The 100 most-cited articles in European Heart Journal, 2023

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication.The ESC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies.Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver.Nor do the ESC Guidelines exempt health…

2 Representing the European Society of Human Genetics (ESHG) ESC Clinical Practice Guidelines (CPG) Committee: listed in the Appendix.

1. Preamble 3629 2. Introduction 3631 3. Chronic heart failure 3631 4. Acute heart failure 3634 4.1. Medical therapy 3634 4.1.1. Diuretics 3634 4.1.2. Sodium–glucose co-transporter 2 inhibitors 3634 4.2. Management strategies 3634 4.2.1. Admission phase 3634 4.2.2. Pre-discharge and early post-discharge phases 3634 5. Comorbidities 3635 5.1. Chronic kidney disease and type 2 diabetes mellitus 3635 5.1.1. Sodium–glucose co-transporter 2 inhibitors 3635 5.1.2. Finerenone 3636 5.2. Iron deficiency 3636 6. Data availability statement 3637 7. Author information 3637 8. Appendix 3638 9. References 3638 Recommendation Table 1 — Recommendation for the treatment of patients with symptomatic heart failure with mildly reduced ejection fraction 3633 Recommendation Table 2 — Recommendation for the treatment of patients with symptomatic heart failure with preserved ejection fraction 3633 Recommendation Table 3 — Recommendation for pre-discharge and early post-discharge follow-up of patients hospitalized for acute heart failure 3635 Recommendation Table 4 — Recommendations for the prevention of…

3 Representing the European Association for Cardio-Thoracic Surgery (EACTS) ESC Clinical Practice Guidelines (CPG) Committee: listed in the Appendix.ESC subspecialty communities having participated in the development of this document: Associations: Association of Cardiovascular Nursing & Allied Professions (ACNAP), Association for Acute CardioVascular Care (ACVC), European Association of Cardiovascular Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), and Heart Failure Association (HFA).Councils: Council for Cardiology Practice, Council on Stroke.

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication.The ESC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies.Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver.Nor do the ESC Guidelines exempt health…

Large-scale genome-wide association studies conducted over the last decade have uncovered numerous genetic variants associated with cardiometabolic traits and risk factors. These discoveries have enabled the Mendelian randomization (MR) design, which uses genetic variation as a natural experiment to improve causal inferences from observational data. By analogy with the random assignment of treatment in randomized controlled trials, the random segregation of genetic alleles when DNA is transmitted from parents to offspring at gamete formation is expected to reduce confounding in genetic associations. Mendelian randomization analyses make a set of assumptions that must hold for valid results. Provided that the assumptions are well justified for the genetic variants that are employed as instrumental variables, MR studies can inform on whether a putative risk factor likely has a causal effect on the disease or not. Mendelian randomization has been increasingly applied over recent years to predict the efficacy and safety of existing and novel drugs targeting cardiovascular risk factors…

BACKGROUND AND AIMS: Previous studies found that frailty was an important risk factor for cardiovascular disease (CVD). However, previous studies only focused on baseline frailty status, not taking into consideration the changes in frailty status during follow-up. The aim of this study was to investigate the associations of changes in frailty status with incident CVD. METHODS: This study used data of three prospective cohorts: China Health and Retirement Longitudinal Study (CHARLS), English Longitudinal Study of Ageing (ELSA), and Health and Retirement Study (HRS). Frailty status was evaluated by the Rockwood frailty index and classified as robust, pre-frail, or frail. Changes in frailty status were assessed by frailty status at baseline and the second survey which was two years after the baseline. Cardiovascular disease was ascertained by self-reported physician-diagnosed heart disease (including angina, heart attack, congestive heart failure, and other heart problems) or stroke. Cox proportional hazard models were used to calculate the hazard ratio (HR) and 95% confidence interval…

Convergent experimental and clinical evidence have established the pathophysiological importance of pro-inflammatory pathways in coronary artery disease. Notably, the interest in treating inflammation in patients suffering acute myocardial infarction (AMI) is now expanding from its chronic aspects to the acute setting. Few large outcome trials have proven the benefits of anti-inflammatory therapies on cardiovascular outcomes by targeting the residual inflammatory risk (RIR), i.e. the smouldering ember of low-grade inflammation persisting in the late phase after AMI. However, these studies have also taught us about potential risks of anti-inflammatory therapy after AMI, particularly related to impaired host defence. Recently, numerous smaller-scale trials have addressed the concept of targeting a deleterious flare of excessive inflammation in the early phase after AMI. Targeting different pathways and implementing various treatment regimens, those trials have met with varied degrees of success. Promising results have come from those studies intervening early on the interleukin-1 and…

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…

AIMS: 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. METHODS AND RESULTS: 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…

BACKGROUND AND AIMS: Cardiovascular disease (CVD) impacts significantly health and social care systems as well as society through premature mortality and disability, with patients requiring care from relatives. Previous pan-European estimates of the economic burden of CVD are now outdated. This study aims to provide novel, up-to-date evidence on the economic burden across the 27 European Union (EU) countries in 2021. METHODS: Aggregate country-specific resource use data on morbidity, mortality, and health, social and informal care were obtained from international sources, such as the Statistical Office of the European Communities, enhanced by data from the European Society of Cardiology Atlas programme and patient-level data from the Survey of Health, Ageing and Retirement in Europe. Country-specific unit costs were used, with cost estimates reported on a per capita basis, after adjustment for price differentials. RESULTS: CVD is estimated to cost the EU €282 billion annually, with health and long-term care accounting for €155 billion (55%), equalling 11% of EU-health expenditure.…

Abdominal aortic aneurysm (AAA) causes ∼170 000 deaths annually worldwide. Most guidelines recommend asymptomatic small AAAs (30 to <50 mm in women; 30 to <55 mm in men) are monitored by imaging and large asymptomatic, symptomatic, and ruptured AAAs are considered for surgical repair. Advances in AAA repair techniques have occurred, but a remaining priority is therapies to limit AAA growth and rupture. This review outlines research on AAA pathogenesis and therapies to limit AAA growth. Genome-wide association studies have identified novel drug targets, e.g. interleukin-6 blockade. Mendelian randomization analyses suggest that treatments to reduce low-density lipoprotein cholesterol such as proprotein convertase subtilisin/kexin type 9 inhibitors and smoking reduction or cessation are also treatment targets. Thirteen placebo-controlled randomized trials have tested whether a range of antibiotics, blood pressure-lowering drugs, a mast cell stabilizer, an anti-platelet drug, or fenofibrate slow AAA growth. None of these trials have shown convincing evidence of drug efficacy and have…

Postoperative atrial fibrillation (POAF) is the most common type of secondary atrial fibrillation (AF) and despite progress in prevention and treatment, remains an important clinical problem for patients undergoing a variety of surgical procedures, and in particular cardiac surgery. POAF significantly increases the duration of postoperative hospital stay, hospital costs, and the risk of recurrent AF in the years after surgery; moreover, POAF has been associated with a variety of adverse cardiovascular events (including stroke, heart failure, and mortality), although it is still unclear if this is due to causal relation or simple association. New data have recently emerged on the pathophysiology of POAF, and new preventive and therapeutic strategies have been proposed and tested in randomized trials. This review summarizes the current evidence on the pathogenesis, incidence, prevention, and treatment of POAF and highlights future directions for clinical research.

AIMS: 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. METHODS AND RESULTS: 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…

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.

BACKGROUND AND AIMS: For patients with symptomatic, severe tricuspid regurgitation (TR), early results of transcatheter tricuspid valve (TV) intervention studies have shown significant improvements in functional status and quality of life associated with right-heart reverse remodelling. Longer-term follow-up is needed to confirm sustained improvements in these outcomes. METHODS: The prospective, single-arm, multicentre TRISCEND study enrolled 176 patients to evaluate the safety and performance of transcatheter TV replacement in patients with ≥moderate, symptomatic TR despite medical therapy. Major adverse events, reduction in TR grade and haemodynamic outcomes by echocardiography, and clinical, functional, and quality-of-life parameters are reported to one year. RESULTS: Enrolled patients were 71.0% female, mean age 78.7 years, 88.0% ≥ severe TR, and 75.4% New York Heart Association classes III-IV. Tricuspid regurgitation was reduced to ≤mild in 97.6% (P < .001), with increases in stroke volume (10.5 ± 16.8 mL, P < .001) and cardiac output (0.6 ± 1.2 L/min, P < .001). New York Heart…

Obesity is a modifiable cardiovascular risk factor, but adipose tissue (AT) depots in humans are anatomically, histologically, and functionally heterogeneous. For example, visceral AT is a pro-atherogenic secretory AT depot, while subcutaneous AT represents a more classical energy storage depot. Perivascular adipose tissue (PVAT) regulates vascular biology via paracrine cross-talk signals. In this position paper, the state-of-the-art knowledge of various AT depots is reviewed providing a consensus definition of PVAT around the coronary arteries, as the AT surrounding the artery up to a distance from its outer wall equal to the luminal diameter of the artery. Special focus is given to the interactions between PVAT and the vascular wall that render PVAT a potential therapeutic target in cardiovascular diseases. This Clinical Consensus Statement also discusses the role of PVAT as a clinically relevant source of diagnostic and prognostic biomarkers of vascular function, which may guide precision medicine in atherosclerosis, hypertension, heart failure, and other cardiovascular diseases.…

Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to…

AIMS: 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. METHODS AND RESULTS: 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…

BACKGROUND AND AIMS: Benefit of tricuspid regurgitation (TR) correction and timing of intervention are unclear. This study aimed to compare survival rates after surgical or transcatheter intervention to conservative management according to a TR clinical stage as assessed using the TRI-SCORE. METHODS: A total of 2,413 patients with severe isolated functional TR were enrolled in TRIGISTRY (1217 conservatively managed, 551 isolated tricuspid valve surgery, and 645 transcatheter valve repair). The primary endpoint was survival at 2 years. RESULTS: The TRI-SCORE was low (≤3) in 32%, intermediate (4-5) in 33%, and high (≥6) in 35%. A successful correction was achieved in 97% and 65% of patients in the surgical and transcatheter groups, respectively. Survival rates decreased with the TRI-SCORE in the three treatment groups (all P < .0001). In the low TRI-SCORE category, survival rates were higher in the surgical and transcatheter groups than in the conservative management group (93%, 87%, and 79%, respectively, P = .0002). In the intermediate category, no significant difference between…

Plant-based diets have become increasingly popular thanks to their purported health benefits and more recently for their positive environmental impact. Prospective studies suggest that consuming vegetarian diets is associated with a reduced risk of developing cardiovascular disease (CVD), diabetes, hypertension, dementia, and cancer. Data from randomized clinical trials have confirmed a protective effect of vegetarian diets for the prevention of diabetes and reductions in weight, blood pressure, glycosylated haemoglobin and low-density lipoprotein cholesterol, but to date, no data are available for cardiovascular event rates and cognitive impairment, and there are very limited data for cancer. Moreover, not all plant-based foods are equally healthy. Unhealthy vegetarian diets poor in specific nutrients (vitamin B12, iron, zinc, and calcium) and/or rich in highly processed and refined foods increase morbidity and mortality. Further mechanistic studies are desirable to understand whether the advantages of healthy, minimally processed vegetarian diets represent an all-or-nothing…

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%…

Since the publication of the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines for the Management of Arterial Hypertension, several high-quality studies, including randomised, sham-controlled trials on catheter-based renal denervation (RDN) were published, confirming both the blood pressure (BP)-lowering efficacy and safety of radiofrequency and ultrasound RDN in a broad range of patients with hypertension, including resistant hypertension. A clinical consensus document by the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on RDN in the management of hypertension was considered necessary to inform clinical practice. This expert group proposes that RDN is an adjunct treatment option in uncontrolled resistant hypertension, confirmed by ambulatory BP measurements, despite best efforts at lifestyle and pharmacological interventions. RDN may also be used in patients who are unable to tolerate antihypertensive medications in the long term. A shared decision-making process is a key…

AIMS: 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. METHODS AND RESULTS: 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…

AIMS: The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to be resolved. METHODS AND RESULTS: Single-nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (TRL/remnant-C) and LDL cholesterol (LDL-C) were identified in the UK Biobank population. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apolipoprotein B (apoB). Likewise, in a multivariable model, TRL/remnant-C and LDL-C also exhibited independent associations with CHD with odds ratios per 1 mmol/L higher cholesterol of 2.59 [95% confidence interval (CI): 1.99-3.36] and 1.37 [95% CI: 1.27-1.48], respectively. To examine the per-particle atherogenicity of TRL/remnants and LDL, SNPs were categorized into two clusters with differing effects on TRL/remnant-C and LDL-C. Cluster 1 contained SNPs in genes related to receptor-mediated lipoprotein removal that affected LDL-C more than TRL/remnant-C, whereas cluster…

AIMS: Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management, and outcome are sparse. METHODS AND RESULTS: This international multicentre 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 centres in 35 countries. In 78 centres 138 patients [0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (P < 0.0001)] were diagnosed with an oesophageal fistula. Peri-procedural 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…

BACKGROUND AND AIMS: Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches. METHODS: Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation. RESULTS: Observational analyses showed associations between high neutrophil counts with high…

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, has 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…

Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association Classes II and III obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten was developed to target the hyper-contractile phenotype, which plays a critical role in the pathophysiology of the disease. In Phase 2 and 3 clinical trials, mavacamten was well tolerated, reduced left ventricular outflow tract gradients, improved exercise capacity and symptoms, and was associated with improvements in other clinically relevant parameters, such as patient-reported outcomes and circulating biomarkers. In addition, treatment with mavacamten was associated with evidence of favourable cardiac remodelling in multi-modality imaging studies. Mavacamten substantially reduced guideline eligibility for septal reduction therapy candidates with oHCM and drug-refractory symptoms. In this article, the available efficacy and safety data from completed and ongoing clinical studies of mavacamten in patients with…

AIMS: To develop a healthy diet score that is associated with health outcomes and is globally applicable using data from the Prospective Urban Rural Epidemiology (PURE) study and replicate it in five independent studies on a total of 245 000 people from 80 countries. METHODS AND RESULTS: A healthy diet score was developed in 147 642 people from the general population, from 21 countries in the PURE study, and the consistency of the associations of the score with events was examined in five large independent studies from 70 countries. The healthy diet score was developed based on six foods each of which has been associated with a significantly lower risk of mortality [i.e. fruit, vegetables, nuts, legumes, fish, and dairy (mainly whole-fat); range of scores, 0-6]. The main outcome measures were all-cause mortality and major cardiovascular events [cardiovascular disease (CVD)]. During a median follow-up of 9.3 years in PURE, compared with a diet score of ≤1 points, a diet score of ≥5 points was associated with a lower risk of mortality [hazard ratio (HR) 0.70; 95% confidence interval…

AIMS: The aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in patients with transthyretin cardiac amyloidosis (ATTR-CA). METHODS AND RESULTS: A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of heart failure medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (interquartile range 10.6-51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARBs discontinued. In contrast, only 7.5% had MRAs discontinued. A propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population…

AIMS: To investigate the prospective associations of the loneliness and social isolation scales with cardiovascular disease (CVD) risk in diabetes patients and compare the relative importance of loneliness and social isolation with traditional risk factors. Also, the interactions of loneliness or isolation with the degree of risk factor control in relation to CVD risk were evaluated. METHODS AND RESULTS: A total of 18 509 participants diagnosed with diabetes from the UK Biobank were included. A two-item scale and a three-item scale were used to assess loneliness and isolation levels, respectively. The degree of risk factor control was defined as numbers of glycated hemoglobin (HbA1c), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), smoking, and kidney condition controlled within the target range. During a mean follow-up of 10.7 years, 3247 total CVD incidents were documented, including 2771 coronary heart disease and 701 strokes. In the fully adjusted model, compared with participants with the lowest loneliness score (zero), hazard ratios (95% confidence interval)…

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…

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.

The role of cardiac implantable electronic device (CIED)-related tricuspid regurgitation (TR) is increasingly recognized as an independent clinical entity. Hence, interventional TR treatment options continuously evolve, surgical risk assessment and peri-operative care improve the management of CIED-related TR, and the role of lead extraction is of high interest. Furthermore, novel surgical and interventional tricuspid valve treatment options are increasingly applied to patients suffering from TR associated with or related to CIEDs. This multidisciplinary review article developed with electrophysiologists, interventional cardiologists, imaging specialists, and cardiac surgeons aims to give an overview of the mechanisms of disease, diagnostics, and proposes treatment algorithms of patients suffering from TR associated with CIED lead(s) or leadless pacemakers.

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…

ABSTRACT Background and Aims Early diagnosis of aortic stenosis (AS) is critical to prevent morbidity and mortality but requires skilled examination with Doppler imaging. This study reports the development and validation of a novel deep learning model that relies on 2-dimensional parasternal long axis (PLAX) videos from transthoracic echocardiography (TTE) without Doppler imaging to identify severe AS, suitable for point-of-care ultrasonography. Methods In a training set of 5,257 studies (17,570 videos) from 2016-2020 (Yale-New Haven Hospital [YNHH], Connecticut), an ensemble of 3-dimensional convolutional neural networks was developed to detect severe AS, leveraging self-supervised contrastive pretraining for label-efficient model development. This deep learning model was validated in a temporally distinct set of 2,040 consecutive studies from 2021 from YNHH as well as two geographically distinct cohorts of 5,572 and 865 studies, from California and other hospitals in New England, respectively. Results The deep learning model achieved an AUROC of 0.978 (95% CI: 0.966, 0.988) for…

BACKGROUND AND AIMS: This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation. METHODS AND RESULTS: Patients undergoing atrial fibrillation ablation and endomyocardial atrial biopsy were included (n = 230; 67 ± 12 years old; 69 women). Electroanatomic mapping was performed during right atrial pacing. Voltage at the biopsy site (Vbiopsy), global left atrial voltage (VGLA), and the proportion of points with fractionated electrograms defined as ≥5 deflections in each electrogram (%Fractionated EGM) were evaluated. SCZtotal was calculated as the total width of slow conduction zones, defined as regions with a conduction velocity of <30 cm/s. Histological factors potentially associated with electroanatomic characteristics were evaluated using multiple linear regression analyses. Ultrastructural features and immune cell infiltration were evaluated by electron microscopy and immunohistochemical staining in 33 and 60 patients, respectively. Fibrosis, intercellular space, myofibrillar loss, and myocardial nuclear density were significantly…

AIMS: The impact of long-term endurance sport participation (on top of a healthy lifestyle) on coronary atherosclerosis and acute cardiac events remains controversial. METHODS AND RESULTS: 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 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. The median age was 55 (50-60) years in all groups. Lifelong and late-onset athletes had higher peak oxygen uptake 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…

BACKGROUND AND AIMS: Physical inactivity, sedentary behaviour (SB), and inadequate sleep are key behavioural risk factors of cardiometabolic diseases. Each behaviour is mainly considered in isolation, despite clear behavioural and biological interdependencies. The aim of this study was to investigate associations of five-part movement compositions with adiposity and cardiometabolic biomarkers. METHODS: Cross-sectional data from six studies (n = 15 253 participants; five countries) from the Prospective Physical Activity, Sitting and Sleep consortium were analysed. Device-measured time spent in sleep, SB, standing, light-intensity physical activity (LIPA), and moderate-vigorous physical activity (MVPA) made up the composition. Outcomes included body mass index (BMI), waist circumference, HDL cholesterol, total:HDL cholesterol ratio, triglycerides, and glycated haemoglobin (HbA1c). Compositional linear regression examined associations between compositions and outcomes, including modelling time reallocation between behaviours. RESULTS: The average daily composition of the sample (age:…

AIMS: Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association. METHODS AND RESULTS: Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased…

AIMS: 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. METHODS AND RESULTS: 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…

AIMS: 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. METHODS AND RESULTS: Both PARAGLIDE-HF and PARAGON-HF were multicentre, 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…

BACKGROUND AND AIMS: Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research. This meta-analysis aimed to characterize the effects of FCM therapy on hospitalizations and mortality. METHODS: Patient-level data from randomized, placebo-controlled FCM trials including adults with HF and iron deficiency with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were (i) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death and (ii) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. Key secondary endpoints included individual composite endpoint components. Event rates were analysed using a negative binomial model. Treatment-emergent adverse events were also examined. RESULTS: Three FCM trials with a total of 4501 patients were included. Ferric carboxymaltose was associated with a significantly…

The leading cause of heart disease in developed countries is coronary atherosclerosis, which is not simply a result of ageing but a chronic inflammatory process that can lead to acute clinical events upon atherosclerotic plaque rupture or erosion and arterial thrombus formation. The composition and location of atherosclerotic plaques determine the phenotype of the lesion and whether it is more likely to rupture or to erode. Although plaque rupture and erosion both initiate platelet activation on the exposed vascular surface, the contribution of platelets to thrombus formation differs between the two phenotypes. In this review, plaque phenotype is discussed in relation to thrombus composition, and an overview of important mediators (haemodynamics, matrix components, and soluble factors) in plaque-induced platelet activation is given. As thrombus formation on disrupted plaques does not necessarily result in complete vessel occlusion, plaque healing can occur. Therefore, the latest findings on plaque healing and the potential role of platelets in this process are summarized. Finally,…

BACKGROUND AND AIMS: Survivors of acute coronary syndromes face an elevated risk of recurrent atherosclerosis-related vascular events despite advanced medical treatments. The underlying causes remain unclear. This study aims to investigate whether myocardial infarction (MI)-induced trained immunity in monocytes could sustain proatherogenic traits and expedite atherosclerosis. METHODS: Apolipoprotein-E deficient (ApoE-/-) mice and adoptive bone marrow transfer chimeric mice underwent MI or myocardial ischaemia-reperfusion (IR). A subsequent 12-week high-fat diet (HFD) regimen was implemented to elucidate the mechanism behind monocyte trained immunity. In addition, classical monocytes were analysed by flow cytometry in the blood of enrolled patients. RESULTS: In MI and IR mice, blood monocytes and bone marrow-derived macrophages exhibited elevated spleen tyrosine kinase (SYK), lysine methyltransferase 5A (KMT5A), and CCHC-type zinc finger nucleic acid-binding protein (CNBP) expression upon exposure to a HFD or oxidized LDL (oxLDL) stimulation. MI-induced trained immunity was…

AIMS: Precision microbiome modulation as a novel treatment strategy is a rapidly evolving and sought goal. The aim of this study is to determine relationships among systemic gut microbial metabolite levels and incident cardiovascular disease risks to identify gut microbial pathways as possible targets for personalized therapeutic interventions. METHODS AND RESULTS: Stable isotope dilution mass spectrometry methods to quantitatively measure aromatic amino acids and their metabolites were used to examine sequential subjects undergoing elective diagnostic cardiac evaluation in two independent cohorts with longitudinal outcome data [US (n = 4000) and EU (n = 833) cohorts]. It was also used in plasma from humans and mice before vs. after a cocktail of poorly absorbed antibiotics to suppress gut microbiota. Multiple aromatic amino acid-derived metabolites that originate, at least in part, from gut bacteria are associated with incident (3-year) major adverse cardiovascular event (MACE) risks (myocardial infarction, stroke, or death) and all-cause mortality independent of traditional risk…

The current treatment algorithm for chronic thromboembolic pulmonary hypertension (CTEPH) as depicted in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines on the diagnosis and treatment of pulmonary hypertension (PH) includes a multimodal approach of combinations of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and medical therapies to target major vessel pulmonary vascular lesions, and microvasculopathy. Today, BPA of >1700 patients has been reported in the literature from centers in Asia, the US, and also Europe; many more patients have been treated outside literature reports. As BPA becomes part of routine care of patients with CTEPH, benchmarks for safe and effective care delivery become increasingly important. In light of this development, the ESC Working Group on Pulmonary Circulation and Right Ventricular Function has decided to publish a document that helps standardize BPA to meet the need of uniformity in patient selection, procedural planning, technical approach, materials and devices, treatment goals,…

Interest in the pathophysiology, etiology, management, and outcomes of patients with tricuspid regurgitation (TR) has grown in the wake of multiple natural history studies showing progressively worse outcomes associated with increasing TR severity, even after adjusting for multiple comorbidities. Historically, isolated tricuspid valve surgery has been associated with high in-hospital mortality rates, leading to the development of transcatheter treatment options. The aim of this first Tricuspid Valve Academic Research Consortium document is to standardize definitions of disease etiology and severity, as well as endpoints for trials that aim to address the gaps in our knowledge related to identification and management of patients with TR. Standardizing endpoints for trials should provide consistency and enable meaningful comparisons between clinical trials. A second Tricuspid Valve Academic Research Consortium document will focus on further defining trial endpoints and will discuss trial design options.

AIMS: 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. METHODS AND RESULTS: 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…

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…

AIMS: 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. METHODS AND RESULTS: 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…

AIMS: Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce. METHODS AND RESULTS: Respirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of…

BACKGROUND AND AIMS: 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. METHODS AND RESULTS: A multi-centre, open-label, randomized, and 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 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin…

AIMS: The best interventional strategy for the treatment of drug-eluting stent (DES) in-stent restenosis (ISR) is still unclear and no data from randomized trials beyond 3-year follow-up are available. We aimed to define 10-year comparative efficacy and safety of plain balloon (PB), paclitaxel-coated balloon (PCB), and paclitaxel-eluting stent (PES) for percutaneous coronary intervention (PCI) of DES-ISR. METHODS AND RESULTS: Clinical follow-up of patients randomly assigned to PB, PCB, and PES in the ISAR-DESIRE 3 trial was extended to 10 years and events were independently adjudicated. The primary endpoint was a composite of cardiac death, target vessel myocardial infarction, target lesion thrombosis, or target lesion revascularization. The major secondary safety endpoint was a composite of cardiac death, target vessel myocardial infarction, or target lesion thrombosis. The major secondary efficacy endpoint was target lesion revascularization. Incidences by the Kaplan-Meier method were compared by the log-rank test. Risk estimation was primarily performed by Cox proportional…

AIMS: This study aimed to report the long-term findings of the Italian programme of cardiovascular preparticipation screening (PPS) in young, competitive athletes. METHODS AND RESULTS: The study assessed the diagnostic yield for diseases at risk of sudden cardiac death (SCD), the costs of serial evaluations, and the long-term outcomes of PPS in a large population of Italian children (age range, 7-18 years). The PPS was repeated annually and included medical history, physical examination, resting electrocardiogram, and stress testing; additional tests were reserved for athletes with abnormal findings. Over an 11-year study period, 22 324 consecutive children [62% males; mean age, 12 (interquartile range, 10-14) years at first screening] underwent a total of 65 397 annual evaluations (median 2.9/child). Cardiovascular diseases at risk of SCD were identified in 69 children (0.3%) and included congenital heart diseases (n = 17), channelopathies (n = 14), cardiomyopathies (n = 15), non-ischaemic left ventricular scar with ventricular arrhythmias (n = 18), and others (n = 5). At-risk…

Natural language processing techniques are having an increasing impact on clinical care from patient, clinician, administrator, and research perspective. Among others are automated generation of clinical notes and discharge letters, medical term coding for billing, medical chatbots both for patients and clinicians, data enrichment in the identification of disease symptoms or diagnosis, cohort selection for clinical trial, and auditing purposes. In the review, an overview of the history in natural language processing techniques developed with brief technical background is presented. Subsequently, the review will discuss implementation strategies of natural language processing tools, thereby specifically focusing on large language models, and conclude with future opportunities in the application of such techniques in the field of cardiology.

AIMS: Whether changes in endothelial tight junctions (TJs) lead to the formation of thoracic aortic aneurysm and dissection (TAAD) and serve as an early indicator and therapeutic target remains elusive. METHODS AND RESULTS: Single-cell RNA sequencing analysis showed aberrant endothelial TJ expressions in the thoracic aortas of patients with TAAD. In a β-aminopropionitrile (BAPN)-induced TAAD mouse model, endothelial TJ function was disrupted in the thoracic aortas at an early stage (5 and 10 days) as observed by a vascular permeability assay, while the intercellular distribution of crucial TJ components was significantly decreased by en face staining. For the non-invasive detection of endothelial TJ function, two dextrans of molecular weights 4 and 70 kDa were conjugated with the magnetic resonance imaging (MRI) contrast agent Gd-DOTA to synthesize FITC-dextran-DOTA-Gd and rhodamine B-dextran-DOTA-Gd. MRI images showed that both probes accumulated in the thoracic aortas of the BAPN-fed mice. Particularly, the mice with increased accumulated signals from 5 to 10 days developed TAAD…

Aortic stenosis (AS) is a serious and complex condition, for which optimal management continues to evolve rapidly. An understanding of current clinical practice guidelines is critical to effective patient care and shared decision-making. This state of the art review of the 2021 European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines and 2020 American College of Cardiology/American Heart Association Guidelines compares their recommendations for AS based on the evidence to date. The European and American guidelines were generally congruent with the exception of three key distinctions. First, the European guidelines recommend intervening at a left ventricular ejection fraction of 55%, compared with 60% over serial imaging by the American guidelines for asymptomatic patients. Second, the European guidelines recommend a threshold of ≥65 years for surgical bioprosthesis, whereas the American guidelines employ multiple age categories, providing latitude for patient factors and preferences. Third, the guidelines endorse different age cut-offs for…

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.

AIMS: The microvascular resistance reserve (MRR) was introduced as a means to characterize the vasodilator reserve capacity of the coronary microcirculation while accounting for the influence of concomitant epicardial disease and the impact of administration of potent vasodilators on aortic pressure. This study aimed to evaluate the diagnostic and prognostic performance of MRR. METHODS AND RESULTS: A total of 1481 patients with stable symptoms and a clinical indication for coronary angiography were included from the global ILIAS Registry. MRR was derived as a function of the coronary flow reserve (CFR) divided by the fractional flow reserve (FFR) and corrected for driving pressure. The median MRR was 2.97 [Q1-Q3: 2.32-3.86] and the overall relationship between MRR and CFR was good [correlation coefficient (Rs) = 0.88, P < 0.005]. The difference between CFR and MRR increased with decreasing FFR [coefficient of determination (R2) = 0.34; Coef.-2.88, 95% confidence interval (CI): -3.05--2.73; P < 0.005]. MRR was independently associated with major adverse cardiac events (MACE) at…

BACKGROUND AND AIMS: Residual leaks are not infrequent after left atrial appendage occlusion. However, there is still uncertainty regarding their prognostic implications. The aim of this study is to evaluate the impact of residual leaks after left atrial appendage occlusion. METHODS: A literature search was conducted until 19 February 2023. Residual leaks comprised peri-device leaks (PDLs) on transoesophageal echocardiography (TEE) or computed tomography (CT), as well as left atrial appendage patency on CT. Random-effects meta-analyses were performed to assess the clinical impact of residual leaks. RESULTS: Overall 48 eligible studies (44 non-randomized/observational and 4 randomized studies) including 61 666 patients with atrial fibrillation who underwent left atrial appendage occlusion were analysed. Peri-device leak by TEE was present in 26.1% of patients. Computed tomography-based left atrial appendage patency and PDL were present in 54.9% and 57.3% of patients, respectively. Transoesophageal echocardiography-based PDL (i.e. any reported PDL regardless of its size) was…

AIMS: 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. METHODS AND RESULTS: 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…

BACKGROUND AND AIMS: HeartMate 3 (HM3) is a fully magnetically levitated continuous flow left ventricular assist device, which received CE marking in 2015. The ELEVATE Registry was initiated to collect real-world outcomes in patients treated with HM3 post-CE Mark approval. METHODS: A total of 540 subjects implanted at 26 centres between March 2015 and February 2017 were included in this registry. Of these, 463 received the device as a primary implant (primary implant cohort, PIC), 19 as a pump exchange (pump exchange cohort), and in 58 patients, only anonymized survival data were collected (anonymized cohort, AC). Patients in the PIC contributed to the baseline demographics, survival, adverse events, quality of life (QoL) (EuroQoL-5 Dimensions-5 Levels visual analogue scale), and functional capacity (6 min walk distance) assessments, while patients in the AC contributed only to survival. RESULTS: Primary implant cohort patients had a mean age of 56 years and were predominantly male (89%) with 48% ischaemic aetiology. The majority of subjects was designated bridge to transplant (66%)…

BACKGROUND AND AIMS: Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive. METHODS: Ascending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a β-aminopropionitrile monofumarate-induced AD model. RESULTS: The transcriptional profiles of 93 397 cells revealed a dynamic…

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…

BACKGROUND AND AIMS: Previous evidence has mainly supported transient changes in cardiac function during interictal or peri-ictal phases in people with epilepsy, but the long-term risk of cardiac arrhythmias is poorly described. This study aimed to assess the long-term association of epilepsy with cardiac arrhythmias, considering the potential role of genetic predisposition and antiseizure medications (ASMs) in any associations observed. METHODS: This population-based study evaluated UK Biobank data for individuals recruited between 2006 and 2010. Cox proportional hazards models and competing risk models were used to examine the association of epilepsy history with the long-term incidence risk of cardiac arrhythmias and arrhythmias subtypes. Polygenic risk scores (PRS) were calculated to investigate the effect of genetic susceptibility. The role of ASMs was also evaluated by integrating observational and drug target Mendelian randomization (MR) evidence. RESULTS: The study included 329 432 individuals, including 2699 people with epilepsy. Compared with those without epilepsy, people…

BACKGROUND AND AIMS: To determine the comparative efficacy of resistance, aerobic, and combined resistance plus aerobic exercise on cardiovascular disease (CVD) risk profile. METHODS: This randomized controlled trial enrolled 406 adults aged 35-70 years with overweight or obesity and elevated blood pressure. Participants were randomly assigned to resistance (n = 102), aerobic (n = 101), combined resistance plus aerobic exercise (n = 101), or no-exercise control (n = 102). All exercise participants were prescribed 1 h of time-matched supervised exercise (the combination group with 30 min of each resistance and aerobic exercise) three times per week for 1 year. The primary outcome was the change from baseline to 1 year in the standardized composite Z-score of four well-established CVD risk factors: systolic blood pressure, low-density lipoprotein (LDL) cholesterol, fasting glucose, and per cent body fat. RESULTS: Among 406 participants (53% women), 381 (94%) completed 1-year follow-up. Compared with the control group, the composite Z-score decreased at 1 year, which indicates improved…

BACKGROUND AND AIMS: 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. METHODS: 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). RESULTS: 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…

BACKGROUND AND AIMS: De novo implanted cardiac resynchronization therapy with defibrillator (CRT-D) reduces the risk of morbidity and mortality in patients with left bundle branch block, heart failure and reduced ejection fraction (HFrEF). However, among HFrEF patients with right ventricular pacing (RVP), the efficacy of CRT-D upgrade is uncertain. METHODS: In this multicentre, randomized, controlled trial, 360 symptomatic (New York Heart Association Classes II-IVa) HFrEF patients with a pacemaker or implantable cardioverter defibrillator (ICD), high RVP burden ≥ 20%, and a wide paced QRS complex duration ≥ 150 ms were randomly assigned to receive CRT-D upgrade (n = 215) or ICD (n = 145) in a 3:2 ratio. The primary outcome was the composite of all-cause mortality, heart failure hospitalization, or <15% reduction of left ventricular end-systolic volume assessed at 12 months. Secondary outcomes included all-cause mortality or heart failure hospitalization. RESULTS: Over a median follow-up of 12.4 months, the primary outcome occurred in 58/179 (32.4%) in the CRT-D arm vs. 101/128…

AIMS: 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. METHODS AND RESULTS: 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…

BACKGROUND AND AIMS: Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias. METHODS: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested. RESULTS: This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95%…

Cardiovascular disease is a leading cause of death, morbidity, disability, and reduced health-related quality of life, as well as economic burden worldwide, with some 80% of disease burden occurring in the low- and middle-income country (LMIC) settings. With increasing numbers of people living longer with symptomatic disease, the effectiveness and accessibility of secondary preventative and rehabilitative health services have never been more important. Whilst LMICs experience the highest prevalence and mortality rates, the global approach to secondary prevention and cardiac rehabilitation, which mitigates this burden, has traditionally been driven from clinical guidelines emanating from high-income settings. This state-of-the art review provides a contemporary global perspective on cardiac rehabilitation and secondary prevention, contrasting the challenges of and opportunities for high vs. lower income settings. Actionable solutions to overcome system, clinician, programme, and patient level barriers to cardiac rehabilitation access in LMICs are provided.

AIMS: The mechanisms underlying ageing-induced vascular remodelling remain unclear. This study investigates the role and underlying mechanisms of the cytoplasmic deacetylase sirtuin 2 (SIRT2) in ageing-induced vascular remodelling. METHODS AND RESULTS: Transcriptome and quantitative real-time PCR data were used to analyse sirtuin expression. Young and old wild-type and Sirt2 knockout mice were used to explore vascular function and pathological remodelling. RNA-seq, histochemical staining, and biochemical assays were used to evaluate the effects of Sirt2 knockout on the vascular transcriptome and pathological remodelling and explore the underlying biochemical mechanisms. Among the sirtuins, SIRT2 had the highest levels in human and mouse aortas. Sirtuin 2 activity was reduced in aged aortas, and loss of SIRT2 accelerated vascular ageing. In old mice, SIRT2 deficiency aggravated ageing-induced arterial stiffness and constriction-relaxation dysfunction, accompanied by aortic remodelling (thickened vascular medial layers, breakage of elastin fibres, collagen deposition, and…

AIMS: Lifestyle risk factors are a modifiable target in atrial fibrillation (AF) management. The relative contribution of individual lifestyle risk factors to AF development has not been described. Development and validation of an AF lifestyle risk score to identify individuals at risk of AF in the general population are the aims of the study. METHODS AND RESULTS: The UK Biobank (UKB) and Framingham Heart Study (FHS) are large prospective cohorts with outcomes measured >10 years. Incident AF was based on International Classification of Diseases version 10 coding. Prior AF was excluded. Cox proportional hazards regression identified independent AF predictors, which were evaluated in a multivariable model. A weighted score was developed in the UKB and externally validated in the FHS. Kaplan-Meier estimates ascertained the risk of AF development. Among 314 280 UKB participants, AF incidence was 5.7%, with median time to AF 7.6 years (interquartile range 4.5-10.2). Hypertension, age, body mass index, male sex, sleep apnoea, smoking, and alcohol were predictive variables (all P < 0.001);…

BACKGROUND AND AIMS: Air pollutants are important contributors to cardiovascular diseases, but associations between long-term exposure to air pollutants and the risk of abdominal aortic aneurysm (AAA) are still unknown. METHODS: This study was conducted using a sample of 449 463 participants from the UK Biobank. Hazard ratios and 95% confidence intervals for the risk of AAA incidence associated with long-term exposure to air pollutants were estimated using the Cox proportional hazards model with time-varying exposure measurements. Additionally, the cumulative incidence of AAA was calculated by using the Fine and Grey sub-distribution hazards regression model. Furthermore, this study investigated the combined effects and interactions between air pollutants exposure and genetic predisposition in relation to the risk of AAA onset. RESULTS: Long-term exposure to particulate matter with an aerodynamic diameter <2.5 µm [PM2.5, 1.21 (1.16, 1.27)], particulate matter with an aerodynamic diameter <10 µm [PM10, 1.21 (1.16, 1.27)], nitrogen dioxide [NO2, 1.16 (1.11, 1.22)], and nitrogen oxides…

AIMS: 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. METHODS AND RESULTS: 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…

AIMS: Recent evidence suggest that the lipoprotein(a)-associated risk of atherosclerotic cardiovascular disease (ASCVD) may be observed only in individuals with low-grade systemic inflammation. It was hypothesized that high lipoprotein(a) is a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis irrespective of C-reactive protein levels. METHODS AND RESULTS: A total of 68 090 individuals from the Copenhagen General Population Study, a prospective cohort study, were included. During a median follow-up of 8.1 years, 5104 individuals developed ASCVD, 2432 myocardial infarction, and 1220 aortic valve stenosis. The risk of ASCVD, myocardial infarction, and aortic valve stenosis increased with higher values of both lipoprotein(a) and C-reactive protein. For individuals with lipoprotein(a) in the 91st-100th percentiles (≥70 mg/dl, ≥147 nmol/l) vs. the 1st-33rd percentiles (≤6 mg/dl, ≤9 nmol/l), the multivariable-adjusted hazard ratio for ASCVD was 1.61 (95% confidence interval 1.43-1.81) for those with C-reactive protein <2 mg/l and 1.57 (1.36-1.82) for those…

BACKGROUND AND AIMS: Identifying patients with hypertrophic cardiomyopathy (HCM) who are candidates for implantable cardioverter defibrillator (ICD) implantation in primary prevention for sudden cardiac death (SCD) is crucial. The aim of this study was to externally validate the 2022 European Society of Cardiology (ESC) model and other guideline-based ICD class of recommendation (ICD-COR) models and explore the utility of late gadolinium enhancement (LGE) in further risk stratification. METHODS: Seven hundred and seventy-four consecutive patients who underwent cardiac magnetic resonance imaging were retrospectively enrolled. RESULTS: Forty-six (5.9%) patients reached the SCD-related endpoint during 7.4 ± 2.5 years of follow-up. Patients suffering from SCD had higher ESC Risk-SCD score (4.3 ± 2.4% vs. 2.8 ± 2.1%, P < .001) and LGE extent (13.7 ± 9.4% vs. 4.9 ± 6.6%, P < .001). Compared with the 2014 ESC model, the 2022 ESC model showed increased area under the curve (.76 vs. .63), sensitivity (76.1% vs. 43.5%), positive predictive value (16.8% vs. 13.6%), and negative predictive…

BACKGROUND AND AIMS: Atrial fibrillation (AF) is a chronic progressive disorder. Persistent forms of AF are associated with increased rates of thromboembolism, heart failure, and death. Catheter ablation modifies the pathogenic mechanism of AF progression. No randomized studies have evaluated the impact of the ablation energy on progression to persistent atrial tachyarrhythmia. METHODS: Three hundred forty-six patients with drug-refractory paroxysmal AF were enrolled and randomly assigned to contact-force-guided RF ablation (CF-RF ablation, 115), 4 min cryoballoon ablation (CRYO-4, 115), or 2 min cryoballoon ablation (CRYO-2, 116). Implantable cardiac monitors placed at study entry were used for follow-up. The main outcome was the first episode of persistent atrial tachyarrhythmia. Secondary outcomes included atrial tachyarrhythmia recurrence and arrhythmia burden on the implantable monitor. RESULTS: At a median of 944.0 (interquartile range [IQR], 612.5-1104) days, 0 of 115 patients (0.0%) randomly assigned to CF-RF, 8 of 115 patients (7.0%) assigned to CRYO-4, and 5 of 116…

AIMS: 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. METHODS AND RESULTS: 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…

AIMS: Complications of coronary artery disease (CAD) represent the leading cause of death among adults globally. This study examined the associations and clinical utilities of genetic, sociodemographic, lifestyle, and clinical risk factors on CAD recurrence. METHODS AND RESULTS: Data were from 7024 UK Biobank middle-aged adults with established CAD at enrolment. Cox proportional hazards regressions modelled associations of age at enrolment, age at first CAD diagnosis, sex, cigarette smoking, physical activity, diet, sleep, Townsend Deprivation Index, body mass index, blood pressure, blood lipids, glucose, lipoprotein(a), C reactive protein, estimated glomerular filtration rate (eGFR), statin prescription, and CAD polygenic risk score (PRS) with first post-enrolment CAD recurrence. Over a median [interquartile range] follow-up of 11.6 [7.2-12.7] years, 2003 (28.5%) recurrent CAD events occurred. The hazard ratio (95% confidence interval [CI]) for CAD recurrence was the most pronounced with current smoking (1.35, 1.13-1.61) and per standard deviation increase in age at first CAD…

BACKGROUND AND AIMS: 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. METHODS AND RESULTS: 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…

Rates of successful surgical repair and life expectancy for patients with congenital heart disease have increased dramatically in recent decades. Thanks to advances in diagnosis, treatment, and follow-up care, an ever-increasing number of individuals with congenital heart disease are reaching advanced age. The exposure to cardiovascular risk factors during their lifetime is modifying the outlook and late clinical trajectory of adult congenital heart disease (ACHD). Their disease burden is shifting from congenital to acquired, primarily atherosclerotic cardiovascular disease (ASCVD) with worrisome consequences. In addition, the complex background of ACHD often curbs appropriate preventive strategies by general practitioners or adult cardiologists. Comprehensive guidance for the prevention and management of acquired heart disease in ACHD patients is currently not available, as this topic has not been covered by the European Society of Cardiology (ESC) guidelines on cardiovascular disease prevention or the ESC guidelines for the management of ACHD. In this document, a state-of-the-art…

BACKGROUND AND AIMS: 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. METHODS AND RESULTS: 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…

AIMS: 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. METHODS AND RESULTS: 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…

AIMS: Optimal endovascular management of intermittent claudication (IC) remains disputed. This systematic review and meta-analysis compares efficacy and safety outcomes for balloon angioplasty (BA), bare-metal stents (BMS), drug-coated balloons (DCB), drug-eluting stents (DES), covered stents, and atherectomy. METHODS AND RESULTS: Electronic databases were searched for randomized, controlled trials (RCT) from inception through November 2021. Efficacy outcomes were primary patency, target-lesion revascularization (TLR), and quality-of-life (QoL). Safety endpoints were all-cause mortality and major amputation. Outcomes were evaluated at short-term (<1 year), mid-term (1-2 years), and long-term (≥2 years) follow-up. The study was registered on PROSPERO (CRD42021292639). Fifty-one RCTs enrolling 8430 patients/lesions were included. In femoropopliteal disease of low-to-intermediate complexity, DCBs were associated with higher likelihood of primary patency [short-term: odds ratio (OR) 3.21, 95% confidence interval (CI) 2.44-4.24; long-term: OR 2.47, 95% CI 1.93-3.16], lower TLR…

AIMS: Calcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored. METHODS AND RESULTS: An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14, and 21 days; and processed for imaging, proteomics, and transcriptomics including single-cell RNA-sequencing (scRNA-seq). The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice vs. littermate controls. Protein studies identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq…

To raise the quality of clinical artificial intelligence (AI) prediction modelling studies in the cardiovascular health domain and thereby improve their impact and relevancy, the editors for digital health, innovation, and quality standards of the European Heart Journal propose five minimal quality criteria for AI-based prediction model development and validation studies: complete reporting, carefully defined intended use of the model, rigorous validation, large enough sample size, and openness of code and software.

Migraine is a chronic neurovascular disease with a complex, not fully understood pathophysiology with multiple causes. People with migraine suffer from recurrent moderate to severe headache attacks varying from 4 to 72 h. The prevalence of migraine is two to three times higher in women compared with men. Importantly, it is the most disabling disease in women <50 years of age due to a high number of years lived with disability, resulting in a very high global socioeconomic burden. Robust evidence exists on the association between migraine with aura and increased incidence of cardiovascular disease (CVD), in particular ischaemic stroke. People with migraine with aura have an increased risk of atrial fibrillation, myocardial infarction, and cardiovascular death compared with those without migraine. Ongoing studies investigate the relation between migraine and angina with non-obstructive coronary arteries and migraine patients with patent foramen ovale. Medication for the treatment of migraine can be preventative medication, such as beta-blockers, angiotensin-converting enzyme…

AIMS: 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. METHODS AND RESULTS: A systematic literature search was performed for randomized clinical trials 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. Three eligible randomized clinical trials were identified that included 1898 outpatients in New York Heart Association functional classes II-IV, either hospitalized for HF in the prior 12 months or with elevated plasma NT-proBNP concentrations. The mean follow-up was 14.7 months, 67.8% of the patients were men, and 65.8% had an ejection fraction ≤40%.…

Patient-reported outcomes (PROs) provide important insights into patients' own perspectives about their health and medical condition, and there is evidence that their use can lead to improvements in the quality of care and to better-informed clinical decisions. Their application in cardiovascular populations has grown over the past decades. This statement describes what PROs are, and it provides an inventory of disease-specific and domain-specific PROs that have been developed for cardiovascular populations. International standards and quality indices have been published, which can guide the selection of PROs for clinical practice and in clinical trials and research; patients as well as experts in psychometrics should be involved in choosing which are most appropriate. Collaborations are needed to define criteria for using PROs to guide regulatory decisions, and the utility of PROs for comparing and monitoring the quality of care and for allocating resources should be evaluated. New sources for recording PROs include wearable digital health devices, medical registries, and…

AIMS: The safety and efficacy of transcatheter aortic valve replacement (TAVR) with contemporary balloon expandable transcatheter valves in patients with cardiogenic shock (CS) remain largely unknown. In this study, the TAVRs performed for CS between June 2015 and September 2022 using SAPIEN 3 and SAPIEN 3 Ultra bioprosthesis from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry were analysed. METHODS AND RESULTS: CS was defined as: (i) coding of CS within 24 h on Transcatheter Valve Therapy Registry form; and/or (ii) pre-procedural use of inotropes or mechanical circulatory support devices and/or (iii) cardiac arrest within 24 h prior to TAVR. The control group was comprised of all the other patients undergoing TAVR. Baseline characteristics, all-cause mortality, and major complications at 30-day and 1-year outcomes were reported. Landmark analysis was performed at 30 days post-TAVR. Cox-proportional multivariable analysis was performed to determine the predictors of all-cause mortality at 1 year. A total of 309 505 patients…

BACKGROUND: 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 vs. delayed AF ablation strategy is associated with differences in arrhythmia outcomes during 12-month follow-up. METHODS AND RESULTS: One hundred patients with symptomatic AF referred to a tertiary centre for management were randomized in a 1:1 ratio to either an early ablation strategy (within 1 month of recruitment) or a delayed ablation strategy (optimized 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…

BACKGROUND AND AIMS: Lerodalcibep, a novel small recombinant fusion protein of a proprotein convertase subtilisin/kexin type 9 gene-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 subcutaneous dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep were evaluated in heterozygous familial hypercholesterolaemia patients requiring additional LDL-C lowering. METHODS: Patients were randomized 2:1 to monthly subcutaneous injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the per cent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24. RESULTS: 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 with placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean (SE); 95% confidence interval -2.30 to -1.87] with a percentage difference of -58.61 (3.25)% at Week 24…

BACKGROUND AND AIMS: In the ADVOR trial, acetazolamide improved decongestion in acute decompensated heart failure (ADHF). Whether the beneficial effects of acetazolamide are consistent across the entire range of renal function remains unclear. METHODS: This is a pre-specified analysis of the ADVOR trial that randomized 519 patients with ADHF to intravenous acetazolamide or matching placebo on top of intravenous loop diuretics. The main endpoints of decongestion, diuresis, natriuresis, and clinical outcomes are assessed according to baseline renal function. Changes in renal function are evaluated between treatment arms. RESULTS: On admission, median estimated glomerular filtration rate (eGFR) was 40 (30-52) mL/min/1.73 m². Acetazolamide consistently increased the likelihood of decongestion across the entire spectrum of eGFR (P-interaction = .977). Overall, natriuresis and diuresis were higher with acetazolamide, with a higher treatment effect for patients with low eGFR (both P-interaction < .007). Acetazolamide was associated with a higher incidence of worsening renal function (WRF;…

In October 2021, the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) jointly agreed to establish a Task Force (TF) to review recommendations of the 2018 ESC/EACTS Guidelines on myocardial revascularization as they apply to patients with left main (LM) disease with low-to-intermediate SYNTAX score (0-32). This followed the withdrawal of support by the EACTS in 2019 for the recommendations about the management of LM disease of the previous guideline. The TF was asked to review all new relevant data since the 2018 guidelines including updated aggregated data from the four randomized trials comparing percutaneous coronary intervention (PCI) with drug-eluting stents vs. coronary artery bypass grafting (CABG) in patients with LM disease. This document represents a summary of the work of the TF; suggested updated recommendations for the choice of revascularization modality in patients undergoing myocardial revascularization for LM disease are included. In stable patients with an indication for revascularization for LM disease, with…

BACKGROUND AND AIMS: 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. METHODS AND RESULTS: 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).…

BACKGROUND AND AIMS: Severe aortic stenosis (AS) is the guideline-based indication for aortic valve replacement (AVR), which has markedly increased with transcatheter approaches, suggesting possible increasing AS incidence. However, reported secular trends of AS incidence remain contradictory and lack quantitative Doppler echocardiographic ascertainment. METHODS: All adults residents in Olmsted County (MN, USA) diagnosed over 20 years (1997-2016) with incident severe AS (first diagnosis) based on quantitatively defined measures (aortic valve area ≤ 1 cm2, aortic valve area index ≤ 0.6 cm2/m2, mean gradient ≥ 40 mmHg, peak velocity ≥ 4 m/s, Doppler velocity index ≤ 0.25) were counted to define trends in incidence, presentation, treatment, and outcome. RESULTS: Incident severe AS was diagnosed in 1069 community residents. The incidence rate was 52.5 [49.4-55.8] per 100 000 patient-year, slightly higher in males vs. females and was almost unchanged after age and sex adjustment for the US population 53.8 [50.6-57.0] per 100 000 residents/year. Over 20 years, severe AS incidence remained…

BACKGROUND AND AIMS: While endomyocardial biopsy (EMB) is recommended in adult patients with fulminant myocarditis, the clinical impact of its timing is still unclear. METHODS: Data were collected from 419 adult patients with clinically suspected fulminant myocarditis admitted to intensive care units across 36 tertiary centres in 15 countries worldwide. The diagnosis of myocarditis was histologically proven in 210 (50%) patients, either by EMB (n = 183, 44%) or by autopsy/explanted heart examination (n = 27, 6%), and clinically suspected cardiac magnetic resonance imaging confirmed in 96 (23%) patients. The primary outcome of survival free of heart transplantation (HTx) or left ventricular assist device (LVAD) at 1 year was specifically compared between patients with early EMB (within 2 days after intensive care unit admission, n = 103) and delayed EMB (n = 80). A propensity score-weighted analysis was done to control for confounders. RESULTS: Median age on admission was 40 (29-52) years, and 322 (77%) patients received temporary mechanical circulatory support. A total of 273 (65%)…