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Publications of our Scientists

Mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: a systematic review and network meta-analysis of 32 randomized trials
Pamporis K, Karakasis P, Sagris M, Zarifis I, Bougioukas KI, Pagkalidou E, Milaras N, Samaras A, Theofilis P, Fragakis N, Tousoulis D, Xanthos T and Giannakoulas G
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.
Oral anticoagulation in patients with left ventricular thrombus - a systematic review and meta-analysis
Haller PM, Kazem N, Agewall S, Borghi C, Ceconi C, Dobrev D, Cerbai E, Grove EL, Kaski JC, Lewis BS, Niessner A, Rocca B, Rosano G, Savarese G, Schnabel R, Semb AG, Sossalla S, Wassmann S and Sulzgruber P
Direct oral anticoagulants (DOACs) are increasingly used off-label to treat patients with left ventricular thrombus (LVT). We analyzed available meta-data comparing DOACs and vitamin K antagonists (VKAs) for efficacy and safety.
MSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease
Urbut SM, Yeung MW, Khurshid S, Cho SMJ, Schuermans A, German J, Taraszka K, Paruchuri K, Fahed AC, Ellinor PT, Trinquart L, Parmigiani G, Gusev A and Natarajan P
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.
Protease-activated receptor 2 at the intersection of thrombo-inflammation and beyond
Fender AC and Dobrev D
Pilot study to evaluate the use of remote patient monitoring to guide the timing of valve intervention in patients with severe asymptomatic aortic stenosis (APRAISE-AS): study protocol for a randomised controlled trial delivered in two tertiary cardiac centres in the UK
Khan N, Steeds RP, Kyte D, Fabritz L, Collis P, Chua W, Stubbs C, Mehta S, Sun Y, Nulty M, Kirkham K and Cotton JM
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.
Compartmentalization proteomics revealed endolysosomal protein network changes in a goat model of atrial fibrillation
Ayagama T, Charles PD, Bose SJ, Boland B, Priestman DA, Aston D, Berridge G, Fischer R, Cribbs AP, Song Q, Mirams GR, Amponsah K, Heather L, Galione A, Herring N, Kramer H, Capel RA, Platt FM, Schotten U, Verheule S and Burton RAB
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.
Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank
Ryu J, Rämö JT, Jurgens SJ, Niiranen T, Sanna-Cherchi S, Bauer KA, Haj A, Choi SH, Palotie A, Daly M, Ellinor PT and Bendapudi PK
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.
Characterization of adipose tissue using magnetic resonance imaging
Kachenoura N
Development and validation of algorithms to predict left ventricular ejection fraction class from healthcare claims data
Logeart D, Doublet M, Gouysse M, Damy T, Isnard R and Roubille F
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.
Detectable troponin below the 99 percentile predicts survival in patients undergoing coronary angiography
Michel L, Jehn S, Dykun I, Anker MS, Ferdinandy P, Dobrev D, Rassaf T, Mahabadi AA and Totzeck M
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.
Safety and efficacy of long-term sodium channel blocker therapy for early rhythm control: the EAST-AFNET 4 trial
Rillig A, Eckardt L, Borof K, Camm AJ, Crijns HJGM, Goette A, Breithardt G, Lemoine MD, Metzner A, Rottner L, Schotten U, Vettorazzi E, Wegscheider K, Zapf A, Heidbuchel H, Willems S, Fabritz L, Schnabel RB, Magnussen C and Kirchhof P
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.
Pregnancy and cardiac maternal outcomes in women with inherited cardiomyopathy: interest of the CARPREG II risk score
Wallet T, Legrand L, Isnard R, Gandjbakhch E, Pousset F, Proukhnitzky J, Dommergues M, Nizard J and Charron P
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.
The Role of Inflammasomes in Heart Failure
Vlachakis PK, Theofilis P, Kachrimanidis I, Giannakopoulos K, Drakopoulou M, Apostolos A, Kordalis A, Leontsinis I, Tsioufis K and Tousoulis D
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.
Using artificial intelligence to study atherosclerosis from computed tomography imaging: A state-of-the-art review of the current literature
Klüner LV, Chan K and Antoniades C
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.
Young and older patients with acute myocardial infarction: differences in risk factors and angiographic characteristics
Sagris M, Theofilis P, Mistakidou V, Oikonomou E, Tsioufis K and Tousoulis D
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.
Direct neuronal protection by the protease-activated receptor PAR4 antagonist ML354 after experimental stroke in mice
Fleischer M, Szepanowski RD, Pesara V, Bihorac JS, Oehler B, Dobrev D, Kleinschnitz C and Fender AC
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.
Rare genetic variation in VE-PTP is associated with central serous chorioretinopathy, venous dysfunction and glaucoma
Rämö JT, Gorman B, Weng LC, Jurgens SJ, Singhanetr P, Tieger MG, van Dijk EH, Halladay CW, Wang X, Brinks J, Choi SH, Luo Y, , , Pyarajan S, Nealon CL, Gorin MB, Wu WC, Sobrin L, Kaarniranta K, Yzer S, Palotie A, Peachey NS, Turunen JA, Boon CJ, Ellinor PT, Iyengar SK, Daly MJ and Rossin EJ
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.
Deep learning of left atrial structure and function provides link to atrial fibrillation risk
Pirruccello JP, Di Achille P, Choi SH, Rämö JT, Khurshid S, Nekoui M, Jurgens SJ, Nauffal V, Kany S, , Ng K, Friedman SF, Batra P, Lunetta KL, Palotie A, Philippakis AA, Ho JE, Lubitz SA and Ellinor PT
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.
Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes
Keener R, Chhetri SB, Connelly CJ, Taub MA, Conomos MP, Weinstock J, Ni B, Strober B, Aslibekyan S, Auer PL, Barwick L, Becker LC, Blangero J, Bleecker ER, Brody JA, Cade BE, Celedon JC, Chang YC, Cupples LA, Custer B, Freedman BI, Gladwin MT, Heckbert SR, Hou L, Irvin MR, Isasi CR, Johnsen JM, Kenny EE, Kooperberg C, Minster RL, Naseri T, Viali S, Nekhai S, Pankratz N, Peyser PA, Taylor KD, Telen MJ, Wu B, Yanek LR, Yang IV, Albert C, Arnett DK, Ashley-Koch AE, Barnes KC, Bis JC, Blackwell TW, Boerwinkle E, Burchard EG, Carson AP, Chen Z, Chen YI, Darbar D, de Andrade M, Ellinor PT, Fornage M, Gelb BD, Gilliland FD, He J, Islam T, Kaab S, Kardia SLR, Kelly S, Konkle BA, Kumar R, Loos RJF, Martinez FD, McGarvey ST, Meyers DA, Mitchell BD, Montgomery CG, North KE, Palmer ND, Peralta JM, Raby BA, Redline S, Rich SS, Roden D, Rotter JI, Ruczinski I, Schwartz D, Sciurba F, Shoemaker MB, Silverman EK, Sinner MF, Smith NL, Smith AV, Tiwari HK, Vasan RS, Weiss ST, Williams LK, Zhang Y, Ziv E, Raffield LM, Reiner AP, , , , Arvanitis M, Greider CW, Mathias RA and Battle A
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 proteins modulate the voltage-gated cardiac sodium channel Nav1.5
Rinné S, Kiper AK, Jacob R, Ortiz-Bonnin B, Schindler RFR, Fischer S, Komadowski M, De Martino E, Schäfer MK, Cornelius T, Fabritz L, Helker CSM, Brand T and Decher N
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.
Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias
Weng LC, Khurshid S, Hall AW, Nauffal V, Morrill VN, Sun YV, Rämö JT, Beer D, Lee S, Nadkarni G, Johnson R, Andreasen L, Clayton A, Pullinger CR, Yoneda ZT, Friedman DJ, Hyman MC, Judy RL, Skanes AC, Orland KM, Jordà P, Treu TM, Oetjens MT, Subbiah R, Hartmann JP, May HT, Kane JP, Issa TZ, Nafissi NA, Leong-Sit P, Dubé MP, Roselli C, Choi SH, , Tardif JC, Khan HR, Knight S, Svendsen JH, Walker B, Karlsson Linnér R, Gaziano JM, Tadros R, Fatkin D, Rader DJ, Shah SH, Roden DM, Marcus GM, Loos RJF, Damrauer SM, Haggerty CM, Cho K, Palotie A, Olesen MS, Eckhardt LL, Roberts JD, Cutler MJ, Shoemaker MB, Wilson PWF, Ellinor PT and Lubitz SA
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).
Noninvasive assessment of organ-specific and shared pathways in multi-organ fibrosis using T1 mapping
Nauffal V, Klarqvist MDR, Hill MC, Pace DF, Di Achille P, Choi SH, Rämö JT, Pirruccello JP, Singh P, Kany S, Hou C, Ng K, Philippakis AA, Batra P, Lubitz SA and Ellinor PT
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.
Congenital heart "Challenges" in Down syndrome
Drakopoulou M, Vlachakis PK, Tsioufis C and Tousoulis D
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.
Inflammatory risk and cardiovascular events in patients without obstructive coronary artery disease: the ORFAN multicentre, longitudinal cohort study
Chan K, Wahome E, Tsiachristas A, Antonopoulos AS, Patel P, Lyasheva M, Kingham L, West H, Oikonomou EK, Volpe L, Mavrogiannis MC, Nicol E, Mittal TK, Halborg T, Kotronias RA, Adlam D, Modi B, Rodrigues J, Screaton N, Kardos A, Greenwood JP, Sabharwal N, De Maria GL, Munir S, McAlindon E, Sohan Y, Tomlins P, Siddique M, Kelion A, Shirodaria C, Pugliese F, Petersen SE, Blankstein R, Desai M, Gersh BJ, Achenbach S, Libby P, Neubauer S, Channon KM, Deanfield J, Antoniades C and
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.
New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2023
Tamargo J, Agewall S, Borghi C, Ceconi C, Cerbai E, Dan GA, Ferdinandy P, Grove EL, Rocca B, Magavern E, Sulzgruber P, Semb AG, Sossalla S, Niessner A, Kaski JC and Dobrev D
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.
Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction
Gibson CM, Duffy D, Korjian S, Bahit MC, Chi G, Alexander JH, Lincoff AM, Heise M, Tricoci P, Deckelbaum LI, Mears SJ, Nicolau JC, Lopes RD, Merkely B, Lewis BS, Cornel JH, Trebacz J, Parkhomenko A, Libby P, Sacks FM, Povsic TJ, Bonaca M, Goodman SG, Bhatt DL, Tendera M, Steg PG, Ridker PM, Aylward P, Kastelein JJP, Bode C, Mahaffey KW, Nicholls SJ, Pocock SJ, Mehran R, Harrington RA and
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.
Clinical Predictors of Device-Detected Atrial Fibrillation During 2.5 Years After Cardiac Surgery: Prospective RACE V Cohort
Gilbers MD, Kawczynski MJ, Bidar E, Maesen B, Isaacs A, Winters J, Linz D, Rienstra M, van Gelder I, Maessen JG and Schotten U
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.
Rationale and design of the PACIFIC-PRESERVED (PhenomApping, ClassIFication and Innovation for Cardiac dysfunction in patients with heart failure and PRESERVED left ventricular ejection fraction) study
Hulot JS, Janiak P, Boutinaud P, Boutouyrie P, Chézalviel-Guilbert F, Christophe JJ, Cohen A, Damy T, Djadi-Prat J, Firat H, Hervé PY, Isnard R, Jondeau G, Mousseaux E, Pernot M, Prot P, Tyl B, Soulat G, Logeart D and
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that is poorly defined, reflecting an incomplete understanding of its pathophysiology.
Brown adipose tissue metabolism in women is dependent on ovarian status
Blondin DP, Haman F, Swibas TM, Hogan-Lamarre S, Dumont L, Guertin J, Richard G, Weissenburger Q, Hildreth KL, Schauer I, Panter S, Wyland L, Carpentier AC, Miao Y, Shi J, Juarez-Colunga E, Kohrt WM and Melanson EL
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.
Cardiovascular Significance and Genetics of Epicardial and Pericardial Adiposity
Rämö JT, Kany S, Hou CR, Friedman SF, Roselli C, Nauffal V, Koyama S, Karjalainen J, Maddah M, Palotie A, Ellinor PT, Pirruccello JP and
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.
Inhibition of oxidized low-density lipoprotein with orticumab inhibits coronary inflammation and reduces residual inflammatory risk in psoriasis: a pilot randomized, double-blind placebo-controlled trial
Farina CJ, Davidson MH, Shah PK, Stark C, Lu W, Shirodaria C, Wright T, Antoniades CA, Nilsson J and Mehta NN
Oral anticoagulation in device-detected atrial fibrillation: effects of age, sex, cardiovascular comorbidities, and kidney function on outcomes in the NOAH-AFNET 6 trial
Lip GYH, Nikorowitsch J, Sehner S, Becher N, Bertaglia E, Blomstrom-Lundqvist C, Brandes A, Beuger V, Calvert M, Camm AJ, Chlouverakis G, Dan GA, Dichtl W, Diener HC, Fierenz A, Goette A, de Groot JR, Hermans A, Lubinski A, Marijon E, Merkely B, Mont L, Ozga AK, Rajappan K, Sarkozy A, Scherr D, Schnabel RB, Schotten U, Simantirakis E, Toennis T, Vardas P, Wichterle D, Zapf A and Kirchhof P
Is stimulation of browning of human adipose tissue a relevant therapeutic target?
Carpentier AC and Blondin DP
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.
Kir2.1-Na1.5 channelosome and its role in arrhythmias in inheritable cardiac diseases
Gutiérrez LK, Moreno-Manuel AI and Jalife J
Sudden cardiac death in children and young adults is a relatively rare but tragic event whose pathophysiology is unknown at the molecular level. Evidence indicates that the main cardiac sodium channel (Na1.5) and the strong inward rectifier potassium channel (Kir2.1) physically interact and form macromolecular complexes (channelosomes) with common partners, including adapter, scaffolding, and regulatory proteins that help them traffic together to their eventual membrane microdomains. Most important, dysfunction of either or both ion channels has direct links to hereditary human diseases. For example, certain mutations in the KCNJ2 gene encoding the Kir2.1 protein result in Andersen-Tawil syndrome type 1 and alter both inward rectifier potassium and sodium inward currents. Similarly, trafficking-deficient mutations in the gene encoding the Na1.5 protein (SCN5A) result in Brugada syndrome and may also disturb both inward rectifier potassium and sodium inward currents. Moreover, gain-of-function mutations in KCNJ2 result in short QT syndrome type 3, which is extremely rare but highly arrhythmogenic, and can modify Kir2.1-Na1.5 interactions in a mutation-specific way, further highlighting the relevance of channelosomes in ion channel diseases. By expressing mutant proteins that interrupt or modify Kir2.1 or Na1.5 function in animal models and patient-specific pluripotent stem cell-derived cardiomyocytes, investigators are defining for the first time the mechanistic framework of how mutation-induced dysregulation of the Kir2.1-Na1.5 channelosome affects cardiac excitability, resulting in arrhythmias and sudden death in different cardiac diseases.
Photon-counting computed tomography: 'one-stop shop' for coronary stenosis, inflammation, and myocardial assessment in ST-segment elevation acute coronary syndrome
Kotronias RA, Raman B, Ferreira V, Neubauer S and Antoniades C
The effects of the β-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis
Dumont L, Caron A, Richard G, Croteau E, Fortin M, Frisch F, Phoenix S, Dubreuil S, Guérin B, Turcotte ÉE, Carpentier AC and Blondin DP
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.
Myocardial Ischemia-Reperfusion Injury: Unraveling Pathophysiology, Clinical Manifestations, and Emerging Prevention Strategies
Sagris M, Apostolos A, Theofilis P, Ktenopoulos N, Katsaros O, Tsalamandris S, Tsioufis K, Toutouzas K and Tousoulis D
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.
The effect of preprandial versus postprandial physical activity on glycaemia: Meta-analysis of human intervention studies
Slebe R, Wenker E, Schoonmade LJ, Bouman EJ, Blondin DP, Campbell DJT, Carpentier AC, Hoeks J, Raina P, Schrauwen P, Serlie MJ, Stenvers DJ, de Mutsert R, Beulens JWJ and Rutters F
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?
Distinct Plasma Extracellular Vesicle Transcriptomes in Acute Decompensated Heart Failure Subtypes: A Liquid Biopsy Approach
Gokulnath P, Spanos M, Lehmann HI, Sheng Q, Rodosthenous R, Chaffin M, Varrias D, Chatterjee E, Hutchins E, Li G, Daaboul G, Rana F, Wang AM, Van Keuren-Jensen K, Ellinor PT, Shah R and Das S
Circulating BMP10 Levels Associate With Late Postoperative Atrial Fibrillation and Left Atrial Endomysial Fibrosis
Winters J, Kawczynski MJ, Gilbers MD, Isaacs A, Zeemering S, Bidar E, Maesen B, Rienstra M, van Gelder I, Verheule S, Maessen JG and Schotten U
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.
Automated interpretations of single-lead electrocardiograms predict incident atrial fibrillation: The VITAL-AF trial
Pipilas DC, Khurshid S, Al-Alusi MA, Atlas SJ, Ashburner JM, Borowsky LH, McManus DD, Singer DE, Lubitz SA, Chang Y and Ellinor PT
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.
Efficacy of intravascular lithotripsy (IVL) in coronary stenosis with severe calcification: A multicenter systematic review and meta-analysis
Sagris M, Ktenopoulos N, Dimitriadis K, Papanikolaou A, Tzoumas A, Terentes-Printzios D, Synetos A, Soulaidopoulos S, Lichtenberg M, Korosoglou G, Honton B, Tousoulis D, Tsioufis C and Toutouzas K
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.
Macrophage activation markers are associated with infection and mortality in patients with acute liver failure
Cavazza A, Triantafyllou E, Savoldelli R, Mujib S, Jerome E, Trovato FM, Artru F, Sheth R, Huang XH, Ma Y, Dazzi F, Pirani T, Antoniades CG, Lee WM, McPhail MJ, Karvellas CJ and
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.
Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease
Liew F, Efstathiou C, Fontanella S, Richardson M, Saunders R, Swieboda D, Sidhu JK, Ascough S, Moore SC, Mohamed N, Nunag J, King C, Leavy OC, Elneima O, McAuley HJC, Shikotra A, Singapuri A, Sereno M, Harris VC, Houchen-Wolloff L, Greening NJ, Lone NI, Thorpe M, Thompson AAR, Rowland-Jones SL, Docherty AB, Chalmers JD, Ho LP, Horsley A, Raman B, Poinasamy K, Marks M, Kon OM, Howard LS, Wootton DG, Quint JK, de Silva TI, Ho A, Chiu C, Harrison EM, Greenhalf W, Baillie JK, Semple MG, Turtle L, Evans RA, Wain LV, Brightling C, Thwaites RS, Openshaw PJM, and
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.
Blood-based cardiometabolic phenotypes in atrial fibrillation and their associated risk: EAST-AFNET 4 biomolecule study
Fabritz L, Chua W, Cardoso VR, Al-Taie C, Borof K, Suling A, Krause L, Kany S, Magnussen C, Wegscheider K, Breithardt G, Crijns HJGM, Camm AJ, Gkoutos G, Ellinor PT, Goette A, Schotten U, Wienhues-Thelen UH, Zeller T, Schnabel RB, Zapf A and Kirchhof P
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. Their role in defining subphenotypes of AF is not known.
Atrial fibrillation in the young: consider heritable conditions like short QT syndrome
Fabritz L and Lemoine MD
The thrombin receptor PAR4 supports visceral adipose tissue inflammation
Kleeschulte S, Fischinger V, Öhlke L, Bode J, Kamler M, Dobrev D, Grandoch M and Fender AC
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.
Adiposity, type 2 diabetes and atherosclerotic cardiovascular disease risk: Use and abuse of the body mass index
Arsenault BJ, Carpentier AC, Poirier P and Després JP
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.
Extracellular Kir2.1 Mutant Upsets Kir2.1-PIP Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome
Cruz FM, Macías Á, Moreno-Manuel AI, Gutiérrez LK, Vera-Pedrosa ML, Martínez-Carrascoso I, Sánchez Pérez P, Ruiz Robles JM, Bermúdez-Jiménez FJ, Díaz-Agustín A, Martínez de Benito F, Arias-Santiago S, Braza-Boils A, Martín-Martínez M, Gutierrez-Rodríguez M, Bernal JA, Zorio E, Jiménez-Jaimez J and Jalife J
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.
Circulating ceramide levels and ratios in Emirati youth under 18 years: associations with cardiometabolic risk factors
Shalaby YM, Al-Zohily B, Raj A, Yasin J, Al Hamad S, Antoniades C, Akawi N and Aburawi EH
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.
Ischemia does not provoke the full immune training repertoire in human cardiac fibroblasts
Mann C, van Alst C, Gorressen S, Nega R, Dobrev D, Grandoch M and Fender AC
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.
TAD boundary deletion causes PITX2-related cardiac electrical and structural defects
Baudic M, Murata H, Bosada FM, Melo US, Aizawa T, Lindenbaum P, van der Maarel LE, Guedon A, Baron E, Fremy E, Foucal A, Ishikawa T, Ushinohama H, Jurgens SJ, Choi SH, Kyndt F, Le Scouarnec S, Wakker V, Thollet A, Rajalu A, Takaki T, Ohno S, Shimizu W, Horie M, Kimura T, Ellinor PT, Petit F, Dulac Y, Bru P, Boland A, Deleuze JF, Redon R, Le Marec H, Le Tourneau T, Gourraud JB, Yoshida Y, Makita N, Vieyres C, Makiyama T, Mundlos S, Christoffels VM, Probst V, Schott JJ and Barc J
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.
Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis
Gudd CLC, Mitchell E, Atkinson SR, Mawhin MA, Turajlic S, Larkin J, Thursz MR, Goldin RD, Powell N, Antoniades CG, Woollard KJ, Possamai LA and Triantafyllou E
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.
Healthcare Resource Utilization Following Single-lead Electrocardiogram Screening for Atrial Fibrillation in Older Individuals at Primary Care Visits
Atlas SJ, Borowsky LH, Chang Y, Ashburner JM, Ellinor PT, Lubitz SA and Singer DE
Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence
Sayour NV, Paál ÁM, Ameri P, Meijers WC, Minotti G, Andreadou I, Lombardo A, Camilli M, Drexel H, Grove EL, Dan GA, Ivanescu A, Semb AG, Savarese G, Dobrev D, Crea F, Kaski JC, de Boer RA, Ferdinandy P and Varga ZV
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.
The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology
Mehdizadeh M, Naud P, Abu-Taha IH, Hiram R, Xiong F, Xiao J, Saljic A, Kamler M, Vuong-Robillard N, Thorin E, Ferbeyre G, Tardif JC, Sirois MG, Tanguay JF, Dobrev D and Nattel S
Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF.
Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human
Roh JD, Castro C, Yu A, Rana S, Shahul S, Gray KJ, Honigberg MC, Ricke-Hoch M, Iwamoto Y, Yeri A, Kitchen R, Guerra JB, Hobson R, Chaudhari V, Chang B, Sarma A, Lerchenmüller C, Al Sayed ZR, Diaz Verdugo C, Xia P, Skarbianskis N, Zeisel A, Bauersachs J, Kirkland JL, Karumanchi SA, Gorcsan J, Sugahara M, Damp J, Hanley-Yanez K, Ellinor PT, Arany Z, McNamara DM, , Hilfiker-Kleiner D and Rosenzweig A
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.
Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction
Fabritz L, Fortmueller L, Gehmlich K, Kant S, Kemper M, Kucerova D, Syeda F, Faber C, Leube RE, Kirchhof P and Krusche CA
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.
MicroRNAs in Atrial Fibrillation: Mechanisms, Vascular Implications, and Therapeutic Potential
Vardas EP, Theofilis P, Oikonomou E, Vardas PE and Tousoulis D
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.
Clonal Hematopoiesis of Indeterminate Potential With Loss of Enhances Risk for Atrial Fibrillation Through Inflammasome Activation
Lin AE, Bapat AC, Xiao L, Niroula A, Ye J, Wong WJ, Agrawal M, Farady CJ, Boettcher A, Hergott CB, McConkey M, Flores-Bringas P, Shkolnik V, Bick AG, Milan D, Natarajan P, Libby P, Ellinor PT and Ebert BL
Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored.
The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3
Moreno-Manuel AI, Macías Á, Cruz FM, Gutiérrez LK, Martínez F, González-Guerra A, Martínez Carrascoso I, Bermúdez-Jimenez FJ, Sánchez-Pérez P, Vera-Pedrosa ML, Ruiz-Robles JM, Bernal JA and Jalife J
Short QT syndrome type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation.
Novel Polygenic Risk Score and Established Clinical Risk Factors for Risk Estimation of Aortic Stenosis
Small AM, Melloni GEM, Kamanu FK, Bergmark BA, Bonaca MP, O'Donoghue ML, Giugliano RP, Scirica BM, Bhatt D, Antman EM, Raz I, Wiviott SD, Truong B, Wilson PWF, Cho K, O'Donnell CJ, Braunwald E, Lubitz SA, Ellinor P, Peloso GM, Ruff CT, Sabatine MS, Natarajan P and Marston NA
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.
Longer and better lives for patients with atrial fibrillation: the 9th AFNET/EHRA consensus conference
Linz D, Andrade JG, Arbelo E, Boriani G, Breithardt G, Camm AJ, Caso V, Nielsen JC, De Melis M, De Potter T, Dichtl W, Diederichsen SZ, Dobrev D, Doll N, Duncker D, Dworatzek E, Eckardt L, Eisert C, Fabritz L, Farkowski M, Filgueiras-Rama D, Goette A, Guasch E, Hack G, Hatem S, Haeusler KG, Healey JS, Heidbuechel H, Hijazi Z, Hofmeister LH, Hove-Madsen L, Huebner T, Kääb S, Kotecha D, Malaczynska-Rajpold K, Merino JL, Metzner A, Mont L, Ng GA, Oeff M, Parwani AS, Puererfellner H, Ravens U, Rienstra M, Sanders P, Scherr D, Schnabel R, Schotten U, Sohns C, Steinbeck G, Steven D, Toennis T, Tzeis S, van Gelder IC, van Leerdam RH, Vernooy K, Wadhwa M, Wakili R, Willems S, Witt H, Zeemering S and Kirchhof P
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).
Focal point-by-point biphasic monopolar pulsed field ablation for posterior wall isolation
Farnir F, Chaldoupi SM, Farnir F, Schotten U, Vernooy K, Luermans J and Linz D
Enhanced Ca2+-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling
Zhang X, Wu Y, Smith C, Louch WE, Morotti S, Dobrev D, Grandi E and Ni H
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.
MMCT-Loop: a mix model-based pipeline for calling targeted 3D chromatin loops
Tang L, Liao J, Hill MC, Hu J, Zhao Y, Ellinor PT and Li M
Protein-specific Chromatin Conformation Capture (3C)-based technologies have become essential for identifying distal genomic interactions with critical roles in gene regulation. The standard techniques include Chromatin Interaction Analysis by Paired-End Tag (ChIA-PET), in situ Hi-C followed by chromatin immunoprecipitation (HiChIP) also known as PLAC-seq. To identify chromatin interactions from these data, a variety of computational methods have emerged. Although these state-of-art methods address many issues with loop calling, only few methods can fit different data types simultaneously, and the accuracy as well as the efficiency these approaches remains limited. Here we have generated a pipeline, MMCT-Loop, which ensures the accurate identification of strong loops as well as dynamic or weak loops through a mixed model. MMCT-Loop outperforms existing methods in accuracy, and the detected loops show higher activation functionality. To highlight the utility of MMCT-Loop, we applied it to conformational data derived from neural stem cell (NSCs) and uncovered several previously unidentified regulatory regions for key master regulators of stem cell identity. MMCT-Loop is an accurate and efficient loop caller for targeted conformation capture data, which supports raw data or pre-processed valid pairs as input, the output interactions are formatted and easily uploaded to a genome browser for visualization.
Tracers and Imaging of Fatty Acid and Energy Metabolism of Human Adipose Tissues
Carpentier AC
White adipose tissue and brown adipose tissue (WAT and BAT) regulate fatty acid metabolism and control lipid fluxes to other organs. Dysfunction of these key metabolic processes contributes to organ insulin resistance and inflammation leading to chronic diseases such as type 2 diabetes, metabolic dysfunction-associated steatohepatitis, and cardiovascular diseases. Metabolic tracers combined with molecular imaging methods are powerful tools for the investigation of these pathogenic mechanisms. Herein, I review some of the positron emission tomography and magnetic resonance imaging methods combined with stable isotopic metabolic tracers to investigate fatty acid and energy metabolism, focusing on human WAT and BAT metabolism. I will discuss the complementary strengths offered by these methods for human investigations and current gaps in the field.
Thrombus aspiration in STEMI: Whom we aspire it may help?
Antonopoulos AS, Simantiris S and Tousoulis D
An inflammation resolution-promoting intervention prevents atrial fibrillation caused by left ventricular dysfunction
Hiram R, Xiong F, Naud P, Xiao J, Sosnowski DK, Le Quilliec E, Saljic A, Abu-Taha IH, Kamler M, LeBlanc CA, Al-U'Datt DGF, Sirois MG, Hebert TE, Tanguay JF, Tardif JC, Dobrev D and Nattel S
Recent studies suggest that bioactive mediators called resolvins promote an active resolution of inflammation. Inflammatory signalling is involved in the development of the substrate for atrial fibrillation (AF). The aim of this study is to evaluate the effects of resolvin-D1 on atrial arrhythmogenic remodelling resulting from left ventricular (LV) dysfunction induced by myocardial infarction (MI) in rats.
Disturbed atrial metabolism, shear stress, and cardiac load contribute to atrial fibrillation after ablation: AXAFA biomolecule study
Chua W, Khashaba A, Canagarajah H, Nielsen JC, di Biase L, Haeusler KG, Hindricks G, Mont L, Piccini J, Schnabel RB, Schotten U, Wienhues-Thelen UH, Zeller T, Fabritz L and Kirchhof P
Different disease processes can combine to cause atrial fibrillation (AF). Their contribution to recurrent AF after ablation in patients is not known. Cardiovascular processes associated with recurrent AF after AF ablation were determined by quantifying biomolecules related to inflammation, metabolism, proliferation, fibrosis, shear stress, atrial pressure, and others in the AXAFA biomolecule study.
Left atrial strain: A memory of the severity of atrial myocardial stress in atrial fibrillation
Soulat-Dufour L, Ichou F, Ponnaiah M, Lang S, Ederhy S, Adavane-Scheuble S, Chauvet-Droit M, Capderou E, Arnaud C, Le Goff W, Boccara F, Hatem SN and Cohen A
Left atrial (LA) strain is a simple marker of LA function. The aim of the study was to evaluate the determinants of atrial cardiomyopathy in AF.
Utilization of and perceived need for simulators in clinical electrophysiology: results from an EHRA physician survey
Tjong FVY, Perrotta L, Goette A, Duncker D, Vernooy K, Boveda S, Chun KJ and Svennberg E
Simulator training has been recently introduced in electrophysiology (EP) programmes in order to improve catheter manipulation skills without complication risks. The aim of this study is to survey the current use of EP simulators and the perceived need for these tools in clinical training and practice.
Delayed Ga-FAPI-46 PET/MR imaging confirms ongoing fibroblast activation in patients after acute myocardial infarction
Kupusovic J, Kessler L, Kazek S, Chodyla MK, Umutlu L, Zarrad F, Nader M, Fendler WP, Varasteh Z, Hermann K, Dobrev D, Wakili R, Rassaf T, Siebermair J and Rischpler C
Combined cardiac Ga-Fibroblast-Activation Protein-alpha inhibitor (FAPI) positron-emission tomography (PET) and cardiac magnetic resonance imaging (MRI) constitute a novel diagnostic tool in patients for the assessment of myocardial damage after an acute myocardial infarction (AMI). Purpose of this pilot study was to evaluate simultaneous Ga-68-FAPI-46-PET/MR imaging in the delayed phase after AMI.
Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse
Sommerfeld LC, Holmes AP, Yu TY, O'Shea C, Kavanagh DM, Pike JM, Wright T, Syeda F, Aljehani A, Kew T, Cardoso VR, Kabir SN, Hepburn C, Menon PR, Broadway-Stringer S, O'Reilly M, Witten A, Fortmueller L, Lutz S, Kulle A, Gkoutos GV, Pavlovic D, Arlt W, Lavery GG, Steeds R, Gehmlich K, Stoll M, Kirchhof P and Fabritz L
Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and P wave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako ), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated P wave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in Na 1.5 membrane clustering in Plako atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use. KEY POINTS: Androgenic male sex hormones, such as testosterone, might increase the risk of atrial fibrillation in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which is often caused by desmosomal gene defects (e.g. reduced plakoglobin expression). In this study, we observed a significantly higher proportion of males who had ARVC compared with females, and atrial arrhythmias and P wave changes represented a common observation in advanced ARVC stages. In mice with reduced plakoglobin expression, chronic administration of 5α-dihydrotestosterone led to P wave abnormalities, atrial conduction slowing, sodium current depletion and a decrease in membrane-localized Na 1.5 clusters. 5α-Dihydrotestosterone, therefore, represents a stimulus aggravating the pro-arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function.
Atrial fibrillation: pathophysiology, genetic and epigenetic mechanisms
Vinciguerra M, Dobrev D and Nattel S
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.
The impact of Twitter/X promotion on visibility of research articles: Results of the #TweetTheJournal study
Betz K, Giordano M, Hillmann HAK, Duncker D, Dobrev D and Linz D
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.
Author Correction: A genomic mutational constraint map using variation in 76,156 human genomes
Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, Alföldi J, Watts NA, Vittal C, Gauthier LD, Poterba T, Wilson MW, Tarasova Y, Phu W, Grant R, Yohannes MT, Koenig Z, Farjoun Y, Banks E, Donnelly S, Gabriel S, Gupta N, Ferriera S, Tolonen C, Novod S, Bergelson L, Roazen D, Ruano-Rubio V, Covarrubias M, Llanwarne C, Petrillo N, Wade G, Jeandet T, Munshi R, Tibbetts K, , O'Donnell-Luria A, Solomonson M, Seed C, Martin AR, Talkowski ME, Rehm HL, Daly MJ, Tiao G, Neale BM, MacArthur DG and Karczewski KJ
Targeting the Gut Microbiome to Treat Cardiometabolic Disease
Theofilis P, Vlachakis PK, Oikonomou E, Tsioufis K and Tousoulis D
Cardiometabolic diseases, which include obesity, type 2 diabetes, and cardiovascular diseases, constitute a worldwide health crisis of unparalleled proportions. The human gut microbiota has emerged as a prominent topic of inquiry in the search for novel treatment techniques. This review summarizes current research on the potential of addressing the gut microbiota to treat cardiometabolic disease.
Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease
Raghavan A, Pirruccello JP, Ellinor PT and Lindsay ME
Aortic disease, including dissection, aneurysm, and rupture, carries significant morbidity and mortality and is a notable cause of sudden cardiac death. Much of our knowledge regarding the genetic basis of aortic disease has relied on the study of individuals with Mendelian aortopathies and, until recently, the genetic determinants of population-level variance in aortic phenotypes remained unclear. However, the application of machine learning methodologies to large imaging datasets has enabled researchers to rapidly define aortic traits and mine dozens of novel genetic associations for phenotypes such as aortic diameter and distensibility. In this review, we highlight the emerging potential of genomics for identifying causal genes and candidate drug targets for aortic disease. We describe how deep learning technologies have accelerated the pace of genetic discovery in this field. We then provide a blueprint for translating genetic associations to biological insights, reviewing techniques for locus and cell type prioritization, high-throughput functional screening, and disease modeling using cellular and animal models of aortic disease.
Practical approach for atrial cardiomyopathy characterization in patients with atrial fibrillation
La Rosa G, Morillo CA, Quintanilla JG, Doltra A, Mont L, Rodríguez-Mañero M, Sarkozy A, Merino JL, Vivas D, Datino T, Calvo D, Pérez-Castellano N, Pérez-Villacastín J, Fauchier L, Lip G, Hatem SN, Jalife J, Sanchis L, Marín F and Filgueiras-Rama D
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.
Interleukin-1 Blockers: A Paradigm Shift in the Treatment of Recurrent Pericarditis
Lazarou E, Koutsianas C, Theofilis P, Lazaros G, Vassilopoulos D, Vlachopoulos C, Tsioufis C, Imazio M, Brucato A and Tousoulis D
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.
In Vivo Cardiac Electrophysiology in Mice: Determination of Atrial and Ventricular Arrhythmic Substrates
Navarro-Garcia JA, Bruns F, Moore OM, Tekook MA, Dobrev D, Miyake CY and Wehrens XHT
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.
Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization
Shang R, Lee CS, Wang H, Dyer R, Noll C, Carpentier A, Sultan I, Alitalo K, Boushel R, Hussein B and Rodrigues B
The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)-mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown.
Characteristics and Attitudes of Wearable Device Users and Nonusers in a Large Health Care System
Venn RA, Khurshid S, Grayson M, Ashburner JM, Al-Alusi MA, Chang Y, Foulkes A, Ellinor PT, McManus DD, Singer DE, Atlas SJ and Lubitz SA
Consumer wearable devices with health and wellness features are increasingly common and may enhance disease detection and management. Yet studies informing relationships between wearable device use, attitudes toward device data, and comprehensive clinical profiles are lacking.
Structural Progression in Patients with Definite and Non-Definite Arrhythmogenic Right Ventricular Cardiomyopathy and Risk of Major Adverse Cardiac Events
Aljehani A, Baig S, Kew T, Kalla M, Sommerfeld LC, Murukutla VA, Fabritz L and Steeds RP
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.
Deep Learning-Based Analysis of Aortic Morphology From Three-Dimensional MRI
Guo J, Bouaou K, Houriez-Gombaud-Saintonge S, Gueda M, Gencer U, Nguyen V, Charpentier E, Soulat G, Redheuil A, Mousseaux E, Kachenoura N and Dietenbeck T
Quantification of aortic morphology plays an important role in the evaluation and follow-up assessment of patients with aortic diseases, but often requires labor-intensive and operator-dependent measurements. Automatic solutions would help enhance their quality and reproducibility.
Protein interaction networks in the vasculature prioritize genes and pathways underlying coronary artery disease
Zhu QM, Hsu YH, Lassen FH, MacDonald BT, Stead S, Malolepsza E, Kim A, Li T, Mizoguchi T, Schenone M, Guzman G, Tanenbaum B, Fornelos N, Carr SA, Gupta RM, Ellinor PT and Lage K
Population-based association studies have identified many genetic risk loci for coronary artery disease (CAD), but it is often unclear how genes within these loci are linked to CAD. Here, we perform interaction proteomics for 11 CAD-risk genes to map their protein-protein interactions (PPIs) in human vascular cells and elucidate their roles in CAD. The resulting PPI networks contain interactions that are outside of known biology in the vasculature and are enriched for genes involved in immunity-related and arterial-wall-specific mechanisms. Several PPI networks derived from smooth muscle cells are significantly enriched for genetic variants associated with CAD and related vascular phenotypes. Furthermore, the networks identify 61 genes that are found in genetic loci associated with risk of CAD, prioritizing them as the causal candidates within these loci. These findings indicate that the PPI networks we have generated are a rich resource for guiding future research into the molecular pathogenesis of CAD.
Adipocyte hypertrophy associates with postprandial fatty acid metabolism and adipose single-cell transcriptional dynamics
Ye RZ, Montastier E, Frisch F, Noll C, Allard-Chamard H, Gévry N, Tchernof A and Carpentier AC
Adipocyte hypertrophy is associated with metabolic complications independent of obesity. We aimed to determine: 1) the association between adipocyte size and postprandial fatty acid metabolism; 2) the potential mechanisms driving the obesity-independent, hypertrophy-associated dysmetabolism and at a single-cell resolution. Tracers with positron emission tomography were used to measure fatty acid metabolism in 40 men and women with normal or impaired glucose tolerance (NCT02808182), and single nuclei RNA-sequencing (snRNA-seq) to determine transcriptional dynamics of subcutaneous adipose tissue (AT) between individuals with AT hypertrophy vs. hyperplasia matched for sex, ethnicity, glucose-tolerance status, BMI, total and percent body fat, and waist circumference. Adipocyte size was associated with high postprandial total cardiac fatty acid uptake and higher visceral AT dietary fatty acid uptake, but lower lean tissue dietary fatty acid uptake. We found major shifts in cell transcriptomal dynamics with AT hypertrophy that were consistent with metabolic changes.
Per-Particle Cardiovascular Risk of Lipoprotein(a) vs Non-Lp(a) Apolipoprotein B-Containing Lipoproteins
Marston NA, Melloni GEM, Murphy SA, Morze J, Kamanu FK, Ellinor PT, Ruff CT and Sabatine MS
Publisher Correction: High resolution optical mapping of cardiac electrophysiology in pre-clinical models
O'Shea C, Winter J, Kabir SN, O'Reilly M, Wells SP, Baines O, Sommerfeld LC, Correia J, Lei M, Kirchhof P, Holmes AP, Fabritz L, Rajpoot K and Pavlovic D
The Contemporary Role of Speckle Tracking Echocardiography in Cirrhotic Cardiomyopathy
Dimitroglou Y, Aggeli C, Alexopoulou A, Tsartsalis D, Patsourakos D, Koukos M, Tousoulis D and Tsioufis K
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.
A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome
Song J, Wu J, Robichaux DJ, Li T, Wang S, Arredondo Sancristobal MJ, Dong B, Dobrev D, Karch J, Thomas SS and Li N
High-protein diets (HPDs) offer health benefits, such as weight management and improved metabolic profiles. The effects of HPD on cardiac arrhythmogenesis remain unclear. Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammasome activation. The role of the Absent-in-Melanoma 2 (AIM2) inflammasome in AF pathogenesis remains unexplored. In this study, we discovered that HPD increased susceptibility to AF. To demonstrate the involvement of AIM2 signaling in the pathogenesis of HPD-induced AF, wildtype (WT) and mice were fed normal-chow (NC) and HPD, respectively. Four weeks later, inflammasome activity was upregulated in the atria of WT-HPD mice, but not in the -HPD mice. The increased AF vulnerability in WT-HPD mice was associated with abnormal sarcoplasmic reticulum (SR) Ca-release events in atrial myocytes. HPD increased the cytoplasmic double-strand (ds) DNA level, causing AIM2 activation. Genetic inhibition of AIM2 in mice reduced susceptibility to AF, cytoplasmic dsDNA level, mitochondrial ROS production, and abnormal SR Ca-release in atrial myocytes. These data suggest that HPD creates a substrate conducive to AF development by activating the AIM2-inflammasome, which is associated with mitochondrial oxidative stress along with proarrhythmic SR Ca-release. Our data imply that targeting the AIM2 inflammasome might constitute a novel anti-AF strategy in certain patient subpopulations.
Silent Myocardial Ischemia: From Pathophysiology to Diagnosis and Treatment
Theofilis P, Antonopoulos AS, Sagris M, Papanikolaou A, Oikonomou E, Tsioufis K and Tousoulis D
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.
'Super Rehab': can we achieve coronary artery disease regression? A feasibility study protocol
Graby J, Khavandi A, Gillison F, Smith T, Murphy D, Peacock O, McLeod H, Dastidar A, Antoniades C, Thompson D and Rodrigues JCL
Patients diagnosed with coronary artery disease (CAD) are currently treated with medications and lifestyle advice to reduce the likelihood of disease progression and risk of future major adverse cardiovascular events (MACE). Where obstructive disease is diagnosed, revascularisation may be considered to treat refractory symptoms. However, many patients with coexistent cardiovascular risk factors, particularly those with metabolic syndrome (MetS), remain at heightened risk of future MACE despite current management.Cardiac rehabilitation is offered to patients post-revascularisation, however, there is no definitive evidence demonstrating its benefit in a primary prevention setting. We propose that an intensive lifestyle intervention (Super Rehab, SR) incorporating high-intensity exercise, diet and behavioural change techniques may improve symptoms, outcomes, and enable CAD regression.This study aims to examine the feasibility of delivering a multicentre randomised controlled trial (RCT) testing SR for patients with CAD, in a primary prevention setting.
Recent highlights on myocarditis and cardiomyopathies from the and
Conti N, Ammirati E, Tedeschi A and Dobrev D
Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes. Reply
Kirchhof P, Schotten U and Zapf A
Women have less progression of paroxysmal atrial fibrillation: data from the RACE V study
Mulder BA, Khalilian Ekrami N, Van De Lande ME, Nguyen BO, Weberndorfer V, Crijns HJ, Geelhoed B, Blaauw Y, Hemels ME, Tieleman RG, Scheerder CO, De Melis M, Schotten U, Linz D, Van Gelder IC and Rienstra M
Sex differences in atrial fibrillation (AF) are observed in terms of comorbidities, symptoms, therapies received, AF progression and cardiovascular complications.
Coagulation Factor Xa Has No Effects on the Expression of PAR1, PAR2, and PAR4 and No Proinflammatory Effects on HL-1 Cells
Ruf L, Bukowska A, Gardemann A and Goette A
Atrial fibrillation (AF), characterised by irregular high-frequency contractions of the atria of the heart, is of increasing clinical importance. The reasons are the increasing prevalence and thromboembolic complications caused by AF. So-called atrial remodelling is characterised, among other things, by atrial dilatation and fibrotic remodelling. As a result, AF is self-sustaining and forms a procoagulant state. But hypercoagulation not only appears to be the consequence of AF. Coagulation factors can exert influence on cells via protease-activated receptors (PAR) and thereby the procoagulation state could contribute to the development and maintenance of AF. In this work, the influence of FXa on Heart Like-1 (HL-1) cells, which are murine adult atrial cardiomyocytes (immortalized), was investigated. PAR1, PAR2, and PAR4 expression was detected. After incubations with FXa (5-50 nM; 4-24 h) or PAR1- and PAR2-agonists (20 µM; 4-24 h), no changes occurred in PAR expression or in the inflammatory signalling cascade. There were no time- or concentration-dependent changes in the phosphorylation of the MAP kinases ERK1/2 or the p65 subunit of NF-κB. In addition, there was no change in the mRNA expression of the cell adhesion molecules (ICAM-1, VCAM-1, fibronectin). Thus, FXa has no direct PAR-dependent effects on HL-1 cells. Future studies should investigate the influence of FXa on human cardiomyocytes or on other cardiac cell types like fibroblasts.
Four-dimensional flow cardiovascular magnetic resonance aortic cross-sectional pressure changes and their associations with flow patterns in health and ascending thoracic aortic aneurysm
Bouaou K, Dietenbeck T, Soulat G, Bargiotas I, Houriez-Gombaud-Saintonge S, De Cesare A, Gencer U, Giron A, Jiménez E, Messas E, Lucor D, Bollache E, Mousseaux E and Kachenoura N
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.
Contemporary Management of Risk Factors in Coronary Artery Disease (Part 2)
Tousoulis D and Theofilis P