Publications of our Scientists

Pulmonary vein isolation (PVI) using pulsed field ablation (PFA) or cryoballoon ablation (CBA) are commonly used single-shot techniques for the treatment of patients with atrial fibrillation (AF). The number of overweight (BMI 25-30 kg/m) and obese (BMI>30 kg/m) patients undergoing PVI is increasing, but data on this patient population is limited.

The vitamin K-dependent coagulation factor protein Z (PZ), encoded by the PROZ gene, is canonically considered to have anticoagulant effects through negative regulation of factor Xa. Paradoxically, higher circulating PZ concentrations have repeatedly been associated with an elevated risk of acute ischemic stroke.

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Achievement of guideline-recommended levels of physical activity (≥150 minutes of moderate-to-vigorous physical activity per week) is associated with lower risk of adverse cardiovascular events and represents an important public health priority. Although physical activity commonly follows a "weekend warrior" pattern, in which most moderate-to-vigorous physical activity is concentrated in 1 or 2 days rather than spread more evenly across the week (regular), the effects of physical activity pattern across a range of incident diseases, including cardiometabolic conditions, are unknown.

Arrhythmia refers to irregularities in the rate and rhythm of the heart, with symptoms spanning from mild palpitations to life-threatening arrhythmias and sudden cardiac death (SCD). The complex molecular nature of arrhythmias complicates the selection of appropriate treatment. Current therapies involve the use of antiarrhythmic drugs (class I-IV) with limited efficacy and dangerous side effects and implantable pacemakers and cardioverter-defibrillators with hardware-related complications and inappropriate shocks. The number of novel antiarrhythmic drug in the development pipeline has decreased substantially during the last decade and underscores uncertainties regarding future developments in this field. Consequently, arrhythmia treatment poses significant challenges, prompting the need for alternative approaches. Remarkably, innovative drug discovery and development technologies show promise in helping advance antiarrhythmic therapies. Here, we review unique characteristics and the transformative potential of emerging technologies that offer unprecedented opportunities for transitioning from traditional antiarrhythmics to next-generation therapies. We assess stem cell technology, emphasizing the utility of innovative cell profiling using multi-omics, high-throughput screening, and advanced computational modeling in developing treatments tailored precisely to individual genetic and physiological profiles. We offer insights into gene therapy, peptide and peptibody approaches for drug delivery. We finally discuss potential strengths and weaknesses of such techniques in reducing adverse effects and enhancing overall treatment outcomes, leading to more effective, specific, and safer therapies. Altogether, this comprehensive overview introduces innovative avenues for personalized rhythm therapy, with particular emphasis on drug discovery, aiming to advance the arrhythmia treatment landscape and the prevention of SCD. Arrhythmias and sudden cardiac death account for 15-20% of deaths worldwide. However, current antiarrhythmic therapies are ineffective and with dangerous side effects. Here, we review the field of arrhythmia treatment underscoring the slow progress in advancing the cardiac rhythm therapy pipeline and the uncertainties regarding evolution of this field. We provide information on how emerging technological and experimental tools can help accelerate progress and address the limitations of antiarrhythmic drug discovery.

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P <  after conditioning on previously reported variants, with effect sizes ranging from -7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.

Human genetic variants are associated with many traits through largely unknown mechanisms. Here, combining approximately 260,000 Japanese study participants, a Japanese-specific genotype reference panel and statistical fine-mapping, we identified 4,423 significant loci across 63 quantitative traits, among which 601 were new, and 9,406 putatively causal variants. New associations included Japanese-specific coding, splicing and noncoding variants, exemplified by a damaging missense variant rs730881101 in TNNT2 associated with lower heart function and increased risk for heart failure (P = 1.4 × 10 and odds ratio = 4.5, 95% confidence interval = 3.1-6.5). Putative causal noncoding variants were supported by state-of-art in silico functional assays and had comparable effect sizes to coding variants. A plausible example of new mechanisms of causal variants is an enrichment of causal variants in 3' untranslated regions (UTRs), including the Japanese-specific rs13306436 in IL6 associated with pro-inflammatory traits and protection against tuberculosis. We experimentally showed that transcripts with rs13306436 are resistant to mRNA degradation by regnase-1, an RNA-binding protein. Our study provides a list of fine-mapped causal variants to be tested for functionality and underscores the importance of sequencing, genotyping and association efforts in diverse populations.

Heart failure (HF) and inflammation have a bidirectional relation leading to activation and adaptation of multiple cellular lines, including leucocyte subtypes and platelets. We aimed to assess and compare the predictive value of the neutrophil-lymphocyte (NLR), monocyte-lymphocyte (MLR) and platelet-lymphocyte (PLR) ratios for all-cause long-term mortality in HF.

The global prevalence of obesity has more than doubled over the past four decades, currently affecting more than a billion individuals. Beyond its recognition as a high-risk condition that is causally linked to many chronic illnesses, obesity has been declared a disease per se that results in impaired quality of life and reduced life expectancy. Notably, two-thirds of obesity-related excess mortality is attributable to cardiovascular disease. Despite the increasingly appreciated link between obesity and a broad range of cardiovascular disease manifestations including atherosclerotic disease, heart failure, thromboembolic disease, arrhythmias, and sudden cardiac death, obesity has been underrecognized and sub-optimally addressed compared with other modifiable cardiovascular risk factors. In the view of major repercussions of the obesity epidemic on public health, attention has focused on population-based and personalized approaches to prevent excess weight gain and maintain a healthy body weight from early childhood and throughout adult life, as well as on comprehensive weight loss interventions for persons with established obesity. This clinical consensus statement by the European Society of Cardiology discusses current evidence on the epidemiology and aetiology of obesity; the interplay between obesity, cardiovascular risk factors and cardiac conditions; the clinical management of patients with cardiac disease and obesity; and weight loss strategies including lifestyle changes, interventional procedures, and anti-obesity medications with particular focus on their impact on cardiometabolic risk and cardiac outcomes. The document aims to raise awareness on obesity as a major risk factor and provide guidance for implementing evidence-based practices for its prevention and optimal management within the context of primary and secondary cardiovascular disease prevention.

The appropriate duration of treatment with beta-blocker drugs after a myocardial infarction is unknown. Data are needed on the safety and efficacy of the interruption of long-term beta-blocker treatment to reduce side effects and improve quality of life in patients with a history of uncomplicated myocardial infarction.

Extensive genetic studies have elucidated cardiomyocyte differentiation and associated gene networks using single-cell RNA-seq, yet the intricate transcriptional mechanisms governing cardiac conduction system (CCS) development and working cardiomyocyte differentiation remain largely unexplored. Here we show that mice deleted for Dhx36 (encoding the Dhx36 helicase) in the embryonic or neonatal heart develop overt dilated cardiomyopathy, surface ECG alterations related to cardiac impulse propagation, and (in the embryonic heart) a lack of a ventricular conduction system (VCS). Heart snRNA-seq and snATAC-seq reveal the role of Dhx36 in CCS development and in the differentiation of working cardiomyocytes. Dhx36 deficiency directly influences cardiomyocyte gene networks by disrupting the resolution of promoter G-quadruplexes in key cardiac genes, impacting cardiomyocyte differentiation and CCS morphogenesis, and ultimately leading to dilated cardiomyopathy and atrioventricular block. These findings further identify crucial genes and pathways that regulate the development and function of the VCS/Purkinje fiber (PF) network.

Atrial fibrillation has an estimated prevalence of 1.5-2%, making it the most common cardiac arrhythmia. The processes that cause and sustain the disease are still not completely understood. An association between atrial fibrillation and systemic, as well as local, inflammatory processes has been reported. However, the exact mechanisms underlying this association have not been established. While it is understood that inflammatory macrophages can influence cardiac electrophysiology, a direct, causative relationship to atrial fibrillation has not been described. This study investigated the pro-arrhythmic effects of activated M1 macrophages on human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes, to propose a mechanistic link between inflammation and atrial fibrillation.

Obesity and underweight are a growing health problem worldwide and a challenge for clinicians concerning antithrombotic therapy, due to the associated risks of thrombosis and/or bleeding. This clinical consensus statement updates a previous one published in 2018, by reviewing the most recent evidence on antithrombotic drugs based on body size categories according to the World Health Organization classification. The document focuses mostly on individuals at the extremes of body weight, i.e. underweight and moderate-to-morbid obesity who require antithrombotic drugs, according to current guidelines, for the treatment or prevention of cardiovascular diseases or venous thromboembolism. Managing antithrombotic therapy or thromboprophylaxis in these individuals is challenging, due to profound changes in body composition, metabolism and organ function, altered drug pharmacokinetics and pharmacodynamics, as well as weak or no evidence from clinical trials. The document also includes artificial intelligence simulations derived from in silico pharmacokinetic/pharmacodynamic models, which can mimic the pharmacokinetic changes and help identify optimal regimens of antithrombotic drugs for severely underweight or severely obese individuals. Further, bariatric surgery in morbidly obese subjects is frequently performed worldwide. Bariatric surgery causes specific and additional changes in metabolism and gastrointestinal anatomy, depending on the type of the procedure, which can also impact the pharmacokinetics of antithrombotic drugs and their management. Based on existing literature, the document provides consensus statements on optimising antithrombotic drug management for underweight and all classes of obese patients, while highlighting the current gaps in knowledge in these complex clinical settings, which require personalized medicine and precision pharmacology.

Rare coding alleles play crucial roles in the molecular diagnosis of genetic diseases. However, the systemic identification of these alleles has been challenging due to their scarcity in the general population. Here, we discovered and characterized rare coding alleles contributing to genetic dyslipidemia, a principal risk for coronary artery disease, among over a million individuals combining three large contemporary genetic datasets (the Million Veteran Program, n = 634,535, UK Biobank, n = 431,178, and the All of Us Research Program, n = 92,304) totaling 1,158,017 multi-ancestral individuals. Unlike previous rare variant studies in lipids, this study included 238,243 individuals (20.6%) from non-European-like populations. Testing 2,997,401 rare coding variants from diverse backgrounds, we identified 800 exome-wide significant associations across 209 genes including 176 predicted loss of function and 624 missense variants. Among these exome-wide associations, 130 associations were driven by non-European-like populations. Associated alleles are highly enriched in functional variant classes, showed significant additive and recessive associations, exhibited similar effects across populations, and resolved pathogenicity for variants enriched in African or South-Asian populations. Furthermore, we identified 5 lipid-related genes associated with coronary artery disease . Among them, is a potentially novel therapeutic target through the down regulation of LDLC by its silencing. This study provides resources and insights for understanding causal mechanisms, quantifying the expressivity of rare coding alleles, and identifying novel drug targets across diverse populations.

Patients presenting with or alerting emergency networks due to acute heart failure (AHF) form a diverse group with a plethora of symptoms, risks, comorbidities, and aetiologies. During AHF, there is an increased risk of destabilizing the functional substrate and modulatory adding to the risk of ventricular arrhythmias (VAs) already created by the structural substrate. New VAs during AHF have previously identified patients with higher intra-hospital and 60-day morbidity and mortality. Risk stratification and criteria/best time point for coronary intervention and implantable cardioverter defibrillator (ICD) implantation, however, are still controversial topics in this difficult clinical setting. The characteristics and logistics of prehospital emergency medicine, as well as the density of centers capable of treating AHF and VAs, differ massively throughout Europe. Scientific guidelines provide clear recommendations for the management of arrhythmias in chronic HF patients. However, the incidence, significance, and management of arrhythmias in patients with AHF have been less studied. This consensus paper aimed to address the identification and treatment of VAs that complicate the course of patients who have AHF, including cardiogenic shock.

Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (n = 4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS.

In the AEGIS-II trial (NCT03473223), CSL112, a human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity, did not significantly reduce the risk of the primary endpoint through 90 days versus placebo after acute myocardial infarction (MI). Nevertheless, given the well-established relationship between higher low-density lipoprotein cholesterol (LDL-C) and plaque burden, as well as greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥100 mg/dL on statin therapy, the efficacy of CSL112 may be influenced by baseline LDL-C.

Little is known about the link between the endocannabinoid system and the in vivo metabolic function of white adipose tissue (WAT).

This study evaluated the feasibility of the intermittent use of direct oral anticoagulants (DOACs) guided by continuous rhythm monitoring via a clinically validated wearable smart device in high-bleeding risk (HBR) patients with symptomatic paroxysmal atrial fibrillation (AF) otherwise subjected to chronic anticoagulation after percutaneous coronary intervention (PCI).

Tea consumption is increasingly recognized for its potential benefits to cardiovascular health. This study reviews the available research, concentrating on the major components of tea and their mechanisms of action in the cardiovascular system. Tea is abundant in bioactive compounds, such as flavonoids and polysaccharides, which possess significant antioxidant and anti-inflammatory properties. These compounds play a crucial role in mitigating oxidative stress and inflammation, thereby supporting cardiovascular health. They enhance endothelial function, leading to improved vascular relaxation and reduced arterial stiffness, and exhibit antithrombotic effects. Additionally, regular tea consumption is potentially associated with better regulation of blood pressure, improved cholesterol profiles, and effective blood sugar control. It has been suggested that incorporating tea into daily dietary habits could be a practical strategy for cardiovascular disease prevention and management. Despite the promising evidence, more rigorous clinical trials are needed to establish standardized consumption recommendations and fully understand long-term effects. This review offers a more comprehensive analysis of the current evidence based on endothelium function and identifies the gaps that future research should address.

Substantial sex-based differences have been reported in atrial fibrillation (AF), but the underlying mechanisms are poorly understood.

Coronary Computed Tomography Angiography (CCTA) is a first line investigation for chest pain in patients with suspected obstructive coronary artery disease (CAD). However, many acute cardiac events occur in the absence of obstructive CAD. We assessed the lifetime cost-effectiveness of integrating a novel artificial intelligence-enhanced image analysis algorithm (AI-Risk) that stratifies the risk of cardiac events by quantifying coronary inflammation, combined with the extent of coronary artery plaque and clinical risk factors, by analysing images from routine CCTA.

Despite a proposed causal role for low-density lipoprotein cholesterol (LDL-C) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in three clinically significant genes for LDL metabolism (, , ). We utilized sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the LOFTEE and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank + All of Us). We included 421,049 unrelated participants (5,621 with AS) in UKB and 195,519 unrelated participants (1,087 with AS) in All of Us. Carriers of protein-disrupting variants in had higher mean LDL-C (UKB: +42.6 mg/dl, P=4.4e-237) and greater risk of AS (meta-analysis: odds ratio [OR] =3.52 [95% CI 2.39-5.20], P=2.3e-10) and aortic valve replacement (meta-analysis: OR=3.78 [95% CI 2.26-6.32], P=4.0e-7). Carriers of protein-disrupting variants in or had lower mean LDL-C (UKB: -32.3 mg/dl, P<5e-324) and lower risk of AS (meta-analysis: OR=0.49 [0.31-0.75], P=0.001) and aortic valve replacement (meta-analysis: OR=0.54 [0.30-0.97], P=0.04). Among 57,371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in LDLR (+12.2cm/s, P=1.6e-5) and lower in carriers of protein-disrupting variants in (-6.9cm/s, P=0.022). Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development.

The optimal antithrombotic therapy in patients with device-detected atrial fibrillation (DDAF) is unknown. Concomitant vascular disease can modify the benefits and risks of anticoagulation.

Mitral regurgitation (MR) is associated with morphological and functional alterations of left atrium (LA) and ventricle (LV), possibly inducing LA-LV misalignment. We aimed to: (1) characterize angulation between LA and mitral annulus from conventional cine MRI data and feature-tracking (FT) contours, (2) assess their associations with functional capacity in MR patients, as assessed by oxygen consumption (peak-VO) and minute ventilation to carbon dioxide production (VE/VCO) slope, in comparison with MRI LA/LV strain indices. Thirty-two asymptomatic primary MR patients (56 [40; 66] years, 12 women) underwent cardiac MRI resulting in LA/LV conventional FT-derived strain indices. Then, end-diastolic angles were derived from FT LA contours: (1) α, centered on the LA centre of mass and defined by mitral valve extremities, (2) γ, centered on the mitral ring anterior/lateral side, and defined by LA centre and the other extremity of the mitral ring. Cardiopulmonary exercise testing with simultaneous echocardiography were also performed; peak-VO and VE/VCO slope were measured. While peak-VO and VE/VCO slope were not correlated to LA/LV strains, they were significantly associated with angles (α: r = 0.50, p = 0.003 and r = - 0.52, p = 0.003; γ: r = - 0.53, p = 0.002 and r = 0.52, p = 0.003; respectively), independently of age and gender (R ≥ 0.29, p ≤ 0.03). In primary MR, the new LA/mitral annulus angles, computed directly from standard-of-care MRI, are better correlated to exercise tolerance than conventional LA/LV strain.

Thrombin supports coagulation-independent inflammation via protease-activated receptors (PAR). PAR4 is specifically increased in obese human atria, correlating with NLRP3 inflammasome activation. PAR4-mediated NLRP3 inflammasome activation in atrial cardiomyocytes is not known, nor have signaling partners been identified. Thrombin transactivates the hepatocyte growth factor receptor in some cancer cells, so we examined PAR4/c-met cross-talk in atrial cardiomyocytes and its possible significance in obesity. Cardiomyocytes from right atrial appendages (RAA) of obese patients expressed more PAR1 and PAR4 compared to non-obese. In HL-1 atrial cardiomyocytes, thrombin induced caspase-1 auto-activation and IL-1β maturation; IL-1β secretion was evoked by PAR4-activating peptide (AP), but not PAR1-AP. PAR4-AP additionally increased phosphorylated CaMKII-Thr287, mTOR-Ser2481, and Akt-Ser473 while suppressing AMPK-Thr172 phosphorylation. Total kinase levels were largely unaltered. PAR4AP rapidly increased phosphorylated c-met in HL-1 cells and over time also transcriptionally upregulated c-met. The c-met inhibitor SGX-523 abrogated the effects of PAR4-AP on CaMKII/AKT/mTOR phosphorylation but did not affect PAR4-stimulated IL-1β production. Obese human RAA contained more IL-1β, phospho-c-met, and phospho-mTOR than non-obese RAA; CamKII phosphorylation was not modified. Atria from high-fat diet (HFD) versus chow-fed mice also contained more IL-1β, together with higher myeloperoxidase activity, Acta2 mRNA total and phosphorylated c-met; these increases were blunted in PAR4 HFD-fed mice. Thrombin cross-activates c-met via PAR4 in atrial cardiomyocytes. Transactivated c-met contributes partially to PAR4-mediated signaling, but NLRP3 inflammasome activation appears to be largely independent of c-met. Abundance of PAR4 and activated c-met increases with obesity, providing therapeutic targets for management of adiposity-driven AF.

Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%-11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research-mechanistic, translational, and clinical-is urgently needed.

The ability to track disease without tissue biopsy in patients is a major goal in biology and medicine. Here, we identify and characterize cardiomyocyte-derived extracellular vesicles in circulation (EVs; "cardiovesicles") through comprehensive studies of induced pluripotent stem cell-derived cardiomyocytes, genetic mouse models, and state-of-the-art mass spectrometry and low-input transcriptomics. These studies identified two markers ( , ) enriched on cardiovesicles for biotinylated antibody-based immunocapture. Captured cardiovesicles were enriched in canonical cardiomyocyte transcripts/pathways with distinct profiles based on human disease type (heart failure, myocardial infarction). In paired myocardial tissue-plasma from patients, highly expressed genes in cardiovesicles were largely cardiac-enriched (vs. "bulk" EVs, which were more organ non-specific) with high expression in myocardial tissue by single nuclear RNA-seq, largely in cardiomyocytes. These results demonstrate the first "liquid" biopsy discovery platform to interrogate cardiomyocyte states non-invasively in model systems and in human disease, allowing non-invasive characterization of cardiomyocyte biology for discovery and therapeutic applications.

COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning.

Thrombo-inflammation is a key feature of stroke pathophysiology and provides multiple candidate drug targets. Thrombin exerts coagulation-independent actions via protease-activated receptors (PAR), of which PAR1 has been implicated in stroke-associated neuroinflammation. The role of PAR4 in this context is less clear. This study examined if the selective PAR4 antagonist ML354 provides neuroprotection in experimental stroke and explored the underlying mechanisms.

Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of cardiovascular (CV) disease in the general population. Currently, it is unclear whether this association is observed in large clinical trial cohorts with a high burden of existing CV disease or whether CV therapies can mitigate CHIP-associated CV risk. To address these questions, we studied 63,700 patients from five randomized trials that tested established therapies for CV disease, including treatments targeting the proteins PCSK9, SGLT2, P2Y12 and FXa. During a median follow-up of 2.5 years, 7,453 patients had at least one CV event (CV death, myocardial infarction (MI), ischemic stroke or coronary revascularization). The adjusted hazard ratio (aHR) for CV events for CHIP+ patients was 1.07 (95% CI: 0.99-1.16, P = 0.08), with consistent risk estimates across each component of CV risk. Significant heterogeneity in the risk of MI was observed, such that CHIP+ patients had a 30% increased risk of first MI (aHR = 1.31 (1.05-1.64), P = 0.02) but no increased risk of recurrent MI (aHR = 0.94 (0.79-1.13), P = 0.008), as compared to CHIP- patients. Moreover, no significant heterogeneity in treatment effect between individuals with and without CHIP was observed for any of the therapies studied in the five trials. These results indicate that in clinical trial populations, CHIP is associated with incident but not recurrent coronary events and that the presence of CHIP does not appear to identify patients who will derive greater benefit from commonly used CV therapies.

Trained immunity of monocytes, endothelial, and smooth muscle cells augments the cytokine response to secondary stimuli. Immune training is characterized by stabilization of hypoxia-inducible factor (HIF)-1α, mTOR activation, and aerobic glycolysis. Cardiac fibroblast (CF)-myofibroblast transition upon myocardial ischemia/reperfusion (I/R) features epigenetic and metabolic adaptations reminiscent of trained immunity. We assessed the impact of I/R on characteristics of immune training in human CF and mouse myocardium. I/R was simulated in vitro with transient metabolic inhibition. CF primed with simulated I/R or control buffer were 5 days later re-stimulated with Pam3CSK for 24 h. Mice underwent transient left anterior descending artery occlusion or sham operation with reperfusion for up to 5 days. HIF-regulated metabolic targets and cytokines were assessed by qPCR, immunoblot, and ELISA and glucose consumption, lactate release, and lactate dehydrogenase (LDH) by chromogenic assay. Simulated I/R increased HIF-1α stabilization, mTOR phosphorylation, glucose consumption, lactate production, and transcription of PFKB3 and F2RL3, a HIF-regulated target gene, in human CF. PGK1 and LDH mRNAs were suppressed. Intracellular LDH transiently increased after simulated I/R, and extracellular LDH showed sustained elevation. I/R priming increased abundance of pro-caspase-1, auto-cleaved active caspase-1, and the expression and secretion of interleukin (IL)-1β, but did not augment Pam3CSK-stimulated cytokine transcription or secretion. Myocardial I/R in vivo increased abundance of HIF-1 and the precursor and cleaved forms of caspase-1, caspase-11, and caspase-8, but not of LDH-A or phospho-mTOR. I/R partially reproduces features of immune training in human CF, specifically HIF-1α stabilization, aerobic glycolysis, mTOR phosphorylation, and PFKB3 transcription. I/R does not augment PGK1 or LDH expression or the cytokine response to Pam3CSK. Regulation of PAR4 and inflammasome caspases likely occurs independently of an immune training repertoire.

Single-lead electrocardiograms (1L ECGs) are increasingly used for atrial fibrillation (AF) detection. Automated 1L ECG interpretation may have prognostic value for future AF in cases in which screening does not result in a short-term AF diagnosis.

Large-scale sequencing has enabled unparalleled opportunities to investigate the role of rare coding variation in human phenotypic variability. Here, we present a pan-ancestry analysis of sequencing data from three large biobanks, including the All of Us research program. Using mixed-effects models, we performed gene-based rare variant testing for 601 diseases across 748,879 individuals, including 155,236 with ancestry dissimilar to European. We identified 363 significant associations, which highlighted core genes for the human disease phenome and identified potential novel associations, including UBR3 for cardiometabolic disease and YLPM1 for psychiatric disease. Pan-ancestry burden testing represented an inclusive and useful approach for discovery in diverse datasets, although we also highlight the importance of ancestry-specific sensitivity analyses in this setting. Finally, we found that effect sizes for rare protein-disrupting variants were concordant between samples similar to European ancestry and other genetic ancestries (β = 0.7-1.0). Our results have implications for multi-ancestry and cross-biobank approaches in sequencing association studies for human disease.

Thrombin inhibition suppresses adiposity, WAT inflammation and metabolic dysfunction in mice. Protease-activated receptor (PAR)1 does not account for thrombin-driven obesity, so we explored the culprit role of PAR4 in this context. Male WT and PAR-4 mice received a high fat diet (HFD) for 8 weeks, WT controls received standard chow. Body fat was quantified by NMR. Epididymal WAT was assessed by histology, immunohistochemistry, qPCR and lipase activity assay. 3T3-L1 preadipocytes were differentiated ± thrombin, acutely stimulated ± PAR4 activating peptide (AP) and assessed by immunoblot, qPCR and U937 monocyte adhesion. Epicardial adipose tissue (EAT) from obese and lean patients was assessed by immunoblot. PAR4 was upregulated in mouse WAT under HFD. PAR4 mice developed less visceral adiposity and glucose intolerance under HFD, featuring smaller adipocytes, fewer macrophages and lower expression of adipogenic (leptin, PPARγ) and pro-inflammatory genes (CCL2, IL-1β) in WAT. HFD-modified activity and expression of lipases or perilipin were unaffected by PAR4 deletion. 3T3-L1 adipocytes differentiated with thrombin retained Ki67 expression, further upregulated IL-1β and CCL2 and were more adhesive for monocytes. In mature adipocytes, PAR4-AP increased phosphorylated ERK1/2 and AKT, upregulated Ki67, CCl2, IL-β and hyaluronan synthase 1 but not TNF-α mRNA, and augmented hyaluronidase-sensitive monocyte adhesion. Obese human EAT expressed more PAR4, CD68 and CD54 than lean EAT. PAR4 upregulated in obesity supports adipocyte hypertrophy, WAT expansion and thrombo-inflammation. The emerging PAR4 antagonists provide a therapeutic perspective in this context beyond their canonical antiplatelet action.

Short and rare episodes of atrial fibrillation (AF) are commonly detected using implanted devices (device-detected AF) in patients with prior stroke or transient ischemic attack (TIA). The effectiveness and safety of oral anticoagulation in patients with prior stroke or TIA and device-detected AF but with no ECG-documented AF is unclear.

Reduced left atrial PITX2 is associated with atrial cardiomyopathy and atrial fibrillation. PITX2 is restricted to left atrial cardiomyocytes in the adult heart. The links between PITX2 deficiency, atrial cardiomyopathy and atrial fibrillation are not fully understood.

This study assessed whether a model incorporating clinical features and a polygenic score for ascending aortic diameter would improve diameter estimation and prediction of adverse thoracic aortic events over clinical features alone.

Repetitive atrial activation patterns (RAAPs) during complex atrial tachycardia could be associated with localized mechanisms that can be targeted. Clinically available electroanatomical mapping systems are limited by either the spatial coverage or electrode density of the mapping catheters, preventing the adequate visualization of transiently occurring RAAPs. This work proposes a technique to overcome this shortcoming by stitching spatially overlapping conduction patterns together to a larger image- called a composite map.

AF risk estimation is feasible using clinical factors, inherited predisposition, and artificial intelligence (AI)-enabled electrocardiogram (ECG) analysis.

Despite advances in managing traditional risk factors, coronary artery disease (CAD) remains the leading cause of mortality. Circulating hematopoietic cells influence risk for CAD, but the role of a key regulating organ, spleen, is unknown. The understudied spleen is a 3-dimensional structure of the hematopoietic system optimally suited for unbiased radiologic investigations toward novel mechanistic insights.

In patients with atrial fibrillation (AF), recurrent AF and sinus rhythm during follow-up are determined by interactions between cardiovascular disease processes and rhythm-control therapy. Predictors of attaining sinus rhythm at follow-up are not well known.

Early postoperative atrial fibrillation (POAF) is common after cardiac surgery and is associated with late-POAF recurrences. However, little is known about the burden of POAF and its potential impact on long-term outcomes after cardiac surgery, particularly on the risk for late-POAF recurrences.

Perivascular adipose tissue (PVAT) interacts with the vascular wall and secretes bioactive factors which regulate vascular wall physiology. Vice versa, vascular wall inflammation affects the adjacent PVAT via paracrine signals, which induce cachexia-type morphological changes in perivascular fat. These changes can be quantified in pericoronary adipose tissue (PCAT), as an increase in PCAT attenuation in coronary computed tomography angiography images. Fat attenuation index (FAI), a novel imaging biomarker, measures PCAT attenuation around coronary artery segments and is associated with coronary artery disease presence, progression, and plaque instability. Beyond its diagnostic capacity, PCAT attenuation can also ameliorate cardiac risk stratification, thus representing an innovative prognostic biomarker of cardiovascular disease (CVD). However, technical, biological, and anatomical factors are weakly related to PCAT attenuation and cause variation in its measurement. Thus, to integrate FAI, a research tool, into clinical practice, a medical device has been designed to provide FAI values standardized for these factors. In this review, we discuss the interplay of PVAT with the vascular wall, the diagnostic and prognostic value of PCAT attenuation, and its integration as a CVD risk marker in clinical practice.

Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration.

In polymicrobial sepsis, the extracellular histones, mainly released from activated neutrophils, significantly contribute to cardiac dysfunction (septic cardiomyopathy), as demonstrated in our previous studies using Echo-Doppler measurements. This study aims to elucidate the roles of extracellular histones and their interactions with Toll-like receptors (TLRs) in cardiac dysfunction. Through ex vivo assessments of ECG, left ventricle (LV) function parameters, and in vivo Echo-Doppler studies in mice perfused with extracellular histones, we aim to provide comprehensive insights into the mechanisms underlying sepsis-induced cardiac dysfunction. Langendorff-perfused hearts from both wild-type and TLR2, TLR3, or TLR4 knockout (KO) mice were examined. Paced mouse hearts were perfused with histones to assess contractility and relaxation. Echo-Doppler studies evaluated cardiac dysfunction after intravenous histone injection. Histone perfusion caused defects in contractility and relaxation, with TLR2 and TLR3 KO mice being partially protected. Specifically, TLR2 KO mice exhibited the greatest reduction in Echo-Doppler abnormalities, while TLR4 KO exacerbated cardiac dysfunction. Among individual histones, H1 induced the most pronounced abnormalities in cardiac function, apoptosis of cardiomyocytes, and LDH release. Our data highlight significant interactions between histones and TLRs, providing insights into histones especially H1 as potential therapeutic targets for septic cardiomyopathy. Further studies are needed to explore specific histone-TLR interactions and their mechanisms.

Clinical medicine requires the integration of various forms of patient data including demographics, symptom characteristics, electrocardiogram findings, laboratory values, biomarker levels, and imaging studies. Decision-making on the optimal management should be based on a high probability that the envisaged treatment is appropriate, provides benefit, and bears no or little potential harm. To that end, personalized risk-benefit considerations should guide the management of individual patients to achieve optimal results. These basic clinical tasks have become more and more challenging with the massively growing data now available; artificial intelligence and machine learning (AI/ML) can provide assistance for clinicians by obtaining and comprehensively preparing the history of patients, analysing face and voice and other clinical features, by integrating laboratory results, biomarkers, and imaging. Furthermore, AI/ML can provide a comprehensive risk assessment as a basis of optimal acute and chronic care. The clinical usefulness of AI/ML algorithms should be carefully assessed, validated with confirmation datasets before clinical use, and repeatedly re-evaluated as patient phenotypes change. This review provides an overview of the current data revolution that has changed and will continue to change the face of clinical medicine radically, if properly used, to the benefit of physicians and patients alike.

Refractory recurrent pericarditis is a troublesome condition that severely impairs the quality of life of affected patients and significantly increases healthcare spending. Until recently, therapeutic options included only a few medications and most of the patients resorted to chronic glucocorticoid treatment with steroid dependence. In the most recent decade, the introduction of interleukin-1 blockers in clinical practice has revolutionized the treatment of glucocorticoid-dependent and colchicine-resistant recurrent pericarditis due to their excellent efficacy and good safety profile. The rationale for the introduction of this class of medications in clinical practice is the autoinflammatory nature of recurrent pericarditis in a substantial rate of cases, with interleukin-1 being the main pro-inflammatory cytokine involved in this context. This review aims to discuss the contemporary available evidence from original research and real-world data on interleukin-1 blocker use in refractory recurrent pericarditis, in terms of indications, mechanism of action, efficacy, side effects, and recommended treatment protocols. Moreover, novel treatment proposals, such as hydroxychloroquine, , and cannabidiol, which showed encouraging preliminary results, are addressed. Finally, gaps in knowledge, unmet needs, and future perspectives related to recurrent pericarditis are thoroughly discussed.

The concept of "atrial cardiomyopathy" (AtCM) had been percolating through the literature since its first mention in 1972. Since then, publications using the term were sporadic until the decision was made to convene an expert working group with representation from four multinational arrhythmia organizations to prepare a consensus document on atrial cardiomyopathy in 2016 (EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication). Subsequently, publications on AtCM have increased progressively.

Bleeding is frequent during transcatheter aortic valve implantation (TAVI), especially when performed through a transapical approach (TA), and is associated with a worse prognosis. The present study aims to test the implication of red blood cell (RBC) transfusion and the optimal transfusion strategy in this context.

Atrial fibrillation (AFib) and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2 macrophages secrete osteopontin (encoded by ), a matricellular signaling protein that engenders fibrosis and AFib. Here we show that silencing in TREM2 cardiac macrophages with an antibody-siRNA conjugate reduces atrial fibrosis and suppresses AFib in mice, thus offering a new immunotherapy for the most common arrhythmia.

Patients with rare, pathogenic cardiomyopathy (CM) and arrhythmia variants can present with atrial fibrillation (AF). The efficacy of AF ablation in these patients is unknown.

Atrial fibrillation (AF) causes progressive structural and electrical changes in the atria that can be summarized within the general concept of atrial remodeling. In parallel, other clinical characteristics and comorbidities may also affect atrial tissue properties and make the atria susceptible to AF initiation and its long-term persistence. Overall, pathological atrial changes lead to atrial cardiomyopathy with important implications for rhythm control. Although there is general agreement on the role of the atrial substrate for successful rhythm control in AF, the current classification oversimplifies clinical management. The classification uses temporal criteria and does not establish a well-defined strategy to characterize the individual-specific degree of atrial cardiomyopathy. Better characterization of atrial cardiomyopathy may improve the decision-making process on the most appropriate therapeutic option. We review current scientific evidence and propose a practical characterization of the atrial substrate based on 3 evaluation steps starting with a clinical evaluation (step 1), then assess outpatient complementary data (step 2), and finally include information from advanced diagnostic tools (step 3). The information from each of the steps or a combination thereof can be used to classify AF patients in 4 stages of atrial cardiomyopathy, which we also use to estimate the success on effective rhythm control.

The global prevalence of obesity has more than doubled over the past four decades, currently affecting more than a billion individuals. Beyond its recognition as a high-risk condition that is causally linked to many chronic illnesses, obesity has been declared a disease per se that results in impaired quality of life and reduced life expectancy. Notably, two-thirds of obesity-related excess mortality is attributable to cardiovascular disease. Despite the increasingly appreciated link between obesity and a broad range of cardiovascular disease manifestations including atherosclerotic disease, heart failure, thromboembolic disease, arrhythmias, and sudden cardiac death, obesity has been underrecognized and sub-optimally addressed compared with other modifiable cardiovascular risk factors. In the view of major repercussions of the obesity epidemic on public health, attention has focused on population-based and personalized approaches to prevent excess weight gain and maintain a healthy body weight from early childhood and throughout adult life, as well as on comprehensive weight loss interventions for persons with established obesity. This clinical consensus statement by the European Society of Cardiology discusses current evidence on the epidemiology and aetiology of obesity; the interplay between obesity, cardiovascular risk factors and cardiac conditions; the clinical management of patients with cardiac disease and obesity; and weight loss strategies including lifestyle changes, interventional procedures, and anti-obesity medications with particular focus on their impact on cardiometabolic risk and cardiac outcomes. The document aims to raise awareness on obesity as a major risk factor and provide guidance for implementing evidence-based practices for its prevention and optimal management within the context of primary and secondary cardiovascular disease prevention.

Whether saline-induced hyperaemia captures exercise-induced coronary flow regulation remains unknown.

Direct oral anticoagulants (DOACs) are increasingly used off-label to treat patients with left ventricular thrombus (LVT). We analysed available meta-data comparing DOACs and vitamin K antagonists (VKAs) for efficacy and safety.

One-time atrial fibrillation (AF) screening trials have produced mixed results; however, it is unclear if there is a subset for whom screening is effective. Identifying such a subgroup would support targeted screening.

Hypertension is a modifiable cardiovascular risk factor and displays a rapidly growing incidence due to aging and the acquisition of an unhealthy lifestyle. Hypertension is linked to the development of target organ damage in several vascular beds such as coronary arteries, peripheral, cerebral, and renal arteries. Besides, along with the presence of other cardiovascular risk factors, it aggravates vascular dysfunction due to the aging process. The mechanisms of vascular dysfunction in hypertension are complex and involve excessive salt intake and water retention, activation of neurohormonal systems, induction of endothelial dysfunction of large arteries and microcirculation, development of arterial stiffness, and complex interactions with cellular pathways of inflammation, oxidative stress, and thrombosis. The extent of vascular dysfunction in patients with hypertension can be assessed by evaluating endothelial function, measuring arterial stiffness, and testing the levels of circulating biomarkers of oxidative stress, pro-inflammatory cytokines, and thrombosis. Assessing these markers in subjects with and without hypertension could aid in identifying those at risk of vascular damage and improving risk prediction for future cardiovascular events. While several lifestyle and pharmacological therapies have shown promise in addressing vascular dysfunction in hypertension, none of these biomarkers have been established as an independent risk factor or treatment target. Therefore, in this article, we review the literature on the evidence that exists regarding the role of vascular dysfunction in the pathophysiology, diagnosis, progression, and treatment of hypertension, highlighting the lack of conclusive evidence in this field.

Heavily calcified peripheral artery lesions increase the risk of vascular complications, constituting a severe challenge for the operator during catheter-based cardiovascular interventions. Intravascular Lithotripsy (IVL) technology disrupts subendothelial calcification by using localized pulsative sonic pressure waves and represents a promising technique for plaque modification in patients with severe calcification in peripheral arteries. Our aim was to systematically review and summarize available data regarding the safety and efficacy of IVL in preparing severely calcified peripheral arteries and its use in Transcatheter Aortic Valve Implantation (TAVI). This study was conducted according to the PRISMA guidelines. We systematically searched PubMed, SCOPUS, and Cochrane databases from their inception to February 23, 2023, for studies assessing the characteristics and outcomes of patients undergoing IVL in the peripheral vasculature. The diameter of the vessel lumen before and after IVL was estimated. The occurrence of peri-procedural complications was assessed using a random-effects model. 20 studies with a total of 1,223 patients with heavily calcified peripheral lesions were analysed. The mean age of the cohort was 70.6 ± 17.4 years. Successful IVL delivery achieved in 100% (95% CI: 100%-100%, I = 0%), with an increase in the luminal diameter (SMD: 4.66, 95% CI: 3.41-5.92, I = 90.8%) and reduction in diameter stenosis (SMD: -4.15, 95% CI: -4.75 to -3.55, I = 92.8%), and a concomitant low rate of complications. The procedure was free from dissection in 97% (95% CI: 91%-100%, I = 81.4%) while dissections of any type (A, B, C, or D) were observed in 6% (95% CI: 2%-10%, I = 85.3%) of the patients. Several rare cases of abrupt closure, no-reflow phenomenon, perforation, thrombus formation, and distal embolization were recorded. Finally, the subgroup analysis of patients who underwent a TAVI with IVL assistance presented successful implantation in 100% (95% CI: 100%-100%, I = 0%) of the cases, with only 4% (95% CI: 0%-12%, I = 68.96%) presenting dissections of any sort. IVL seems to be an effective and safe technique for modifying severely calcified lesions in peripheral arteries and it is a promising modality in TAVI settings. Future prospective studies are needed to validate our results.

Acute heart failure (HF) presents a significant mortality burden, necessitating continuous therapeutic advancements. Temporary mechanical circulatory support (MCS) is crucial in managing cardiogenic shock (CS) secondary to acute HF, serving as a bridge to recovery or durable support. Currently, MCS options include the Intra-Aortic Balloon Pump (IABP), TandemHeart (TH), Impella, and Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO), each offering unique benefits and risks tailored to patient-specific factors and clinical scenarios. This review examines the clinical implications of recent advancements in temporary MCS, identifies knowledge gaps, and explores promising avenues for future research and clinical application. Understanding each device's unique attributes is crucial for their efficient implementation in various clinical scenarios, ultimately advancing towards intelligent, personalized support strategies.

We aimed to evaluate the association between atrial fibrillation (AF) burden, duration and number of episodes with healthcare utilisation and quality of life in patients with early paroxysmal AF without a history of AF.

Pulsed field ablation (PFA) is an emerging technology for the treatment of atrial fibrillation (AF), for which pre-clinical and early-stage clinical data are suggestive of some degree of preferentiality to myocardial tissue ablation without damage to adjacent structures. Here in the MANIFEST-17K study we assessed the safety of PFA by studying the post-approval use of this treatment modality. Of the 116 centers performing post-approval PFA with a pentaspline catheter, data were received from 106 centers (91.4% participation) regarding 17,642 patients undergoing PFA (mean age 64, 34.7% female, 57.8% paroxysmal AF and 35.2% persistent AF). No esophageal complications, pulmonary vein stenosis or persistent phrenic palsy was reported (transient palsy was reported in 0.06% of patients; 11 of 17,642). Major complications, reported for ~1% of patients (173 of 17,642), were pericardial tamponade (0.36%; 63 of 17,642) and vascular events (0.30%; 53 of 17,642). Stroke was rare (0.12%; 22 of 17,642) and death was even rarer (0.03%; 5 of 17,642). Unexpected complications of PFA were coronary arterial spasm in 0.14% of patients (25 of 17,642) and hemolysis-related acute renal failure necessitating hemodialysis in 0.03% of patients (5 of 17,642). Taken together, these data indicate that PFA demonstrates a favorable safety profile by avoiding much of the collateral damage seen with conventional thermal ablation. PFA has the potential to be transformative for the management of patients with AF.

Coupling between left ventricle (LV) and left atrium (LA) plays a central role in the process of cardiac remodeling during aging and development of cardiac disease. The hydraulic force (HyF) is related to variation in size between LV and LA. The objectives of this study were to: (1) derive an estimate of left atrioventricular HyF using cine- Magnetic Resonance Imaging (MRI) in healthy subjects with a wide age range, and (2) study its relationship with age and conventional diastolic function parameters, as estimated by reference echocardiography.

Serum bone morphogenetic protein 10 (BMP10) blood levels are a marker for history of atrial fibrillation (AF) and for major adverse cardiovascular events in patients with AF, including stroke, AF recurrences after catheter ablations, and mortality. The predictive value of BMP10 in patients undergoing cardiac surgery and association with morphologic properties of atrial tissues are unknown.

The worldwide prevalence of individuals with an elevated body weight has increased steadily over the past five decades. Billions of research dollars have been invested to improve our understanding of the causes and consequences of having an elevated body weight. All this knowledge has, however, failed to influence populational body weight trajectories of most countries around the world. Research on the definition of "obesity" has also evolved. Body mass index (BMI), the most commonly used tool to make its diagnosis, has major limitations. In this review article, we will highlight evidence from observational studies, genetic association studies and randomized clinical trials that have shown the remarkable inter-individual differences in the way humans store energy as body fat. Increasing evidence also suggests that, as opposed to weight inclusive, lifestyle-based approaches, weight-centric approaches advising people to simply eat less and move more are not sustainable for most people for long-term weight loss and maintenance. It is time to recognize that this outdated approach may have produced more harm than good. On the basis of pathophysiological, genetic and clinical evidence presented in this review, we propose that it may be time to shift away from the traditional clinical approach, which is BMI-centric. Rather, emphasis should be placed on actionable lifestyle-related risk factors aiming at improving overall diet quality and increasing physical activity level in the general population.

Syncope remains a common medical problem. Recently, the role of dedicated syncope units and implantable loop recorders has emerged in the investigation of unexplained syncope. This study aims to investigate the possibilities for a more rational and targeted use of various diagnostic tools.

Disorders affecting cardiac conduction are associated with substantial morbidity. Understanding the epidemiology and risk factors for conduction disorders may enable earlier diagnosis and preventive efforts.

Several randomized controlled trials (RCTs) have examined mineralocorticoid receptor antagonists (MRAs) in heart failure (HF) with reduced ejection fraction (HFrEF). This systematic review and network meta-analysis (NMA) evaluated the comparative efficacy and safety of MRAs in HFrEF.

Dark-blood late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) has better correlation with bipolar voltage (BiV) to define ablation scar in the left atrium (LA) compared to conventional bright-blood LGE CMR.

Atrial fibrillation (AF) and concomitant cardiometabolic disease processes interact and combine to lead to adverse events, such as stroke, heart failure, myocardial infarction, and cardiovascular death. Circulating biomolecules provide quantifiable proxies for cardiometabolic disease processes. The aim of this study was to test whether biomolecule combinations can define phenotypes in patients with AF.

Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).

Fibrotic diseases affect multiple organs and are associated with morbidity and mortality. To examine organ-specific and shared biologic mechanisms that underlie fibrosis in different organs, we developed machine learning models to quantify T1 time, a marker of interstitial fibrosis, in the liver, pancreas, heart and kidney among 43,881 UK Biobank participants who underwent magnetic resonance imaging. In phenome-wide association analyses, we demonstrate the association of increased organ-specific T1 time, reflecting increased interstitial fibrosis, with prevalent diseases across multiple organ systems. In genome-wide association analyses, we identified 27, 18, 11 and 10 independent genetic loci associated with liver, pancreas, myocardial and renal cortex T1 time, respectively. There was a modest genetic correlation between the examined organs. Several loci overlapped across the examined organs implicating genes involved in a myriad of biologic pathways including metal ion transport (SLC39A8, HFE and TMPRSS6), glucose metabolism (PCK2), blood group antigens (ABO and FUT2), immune function (BANK1 and PPP3CA), inflammation (NFKB1) and mitosis (CENPE). Finally, we found that an increasing number of organs with T1 time falling in the top quintile was associated with increased mortality in the population. Individuals with a high burden of fibrosis in ≥3 organs had a 3-fold increase in mortality compared to those with a low burden of fibrosis across all examined organs in multivariable-adjusted analysis (hazard ratio = 3.31, 95% confidence interval 1.77-6.19; P = 1.78 × 10). By leveraging machine learning to quantify T1 time across multiple organs at scale, we uncovered new organ-specific and shared biologic pathways underlying fibrosis that may provide therapeutic targets.

Coronary computed tomography angiography (CCTA) is the first line investigation for chest pain, and it is used to guide revascularisation. However, the widespread adoption of CCTA has revealed a large group of individuals without obstructive coronary artery disease (CAD), with unclear prognosis and management. Measurement of coronary inflammation from CCTA using the perivascular fat attenuation index (FAI) Score could enable cardiovascular risk prediction and guide the management of individuals without obstructive CAD. The Oxford Risk Factors And Non-invasive imaging (ORFAN) study aimed to evaluate the risk profile and event rates among patients undergoing CCTA as part of routine clinical care in the UK National Health Service (NHS); to test the hypothesis that coronary arterial inflammation drives cardiac mortality or major adverse cardiac events (MACE) in patients with or without CAD; and to externally validate the performance of the previously trained artificial intelligence (AI)-Risk prognostic algorithm and the related AI-Risk classification system in a UK population.

Endolysosomes (EL) are known for their role in regulating both intracellular trafficking and proteostasis. EL facilitate the elimination of damaged membranes, protein aggregates, membranous organelles and play an important role in calcium signaling. The specific role of EL in cardiac atrial fibrillation (AF) is not well understood. We isolated atrial EL organelles from AF goat biopsies and conducted a comprehensive integrated omics analysis to study the EL-specific proteins and pathways. We also performed electron tomography, protein and enzyme assays on these biopsies. Our results revealed the upregulation of the AMPK pathway and the expression of EL-specific proteins that were not found in whole tissue lysates, including GAA, DYNLRB1, CLTB, SIRT3, CCT2, and muscle-specific HSPB2. We also observed structural anomalies, such as autophagic-vacuole formation, irregularly shaped mitochondria, and glycogen deposition. Our results provide molecular information suggesting EL play a role in AF disease process over extended time frames.

: Real-world data show limited utilization of direct oral anticoagulants (DOACs) in obese patients (body mass index [BMI] ≥ 30 kg/m) due to concerns regarding their efficacy and safety in this demographic. : This review aimed to consolidate current evidence on the efficacy and safety of DOACs versus warfarin in obese patients with non-valvular atrial fibrillation (AF) or venous thromboembolism (VTE). The primary efficacy outcome assessed a composite of all-cause mortality, stroke, systemic embolism (SE), and myocardial infarction (MI). : A systematic search was conducted in MEDLINE, SCOPUS, and Cochrane databases from inception to December 28, 2023. Data were synthesized using random-effects meta-analysis. : A total of 35 studies involving 434,320 participants were analyzed. DOAC use was associated with a significant reduction in the risk of the composite outcome (RR = 0.80, 95% CI [0.65, 0.98], I = 95%), hemorrhagic stroke (RR = 0.58, 95% CI [0.38, 0.88], I = 92%), major bleeding (RR = 0.76, 95% CI [0.63, 0.92], I = 94%), gastrointestinal bleeding (RR = 0.59, 95% CI [0.49, 0.72], I = 88%), and intracranial bleeding (RR = 0.45, 95% CI [0.34, 0.60], I = 44%) compared to warfarin. A non-significant benefit of DOACs was observed for all-cause mortality, MI, the composite of stroke or SE, ischemic stroke, SE, VTE, and minor bleeding compared to warfarin. Subgroup analysis indicated no significant effect modification based on the indication for anticoagulation or study design. : DOACs demonstrated a favorable efficacy and safety profile in obese individuals compared to warfarin.

Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk. We designed a general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. This model is designed to handle longitudinal data over the lifetime to address this unmet need and support clinical decision-making. We analyze longitudinal data from 480,638 UK Biobank participants and compared predicted lifetime risk with the 30-year Framingham risk score. MSGene improves discrimination (C-index 0.71 vs 0.66), age of high-risk detection (C-index 0.73 vs 0.52), and overall prediction (RMSE 1.1% vs 10.9%), in held-out data. We also use MSGene to refine estimates of lifetime absolute risk reduction from statin initiation. Our findings underscore our multistate model's potential public health value for accurate lifetime CAD risk estimation using clinical factors and increasingly available genetics toward earlier more effective prevention.

Aortic stenosis (AS) is common affecting >13% of adults over the age of 75 years. In people who develop symptoms, without valve replacement, prognosis is dismal with mortality as high as 50% at 1 year. In asymptomatic patients, the timing of valve intervention is less well defined and a strategy of watchful waiting is recommended. Many, however, may develop symptoms and attribute this to age related decline, rather than worsening AS. Timely intervention in asymptomatic severe AS is critical, since delayed intervention often results in poor outcomes. Proactive surveillance of symptoms, quality of life and functional capacity should enable timely identification of people who will benefit from aortic valve replacement. There are no data however, to support the clinical and cost effectiveness of such an approach in a healthcare setting in the UK. The aim of this pilot trial is to test the feasibility of a full-scale randomised controlled trial (RCT) to determine the utility of proactive surveillance in people with asymptomatic severe AS to guide the timing of intervention.

Brown adipose tissue (BAT) and beige adipose tissues are important contributors to cold-induced whole body thermogenesis in rodents. The documentation in humans of cold- and ß-adrenergic receptor agonist-stimulated BAT glucose uptake using positron emission tomography (PET) and of a decrease of this response in individuals with cardiometabolic disorders led to the suggestion that BAT/beige adipose tissues could be relevant targets for prevention and treatment of these conditions. In this brief review, we will critically assess this question by first describing the basic rationale for this affirmation, second by examining the evidence in human studies, and third by discussing the possible means to activate the thermogenic response of these tissues in humans.

Inflammatory signalling via the nod-like receptor (NLR) family pyrin domain-containing protein-3 (NLRP3) inflammasome has recently been implicated in the pathophysiology of atrial fibrillation (AF). However, the precise role of the NLRP3 inflammasome in various cardiac cell types is poorly understood. Targeting components or products of the inflammasome and preventing their proinflammatory consequences may constitute novel therapeutic treatment strategies for AF. In this review, we summarise the current understanding of the role of the inflammasome in AF pathogenesis. We first review the NLRP3 inflammasome pathway and inflammatory signalling in cardiomyocytes, (myo)fibroblasts and immune cells, such as neutrophils, macrophages and monocytes. Because numerous compounds targeting NLRP3 signalling are currently in preclinical development, or undergoing clinical evaluation for other indications than AF, we subsequently review known therapeutics, such as colchicine and canakinumab, targeting the NLRP3 inflammasome and evaluate their potential for treating AF.

Our aim was to assess whether systemic endothelial dysfunction, evaluated non-invasively by flow mediated dilation (FMD), is associated with diabetic macular edema (DME) and to determine if it is further impaired in patients with diffuse-DME. Consecutive patients ( = 84) with type-2 diabetes mellitus (T2DM) and diabetic retinopathy were enrolled. DME was not present in 38 (non-DME) and present in 46 patients; 25 with focal and 21 with diffuse-DME. No differences were detected between DME and non-DME groups regarding the clinical and demographic characteristics, except for the age of T2DM initiation (lower in non-DME). FMD values were significantly impaired in DME compared with non-DME patients, even after adjustment for multiple covariates (3.56 ± 1.03 vs 4.57 ± 1.25%, = .003). Among DME patients, no differences were found concerning the clinical and demographic data, while FMD levels were significantly lower in diffuse-DME patients, compared with the focal-DME ones, regardless of the impact several confounders (2.88 ± 0.65 vs 4.08 ± 0.95%, = .002). It is noteworthy that FMD values of non-DME and focal-DME patients did not differ significantly (4.52 ± 1.24 vs 4.21 ± 1.06%, = .307). Moreover, among DME patients, impaired FMD was an independent predictor of diffuse-DME (odds ratio: 0.06, 95% CI 0.01-0.47, = .007).

Inherited cardiomyopathies are relatively rare but carry a high risk of cardiac maternal morbidity and mortality during pregnancy and postpartum. However, data for risk stratification are scarce. The new CARPREG II score improves prediction of prognosis in pregnancies associated with heart disease, though its role in inherited cardiomyopathies is unclear. We aim to describe characteristics and cardiac maternal outcomes in patients with inherited cardiomyopathy during pregnancy, and to evaluate the interest of the CARPREG II risk score in this population.

Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4.

The use of large medical or healthcare claims databases is very useful for population-based studies on the burden of heart failure (HF). Clinical characteristics and management of HF patients differ according to categories of left ventricular ejection fraction (LVEF), but this information is often missing in such databases. We aimed to develop and validate algorithms to identify LVEF in healthcare databases where the information is lacking.

Cardiac troponin I (cTnI) above the 99 percentile is associated with an increased risk of major adverse events. Patients with detectable cTnI below the 99 percentile are a heterogeneous group with a less well-defined risk profile. The purpose of this study is to investigate the prognostic relevance of detectable cTnI below the 99 percentile in patients undergoing coronary angiography.

The factor V Leiden (FVL; rs6025) and prothrombin G20210A (PTGM; rs1799963) polymorphisms are 2 of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with previous studies showing marked disagreement regarding thrombosis risk conferred by the DH genotype. Using multidimensional data from the UK Biobank (UKB) and FinnGen biorepositories, we evaluated the clinical impact of DH carrier status across 937 939 individuals. We found that 662 participants (0.07%) were DH carriers. After adjustment for age, sex, and ancestry, DH individuals experienced a markedly elevated risk of VTE compared with wild-type individuals (odds ratio [OR] = 5.24; 95% confidence interval [CI], 4.01-6.84; P = 4.8 × 10-34), which approximated the risk conferred by FVL homozygosity. A secondary analysis restricted to UKB participants (N = 445 144) found that effect size estimates for the DH genotype remained largely unchanged (OR = 4.53; 95% CI, 3.42-5.90; P < 1 × 10-16) after adjustment for commonly cited VTE risk factors, such as body mass index, blood type, and markers of inflammation. In contrast, the DH genotype was not associated with a significantly higher risk of any arterial thrombosis phenotype, including stroke, myocardial infarction, and peripheral artery disease. In summary, we leveraged population-scale genomic data sets to conduct, to our knowledge, the largest study to date on the DH genotype and were able to establish far more precise effect size estimates than previously possible. Our findings indicate that the DH genotype may occur as frequently as FVL homozygosity and may confer a similarly increased risk of VTE.

In this editorial, we comment on the article by Kong published in the recent issue of the . In this interesting case, the authors present the challenges faced in managing a 13-year-old patient with Down syndrome (DS) and congenital heart disease (CHD) associated with pulmonary arterial hypertension. In this distinct population, the Authors underscore the need for early diagnosis and management as well as the need of a multidisciplinary approach for decision making. It seems that the occurrence of CHD in patients with DS adds layers of complexity to their clinical management. This editorial aims to provide a comprehensive overview of the intricate interplay between DS and congenital heart disorders, offering insights into the nuanced diagnostic and therapeutic considerations for physicians.

Heart failure (HF) poses a significant world health challenge due to the increase in the aging population and advancements in cardiac care. In the pathophysiology of HF, the inflammasome has been correlated with the development, progression, and complications of HF disease. Discovering biomarkers linked to inflammasomes enhances understanding of HF diagnosis and prognosis. Directing inflammasome signaling emerges as an innovative therapeutic strategy for managing HF. The present review aims to delve into this inflammatory cascade, understanding its role in the development of HF, its potential role as biomarker, as well as the prospects of modulating inflammasomes as a therapeutic approach for HF.

Although coronary artery disease mainly affects older individuals, the incidence of myocardial infarction (MI) among younger adults (<55 years) has increased during the past decade. Young and older MI patients have different underlying pathophysiologic characteristics, atherosclerotic plaque morphology, and risk factor profiles.

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Popeye domain containing (POPDC) proteins are predominantly expressed in the heart and skeletal muscle, modulating the K potassium channel TREK-1 in a cAMP-dependent manner. and variants cause cardiac conduction disorders with or without muscular dystrophy. Searching for POPDC2-modulated ion channels using a functional co-expression screen in oocytes, we found POPDC proteins to modulate the cardiac sodium channel Nav1.5. POPDC proteins downregulate Nav1.5 currents in a cAMP-dependent manner by reducing the surface expression of the channel. POPDC2 and Nav1.5 are both expressed in different regions of the murine heart and consistently POPDC2 co-immunoprecipitates with Nav1.5 from native cardiac tissue. Strikingly, the knock-down of in embryonic zebrafish caused an increased upstroke velocity and overshoot of cardiac action potentials. The POPDC modulation of Nav1.5 provides a new mechanism to regulate cardiac sodium channel densities under sympathetic stimulation, which is likely to have a functional impact on cardiac physiology and inherited arrhythmias.

Vascular inflammation is a major contributor to cardiovascular disease, particularly atherosclerotic disease, and early detection of vascular inflammation may be key to the ultimate reduction of residual cardiovascular morbidity and mortality. This review paper discusses the progress toward the clinical utility of noninvasive imaging techniques for assessing vascular inflammation, with a focus on coronary atherosclerosis. A discussion of multiple modalities is included: computed tomography (CT) imaging (the major focus of the review), cardiac magnetic resonance, ultrasound, and positron emission tomography imaging. The review covers recent progress in new technologies such as the novel CT biomarkers of coronary inflammation (eg, the perivascular fat attenuation index), new inflammation-specific tracers for positron emission tomography-CT imaging, and others. The strengths and limitations of each modality are explored, highlighting the potential for multi-modality imaging and the use of artificial intelligence image interpretation to improve both diagnostic and prognostic potential for common conditions such as coronary artery disease.

Plaque erosion (PE), a distinct etiology of acute coronary syndromes (ACSs), is often overshadowed by plaque ruptures (PRs). Concerning its epidemiology, PE has garnered increasing recognition, with recent studies revealing its prevalence to be approximately 40% among ACS patients, challenging earlier assumptions based on autopsy data. Notably, PE exhibits distinct epidemiological features, preferentially affecting younger demographics, particularly women, and often manifesting as a non-ST-segment elevation myocardial infarction. There are seasonal variations, with PE events being less common in winter, potentially linked to physiological changes and cholesterol solidification, while peaking in summer, warranting further investigation. Moving to molecular mechanisms, PE presents a unique profile characterized by a lesser degree of inflammation compared to PR, with endothelial shear stress emerging as a plausible molecular mechanism. Neutrophil activation, toll-like receptor-2 pathways, and hyaluronidase 2 expression are among the factors implicated in PE pathophysiology, underscoring its multifactorial nature. Advancements in intravascular imaging diagnostics, particularly optical coherence tomography and near-infrared spectroscopy coupled with intravascular ultrasound, offer unprecedented insights into plaque composition and morphology. Artificial intelligence algorithms show promise in enhancing diagnostic accuracy and streamlining image interpretation, augmenting clinician decision-making. Therapeutically, the management of PE evolves, with studies exploring less invasive approaches such as antithrombotic therapy without stenting, particularly in cases identified early through intravascular imaging. Additionally, the potential role of drug-coated balloons in reducing thrombus burden and minimizing future major adverse cardiovascular events warrants further investigation. Looking ahead, the integration of advanced imaging modalities, biomarkers, and artificial intelligence promises to revolutionize the diagnosis and treatment of coronary PE, ushering in a new era of personalized and precise cardiovascular care.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that is poorly defined, reflecting an incomplete understanding of its pathophysiology.

With the enormous progress in the field of cardiovascular imaging in recent years, computed tomography (CT) has become readily available to phenotype atherosclerotic coronary artery disease. New analytical methods using artificial intelligence (AI) enable the analysis of complex phenotypic information of atherosclerotic plaques. In particular, deep learning-based approaches using convolutional neural networks (CNNs) facilitate tasks such as lesion detection, segmentation, and classification. New radiotranscriptomic techniques even capture underlying bio-histochemical processes through higher-order structural analysis of voxels on CT images. In the near future, the international large-scale Oxford Risk Factors And Non-invasive Imaging (ORFAN) study will provide a powerful platform for testing and validating prognostic AI-based models. The goal is the transition of these new approaches from research settings into a clinical workflow. In this review, we present an overview of existing AI-based techniques with focus on imaging biomarkers to determine the degree of coronary inflammation, coronary plaques, and the associated risk. Further, current limitations using AI-based approaches as well as the priorities to address these challenges will be discussed. This will pave the way for an AI-enabled risk assessment tool to detect vulnerable atherosclerotic plaques and to guide treatment strategies for patients.

Postoperative atrial fibrillation (POAF) is a frequent complication after cardiac surgery that is associated with late atrial fibrillation (AF) recurrences (late-POAF) and increased morbidity and long-term mortality.

In rodents, loss of estradiol (E) reduces brown adipose tissue (BAT) metabolic activity. Whether E impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal ( = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m) and postmenopausal ( = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m) women at room temperature and during acute cold exposure using [C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women ( = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min) and postmenopausal women (0.63 ± 0.28 min). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min, = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g·min, < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min to 0.91 ± 0.41 min) to that observed in postmenopausal women (0.91 ± 0.63 min). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women. In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.

Increased left atrial volume and decreased left atrial function have long been associated with atrial fibrillation. The availability of large-scale cardiac magnetic resonance imaging data paired with genetic data provides a unique opportunity to assess the genetic contributions to left atrial structure and function, and understand their relationship with risk for atrial fibrillation. Here, we use deep learning and surface reconstruction models to measure left atrial minimum volume, maximum volume, stroke volume, and emptying fraction in 40,558 UK Biobank participants. In a genome-wide association study of 35,049 participants without pre-existing cardiovascular disease, we identify 20 common genetic loci associated with left atrial structure and function. We find that polygenic contributions to increased left atrial volume are associated with atrial fibrillation and its downstream consequences, including stroke. Through Mendelian randomization, we find evidence supporting a causal role for left atrial enlargement and dysfunction on atrial fibrillation risk.

Central serous chorioretinopathy (CSC) is a fluid maculopathy whose etiology is not well understood. Abnormal choroidal veins in CSC patients have been shown to have similarities with varicose veins. To identify potential mechanisms, we analyzed genotype data from 1,477 CSC patients and 455,449 controls in FinnGen. We identified an association for a low-frequency (AF=0.5%) missense variant (rs113791087) in the gene encoding vascular endothelial protein tyrosine phosphatase (VE-PTP) (OR=2.85, P=4.5×10). This was confirmed in a meta-analysis of 2,452 CSC patients and 865,767 controls from 4 studies (OR=3.06, P=7.4×10). Rs113791087 was associated with a 56% higher prevalence of retinal abnormalities (35.3% vs 22.6%, P=8.0×10) in 708 UK Biobank participants and, surprisingly, with varicose veins (OR=1.31, P=2.3×10) and glaucoma (OR=0.82, P=6.9×10). Predicted loss-of-function variants in VEPTP, though rare in number, were associated with CSC in All of Us (OR=17.10, P=0.018). These findings highlight the significance of VE-PTP in diverse ocular and systemic vascular diseases.

Epicardial and pericardial adipose tissue (EPAT) has been associated with cardiovascular diseases such as atrial fibrillation or flutter (AF) and coronary artery disease (CAD), but studies have been limited in sample size or drawn from selected populations. It has been suggested that the association between EPAT and cardiovascular disease could be mediated by local or paracrine effects.

Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear.

Although cardiovascular diseases (CVDs) are the leading cause of death worldwide, their pharmacotherapy remains suboptimal. Thus, there is a clear unmet need to develop more effective and safer pharmacological strategies. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2023, including the approval of first-in-class drugs that open new avenues for the treatment of atherosclerotic CVD and heart failure (HF). The new indications of drugs already marketed (repurposing) for the treatment of obstructive hypertrophic cardiomyopathy, hypercholesterolaemia, type 2 diabetes, obesity, and HF; the impact of polypharmacy on guideline-directed drug use is highlighted as well as results from negative clinical trials. Finally, we end with a summary of the most important phase 2 and 3 clinical trials assessing the efficacy and safety of cardiovascular drugs under development for the prevention and treatment of CVDs.

Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β-adrenergic receptor (β-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a β-AR antagonist could suppress these unwanted effects and increase the stimulation of the β-AR and β-AR in BAT.

This meta-analysis aims to investigate the effect of preprandial physical activity (PA) versus postprandial PA on glycaemia in human intervention studies. Medline and Embase.com were searched until February 2023 for intervention studies in adults, directly comparing preprandial PA versus postprandial PA on glycaemia. Studies were screened using ASReview (34,837) and full texts were read by two independent reviewers (42 full text, 28 included). Results were analysed using pooled mean differences in random-effects models. Studies were either acute response studies (n = 21) or Randomized Controlled Trials (RCTs) over multiple weeks (n = 7). In acute response studies, postprandial outcomes followed the expected physiological patterns, and outcomes measured over 24 h showed no significant differences. For the RCTs, glucose area under the curve during a glucose tolerance test was slightly, but not significantly lower in preprandial PA vs postprandial PA (-0.29 [95 %CI:-0.66, 0.08] mmol/L, I = 64.36 %). Subgroup analyses (quality, health status, etc.) did not significantly change the outcomes. In conclusion, we found no differences between preprandial PA versus postprandial PA on glycaemia both after one PA bout as well as after multiple weeks of PA. The studies were of low to moderate quality of evidence as assessed by GRADE, showed contradictive results, included no long-term studies and used various designs and populations. We therefore need better RCTs, with more similar designs, in larger populations and longer follow-up periods (≥12 weeks) to have a final answer on the questions eat first, then exercise, or the reverse?

Circulating ceramide (Cer) drives various pathological processes associated with cardiovascular diseases, liver illness, and diabetes mellitus. Although recognized as predictors of cardiometabolic diseases (CMD) in research and clinical settings, their potential for predicting CMD risk in individuals under 18 remains unexplored.

Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterize the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology.

Myocardial ischemia-reperfusion injury (MIRI) remains a challenge in the context of reperfusion procedures for myocardial infarction (MI). While early revascularization stands as the gold standard for mitigating myocardial injury, recent insights have illuminated the paradoxical role of reperfusion, giving rise to the phenomenon known as ischemia-reperfusion injury. This comprehensive review delves into the intricate pathophysiological pathways involved in MIRI, placing a particular focus on the pivotal role of endothelium. Beyond elucidating the molecular intricacies, we explore the diverse clinical manifestations associated with MIRI, underscoring its potential to contribute substantially to the final infarct size, up to 50%. We further navigate through current preventive approaches and highlight promising emerging strategies designed to counteract the devastating effects of the phenomenon. By synthesizing current knowledge and offering a perspective on evolving preventive interventions, this review serves as a valuable resource for clinicians and researchers engaged in the dynamic field of MIRI.

Desmoglein-2 mutations are detected in 5-10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of the ARVC phenotype, leading to earlier arrhythmic events. Homozygous mutant mice develop a severe ARVC-like phenotype. The phenotype of heterozygous mutant () or haploinsufficient () mice is still not well understood. To assess the effects of age and endurance swim training, we studied cardiac morphology and function in sedentary one-year-old and mice and in young mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged and mice manifesting as small fibrotic foci and displacement of Connexin 43. Endurance swim training increased the right ventricular (RV) diameter and decreased RV function in mice but not in wild types. hearts showed increased ventricular activation times and pacing-induced ventricular arrhythmia without obvious fibrosis or inflammation. Preload-reducing therapy during training prevented RV enlargement and alleviated the electrophysiological phenotype. Taken together, endurance swim training induced features of ARVC in young adult mice. Prolonged ventricular activation times in the hearts of trained mice are therefore a potential mechanism for increased arrhythmia risk. Preload-reducing therapy prevented training-induced ARVC phenotype pointing to beneficial treatment options in human patients.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator-activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Atrial fibrillation (AFib), the most prevalent arrhythmia in clinical practice, presents a growing global health concern, particularly with the aging population, as it is associated with devastating complications and an impaired quality of life. Its pathophysiology is multifactorial, including the pathways of fibrosis, inflammation, and oxidative stress. MicroRNAs (miRNAs), small non-coding RNA molecules, have emerged as substantial contributors in AFib pathophysiology, by affecting those pathways. In this review, we explore the intricate relationship between miRNAs and the aforementioned aspects of AFib, shedding light on the molecular pathways as well as the potential diagnostic applications. Recent evidence also suggests a possible role of miRNA therapeutics in maintenance of sinus rhythm via the antagonism of miR-1 and miR-328, or the pharmacological upregulation of miR-27b and miR-223-3p. Unraveling the crosstalk between specific miRNA profiles and genetic predispositions may pave the way for personalized therapeutic approaches, setting the tone for precision medicine in atrial fibrillation.

Polygenic risk scores (PRSs) have proven to be as strong as or stronger than established clinical risk factors for many cardiovascular phenotypes. Whether this is true for aortic stenosis remains unknown.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

With heavily calcified coronary and peripheral artery lesions, lesion preparation is crucial before stent placement to avoid underexpansion, associated with stent thrombosis or restenosis and patency failure in the long-term. Intravascular lithotripsy (IVL) technology disrupts superficial and deep calcium by using localized pulsative sonic pressure waves, making it to a promising tool for patients with severe calcification in coronary bed.

Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K channel Kir2.1. The extracellular Cys (cysteine)-to-Cys disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys-to-Cys disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state.

Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA).

Refractory angina is a frequently encountered phenomenon in patients with coronary artery disease, often presenting therapeutic challenges to the clinical cardiologist. Novel treatment methods have been explored in this direction, with the coronary sinus reducer (CSR) being among the most extensively-investigated.

Substantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, increased complications from drug side effects or ablation, and elevated risk of AF-related stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca2+ dysregulation, whereby female cardiomyocytes more frequently exhibit potentially proarrhythmic Ca2+-driven instabilities compared to male cardiomyocytes. In this study, we aim to gain a mechanistic understanding of the Ca2+-handling disturbances and Ca2+-driven arrhythmogenic events in males vs females and establish their responses to Ca2+-targeted interventions.

Recurrent pericarditis is a problematic clinical condition that impairs the quality of life of the affected patients due to the need for repeated hospital admissions, emergency department visits, and complications from medications, especially glucocorticoids. Unfortunately, available treatments for recurrent pericarditis are very limited, including only a handful of medications such as aspirin/NSAIDs, glucocorticoids, colchicine, and immunosuppressants (such as interleukin-1 (IL-1) blockers, azathioprine, and intravenous human immunoglobulins). Until recently, the clinical experience with the latter class of medications was very limited. Nevertheless, in the last decade, experience with IL-1 blockers has consistently grown, and valid clinical data have emerged from randomized clinical trials. Accordingly, IL-1 blockers are a typical paradigm shift in the treatment of refractory recurrent pericarditis with a clearly positive cost/benefit ratio for those unfortunate patients with multiple recurrences. A drawback related to the above-mentioned medications is the absence of universally accepted and established treatment protocols regarding the full dose administration period and the need for a tapering protocol for individual medications. Another concern is the need for long-standing treatments, which should be discussed with the patients. The above-mentioned unmet needs are expected to be addressed in the near future, such as further insights into pathophysiology and an individualized approach to affected patients.

Social media (SoMe) are emerging as important tools for research dissemination. Twitter/X promotion has been shown to increase citation rates in well-established journals. We aimed to test the effect of a SoMe promotion strategy on the Mendeley reader counts, the Altmetric Attention Score and the number of citations in an upcoming open-access journal.

Cardiac arrhythmias are a common cardiac condition that might lead to fatal outcomes. A better understanding of the molecular and cellular basis of arrhythmia mechanisms is necessary for the development of better treatment modalities. To aid these efforts, various mouse models have been developed for studying cardiac arrhythmias. Both genetic and surgical mouse models are commonly used to assess the incidence and mechanisms of arrhythmias. Since spontaneous arrhythmias are uncommon in healthy young mice, intracardiac programmed electrical stimulation (PES) can be performed to assess the susceptibility to pacing-induced arrhythmias and uncover the possible presence of a proarrhythmogenic substrate. This procedure is performed by positioning an octopolar catheter inside the right atrium and ventricle of the heart through the right jugular vein. PES can provide insights into atrial and ventricular electrical activity and reveal whether atrial and/or ventricular arrhythmias are present or can be induced. Here, we explain detailed procedures used to perform this technique, possible troubleshooting scenarios, and methods to interpret the results obtained. © 2024 Wiley Periodicals LLC. Basic Protocol: Programmed electrical stimulation in mice.

Atrial fibrillation (AF) is the most common supraventricular arrhythmia affecting up to 1% of the general population. Its prevalence dramatically increases with age and could reach up to ∼10% in the elderly. The management of AF is a complex issue that is object of extensive ongoing basic and clinical research, it depends on its genetic and epigenetic causes, and it varies considerably geographically and also according to the ethnicity. Mechanistically, over the last decade, Genome Wide Association Studies have uncovered over 100 genetic loci associated with AF, and have shown that European ancestry is associated with elevated risk of AF. These AF-associated loci revolve around different types of disturbances, including inflammation, electrical abnormalities, and structural remodeling. Moreover, the discovery of epigenetic regulatory mechanisms, involving non-coding RNAs, DNA methylation and histone modification, has allowed unravelling what modifications reshape the processes leading to arrhythmias. Our review provides a current state of the field regarding the identification and functional characterization of AF-related genetic and epigenetic regulatory networks, including ethnic differences. We discuss clear and emerging connections between genetic regulation and pathophysiological mechanisms of AF.

Silent myocardial ischemia (SMI), characterized by a lack of overt symptoms despite an inadequate blood supply to the myocardium, remains a challenging entity in cardiovascular medicine. The pathogenesis involves intricate interactions of vascular, neurohormonal, and metabolic factors, contributing to perfusion deficits without the characteristic chest pain. Understanding these mechanisms is pivotal for recognizing diverse clinical presentations and designing targeted interventions. Diagnostic strategies for SMI have evolved from traditional electrocardiography to advanced imaging modalities, including stress echocardiography, single-photon emission computed tomography (SPECT), positron emission tomography (PET), and cardiac magnetic resonance imaging (MRI). Treating SMI is a matter of ongoing debate, as the available evidence on the role of invasive versus medical management is controversial. This comprehensive review synthesizes current knowledge of silent myocardial ischemia, addressing its pathophysiology, diagnostic modalities, and therapeutic interventions.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited disease characterised by early arrhythmias and structural changes. Still, there are limited echocardiography data on its structural progression. We studied structural progression and its impact on the occurrence of major adverse cardiovascular events (MACE). In this single-centre observational cohort study, structural progression was defined as the development of new major or minor imaging 2010 Task Force Criteria during follow-up. Of 101 patients, a definite diagnosis of ARVC was made in 51 patients, while non-definite 'early' disease was diagnosed in 50 patients. During 4 years of follow-up (IQR: 2-6), 23 (45%) patients with a definite diagnosis developed structural progression while only 1 patient in the non-definite (early) group gained minor imaging Task Force Criteria. Male gender was strongly associated with structural progression (62% of males progressed structurally, while 88% of females remained stable). Patients with structural progression were at higher risk of MACE (64% of patients with MACE had structural progression). Therefore, the rate of structural progression is an essential factor to be considered in ARVC studies.

Cirrhotic cardiomyopathy (CCM) is characterized by elevated cardiac output at rest, an inability to further increase contractility under stress, and diastolic dysfunction. The diagnosis of CCM is crucial as it can lead to complications during liver transplantation. However, its recognition poses challenges with conventional echocardiography techniques. Speckle tracking echocardiography (STE), particularly global longitudinal strain (GLS), is a novel index that enhances the diagnostic efficacy of echocardiography for both ischemic and non-ischemic cardiomyopathies. GLS proves more sensitive in identifying early systolic dysfunction and is also influenced by advanced diastolic dysfunction. Consequently, there is an expanding scope for GLS utilization in cirrhotic cases, with newly updated diagnostic criteria for CCM incorporating GLS. Specifically, systolic dysfunction is now defined as either a left ventricular ejection fraction below 50% or an absolute GLS below 18%. However, conflicting data on GLS alterations in liver cirrhosis patients persist, as many individuals with advanced disease and a poor prognosis exhibit a hyperdynamic state with preserved or increased GLS. Consequently, the presence of CCM, according to the updated criteria, does not exhibit a significant association-in the majority of studies-with the severity of liver disease and prognosis. Furthermore, information on other indices measured with STE, such as left atrial and right ventricular strain, is promising but currently limited. This review aims to offer a critical assessment of the existing evidence concerning the application of STE in patients with liver cirrhosis.

The growing interest in epicardial adipose tissue (EAT) as a biomarker of atrial fibrillation is limited by the difficulties in isolating EAT from other paracardial adipose tissues. We tested the feasibility and value of measuring the pure EAT contained in the atrioventricular groove (GEAT) using cardiovascular magnetic resonance (CMR) imaging in patients with distinct metabolic disorders.

Ventricular fibrillation (VF) is a leading immediate cause of sudden cardiac death. There is a strong association between aging and VF, although the mechanisms are unclear, limiting the availability of targeted therapeutic interventions. Here we found that the stress kinases p38γ and p38δ are activated in the ventricles of old mice and mice with genetic or drug-induced arrhythmogenic conditions. We discovered that, upon activation, p38γ and p38δ cooperatively increase the susceptibility to stress-induced VF. Mechanistically, our data indicate that activated p38γ and p38δ phosphorylate ryanodine receptor 2 (RyR2) disrupt Kv4.3 channel localization, promoting sarcoplasmic reticulum calcium leak, I current reduction and action potential duration prolongation. In turn, this led to aberrant intracellular calcium handling, premature ventricular complexes and enhanced susceptibility to VF. Blocking this pathway protected genetically modified animals from VF development and reduced the VF duration in aged animals. These results indicate that p38γ and p38δ are a potential therapeutic target for sustained VF prevention.

Handheld single-lead electrocardiographic (1L ECG) devices are increasingly used for atrial fibrillation (AF) screening, but their real-world performance is not well understood.

The mechanisms leading to the conversion of atrial fibrillation (AF) to sinus rhythm are poorly understood. This study describes the dynamic behavior of electrophysiological parameters and conduction patterns leading to spontaneous and pharmacological AF termination.

Ascending thoracic aortic aneurysm (ATAA) is a silent and threatening dilation of the ascending aorta (AscAo). Maximal aortic diameter which is currently used for ATAA patients management and surgery planning has been shown to inadequately characterize risk of dissection in a large proportion of patients. Our aim was to propose a comprehensive quantitative evaluation of aortic morphology and pressure-flow-wall associations from four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) data in healthy aging and in patients with ATAA.