<div><h4>Birth weight influences cardiac structure, function, and disease risk: evidence of a causal association.</h4><i>Ardissino M, Morley AP, Slob EAW, Schuermans A, ... Honigberg MC, Ng FS</i><br /><b>Background:</b><br/>and aims</b><br />Low birth weight is a common pregnancy complication, which has been associated with higher risk of cardiometabolic disease in later life. Prior Mendelian randomization (MR) studies exploring this question do not distinguish the mechanistic contributions of variants that directly influence birth weight through the foetal genome (direct foetal effects), vs. variants influencing birth weight indirectly by causing an adverse intrauterine environment (indirect maternal effects). In this study, MR was used to assess whether birth weight, independent of intrauterine influences, is associated with cardiovascular disease risk and measures of adverse cardiac structure and function.<br /><b>Methods</b><br />Uncorrelated (r2 < .001), genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms were extracted from genome-wide association studies summary statistics for birth weight overall, and after isolating direct foetal effects only. Inverse-variance weighted MR was utilized for analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 16 measures of cardiac structure and function. Multiple comparisons were accounted for by Benjamini-Hochberg correction.<br /><b>Results</b><br />Lower genetically-predicted birth weight, isolating direct foetal effects only, was associated with an increased risk of coronary artery disease (odds ratio 1.21, 95% confidence interval 1.06-1.37; P = .031), smaller chamber volumes, and lower stroke volume, but higher contractility.<br /><b>Conclusions</b><br />The results of this study support a causal role of low birth weight in cardiovascular disease, even after accounting for the influence of the intrauterine environment. This suggests that individuals with a low birth weight may benefit from early targeted cardiovascular disease prevention strategies, independent of whether this was linked to an adverse intrauterine environment during gestation.<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: 20 Sep 2023; epub ahead of print</small></div>

<div><h4>Acquired risk factors and incident atrial fibrillation according to age and genetic predisposition.</h4><i>Wang N, Yu Y, Sun Y, Zhang H, ... Wang B, Lu Y</i><br /><b>Background:</b><br/>and aims</b><br />Atrial fibrillation (AF) is the most common sustained arrhythmia in adults. Investigations of risk factor profiles for AF according to age and genetic risk groups are essential to promote individualized strategies for the prevention and control of AF.<br /><b>Methods</b><br />A total of 409 661 participants (mean age, 56 years; 46% men) free of AF at baseline and with complete information about risk factors were included from the UK Biobank cohort. The hazard ratios and population-attributable risk (PAR) percentages of incident AF associated with 23 risk factors were examined, including 3 social factors, 7 health behaviours, 6 cardiometabolic factors, 6 clinical comorbidities, and the genetic risk score (GRS), across 3 age groups (40-49, 50-59, and 60-69 years) and 3 genetic risk groups (low, moderate, and high GRS).<br /><b>Results</b><br />After a follow-up of 5 027 587 person-years, 23 847 participants developed AF. Most cardiometabolic factors and clinical comorbidities showed a significant interaction with age, whereby the associations were generally strengthened in younger groups (Pinteraction < .002). However, only low LDL cholesterol, renal dysfunction, and cardiovascular disease showed a significant interaction with genetic risk, and the associations with these factors were stronger in lower genetic risk groups (Pinteraction < .002). Cardiometabolic factors consistently accounted for the largest number of incident AF cases across all age groups (PAR: 36.2%-38.9%) and genetic risk groups (34.0%-41.9%), with hypertension and overweight/obesity being the two leading modifiable factors. Health behaviours (PAR: 11.5% vs. 8.7%) and genetic risk factors (19.1% vs. 14.3%) contributed to more AF cases in the 40-49 years group than in the 60-69 years group, while the contribution of clinical comorbidities remained relatively stable across different age groups. The AF risk attributable to overall cardiometabolic factors (PAR: 41.9% in the low genetic risk group and 34.0% in the high genetic risk group) and clinical comorbidities (24.7% and 15.9%) decreased with increasing genetic risk. The impact of social factors on AF was relatively low across the groups by age and genetic risk.<br /><b>Conclusions</b><br />This study provided comprehensive information about age- and genetic predisposition-related risk factor profiles for AF in a cohort of UK adults. Prioritizing risk factors according to age and genetic risk stratifications may help to achieve precise and efficient prevention of AF.<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: 19 Sep 2023; epub ahead of print</small></div>

<div><h4>Lack of association between fluoroquinolone and aortic aneurysm or dissection.</h4><i>Huh K, Kang M, Jung J</i><br /><b>Background:</b><br/>and aims</b><br />An increased risk of aortic aneurysm and aortic dissection (AA/AD) has been reported with fluoroquinolone (FQ) use. However, recent studies suggested confounding factors by indication. This study aimed to investigate the risk of AA/AD associated with FQ use.<br /><b>Methods</b><br />This nationwide population-based study included adults aged ≥20 years who received a prescription of oral FQ or third-generation cephalosporins (3GC) during outpatient visits from 2005 to 2016. Data source was the National Health Insurance Service reimbursement database. The primary outcome was hospitalization or in-hospital death with a primary diagnosis of AA/AD. A self-controlled case series (SCCS) and Cox proportional hazards model were used. Self-controlled case series compared the incidence of the primary outcome in the risk period vs. the control periods.<br /><b>Results</b><br />A total of 954 308 patients (777 109 with FQ and 177 199 with 3GC use) were included. The incidence rate ratios for AA/AD between the risk period and the pre-risk period were higher in the 3GC group [11.000; 95% confidence interval (CI) 1.420-85.200] compared to the FQ group (2.000; 95% CI 0.970-4.124). The overall incidence of AA/AD among the patients who received FQ and 3GC was 5.40 and 8.47 per 100 000 person-years. There was no significant difference in the risk between the two groups (adjusted hazard ratio 0.752; 95% CI 0.515-1.100) in the inverse probability of treatment-weighted Cox proportional hazards model. Subgroup and sensitivity analysis showed consistent results.<br /><b>Conclusions</b><br />There was no significant difference in the risk of AA/AD in patients who were administered oral FQ compared to those administered 3GC. The study findings suggest that the use of FQ should not be deterred when clinically indicated.<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 Sep 2023; epub ahead of print</small></div>

<div><h4>Cardiac magnetic resonance biomarkers as surrogate endpoints in cardiovascular trials for myocardial diseases.</h4><i>Benz DC, Gräni C, Antiochos P, Heydari B, ... Dorbala S, Kwong RY</i><br /><AbstractText>Cardiac magnetic resonance offers multiple facets in the diagnosis, risk stratification, and management of patients with myocardial diseases. Particularly, its feature to precisely monitor disease activity lends itself to quantify response to novel therapeutics. This review critically appraises the value of cardiac magnetic resonance imaging biomarkers as surrogate endpoints for prospective clinical trials. The primary focus is to comprehensively outline the value of established cardiac magnetic resonance parameters in myocardial diseases. These include heart failure, cardiac amyloidosis, iron overload cardiomyopathy, hypertrophic cardiomyopathy, cardio-oncology, and inflammatory cardiomyopathies like myocarditis and sarcoidosis.</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: 13 Sep 2023; epub ahead of print</small></div>

<div><h4>Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction.</h4><i>Pandey AK, Bhatt DL, Pandey A, Marx N, ... Pandey A, Verma S</i><br /><AbstractText>For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.</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 Sep 2023; epub ahead of print</small></div>

<div><h4>Electronic health record alerts for management of heart failure with reduced ejection fraction in hospitalized patients: the PROMPT-AHF trial.</h4><i>Ghazi L, Yamamoto Y, Fuery M, O\'Connor K, ... Desai NR, Ahmad T</i><br /><b>Background:</b><br/>and aims</b><br />Patients hospitalized for acute heart failure (AHF) continue to be discharged on an inadequate number of guideline-directed medical therapies (GDMT) despite evidence that inpatient initiation is beneficial. This study aimed to examine whether a tailored electronic health record (EHR) alert increased rates of GDMT prescription at discharge in eligible patients hospitalized for AHF.<br /><b>Methods</b><br />Pragmatic trial of messaging to providers about treatment of acute heart failure (PROMPT-AHF) was a pragmatic, multicenter, EHR-based, and randomized clinical trial. Patients were automatically enrolled 48 h after admission if they met pre-specified criteria for an AHF hospitalization. Providers of patients in the intervention arm received an alert during order entry with relevant patient characteristics along with individualized GDMT recommendations with links to an order set. The primary outcome was an increase in the number of GDMT prescriptions at discharge.<br /><b>Results</b><br />Thousand and twelve patients were enrolled between May 2021 and November 2022. The median age was 74 years; 26% were female, and 24% were Black. At the time of the alert, 85% of patients were on β-blockers, 55% on angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, 20% on mineralocorticoid receptor antagonist (MRA) and 17% on sodium-glucose cotransporter 2 inhibitor. The primary outcome occurred in 34% of both the alert and no alert groups [adjusted risk ratio (RR): 0.95 (0.81, 1.12), P = .99]. Patients randomized to the alert arm were more likely to have an increase in MRA [adjusted RR: 1.54 (1.10, 2.16), P = .01]. At the time of discharge, 11.2% of patients were on all four pillars of GDMT.<br /><b>Conclusions</b><br />A real-time, targeted, and tailored EHR-based alert system for AHF did not lead to a higher number of overall GDMT prescriptions at discharge. Further refinement and improvement of such alerts and changes to clinician incentives are needed to overcome barriers to the implementation of GDMT during hospitalizations for AHF. GDMT remains suboptimal in this setting, with only one in nine patients being discharged on a comprehensive evidence-based regimen for heart failure.<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: 31 Aug 2023; epub ahead of print</small></div>

<div><h4>Stroke risk in women with atrial fibrillation.</h4><i>Buhari H, Fang J, Han L, Austin PC, ... Lee DS, Abdel-Qadir H</i><br /><b>Background:</b><br/>and aims</b><br />Female sex is associated with higher rates of stroke in atrial fibrillation (AF) after adjustment for other CHA2DS2-VASc factors. This study aimed to describe sex differences in age and cardiovascular care to examine their relationship with stroke hazard in AF.<br /><b>Methods</b><br />Population-based cohort study using administrative datasets of people aged ≥66 years diagnosed with AF in Ontario between 2007 and 2019. Cause-specific hazard regression was used to estimate the adjusted hazard ratio (HR) for stroke associated with female sex over a 2-year follow-up. Model 1 included CHA2DS2-VASc factors, with age modelled as 66-74 vs. ≥ 75 years. Model 2 treated age as a continuous variable and included an age-sex interaction term. Model 3 further accounted for multimorbidity and markers of cardiovascular care.<br /><b>Results</b><br />The cohort consisted of 354 254 individuals with AF (median age 78 years, 49.2% female). Females were more likely to be diagnosed in emergency departments and less likely to receive cardiologist assessments, statins, or LDL-C testing, with higher LDL-C levels among females than males. In Model 1, the adjusted HR for stroke associated with female sex was 1.27 (95% confidence interval 1.21-1.32). Model 2 revealed a significant age-sex interaction, such that female sex was only associated with increased stroke hazard at age >70 years. Adjusting for markers of cardiovascular care and multimorbidity further decreased the HR, so that female sex was not associated with increased stroke hazard at age ≤80 years.<br /><b>Conclusion</b><br />Older age and inequities in cardiovascular care may partly explain higher stroke rates in females with AF.<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 Aug 2023; epub ahead of print</small></div>

<div><h4>Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial.</h4><i>Raal F, Fourie N, Scott R, Blom D, ... Stein E, LIBerate-HeFH Investigators</i><br /><b>Background:</b><br/>and aims</b><br />Lerodalcibep, a novel small recombinant fusion protein of a PCSK9-binding domain (adnectin) and human serum albumin demonstrated highly effective low-density lipoprotein cholesterol (LDL-C) reduction with monthly 300 mg in 1.2 ml SC dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep was evaluated in heterozygous familial hypercholesterolaemia (HeFH) patients requiring additional LDL-C lowering.<br /><b>Methods</b><br />Patients were randomized 2:1 to monthly SC injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the percent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24.<br /><b>Results</b><br />In 478 randomized subjects [mean age (range); 53 (18-80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L] lerodalcibep reduced LDL-C, compared to placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean(SE); 95% CI -2.30 to -1.87] with a percentage difference of -58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% CI -2.47 to -2.09) with a percentage difference of -65.0 (2.87)% at the mean of Weeks 22 and 24 (P < 0.0001 for all). With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended ESC LDL-C targets during the study. Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo.<br /><b>Conclusions</b><br />Lerodalcibep, a novel anti-PCSK9 small binding protein dosed monthly as an alternative to monoclonal antibodies, significantly reduced LDL-C in subjects with HeFH with a safety profile similar to placebo.<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: 28 Aug 2023; epub ahead of print</small></div>

<div><h4>Emery-Dreifuss Muscular Dystrophy 1 is associated with high risk of malignant ventricular arrhythmias and end-stage heart failure.</h4><i>Cannie DE, Syrris P, Protonotarios A, Bakalakos A, ... Wahbi K, Elliott PM</i><br /><b>Background:</b><br/>and aims</b><br />Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterise the cardiac complications of EMD variants.<br /><b>Methods</b><br />Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidence in male and female variant-carriers was determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared to consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC).<br /><b>Results</b><br />Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers (mean [SD] ages 33.4 [13.3] and 43.3 [16.8] years, respectively). Nine (23.6%) males developed MVA and five (13.2%) developed ESHF during a median [IQR] follow-up of 65.0 [24.3, 109.5] months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median [IQR] age of 58.6 [53.2, 60.4] years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank p = 0.49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank p = 0.09).<br /><b>Conclusions</b><br />Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac 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: 28 Aug 2023; epub ahead of print</small></div>

<div><h4>Prevalence and Incidence of Diastolic Dysfunction in Atrial Fibrillation: Clinical Implications.</h4><i>Naser JA, Lee E, Scott CG, Kennedy AM, ... Pislaru SV, Borlaug BA</i><br /><b>Background:</b><br/>and aims</b><br />Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) are intimately associated disorders. HFpEF may be overlooked in AF when symptoms are simply attributed to dysrhythmia, and incident AF may identify patients at risk for developing diastolic dysfunction (DD). This study aimed to investigate the prevalence and incidence of DD in patients with new-onset AF compared to sinus rhythm (SR).<br /><b>Methods</b><br />Adults with new-onset AF (n = 1,747) or SR (n = 29,623) and no structural heart disease were identified. Propensity-score matching was performed (1:3 ratio) between AF and SR based on age, sex, body mass index, and comorbidities. Severe DD (SDD) was defined by ≥3/4 abnormal parameters (medial e\', medial E/e\', tricuspid regurgitation velocity, left atrial volume index) and ≥moderate (MDD) by ≥2/4. Annualised changes in DD indices were determined.<br /><b>Results</b><br />New-onset AF was independently associated with SDD (8% vs 3%) and ≥MDD (25% vs 16%). 62% of patients with AF had high-risk H2FPEF scores and 5% had clinically-recognised HFpEF. Over a median follow-up of 3.2 (interquartile range 1.6-5.8) years, DD progressed 2-4-fold more rapidly in those with new-onset AF (p < 0.001 for all). Risk for incident DD was increased i new-onset AF [hazard ratio (95% confidence interval) 2.69 (2.19-3.32) for SDD and 1.73 (1.49-2.02) for ≥MDD].<br /><b>Conclusions</b><br />Patients with new-onset AF display high-risk features for HFpEF at diagnosis, emphasizing the importance of evaluating for HFpEF among symptomatic patients with AF. Patients with new-onset AF have accelerated progression in DD over time, which may identify patients with preclinical HFpEF, where preventive therapies may be tested.<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: 28 Aug 2023; epub ahead of print</small></div>

<div><h4>Quality and transparency of evidence for implantable cardiovascular medical devices assessed by the CORE-MD Consortium.</h4><i>Siontis GC, Coles B, Häner JD, McGovern L, ... Windecker S, CORE-MD investigators</i><br /><b>Background:</b><br/>and aims</b><br />The European Union Medical Device Regulation 2017/745 challenges key stakeholders to follow transparent and rigorous approaches to the clinical evaluation of medical devices. The purpose of this study is a systematic evaluation of published clinical evidence underlying selected high-risk cardiovascular medical devices before and after market access in the European Union (CE marking) between 2000 and 2021.<br /><b>Methods</b><br />Prespecified strategies were applied to identify published studies of prospective design evaluating 71 high-risk cardiovascular devices in 7 different classes (bioresorbable coronary scaffolds, left atrial appendage occlusion devices, transcatheter aortic valve implantation systems, transcatheter mitral valve repair/replacement systems, surgical aortic and mitral heart valves, leadless pacemakers, subcutaneous implantable cardioverter-defibrillator). The search time-span covered 20 years (2000-2021). Details of study design, patient population, intervention(s) and primary outcome(s) were summarized, and assessed with respect to timing of the corresponding CE-mark approval.<br /><b>Results</b><br />At least one prospective clinical trial was identified for 70% (50/71) of the prespecifed devices. Overall, 473 reports of 308 prospectively designed studies (enrolling 97,886 individuals) were deemed eligible, including 81% (251/308) prospective non-randomized clinical trials (66,186 individuals) and 19% (57/308) randomized clinical trials (31,700 individuals). Preregistration of the study protocol was available in 49% (150/308) studies, and 16% (48/308) had a peer-reviewed publicly available protocol. Device-related adverse events were evaluated in 82% (253/308) of studies. An outcome adjudication process was reported in 39% (120/308) of the studies. Sample size was larger for randomized in comparison to non-randomized trials (median of 304 versus 100 individuals, p<0.001). No randomized clinical trial published before CE-mark approval for any of the devices was identified. Non-randomized clinical trials were predominantly published after the corresponding CE-mark approval of the device under evaluation (89%, 224/251). Sample sizes were smaller for studies published before (median of 34 individuals) than after (median of 135 individuals) CE-mark approval (p<0.001). Clinical trials with larger sample sizes (>50 individuals) and those with longer recruitment periods were more likely to be published after CE-mark approval, and were more frequent during the period 2016-2021.<br /><b>Conclusions</b><br />The quantity and quality of publicly available data from prospective clinical investigations across selected categories of cardiovascular devices, before and after CE approval during the period 2000-2021, was deemed insufficient. The majority of studies were non-randomized, with increased risk of bias, and performed in small populations without provision of power calculations, and none of the reviewed devices had randomized trial results published prior to CE mark certification.<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: 28 Aug 2023; epub ahead of print</small></div>

<div><h4>Atrial pacing minimization in sinus node dysfunction and risk of incident atrial fibrillation: a randomized trial.</h4><i>Kronborg MB, Frausing MHJP, Malczynski J, Riahi S, ... Nielsen JC, DANPACE II Investigators </i><br /><b>Background:</b><br/>and aims</b><br />High percentages of atrial pacing have been associated with an increased risk of atrial fibrillation. This study aimed at evaluating whether atrial pacing minimization in patients with sinus node dysfunction reduces the incidence of atrial fibrillation.<br /><b>Methods</b><br />In a nationwide, randomized controlled trial, 540 patients with sinus node dysfunction and an indication for first pacemaker implantation were assigned to pacing programmed to a base rate of 60 bpm and rate-adaptive pacing (DDDR-60) or pacing programmed to a base rate of 40 bpm without rate-adaptive pacing (DDD-40). Patients were followed on remote monitoring for 2 years. The primary endpoint was time to first episode of atrial fibrillation longer than 6 min. Secondary endpoints included longer episodes of atrial fibrillation, and the safety endpoint comprised a composite of syncope or presyncope.<br /><b>Results</b><br />The median percentage of atrial pacing was 1% in patients assigned to DDD-40 and 49% in patients assigned to DDDR-60. The primary endpoint occurred in 124 patients (46%) in each treatment group (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.76-1.25, P=0.83). There were no between-group differences in atrial fibrillation exceeding 6- or 24 hours, persistent atrial fibrillation, or cardioversions for atrial fibrillation. The incidence of syncope or presyncope was higher in patients assigned to DDD-40 (HR 1.71 95% CI 1.13-2.59, P=0.01).<br /><b>Conclusions</b><br />Atrial pacing minimization in patients with sinus node dysfunction does not reduce the incidence of atrial fibrillation. Programming a base rate of 40 bpm without rate-adaptive pacing is associated with an increased risk of syncope or presyncope.<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: 28 Aug 2023; epub ahead of print</small></div>

<div><h4>Frailty and outcomes in heart failure patients from high-, middle- and low-Income countries.</h4><i>Leong DP, Joseph P, McMurray JJV, Rouleau J, ... Joseph P, G-CHF Investigators </i><br /><b>Background:</b><br/>and aims</b><br />There is little information on the incremental prognostic importance of frailty beyond conventional prognostic variables in heart failure (HF) populations from different country income levels.<br /><b>Methods</b><br />3429 adults with HF (age 61±14 years, 33% women) from 27 high-, middle- and low-income countries were prospectively studied. Baseline frailty was evaluated by the Fried index, incorporating handgrip strength, gait speed, physical activity, unintended weight loss and self-reported exhaustion. Mean left ventricular ejection fraction was 39±14% and 26% had New York Heart Association (NYHA) class III/IV symptoms. Participants were followed for a median (25th-75th percentile) 3.1 (2.0-4.3) years. Cox proportional hazards models for death and HF hospitalization adjusted for country income level; age; sex; education; HF etiology; left ventricular ejection fraction; diabetes; tobacco and alcohol use; NYHA functional class; HF medication use; blood pressure; hemoglobin, sodium and creatinine concentrations were performed. The incremental discriminatory value of frailty over and above the MAGGIC risk score was evaluated by the area under the receiver-operating characteristic curve.<br /><b>Results</b><br />At baseline, 18% of participants were robust, 61% pre-frail and 21% frail. During follow-up, 565 (16%) participants died and 471 (14%) were hospitalized for HF. Respective adjusted hazard ratios [HRs (95% CI)] for death among the prefrail and frail were 1.59 (1.12-2.26) and 2.92 (1.99-4.27). Respective adjusted HRs (95% CI) for HF hospitalization were 1.32 (0.93-1.87) and 1.97 (1.33-2.91). Findings were consistent among different country income levels and by most subgroups. Adding frailty to the MAGGIC risk score improved the discrimination of future death and HF hospitalization.<br /><b>Conclusions</b><br />Frailty confers substantial incremental prognostic information to prognostic variables for predicting death and HF hospitalization. The relationship between frailty and these outcomes is consistent across countries at all income levels.<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: 28 Aug 2023; epub ahead of print</small></div>

<div><h4>Recommendations for statin management in primary prevention: disparities among international risk scores.</h4><i>Mancini GBJ, Ryomoto A, Yeoh E, Brunham LR, Hegele RA</i><br /><b>Background:</b><br/>and aims</b><br />Statin recommendations in primary prevention depend upon risk algorithms. Moreover, with intermediate risk, risk enhancers and de-enhancers are advocated to aid decisions. The aim of this study was to compare algorithms used in North America and Europe for the identification of patients warranting statin or consideration of risk enhancers and de-enhancers.<br /><b>Methods</b><br />A simulated population (n = 7680) equal in males and females, with/without smoking, aged 45-70 years, total cholesterol 3.5-7.0 mmol/L, high-density lipoprotein cholesterol 0.6-2.2 mmol/L, and systolic blood pressure 100-170 mmHg, was evaluated. High, intermediate, and low risks were determined using the Framingham Risk Score (FRS), Pooled Cohort Equation (PCE), four versions of Systematic Coronary Risk Evaluation 2 (SCORE2), and Multi-Ethnic Study of Atherosclerosis (MESA) algorithm (0-1000 Agatston Units).<br /><b>Results</b><br />Concordance for the three levels of risk varied from 19% to 85%. Both sexes might be considered to have low, intermediate, or high risk depending on the algorithm applied, even with the same burden of risk factors. Only SCORE2 (High Risk and Very High Risk versions) identified equal proportions of males and females with high risk. Excluding MESA, the proportion with moderate risk was 25% (SCORE2, Very High Risk Region), 32% (FRS), 39% (PCE), and 45% (SCORE2, Low Risk Region).<br /><b>Conclusion</b><br />Risk algorithms differ substantially in their estimation of risk, recommendations for statin treatment, and use of ancillary testing, even in identical patients. These results highlight the limitations of currently used risk-based approaches for addressing lipid-specific risk in primary prevention.<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: 28 Aug 2023; epub ahead of print</small></div>

<div><h4>Type A aortic dissection: optimal annual case volume for surgery.</h4><i>Kawczynski MJ, van Kuijk SMJ, Olsthoorn JR, Maessen JG, ... Bidar E, Heuts S</i><br /><b>Background:</b><br/>and aims</b><br />The current study proposes a novel volume-outcome (V-O) meta-analytical approach to determine the optimal annual hospital case volume threshold for cardiovascular interventions in need of centralization. This novel method is applied to surgery for acute type A aortic dissection (ATAAD) as an illustrative example.<br /><b>Methods</b><br />A systematic search was applied to three electronic databases (January 1st 2012 - March 29th 2023). The primary outcome was early mortality in relation to annual hospital case volume. Data were presented by volume quartiles (Qs). Restricted cubic splines were used to demonstrate the V-O relation, and the elbow method was applied to determine the optimal case volume. For clinical interpretation, numbers needed to treat (NNT) were calculated.<br /><b>Results</b><br />140 studies were included, comprising 38276 patients. A significant non-linear V-O effect was observed (p<0.001), with a significant between-quartile difference for early mortality (10.3% [Q4] vs. 16.2% [Q1], p<0.001). The optimal annual case volume was determined at 38 cases/year (95% CI 37-40 cases/year, NNT to save a life in a centre with the optimal volume vs. 10 cases/year = 21). More pronounced between-quartile survival differences were observed for long-term survival (10-year survival [Q4] 69% vs. [Q1] 51%, p<0.001, adjusted HR 0.83, 95% CI 0.75-0.91 per quartile, NNT to save a life in a high-volume [Q4] vs. low-volume centre [Q1) = 6).<br /><b>Conclusions</b><br />Using this novel approach, the optimal hospital case volume threshold was statistically determined. Centralization of ATAAD care to high-volume centres may lead to improved outcomes. This method can be applied to various other cardiovascular procedures requiring centralization.<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: 28 Aug 2023; epub ahead of print</small></div>

<div><h4>Critical limb-threatening ischemia and microvascular transformation: clinical implications.</h4><i>Tarvainen S, Wirth G, Juusola G, Hautero O, ... Ylä-Herttuala S, Korpisalo P</i><br /><b>Background:</b><br/>and aims</b><br />Clinical management of critical limb-threatening ischemia (CLTI) is focused on prevention and treatment of atherosclerotic arterial occlusions. The role of microvascular pathology in disease progression is still largely unspecified and more importantly not utilized for treatment. The aim of this explorative study was to characterize the role of the microvasculature in CLTI pathology.<br /><b>Methods</b><br />Clinical high-resolution imaging of CLTI patients (n=50) and muscle samples from amputated CLTI limbs (n=40) were used to describe microvascular pathology of CLTI at the level of resting muscle blood flow and microvascular structure, respectively. Furthermore, a chronic, low arterial driving pressure-simulating ischemia model in rabbits (n=24) was used together with adenoviral vascular endothelial growth factor A gene transfers to study the effect of microvascular alterations on muscle outcome.<br /><b>Results</b><br />Resting microvascular blood flow was not depleted but displayed decreased capillary transit time (P<0.01) in CLTI muscles. CLTI muscle microvasculature also exhibited capillary enlargement (P<0.001) and further arterialization along worsening of myofiber atrophy and detaching of capillaries from myofibers. Furthermore, CLTI-like capillary transformation was shown to worsen calf muscle force production (P<0.05) and tissue outcome (P<0.01) under chronic ischemia in rabbits and in healthy, normal rabbit muscle.<br /><b>Conclusions</b><br />These findings depict a progressive, hypoxia-driven transformation of the microvasculature in CLTI muscles, which pathologically alters blood flow dynamics and aggravates tissue damage under low arterial driving pressure. Hypoxia-driven capillary enlargement can be highly important for CLTI outcomes and should therefore be considered in further development of diagnostics and treatment of CLTI.<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 Aug 2023; epub ahead of print</small></div>

<div><h4>Five-year major cardiovascular events are increased when coronary revascularization is guided by instantaneous wave-free ratio compared to fractional flow reserve: a pooled analysis of iFR-SWEDEHEART and DEFINE-FLAIR trials.</h4><i>Eftekhari A, Holck EN, Westra J, Olsen NT, ... Engstrøm T, Christiansen EH</i><br /><b>Background:</b><br/>and aims</b><br />Guidelines recommend revascularization of intermediate epicardial artery stenosis to be guided by evidence of ischemia. Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are equally recommended. Individual 5-year results of two major randomized trials comparing FFR with iFR-guided revascularization suggested increased all-cause mortality following iFR-guided revascularization. The aim of this study was a study-level meta-analysis of the 5-year outcome data in iFR-SWEDEHEART (NCT02166736) and DEFINE-FLAIR (NCT02053038).<br /><b>Methods</b><br />Composite of major adverse cardiovascular events (MACE) and its individual components [all-cause death, myocardial infarction (MI), and unplanned revascularisation] were analysed. Raw Kaplan-Meier estimates, numbers at risk and number of events were extracted at 5-year follow-up and analysed using the ipdfc package (Stata version 18, StataCorp College Station, TX USA).<br /><b>Results</b><br />In total, iFR and FFR-guided revascularization was performed in 2,254 and 2,257 patients, respectively. Revascularization was more often deferred in the iFR-group [n = 1,128 (50.0 %)] vs. the FFR-group [n = 1021 (45.2 %); p=0.001]. In the iFR-guided group the number of deaths, MACE, unplanned revascularization, and MI were 188 (8.3%), 484 (21.5%), 235 (10.4%), and 123 (5.5%) vs. 143 (6.3%), 420 (18.6%), 241 (10.7%), and 123 (5.4%) in the FFR-group. Hazard ratio [95% confidence interval (CI)] estimates for MACE were 1.18 [1.035; 1.34], all-cause mortality 1.34 [1.08; 1.67], unplanned revascularization 0.99 [0.83; 1.19], and MI 1.02 [0.80; 1.32].<br /><b>Conclusions</b><br />Five-year all-cause mortality and MACE rates were increased with revascularization guided by iFR compared to FFR. Rates of unplanned revascularization and MI were equal in the two groups.<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: 27 Aug 2023; epub ahead of print</small></div>

<div><h4>New-onset atrial fibrillation in chronic coronary syndrome: the CLARIFY registry.</h4><i>Gautier A, Picard F, Ducrocq G, Elbez Y, ... Tendera M, Steg PG</i><br /><b>Background:</b><br/>and aims</b><br />Data on new-onset atrial fibrillation (NOAF) in patients with chronic coronary syndromes (CCS) are scarce. This study aims to describe the incidence, predictors and impact on cardiovascular outcomes of NOAF in CCS patients.<br /><b>Methods</b><br />Data from the international (45 countries) CLARIFY registry (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) were used. Among 29,001 CCS outpatients without previously reported AF at baseline, patients with at least one episode of AF/flutter diagnosed during 5-year follow-up were compared with patients in sinus rhythm throughout the study.<br /><b>Results</b><br />The incidence rate of NOAF was 1.12 [95% confidence interval (CI) 1.06-1.18] per 100 patient-years (cumulative incidence at 5 years: 5.0%). Independent predictors of NOAF were increasing age, increasing body mass index, low estimated glomerular filtration rate, Caucasian ethnicity, alcohol intake and low left ventricular ejection fraction, while high triglycerides were associated with lower incidence. NOAF was associated with a substantial increase in the risk of adverse outcomes, with adjusted hazard ratios of 2.01 (95% CI 1.61-2.52) for the composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, 2.61 (95% CI 2.04-3.34) for cardiovascular death, 1.64 (95% CI 1.07-2.50) for non-fatal myocardial infarction, 2.27 (95% CI 1.85-2.78) for all-cause death, 8.44 (95% CI 7.05-10.10) for hospitalization for heart failure and 4.46 (95% CI 2.85-6.99) for major bleeding.<br /><b>Conclusions</b><br />Among CCS patients, NOAF is common and is strongly associated with worse outcomes. Whether more intensive preventive measures and more systematic screening for AF would improve prognosis in this population deserves 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: 27 Aug 2023; epub ahead of print</small></div>

<div><h4>Coronary Flow Capacity And Survival Prediction After Revascularization: Physiological Basis And Clinical Implications.</h4><i>Gould KL, Johnson NP, Roby AE, Bui L, ... McPherson D, Narula J</i><br /><b>Background:</b><br/>and aims</b><br />Coronary Flow Capacity (CFC) associates with an Observed 10-yearsurvival probability for individual patients before and after actual revascularization for comparison to Virtual hypothetical ideal complete revascularization.<br /><b>Methods</b><br />Stress myocardial perfusion (mL/min/g) and coronary flow reserve (CFR) per pixel were quantified in 6979 coronary artery disease (CAD) subjects using Rb-82 positron emission tomography (PET) for CFC maps of artery-specific size-severity abnormalities expressed as percent left ventricle (%LV) with prospective follow-up to define survival probability per-decade as fraction of 1.0.<br /><b>Results</b><br />Severely reduced CFC in 6979 subjects predicted low survival probability that improved by 42% after revascularization compared with no revascularization for comparable severity (P=0.0015). For 283 pre-and-post-procedure PET pairs, severely reduced regional CFC-associated survival probability improved heterogeneously after revascularization (P<0.001), more so after bypass surgery than percutaneous coronary interventions (P<0.001) but normalized in only 5.7%; non-severe baseline CFC or survival probability did not improve compared with severe CFC (P=0.00001). Observed CFC=associated survival probability after actual revascularization was lower than Virtual ideal hypothetical complete post-revascularization survival probability due to residual CAD or failed revascularization (P<0.001) unrelated to gender or microvascular dysfunction. Severely reduced CFC in 2552 post-revascularization subjects associated with low survival probability also improved after repeat revascularization compared with no repeat procedures (P=0.025).<br /><b>Conclusions</b><br />Severely reduced CFC and associated Observed survival probability improved after first and repeat revascularization compared with no revascularization for comparable CFC severity. Non-severe CFC showed no benefit. Discordance between Observed actual and Virtual hypothetical post=revascularization survival probability revealed residual CAD or failed revascularization.<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 Aug 2023; epub ahead of print</small></div>