95% CI 4.8%-7.9%) and in a landmark analysis excluding the first 2 weeks after the index stroke and only including patients without permanent study drug discontinuation since then (6.8%, 95% CI 4.6%-8.9%).<br /><b>Conclusion</b><br />Patients with AF and ischemic stroke while on oral anticoagulation are at increased risk of recurrent ischemic stroke and death. These patients currently have an unmet medical need.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 11 Apr 2023; epub ahead of print</small></div>

<div><h4>Proteomic cardiovascular risk assessment in chronic kidney disease.</h4><i>Deo R, Dubin RF, Ren Y, Murthy AC, ... Li H, Ganz P</i><br /><b>Aims</b><br />Chronic kidney disease (CKD) is widely prevalent and independently increases cardiovascular risk. Cardiovascular risk prediction tools derived in the general population perform poorly in CKD. Through large-scale proteomics discovery, this study aimed to create more accurate cardiovascular risk models.<br /><b>Methods and results</b><br />Elastic net regression was used to derive a proteomic risk model for incident cardiovascular risk in 2182 participants from the Chronic Renal Insufficiency Cohort. The model was then validated in 485 participants from the Atherosclerosis Risk in Communities cohort. All participants had CKD and no history of cardiovascular disease at study baseline when ∼5000 proteins were measured. The proteomic risk model, which consisted of 32 proteins, was superior to both the 2013 ACC/AHA Pooled Cohort Equation and a modified Pooled Cohort Equation that included estimated glomerular filtrate rate. The Chronic Renal Insufficiency Cohort internal validation set demonstrated annualized receiver operating characteristic area under the curve values from 1 to 10 years ranging between 0.84 and 0.89 for the protein and 0.70 and 0.73 for the clinical models. Similar findings were observed in the Atherosclerosis Risk in Communities validation cohort. For nearly half of the individual proteins independently associated with cardiovascular risk, Mendelian randomization suggested a causal link to cardiovascular events or risk factors. Pathway analyses revealed enrichment of proteins involved in immunologic function, vascular and neuronal development, and hepatic fibrosis.<br /><b>Conclusion</b><br />In two sizeable populations with CKD, a proteomic risk model for incident cardiovascular disease surpassed clinical risk models recommended in clinical practice, even after including estimated glomerular filtration rate. New biological insights may prioritize the development of therapeutic strategies for cardiovascular risk reduction in the CKD population.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 04 Apr 2023; epub ahead of print</small></div>

<div><h4>Exercise benefits in cardiovascular diseases: from mechanisms to clinical implementation.</h4><i>Valenzuela PL, Ruilope LM, Santos-Lozano A, Wilhelm M, ... Fiuza-Luces C, Lucia A</i><br /><AbstractText>There is a pandemic of physical inactivity that appears to parallel the widespread prevalence of cardiovascular disease (CVD). Yet, regular physical activity (PA) and exercise can play an important role not only in primary cardiovascular prevention but also in secondary prevention. This review discusses some of the main cardiovascular effects of PA/exercise and the mechanisms involved, including a healthier metabolic milieu with attenuation of systemic chronic inflammation, as well as adaptations at the vascular (antiatherogenic effects) and heart tissue (myocardial regeneration and cardioprotection) levels. The current evidence for safe implementation of PA and exercise in patients with CVD is also summarized.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 03 Apr 2023; epub ahead of print</small></div>

<div><h4>Fate of the unoperated ascending thoracic aortic aneurysm: three-decade experience from the Aortic Institute at Yale University.</h4><i>Wu J, Zafar MA, Liu Y, Chen JF, ... Rizzo JA, Elefteriades JA</i><br /><b>Aims</b><br />This study aims to outline the \'true\' natural history of ascending thoracic aortic aneurysm (ATAA) based on a cohort of patients not undergoing surgical intervention.<br /><b>Methods and results</b><br />The outcomes, risk factors, and growth rates of 964 unoperated ATAA patients were investigated, over a median follow-up of 7.9 (maximum of 34) years. The primary endpoint was adverse aortic events (AAE), including dissection, rupture, and aortic death. At aortic sizes of 3.5-3.9, 4.0-4.4, 4.5-4.9, 5.0-5.4, 5.5-5.9, and ≥6.0 cm, the average yearly risk of AAE was 0.2%, 0.2%, 0.3%, 1.4%, 2.0%, and 3.5%, respectively (P < 0.001), and the 10-year survival free from AAE was 97.8%, 98.2%, 97.3%, 84.6%, 80.4%, and 70.9%, respectively (P < 0.001). The risk of AAE was relatively flat until 5 cm of aortic size, at which it began to increase rapidly (P for non-linearity <0.001). The mean annual growth rate was estimated to be 0.10 ± 0.01 cm/year. Ascending thoracic aortic aneurysms grew in a very slow manner, and aortic growth over 0.2 cm/year was rarely seen. Multivariable Cox regression identified aortic size [hazard ratio (HR): 1.78, 95% confidence interval (CI): 1.50-2.11, P < 0.001] and age (HR: 1.02, 95% CI: 1.00-1.05, P = 0.015) as significant independent risk factors for AAE. Interestingly, hyperlipidemia (HR: 0.46, 95% CI: 0.23-0.91, P = 0.025) was found to be a significant protective factor for AAE in univariable Cox regression.<br /><b>Conclusion</b><br />An aortic size of 5 cm, rather than 5.5 cm, may be a more appropriate intervention criterion for prophylactic ATAA repair. Aortic growth may not be an applicable indicator for intervention.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 30 Mar 2023; epub ahead of print</small></div>

<div><h4>Proteomics and lipidomics in atherosclerotic cardiovascular disease risk prediction.</h4><i>Nurmohamed NS, Kraaijenhof JM, Mayr M, Nicholls SJ, ... Catapano AL, Stroes ESG</i><br /><AbstractText>Given the limited accuracy of clinically used risk scores such as the Systematic COronary Risk Evaluation 2 system and the Second Manifestations of ARTerial disease 2 risk scores, novel risk algorithms determining an individual\'s susceptibility of future incident or recurrent atherosclerotic cardiovascular disease (ASCVD) risk are urgently needed. Due to major improvements in assay techniques, multimarker proteomic and lipidomic panels hold the promise to be reliably assessed in a high-throughput routine. Novel machine learning-based approaches have facilitated the use of this high-dimensional data resulting from these analyses for ASCVD risk prediction. More than a dozen of large-scale retrospective studies using different sets of biomarkers and different statistical methods have consistently demonstrated the additive prognostic value of these panels over traditionally used clinical risk scores. Prospective studies are needed to determine the clinical utility of a biomarker panel in clinical ASCVD risk stratification. When combined with the genetic predisposition captured with polygenic risk scores and the actual ASCVD phenotype observed with coronary artery imaging, proteomics and lipidomics can advance understanding of the complex multifactorial causes underlying an individual\'s ASCVD risk.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 29 Mar 2023; epub ahead of print</small></div>

<div><h4>Reversal agents for current and forthcoming direct oral anticoagulants.</h4><i>van Es N, De Caterina R, Weitz JI</i><br /><AbstractText>Over the past 20 years, there has been a shift from vitamin K antagonists to direct oral anticoagulants (DOACs), which include the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban. Although DOACs are associated with less serious bleeding than vitamin K antagonists, bleeding still occurs with DOACs, particularly in the elderly and in those with comorbidities. Reversal of the anticoagulant effects of the DOACs may be needed in patients with serious bleeding and in those requiring urgent surgery or intervention. Reversal can be effected with specific agents, such as idarucizumab for dabigatran and andexanet alfa for apixaban, edoxaban, and rivaroxaban, or with non-specific agents, such as prothrombin complex concentrates, activated prothrombin complex concentrate, and recombinant activated factor VII. This paper (i) provides an update on when and how to reverse the DOACs, (ii) describes new reversal agents under development, and (iii) provides a strategic framework for the reversal of the factor XI inhibitors currently under investigation in phase three clinical trials.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 29 Mar 2023; epub ahead of print</small></div>

<div><h4>Reversal and removal of oral antithrombotic drugs in patients with active or perceived imminent bleeding.</h4><i>Cao D, Amabile N, Chiarito M, Lee VT, ... Deliargyris EN, Mehran R</i><br /><AbstractText>Remarkable progress has been made in the pharmacological management of patients with cardiovascular disease, including the frequent use of antithrombotic agents. Nonetheless, bleeding complications remain frequent and potentially life-threatening. Therapeutic interventions relying on prompt antithrombotic drug reversal or removal have been developed to assist clinicians in treating patients with active bleeding or an imminent threat of major bleeding due to urgent surgery or invasive procedures. Early phase studies on these novel strategies have shown promising results using surrogate pharmacodynamic endpoints. However, the benefit of reversing/removing antiplatelet or anticoagulant drugs should always be weighed against the possible prothrombotic effects associated with withdrawal of antithrombotic protection, bleeding, and surgical trauma. Understanding the ischemic-bleeding risk tradeoff of antithrombotic drug reversal and removal strategies in the context of urgent high-risk settings requires dedicated clinical investigations, but challenges in trial design remain, with relevant practical, financial, and ethical implications.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 29 Mar 2023; epub ahead of print</small></div>

<div><h4>Genetic analyses identify brain structures related to cognitive impairment associated with elevated blood pressure.</h4><i>Siedlinski M, Carnevale L, Xu X, Carnevale D, ... Holmes MV, Guzik TJ</i><br /><b>Background:</b><br/>and aims</b><br />Observational studies have linked elevated blood pressure (BP) to impaired cognitive function. However, the functional and structural changes in the brain that mediate the relationship between BP elevation and cognitive impairment remain unknown. Using observational and genetic data from large consortia, this study aimed to identify brain structures potentially associated with BP values and cognitive function.<br /><b>Methods and results</b><br />Data on BP were integrated with 3935 brain magnetic resonance imaging-derived phenotypes (IDPs) and cognitive function defined by fluid intelligence score. Observational analyses were performed in the UK Biobank and a prospective validation cohort. Mendelian randomisation (MR) analyses used genetic data derived from the UK Biobank, International Consortium for Blood Pressure, and COGENT consortium. Mendelian randomisation analysis identified a potentially adverse causal effect of higher systolic BP on cognitive function [-0.044 standard deviation (SD); 95% confidence interval (CI) -0.066, -0.021] with the MR estimate strengthening (-0.087 SD; 95% CI -0.132, -0.042), when further adjusted for diastolic BP. Mendelian randomisation analysis found 242, 168, and 68 IDPs showing significant (false discovery rate P < 0.05) association with systolic BP, diastolic BP, and pulse pressure, respectively. Most of these IDPs were inversely associated with cognitive function in observational analysis in the UK Biobank and showed concordant effects in the validation cohort. Mendelian randomisation analysis identified relationships between cognitive function and the nine of the systolic BP-associated IDPs, including the anterior thalamic radiation, anterior corona radiata, or external capsule.<br /><b>Conclusion</b><br />Complementary MR and observational analyses identify brain structures associated with BP, which may be responsible for the adverse effects of hypertension on cognitive performance.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 27 Mar 2023; epub ahead of print</small></div>

<div><h4>Anthropometric measures and adverse outcomes in heart failure with reduced ejection fraction: revisiting the obesity paradox.</h4><i>Butt JH, Petrie MC, Jhund PS, Sattar N, ... Packer M, McMurray JJV</i><br /><b>Aims</b><br />Although body mass index (BMI) is the most commonly used anthropometric measure, newer indices such as the waist-to-height ratio, better reflect the location and amount of ectopic fat, as well as the weight of the skeleton, and may be more useful.<br /><b>Methods and results</b><br />The prognostic value of several newer anthropometric indices was compared with that of BMI in patients with heart failure (HF) and reduced ejection fraction (HFrEF) enrolled in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure. The primary outcome was HF hospitalization or cardiovascular death. The association between anthropometric indices and outcomes were comprehensively adjusted for other prognostic variables, including natriuretic peptides. An \'obesity-survival paradox\' related to lower mortality risk in those with BMI ≥25 kg/m2 (compared with normal weight) was identified but this was eliminated by adjustment for other prognostic variables. This paradox was less evident for waist-to-height ratio (as an exemplar of indices not incorporating weight) and eliminated by adjustment: the adjusted hazard ratio (aHR) for all-cause mortality, for quintile 5 vs. quintile 1, was 1.10 [95% confidence interval (CI) 0.87-1.39]. However, both BMI and waist-to-height ratio showed that greater adiposity was associated with a higher risk of the primary outcome and HF hospitalization; this was more evident for waist-to-height ratio and persisted after adjustment e.g. the aHR for HF hospitalization for quintile 5 vs. quintile 1 of waist-to-height ratio was 1.39 (95% CI 1.06-1.81).<br /><b>Conclusion</b><br />In patients with HFrEF, alternative anthropometric measurements showed no evidence for an \'obesity-survival paradox\'. Newer indices that do not incorporate weight showed that greater adiposity was clearly associated with a higher risk of HF hospitalization.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 22 Mar 2023; epub ahead of print</small></div>

<div><h4>Tc-99m labelled bone scintigraphy in suspected cardiac amyloidosis.</h4><i>Rauf MU, Hawkins PN, Cappelli F, Perfetto F, ... Fontana M, Gillmore JD</i><br /><b>Aims</b><br />To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease.<br /><b>Methods and results</b><br />A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM.<br /><b>Conclusion</b><br />The NBDC for ATTR-CM are highly specific [97% (95% CI 0.91-0.99)] in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 22 Mar 2023; epub ahead of print</small></div>

<div><h4>Vitamin D in atherosclerosis and cardiovascular events.</h4><i>Carbone F, Liberale L, Libby P, Montecucco F</i><br /><AbstractText>Both experimental and clinical findings linking vitamin D to cardiovascular (CV) risk have prompted consideration of its supplementation to improve overall health. Yet several meta-analyses do not provide support for the clinical effectiveness of this strategy. Meanwhile, the understanding of the roles of vitamin D in the pathophysiology of CV diseases has evolved. Specifically, recent work has revealed some non-classical pleiotropic effects of vitamin D, increasing the complexity of vitamin D signalling. Within particular microenvironments (e.g. dysfunctional adipose tissue and atherosclerotic plaque), vitamin D can act locally at cellular level through intracrine/autocrine/paracrine feedforward and feedback circuits. Within atherosclerotic tissues, \'local\' vitamin D levels may influence relevant systemic consequences independently of its circulating pool. Moreover, vitamin D links closely to other signalling pathways of CV relevance including those driving cellular senescence, ageing, and age-related diseases-among them CV conditions. This review updates knowledge on vitamin D biology aiming to clarify the widening gap between experimental and clinical evidence. It highlights the potential reverse causation confounding correlation between vitamin D status and CV health, and the need to consider novel pathophysiological concepts in the design of future clinical trials that explore the effects of vitamin D on atherosclerosis and risk of CV events.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 21 Mar 2023; epub ahead of print</small></div>

<div><h4>Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.</h4><i>Mahmood SS, Riedell PA, Feldman S, George G, ... Neilan TG, Steingart RM</i><br /><b>Aims</b><br />Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient\'s immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality.<br /><b>Methods and results</b><br />From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden.<br /><b>Conclusion</b><br />Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 20 Mar 2023; epub ahead of print</small></div>

<div><h4>Mosaic loss of Y chromosome in monocytes is associated with lower survival after transcatheter aortic valve replacement.</h4><i>Mas-Peiro S, Abplanalp WT, Rasper T, Berkowitsch A, ... Dimmeler S, Zeiher AM</i><br /><b>Aims</b><br />Mosaic loss of Y chromosome (LOY) in blood cells is the most common acquired mutation, increases with age, and is related to cardiovascular disease. Loss of Y chromosome induces cardiac fibrosis in murine experiments mimicking the consequences of aortic valve stenosis, the prototypical age-related disease. Cardiac fibrosis is the major determinant of mortality even after transcatheter aortic valve replacement (TAVR). It was hypothesized that LOY affects long-term outcome in men undergoing TAVR.<br /><b>Methods and results</b><br />Using digital PCR in DNA of peripheral blood cells, LOY (Y/X ratio) was assessed by targeting a 6 bp sequence difference between AMELX and AMELY genes using TaqMan. The genetic signature of monocytes lacking the Y chromosome was deciphered by scRNAseq. In 362 men with advanced aortic valve stenosis undergoing successful TAVR, LOY ranged from -4% to 83.4%, and was >10% in 48% of patients. Three-year mortality increased with LOY. Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off of LOY >17% to predict mortality. In multivariate analysis, LOY remained a significant (P < 0.001) independent predictor of death during follow-up. scRNAseq disclosed a pro-fibrotic gene signature with LOY monocytes displaying increased expression of transforming growth factor (TGF) β-associated signaling, while expression of TGFβ-inhibiting pathways was down-regulated.<br /><b>Conclusion</b><br />This is the first study to demonstrate that LOY in blood cells is associated with profoundly impaired long-term survival even after successful TAVR. Mechanistically, the pro-fibrotic gene signature sensitizing the patient-derived circulating LOY monocytes for the TGFβ signaling pathways supports a prominent role of cardiac fibrosis in contributing to the effects of LOY observed in men undergoing TAVR.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 18 Mar 2023; epub ahead of print</small></div>

<div><h4>Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis.</h4><i>Lehtonen J, Uusitalo V, Pöyhönen P, Mäyränpää MI, Kupari M</i><br /><AbstractText>Cardiac sarcoidosis (CS) results from epithelioid cell granulomas infiltrating the myocardium and predisposing to conduction disturbances, ventricular tachyarrhythmias, and heart failure. Manifest CS, however, constitutes only the top of an iceberg as advanced imaging uncovers cardiac involvement 4 to 5 times more commonly than what is clinically detectable. Definite diagnosis of CS requires myocardial biopsy and histopathology, but a sufficient diagnostic likelihood can be achieved by combining extracardiac histology of sarcoidosis with clinical manifestations and findings on cardiac imaging. CS can appear as the first or only organ manifestation of sarcoidosis or on top of pre-existing extracardiac disease. Due to the lack of controlled trials, the care of CS is based on observational evidence of low quality. Currently, the treatment involves corticosteroid-based, tiered immunosuppression to control myocardial inflammation with medical and device-based therapy for symptomatic atrioventricular block, ventricular tachyarrhythmias, and heart failure. Recent outcome data indicate 90% to 96% 5-year survival in manifest CS with the 10-year figures ranging from 80% to 90%. Major progress in the care of CS awaits the key to its molecular-genetic pathogenesis and large-scale controlled clinical trials.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Heart failure with preserved ejection fraction: relevance of a dedicated dyspnoea clinic.</h4><i>Verwerft J, Soens L, Wynants J, Meysman M, ... Herbots L, Verbrugge FH</i><br /><b>Background:</b><br/>and aims</b><br />Heart failure with preserved ejection fraction (HFpEF) is a syndrome with a heterogeneous presentation. This study provides an in-;depth description of haemodynamic and metabolic alterations revealed by systematic assessment through cardiopulmonary exercise testing combined with exercise echocardiography (CPETecho) within a dedicated dyspnoea clinic.<br /><b>Methods and results</b><br />Consecutive patients (n = 297), referred to a dedicated dyspnoea clinic using a standardized workup including CPETecho, with HFpEF diagnosed through a H2FPEF score ≥6 or HFA-PEFF score ≥5, were evaluated. A median of four haemodynamic/metabolic alterations was uncovered per patient: impaired stroke volume reserve (73%), impaired chronotropic reserve (72%), exercise pulmonary hypertension (65%), and impaired diastolic reserve (64%) were the most frequent cardiac alterations. Impaired peripheral oxygen extraction and a ventilatory limitation were present in 40% and 39%, respectively. In 267 patients (90%), 575 further diagnostic examinations were recommended (median of two tests per patient). Cardiac magnetic resonance imaging, coronary or amyloidosis workup, ventilation-perfusion scanning, and pulmonology referral were each recommended in approximately one out of three patients. In 293 patients (99%), 929 cardiovascular drug optimizations were performed (median of 3 modifications per patient). In 110 patients (37%), 132 cardiovascular interventions were performed, with ablation as the most frequent procedure.<br /><b>Conclusion</b><br />Holistic workup of HFpEF patients within a multidisciplinary, dedicated dyspnoea clinic, including systematic implementation of CPETecho reveals various haemodynamic/metabolic alterations, leading to further diagnostic testing and potential treatment changes in the majority of cases.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Unmet needs in valvular heart disease.</h4><i>Messika-Zeitoun D, Baumgartner H, Burwash IG, Vahanian A, ... Mesana T, Iung B</i><br /><AbstractText>Valvular heart disease (VHD) is the next epidemic in the cardiovascular field, affecting millions of people worldwide and having a major impact on health care systems. With aging of the population, the incidence and prevalence of VHD will continue to increase. However, VHD has not received the attention it deserves from both the public and policymakers. Despite important advances in the pathophysiology, natural history, management, and treatment of VHD including the development of transcatheter therapies, VHD remains underdiagnosed, identified late, and often undertreated with inequality in access to care and treatment options, and there is no medication that can prevent disease progression. The present review article discusses these gaps in the management of VHD and potential actions to undertake to improve the outcome of patients with VHD.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Long-term outcomes of phenoclusters in severe tricuspid regurgitation.</h4><i>Rao VN, Giczewska A, Chiswell K, Felker GM, ... Parikh KS, Vemulapalli S</i><br /><b>Aims</b><br />Severe tricuspid regurgitation (TR) exhibits high 1-year morbidity and mortality, yet long-term cardiovascular risk overall and by subgroups remains unknown. This study characterizes 5-year outcomes and identifies distinct clinical risk profiles of severe TR.<br /><b>Methods and results</b><br />Patients were included from a large US tertiary referral center with new severe TR by echocardiography based on four-category American Society of Echocardiography grading scale between 2007 and 2018. Patients were categorized by TR etiology (with lead present, primary, and secondary) and by supervised recursive partitioning (survival trees) for outcomes of death and the composite of death or heart failure hospitalization. The Kaplan-Meier estimates and Cox regression models were used to evaluate any association by (i) TR etiology and (ii) groups identified by survival trees and outcomes over 5 years. Among 2379 consecutive patients with new severe TR, median age was 70 years, 61% were female, and 40% were black. Event rates (95% confidence interval) were 30.9 (29.0-32.8) events/100 patient-years for death and 49.0 (45.9-52.2) events/100 patient-years for the composite endpoint, with no significant difference by TR etiology. After applying supervised survival tree modeling, two separate groups of four phenoclusters with distinct clinical prognoses were separately identified for death and the composite endpoint. Variables discriminating both outcomes were age, albumin, blood urea nitrogen, right ventricular function, and systolic blood pressure (all P < 0.05).<br /><b>Conclusion</b><br />Patients with newly identified severe TR have high 5-year risk for death and death or heart failure hospitalization. Partitioning patients using supervised survival tree models, but not TR etiology, discriminated clinical risk. These data aid in identifying relevant subgroups in clinical trials of TR and clinical risk/benefit analysis for TR therapies.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Intrapericardial long non-coding RNA-Tcf21 antisense RNA inducing demethylation administration promotes cardiac repair.</h4><i>Zhu D, Liu S, Huang K, Li J, ... Li Z, Cheng K</i><br /><b>Aims</b><br />Epicardium and epicardium-derived cells are critical players in myocardial fibrosis. Mesenchymal stem cell-derived extracellular vesicles (EVs) have been studied for cardiac repair to improve cardiac remodelling, but the actual mechanisms remain elusive. The aim of this study is to investigate the mechanisms of EV therapy for improving cardiac remodelling and develop a promising treatment addressing myocardial fibrosis.<br /><b>Methods and results</b><br />Extracellular vesicles were intrapericardially injected for mice myocardial infarction treatment. RNA-seq, in vitro gain- and loss-of-function experiments, and in vivo studies were performed to identify targets that can be used for myocardial fibrosis treatment. Afterward, a lipid nanoparticle-based long non-coding RNA (lncRNA) therapy was prepared for mouse and porcine models of myocardial infarction treatment. Intrapericardial injection of EVs improved adverse myocardial remodelling in mouse models of myocardial infarction. Mechanistically, Tcf21 was identified as a potential target to improve cardiac remodelling. Loss of Tcf21 function in epicardium-derived cells caused increased myofibroblast differentiation, whereas forced Tcf21 overexpression suppressed transforming growth factor-β signalling and myofibroblast differentiation. LncRNA-Tcf21 antisense RNA inducing demethylation (TARID) that enriched in EVs was identified to up-regulate Tcf21 expression. Formulated lncRNA-TARID-laden lipid nanoparticles up-regulated Tcf21 expression in epicardium-derived cells and improved cardiac function and histology in mouse and porcine models of myocardial infarction.<br /><b>Conclusion</b><br />This study identified Tcf21 as a critical target for improving cardiac fibrosis. Up-regulating Tcf21 by using lncRNA-TARID-laden lipid nanoparticles could be a promising way to treat myocardial fibrosis. This study established novel mechanisms underlying EV therapy for improving adverse remodelling and proposed a lncRNA therapy for cardiac fibrosis.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 14 Mar 2023; epub ahead of print</small></div>

<div><h4>Acyl ghrelin improves cardiac function in heart failure and increases fractional shortening in cardiomyocytes without calcium mobilization.</h4><i>Lund LH, Hage C, Pironti G, Thorvaldsen T, ... Andersson DC, Ståhlberg M</i><br /><b>Background:</b><br/>and aims</b><br />Ghrelin is an endogenous appetite-stimulating peptide hormone with potential cardiovascular benefits. Effects of acylated (activated) ghrelin were assessed in patients with heart failure and reduced ejection fraction (HFrEF) and in ex vivo mouse cardiomyocytes.<br /><b>Methods and results</b><br />In a randomized placebo-controlled double-blind trial, 31 patients with chronic HFrEF were randomized to synthetic human acyl ghrelin (0.1 µg/kg/min) or placebo intravenously over 120 min. The primary outcome was change in cardiac output (CO). Isolated mouse cardiomyocytes were treated with acyl ghrelin and fractional shortening and calcium transients were assessed. Acyl ghrelin but not placebo increased cardiac output (acyl ghrelin: 4.08 ± 1.15 to 5.23 ± 1.98 L/min; placebo: 4.26 ± 1.23 to 4.11 ± 1.99 L/min, P < 0.001). Acyl ghrelin caused a significant increase in stroke volume and nominal increases in left ventricular ejection fraction and segmental longitudinal strain and tricuspid annular plane systolic excursion. There were no effects on blood pressure, arrhythmias, or ischaemia. Heart rate decreased nominally (acyl ghrelin: 71 ± 11 to 67 ± 11  b.p.m.; placebo 69 ± 8 to 68 ± 10  b.p.m.). In cardiomyocytes, acyl ghrelin increased fractional shortening, did not affect cellular Ca2+ transients, and reduced troponin I phosphorylation. The increase in fractional shortening and reduction in troponin I phosphorylation was blocked by the acyl ghrelin antagonist D-Lys 3.<br /><b>Conclusion</b><br />In patients with HFrEF, acyl ghrelin increased cardiac output without causing hypotension, tachycardia, arrhythmia, or ischaemia. In isolated cardiomyocytes, acyl ghrelin increased contractility independently of preload and afterload and without Ca2+ mobilization, which may explain the lack of clinical side effects. Ghrelin treatment should be explored in additional randomized trials.<br /><b>Clinical trial registration</b><br />ClinicalTrials.gov Identifier: NCT05277415.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 14 Mar 2023; epub ahead of print</small></div>

<div><h4>Cardiac rehabilitation for heart failure: \'Cinderella\' or evidence-based pillar of care?</h4><i>Taylor RS, Dalal HM, Zwisler AD</i><br /><AbstractText>Cardiac rehabilitation remains the \'Cinderella\' of treatments for heart failure. This state-of-the-art review provides a contemporary update on the evidence base, clinical guidance, and status of cardiac rehabilitation delivery for patients with heart failure. Given that cardiac rehabilitation participation results in important improvements in patient outcomes, including health-related quality of life, this review argues that an exercise-based rehabilitation is a key pillar of heart failure management alongside drug and medical device provision. To drive future improvements in access and uptake, health services should offer heart failure patients a choice of evidence-based modes of rehabilitation delivery, including home, supported by digital technology, alongside traditional centre-based programmes (or combinations of modes, \'hybrid\') and according to stage of disease and patient preference.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 11 Mar 2023; epub ahead of print</small></div>

<div><h4>Ozone pollution and hospital admissions for cardiovascular events.</h4><i>Jiang Y, Huang J, Li G, Wang W, ... Guo X, Wu S</i><br /><b>Aims</b><br />The available literature on morbidity risk of cardiovascular diseases associated with ambient ozone pollution is still limited. This study examined the potential acute effects of exposure to ambient ozone pollution on hospital admissions of cardiovascular events in China.<br /><b>Methods and results</b><br />A two-stage multi-city time-series study approach was used to explore the associations of exposure to ambient ozone with daily hospital admissions (n = 6 444 441) for cardiovascular events in 70 Chinese cities of prefecture-level or above during 2015-17. A 10 μg/m3 increment in 2-day average daily 8 h maximum ozone concentrations was associated with admission risk increases of 0.46% [95% confidence interval (CI): 0.28%, 0.64%] in coronary heart disease, 0.45% (95% CI: 0.13%, 0.77%) in angina pectoris, 0.75% (95% CI: 0.38%, 1.13%) in acute myocardial infarction (AMI), 0.70% (95% CI: 0.41%, 1.00%) in acute coronary syndrome, 0.50% (95% CI: 0.24%, 0.77%) in heart failure, 0.40% (95% CI: 0.23%, 0.58%) in stroke and 0.41% (95% CI: 0.22%, 0.60%) in ischemic stroke, respectively. The excess admission risks for these cardiovascular events associated with high ozone pollution days (with 2-day average 8-h maximum concentrations ≥100 µg/m3 vs. < 70 µg/m3) ranged from 3.38% (95% CI: 1.73%, 5.06%) for stroke to 6.52% (95% CI: 2.92%, 10.24%) for AMI.<br /><b>Conclusion</b><br />Ambient ozone was associated with increased hospital admission risk for cardiovascular events. Greater admission risks for cardiovascular events were observed under high ozone pollution days. These results provide evidence for the harmful cardiovascular effects of ambient ozone and call for special attention on the control of high ozone pollution.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 10 Mar 2023; epub ahead of print</small></div>

<div><h4>Trimethylamine N-oxide is associated with long-term mortality risk: the multi-ethnic study of atherosclerosis.</h4><i>Wang M, Li XS, Wang Z, de Oliveira Otto MC, ... Hazen SL, Mozaffarian D</i><br /><b>Aims</b><br />Little is known about associations of trimethylamine N-oxide (TMAO), a novel gut microbiota-generated metabolite of dietary phosphatidylcholine and carnitine, and its changes over time with all-cause and cause-specific mortality in the general population or in different race/ethnicity groups. The study aimed to investigate associations of serially measured plasma TMAO levels and changes in TMAO over time with all-cause and cause-specific mortality in a multi-ethnic community-based cohort.<br /><b>Methods and results</b><br />The study included 6,785 adults from the Multi-Ethnic Study of Atherosclerosis. TMAO was measured at baseline and year 5 using mass spectrometry. Primary outcomes were adjudicated all-cause mortality and cardiovascular disease (CVD) mortality. Secondary outcomes were deaths due to kidney failure, cancer, or dementia obtained from death certificates. Cox proportional hazards models with time-varying TMAO and covariates assessed the associations with adjustment for sociodemographics, lifestyles, diet, metabolic factors, and comorbidities. During a median follow-up of 16.9 years, 1704 participants died and 411 from CVD. Higher TMAO levels associated with higher risk of all-cause mortality [hazard ratio (HR): 1.12, 95% confidence interval (CI): 1.08-1.17], CVD mortality (HR: 1.09, 95% CI: 1.00-1.09), and death due to kidney failure (HR: 1.44, 95% CI: 1.25-1.66) per inter-quintile range, but not deaths due to cancer or dementia. Annualized changes in TMAO levels associated with higher risk of all-cause mortality (HR: 1.10, 95% CI: 1.05-1.14) and death due to kidney failure (HR: 1.54, 95% CI: 1.26-1.89) but not other deaths.<br /><b>Conclusion</b><br />Plasma TMAO levels were positively associated with mortality, especially deaths due to cardiovascular and renal disease, in a multi-ethnic US cohort.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 08 Mar 2023; epub ahead of print</small></div>

<div><h4>Treatment of late paravalvular regurgitation after transcatheter aortic valve implantation: prognostic implications.</h4><i>Landes U, Hochstadt A, Manevich L, Webb JG, ... Rubinshtein R, Danenberg H</i><br /><b>Background:</b><br/>and aims</b><br />Paravalvular regurgitation (PVR) after transcatheter aortic valve implantation (TAVI) is associated with increased morbidity and mortality. The effect of transcatheter interventions to treat PVR after the index TAVI was investigated.<br /><b>Methods</b><br />A registry of consecutive patients who underwent transcatheter intervention for ≥ moderate PVR after the index TAVI at 22 centers. Principal outcomes were residual aortic regurgitation (AR) and mortality at 1 year after PVR treatment.<br /><b>Results</b><br />A total of 201 patients were identified: 87 (43%) underwent redo-TAVI, 79 (39%) plug closure and 35 (18%) balloon valvuloplasty. Median TAVI-to-re-intervention time was 207 (35; 765) days. The failed valve was self-expanding in 129 (63.9%) patients. Most frequent devices utilized were a Sapien 3 valve for redo-TAVI (55, 64%), an AVP II as plug (33, 42%) and a True balloon for valvuloplasty (20, 56%). At 30 days, AR ≥ moderate persisted in 33 (17.4%) patients: 8 (9.9%) after redo-TAVI, 18 (25.9%) after plug and 7 (21.9%) after valvuloplasty (p=0.036). Overall mortality was 10 (5.0%) at 30 days and 29 (14.4%) at 1 year: 0, 8 (10.1%) and 2 (5.7%) at 30 days (p=0.010); and 11 (12.6%), 14 (17.7%) and 4 (11.4%) at 1 year (p=0.418), after redo-TAVI, plug and valvuloplasty, respectively. Regardless of treatment strategy, patients in whom AR was reduced to ≤ mild had lower mortality at 1 year compared to those with AR persisting ≥ moderate [11 (8.0%) vs. 6 (21.4%); p=0.007].<br /><b>Conclusions</b><br />This study describes the efficacy of transcatheter treatments for PVR after TAVI. Patients in whom PVR was successfully reduced had better prognosis. The selection of patients and optimal PVR treatment modality require further investigation.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 08 Mar 2023; epub ahead of print</small></div>

<div><h4>Dual antiplatelet therapy de-escalation in acute coronary syndrome: an individual patient meta-analysis.</h4><i>Kang J, Rizas KD, Park KW, Chung J, ... Koo BK, Kim HS</i><br /><b>Aims</b><br />Dual-antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor is the standard treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). De-escalation of the potent P2Y12 inhibtor is an appealing concept to balance the ischaemic and bleeding risks after PCI. An individual patient data meta-analysis was performed to compare de-escalation versus standard DAPT in patients with ACS.<br /><b>Methods and results</b><br />Electronic databases, including PubMed, Embase, and the Cochrane database, were searched to identify randomised clinical trials (RCTs) comparing the de-escalation strategy with the standard DAPT after PCI in patients with ACS. Individual patient-level data were collected from the relevant trials. The co-primary endpoints of interest were the ischaemic composite endpoint (a composite of cardiac death, myocardial infarction, and cerebrovascular events) and bleeding endpoint (any bleeding) at 1-year post-PCI. Four RCTs (the TROPICAL-ACS, POPular Genetics, HOST-REDUCE-POLYTECH-ACS, and TALOS-AMI trials) including 10 133 patients were analysed. The ischaemic endpoint was significantly lower in the patients assigned to the de-escalation strategy than in those assigned to the standard strategy (2.3% vs. 3.0%, hazard ratio [HR] 0.761, 95% confidence interval [CI] 0.597-0.972, log rank P = 0.029). Bleeding was also significantly lower in the de-escalation strategy group (6.5% vs. 9.1%, HR 0.701, 95% CI 0.606-0.811, log rank P < 0.001). No significant intergroup differences were observed in terms of all-cause death and major bleeding events. Subgroup analyses revealed that compared to guided de-escalation, unguided de-escalation had a significantly larger impact on bleeding endpoint reduction (P for interaction = 0.007); no intergroup differences were observed for the ischaemic endpoints.<br /><b>Conclusion</b><br />In this individual patient data meta-analysis, DAPT-based de-escalation was associated with both decreased ischaemic and bleeding endpoints. Reduction in bleeding endpoints was more prominent for the unguided than the guided de-escalation strategy.<br /><b>Study registration number</b><br />This study was registered in the PROSPERO (ID: CRD42021245477).<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 08 Mar 2023; epub ahead of print</small></div>

<div><h4>Overcoming professional barriers encountered by women in interventional cardiology: an EAPCI statement.</h4><i>Buchanan GL, Paradies V, Karam N, Holmvang L, ... Dudek D, Chieffo A</i><br /><AbstractText>Despite the increasing proportion of female medical and nursing students, there is still a significant under-representation of women working as healthcare providers in interventional cardiology, with very few of them reaching senior leadership, academic positions, or acting principal investigators, as well as actively involved in company advisory boards. In this position paper, we will describe the current status of women working in interventional cardiology across Europe. We will also provide an overview of the most relevant determinants of the under-representation of women at each stage of the interventional cardiology career path and offer practical suggestions for overcoming these challenges.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 07 Mar 2023; epub ahead of print</small></div>

<div><h4>Circulating ketone bodies and cardiovascular outcomes: the MESA study.</h4><i>Shemesh E, Chevli PA, Islam T, German CA, ... Vaduganathan M, Shapiro MD</i><br /><b>Aims</b><br />Ketone bodies (KB) are an important alternative metabolic fuel source for the myocardium. Experimental and human investigations suggest that KB may have protective effects in patients with heart failure. This study aimed to examine the association between KB and cardiovascular outcomes and mortality in an ethnically diverse population free from cardiovascular disease (CVD).<br /><b>Methods and results</b><br />This analysis included 6796 participants (mean age 62 ± 10 years, 53% women) from the Multi-Ethnic Study of Atherosclerosis. Total KB was measured by nuclear magnetic resonance spectroscopy. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with cardiovascular outcomes. At a mean follow-up of 13.6 years, after adjusting for traditional CVD risk factors, increasing total KB was associated with a higher rate of hard CVD, defined as a composite of myocardial infarction, resuscitated cardiac arrest, stroke, and cardiovascular death, and all CVD (additionally included adjudicated angina) [hazard ratio, HR (95% confidence interval, CI): 1.54 (1.12-2.12) and 1.37 (1.04-1.80) per 10-fold increase in total KB, respectively]. Participants also experienced an 87% (95% CI: 1.17-2.97) increased rate of CVD mortality and an 81% (1.45-2.23) increased rate of all-cause mortality per 10-fold increase in total KB. Moreover, a higher rate of incident heart failure was observed with increasing total KB [1.68 (1.07-2.65), per 10-fold increase in total KB].<br /><b>Conclusion</b><br />The study found that elevated endogenous KB in a healthy community-based population is associated with a higher rate of CVD and mortality. Ketone bodies could serve as a potential biomarker for cardiovascular risk assessment.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 06 Mar 2023; epub ahead of print</small></div>

<div><h4>Lifelong endurance exercise and its relation with coronary atherosclerosis.</h4><i>De Bosscher R, Dausin C, Claus P, Bogaert J, ... Claessen G, Master@Heart Consortium </i><br /><b>Background:</b><br/>and aims</b><br />The impact of long-term endurance sport participation (on top of a healthy lifestyle) on coronary atherosclerosis and acute cardiac events remains controversial.<br /><b>Methods</b><br />The Master@Heart study is a well-balanced prospective observational cohort study. Overall, 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after 30 years of age), and 176 healthy non-athletes, all male with a low cardiovascular risk profile, were included. Peak oxygen uptake (VO2peak) quantified fitness. The primary endpoint was the prevalence of coronary plaques (calcified, mixed, and non-calcified) on computed tomography coronary angiography. Analyses were corrected for multiple cardiovascular risk factors.<br /><b>Results</b><br />The median age was 55 (50-60) years in all groups. Lifelong and late-onset athletes had higher VO2peak than non-athletes (159 [143-177] vs 155 [138-169] vs 122 [108-138] % predicted). Lifelong endurance sports was associated with having ≥1 coronary plaque (odds ratio [OR] 1.86, 95% confidence interval [CI] 1.17-2.94), ≥1 proximal plaque (OR 1.96, 95% CI 1.24-3.11), ≥1 calcified plaques (OR 1.58, 95% CI 1.01-2.49), ≥1 calcified proximal plaque (OR 2.07, 95% CI 1.28-3.35), ≥1 non-calcified plaque (OR 1.95, 95% CI 1.12-3.40), ≥1 non-calcified proximal plaque (OR 2.80, 95% CI 1.39-5.65) and ≥1 mixed plaque (OR 1.78, 95% CI 1.06-2.99) as compared to a healthy non-athletic lifestyle.<br /><b>Conclusion</b><br />Lifelong endurance sport participation is not associated with a more favorable coronary plaque composition compared to a healthy lifestyle. Lifelong endurance athletes had more coronary plaques, including more non-calcified plaques in proximal segments, than fit and healthy individuals with a similarly low cardiovascular risk profile. Longitudinal research is needed to reconcile these findings with the risk of cardiovascular events at the higher end of the endurance exercise spectrum.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 06 Mar 2023; epub ahead of print</small></div>

<div><h4>Transiently achieved very low LDL-cholesterol levels by statin and alirocumab after acute coronary syndrome are associated with cardiovascular risk reduction: the ODYSSEY OUTCOMES trial.</h4><i>Schwartz GG, Szarek M, Bhatt DL, Bittner VA, ... Steg PG, ODYSSEY OUTCOMES Investigators</i><br /><b>Aims</b><br />Long-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus PCSK9 inhibitor.<br /><b>Methods and results</b><br />In 18,924 patients post-acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score-matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median 8.3 months from randomization, after a median 6.0 months with LDL-C < 0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C versus 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047).<br /><b>Conclusions</b><br />A short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years.<br /><b>Trial registration</b><br />ClinicalTrials.gov NCT01663402.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 05 Mar 2023; epub ahead of print</small></div>