Publications of our Scientists

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
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.
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
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.
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
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.
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.
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.
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.
Seeing Is Believing: Photon Counting Computed Tomography Clearly Images Directional Deep Brain Stimulation Lead Segments and Markers After Implantation
Manfield J, Thomas S, Bogdanovic M, Sarangmat N, Antoniades C, Green AL and FitzGerald JJ
Directional deep brain stimulation (DBS) electrodes are increasingly used, but conventional computed tomography (CT) is unable to directly image segmented contacts owing to physics-based resolution constraints. Postoperative electrode segment orientation assessment is necessary because of the possibility of significant deviation during or immediately after insertion. Photon-counting detector (PCD) CT is a relatively novel technology that enables high resolution imaging while addressing several limitations intrinsic to CT. We show how PCD CT can enable clear in vivo imaging of DBS electrodes, including segmented contacts and markers for all major lead manufacturers.
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.
Thrombosis Risk in 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 two of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with prior studies in marked disagreement about the thrombosis risk conferred by the DH genotype. Utilizing multi-dimensional data from the UK Biobank (UKB) and the 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 to wild-type individuals (OR=5.24, 95% CI: 4.01 - 6.84; P=4.8 x 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 x 10-16) after adjustment for commonly cited VTE risk factors such as body mass index, blood type, and markers of inflammation. By 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 datasets to conduct the largest study to date of 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 confers a similarly increased risk of VTE.
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.
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.
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, Jan Stenvers D, 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?
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.
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
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 IE, Panter S, Wayland L, Carpentier AC, Miao Y, Shi J, Jaruez-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 (N=27, 35±9 years, body mass index (BMI) = 26.0±5.3 kg/m) and postmenopausal (N=25, 51±8 years, BMI = 28.0±5.0 kg/m) women at room temperature (RT) and during acute cold exposure using [C]-acetate with positron emission tomography coupled with computed tomography (PET/CT). BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG). To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (N=8, 40±4 years, BMI = 28.0±7.2 kg/m) after 6 months of gonadotropin-releasing hormone agonist (GnRH) therapy to suppress ovarian hormones. At RT, there was no difference in BAT oxidative metabolism between premenopausal (0.56±0.31min) and postmenopausal women (0.63±0.28min). During cold exposure, BAT oxidative metabolism (1.28±0.85 vs. 0.91±0.63min, P=0.03) and net BAT glucose uptake (84.4±82.5 vs. 29.7±31.4 nmolgmin, P<0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent GnRH, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36±0.66min to 0.91±0.41min) to that observed in postmenopausal women (0.91±0.63min). 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.
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
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.
Thrombus aspiration in STEMI: Whom we aspire it may help?
Antonopoulos AS, Simantiris S and Tousoulis D
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).
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.
Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias
Schuermans A, Vlasschaert C, Nauffal V, Cho SMJ, Uddin MM, Nakao T, Niroula A, Klarqvist MDR, Weeks LD, Lin AE, Saadatagah S, Lannery K, Wong M, Hornsby W, Lubitz SA, Ballantyne C, Jaiswal S, Libby P, Ebert BL, Bick AG, Ellinor PT, Natarajan P and Honigberg MC
Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias.
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.
Direct Oral Anticoagulants for Stroke Prevention in Patients With Device-Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESiA Trials
McIntyre WF, Benz AP, Becher N, Healey JS, Granger CB, Rivard L, Camm AJ, Goette A, Zapf A, Alings M, Connolly SJ, Kirchhof P and Lopes RD
Device-detected atrial fibrillation (also known as subclinical atrial fibrillation or atrial high-rate episodes) is a common finding in patients with an implanted cardiac rhythm device and is associated with an increased risk of ischemic stroke. Whether oral anticoagulation is effective and safe in this patient population is unclear.
Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24 h
Becher N, Toennis T, Bertaglia E, Blomström-Lundqvist C, Brandes A, Cabanelas N, Calvert M, Camm AJ, Chlouverakis G, Dan GA, Dichtl W, Diener HC, Fierenz A, Goette A, de Groot JR, Hermans ANL, Lip GYH, Lubinski A, Marijon E, Merkely B, Mont L, Ozga AK, Rajappan K, Sarkozy A, Scherr D, Schnabel RB, Schotten U, Sehner S, Simantirakis E, Vardas P, Velchev V, Wichterle D, Zapf A and Kirchhof P
Patients with long atrial high-rate episodes (AHREs) ≥24 h and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared with no anticoagulation in these patients.
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.
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.
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.
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.
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.
Atrial fibrillation in the young: consider heritable conditions like short QT syndrome
Fabritz L and Lemoine MD
DNA-pools targeted-sequencing as a robust cost-effective method to detect rare variants: Application to dilated cardiomyopathy genetic diagnosis
Perret C, Proust C, Esslinger U, Ader F, Haas J, Pruny JF, Isnard R, Richard P, Trégouët DA, Charron P, Cambien F and Villard E
Dilated cardiomyopathy (DCM) is a heart disease characterized by left ventricular dilatation and systolic dysfunction. In 30% of cases, pathogenic variants, essentially private to each patient, are identified in at least one of almost 50 reported genes. Thus, while costly, exons capture-based Next Generation Sequencing (NGS) of a targeted gene panel appears as the best strategy to genetically diagnose DCM. Here, we report a NGS strategy applied to pools of 8 DNAs from DCM patients and validate its robustness for rare variants detection at 4-fold reduced cost. Our pipeline uses Freebayes to detect variants with the expected 1/16 allele frequency. From the whole set of detected rare variants in 96 pools we set the variants quality parameters optimizing true positives calling. When compared to simplex DNA sequencing in a shared subset of 50 DNAs, 96% of SNVs/InsDel were accurately identified in pools. Extended to the 384 DNAs included in the study, we detected 100 variants (ACMG class 4 and 5), mostly in well-known morbid gene causing DCM such as TTN, MYH7, FLNC, and TNNT2. To conclude, we report an original pool-sequencing NGS method accurately detecting rare variants. This innovative approach is cost-effective for genetic diagnostic in rare diseases.
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.
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.
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.
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 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 cardiovascular disease and heart failure. The new indications of drugs already marketed (repurposing) for the treatment of obstructive hypertrophic cardiomyopathy, hypercholesterolemia, type 2 diabetes, obesity and heart failure, 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 cardiovascular diseases.
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.
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.
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.
Multimodal characterization of dilated cardiomyopathy: Geno- And Phenotyping of PrImary Cardiomyopathy (GrAPHIC)
Keil L, Berisha F, Ritter S, Skibowski J, Subramanian H, Nikolaev VO, Kubisch C, Woitschach R, Fabritz L, Twerenbold R, Blankenberg S, Weidemann S, Zeller T, Kirchhof P, Reichart D and Magnussen C
Cardiomyopathies (CMPs) are a heterogeneous group of diseases that are defined by structural and functional abnormalities of the cardiac muscle. Dilated cardiomyopathy (DCM), the most common CMP, is defined by left ventricular dilation and impaired contractility and represents a common cause of heart failure. Different phenotypes result from various underlying genetic and acquired causes with variable effects on disease development and progression, prognosis, and response to medical treatment. Current treatment algorithms do not consider these different aetiologies, due to lack of insights into treatable drivers of cardiac failure in patients with DCM. Our study aims to precisely phenotype and genotype the various subtypes of DCM and hereby lay the foundation for individualized therapy.
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.
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.
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.
Adipose Tissue in Cardiovascular Disease: From Basic Science to Clinical Translation
Polkinghorne MD, West HW and Antoniades C
The perception of adipose tissue as a metabolically quiescent tissue, primarily responsible for lipid storage and energy balance (with some endocrine, thermogenic, and insulation functions), has changed. It is now accepted that adipose tissue is a crucial regulator of metabolic health, maintaining bidirectional communication with other organs including the cardiovascular system. Additionally, adipose tissue depots are functionally and morphologically heterogeneous, acting not only as sources of bioactive molecules that regulate the physiological functioning of the vasculature and myocardium but also as biosensors of the paracrine and endocrine signals arising from these tissues. In this way, adipose tissue undergoes phenotypic switching in response to vascular and/or myocardial signals (proinflammatory, profibrotic, prolipolytic), a process that novel imaging technologies are able to visualize and quantify with implications for clinical prognosis. Furthermore, a range of therapeutic modalities have emerged targeting adipose tissue metabolism and altering its secretome, potentially benefiting those at risk of cardiovascular 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.
Natural Language Processing for Adjudication of Heart Failure in a Multicenter Clinical Trial: A Secondary Analysis of a Randomized Clinical Trial
Cunningham JW, Singh P, Reeder C, Claggett B, Marti-Castellote PM, Lau ES, Khurshid S, Batra P, Lubitz SA, Maddah M, Philippakis A, Desai AS, Ellinor PT, Vardeny O, Solomon SD and Ho JE
The gold standard for outcome adjudication in clinical trials is medical record review by a physician clinical events committee (CEC), which requires substantial time and expertise. Automated adjudication of medical records by natural language processing (NLP) may offer a more resource-efficient alternative but this approach has not been validated in a multicenter setting.
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.
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
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.
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
The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.
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.
Photon-Counting Computed Tomography: "One-Stop Shop" For Coronary Stenosis, Inflammation And Myocardial Assessment in STEACS
Kotronias RA, Raman B, Ferreira V, Neubauer S and Antoniades C
The role of cellular senescence in profibrillatory atrial remodeling 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: 1) Evaluate AF-susceptibility and senescence-marker expression in rat models of aging and myocardial infarction (MI); 2) Study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI-rats; 3) Assess senescence markers in human atrial tissue as a function of age and the presence of AF.
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
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
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.
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 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.
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.
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.
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.
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.
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.
Inferring compound heterozygosity from large-scale exome sequencing data
Guo MH, Francioli LC, Stenton SL, Goodrich JK, Watts NA, Singer-Berk M, Groopman E, Darnowsky PW, Solomonson M, Baxter S, , Tiao G, Neale BM, Hirschhorn JN, Rehm HL, Daly MJ, O'Donnell-Luria A, Karczewski KJ, MacArthur DG and Samocha KE
Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.
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.
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.
Recent highlights on coronary artery disease from the
Tedeschi A, Ammirati E, Conti N and Dobrev D
Multi-modal characterization of the left atrium by a fully automated integration of pre-procedural cardiac imaging and electro-anatomical mapping
Hermans BJM, Bijvoet GP, Holtackers RJ, Mihl C, Luermans JGLM, Maesen B, Vernooy K, Linz D, Chaldoupi SM and Schotten U
The combination of information obtained from pre-procedural cardiac imaging and electro-anatomical mapping (EAM) can potentially help to locate new ablation targets. In this study we developed and evaluated a fully automated technique to align left atrial (LA) anatomies obtained from CT- and MRI-scans with LA anatomies obtained from EAM.
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.
Selenoprotein deficiency disorder predisposes to aortic aneurysm formation
Schoenmakers E, Marelli F, Jørgensen HF, Visser WE, Moran C, Groeneweg S, Avalos C, Jurgens SJ, Figg N, Finigan A, Wali N, Agostini M, Wardle-Jones H, Lyons G, Rusk R, Gopalan D, Twiss P, Visser JJ, Goddard M, Nashef SAM, Heijmen R, Clift P, Sinha S, Pirruccello JP, Ellinor PT, Busch-Nentwich EM, Ramirez-Solis R, Murphy MP, Persani L, Bennett M and Chatterjee K
Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.
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.
'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.
Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes. Reply
Kirchhof P, Schotten U and Zapf A
Human brown adipose tissue is not enough to combat cardiometabolic diseases
Carpentier AC and Blondin DP
Recent highlights on myocarditis and cardiomyopathies from the and
Conti N, Ammirati E, Tedeschi A and Dobrev D
Recent highlights on the prevalence and role of sleep disordered breathing in cardiovascular diseases from the
Linz D and Dobrev D
Detection of brain lesions after catheter ablation depends on imaging criteria: insights from AXAFA-AFNET 5 trial
Haeusler KG, Eichner FA, Heuschmann PU, Fiebach JB, Engelhorn T, Callans D, De Potter T, Debruyne P, Scherr D, Hindricks G, Al-Khalidi HR, Mont L, Kim WY, Piccini JP, Schotten U, Themistoclakis S, Di Biase L and Kirchhof P
Left atrial catheter ablation is well established in patients with symptomatic atrial fibrillation (AF) but associated with risk of embolism to the brain. The present analysis aims to assess the impact of diffusion-weighted imaging (DWI) slice thickness on the rate of magnetic resonance imaging (MRI)-detected ischaemic brain lesions after ablation.
Humero-femoral index and diabetes risk in the US population- a case study
Lemdjo G, Kengne AP, Nouthe B, Lucas M, Carpentier A and Ngueta G
The between-subject variability in diabetes risk persists in epidemiological studies, even after accounting for obesity. We investigated whether the humero-femoral index (HFI) was associated with prevalence of type 2 diabetes mellitus (T2DM) and assessed the incremental value of HFI as a marker of T2DM.
Repurposing catheter ablation work-up to detect expiratory airflow limitation in patients with atrial fibrillation
Hereijgers MJM, van der Velden RMJ, El Moussaoui N, Verhaert DVM, Habibi Z, Luermans J, den Uijl D, Chaldoupi SM, Vernooy K, Schotten U, Baumert M, Gietema HA, Mihl C, Koltowski L, Franssen FME, Simons SO and Linz D
In atrial fibrillation (AF) patients, presence of expiratory airflow limitation may negatively impact treatment outcomes. AF patients are not routinely screened for expiratory airflow limitation, but existing examinations can help identify at-risk individuals. We aimed to assess the diagnostic value of repurposing existing assessments from the pre-ablation work-up to identify and understand the characteristics of affected patients.
Ultrasonographic assessment and clinical outcomes after deployment of a suture-mediated femoral vascular closure device
Papoutsis D, Mourouzis K, Bozini N, Aznaouridis K, Oikonomou E, Chatzimichael K, Brountzos E, Vavuranakis M, Tsioufis C, Lekakis J, Siasos G and Tousoulis D
Data regarding changes in the arterial vascular wall after the deployment of suture-mediated vascular closure devices (VCD) at the femoral site in patients undergoing percutaneous coronary angiography (CAG) or percutaneous coronary intervention (PCI) are sparse. This study investigated the occurrence of structural vascular changes or adverse vascular complications at the access site in the short term after the deployment of a suture-mediated intravascular VCD.
MSGene: Derivation and validation of a multistate model for lifetime risk of coronary artery disease using genetic risk and the electronic health record
Urbut SM, Yeung MW, Khurshid S, Cho SMJ, Schuermans A, German J, Taraszka K, Fahed AC, Ellinor P, Trinquart L, Parmigiani G, Gusev A and Natarajan P
Currently, coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. We designed a novel and general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. MSGene supports decision making about CAD prevention related to any of these states. We analyzed longitudinal data from 480,638 UK Biobank participants and compared predicted lifetime risk with the 30-year Framingham risk score. MSGene improved 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%), with external validation. We also used MSGene to refine estimates of lifetime absolute risk reduction from statin initiation. Our findings underscore the potential public health value of our novel multistate model for accurate lifetime CAD risk estimation using clinical factors and increasingly available genetics.
Radiomics of pericardial fat: a new frontier in heart failure discrimination and prediction
Szabo L, Salih A, Pujadas ER, Bard A, McCracken C, Ardissino M, Antoniades C, Vago H, Maurovich-Horvat P, Merkely B, Neubauer S, Lekadir K, Petersen SE and Raisi-Estabragh Z
To use pericardial adipose tissue (PAT) radiomics phenotyping to differentiate existing and predict future heart failure (HF) cases in the UK Biobank.
Acute Coronary Syndromes in Women: A Narrative Review of Sex-Specific Characteristics
Theofilis P, Vlachakis PK, Mantzouranis E, Sakalidis A, Chrysohoou C, Leontsinis I, Lazaros G, Dimitriadis K, Drakopoulou M, Vordoni A, Oikonomou E, Tsioufis K and Tousoulis D
Acute coronary syndromes (ACSs) encompass a spectrum of life-threatening cardiovascular conditions, including unstable angina (UA) and myocardial infarction. While significant progress has been made in the understanding and management of ACS over the years, it has become increasingly evident that sex-based differences play a pivotal role in the pathophysiology, presentation, and outcomes of these conditions. Despite this recognition, the majority of clinical research in the field has historically focused on male populations, leading to a significant knowledge gap in understanding the unique aspects of ACS in women. This review article aims to comprehensively explore and synthesize the current body of literature concerning the sex-specific characteristics of ACS, shedding light on the epidemiology, risk factors, clinical presentation, diagnostic challenges, treatment strategies, and prognosis in women. By elucidating the distinct aspects of ACS in women, this review intends to foster greater awareness and improved clinical management, ultimately contributing to enhanced cardiovascular care for female patients.
Diabetes Mellitus in Acute Coronary Syndrome
Stampouloglou PK, Anastasiou A, Bletsa E, Lygkoni S, Chouzouri F, Xenou M, Katsarou O, Theofilis P, Zisimos K, Tousoulis D, Vavuranakis M, Siasos G and Oikonomou E
The global prevalence of diabetes mellitus (DM) has led to a pandemic, with significant microvascular and macrovascular complications including coronary artery disease (CAD), which worsen clinical outcomes and cardiovascular prognosis. Patients with both acute coronary syndrome (ACS) and DM have worse prognosis and several pathophysiologic mechanisms have been implicated including, insulin resistance, hyperglycemia, endothelial dysfunction, platelet activation and aggregations as well as plaque characteristics and extent of coronary lesions. Therefore, regarding reperfusion strategies in the more complex anatomies coronary artery bypass surgery may be the preferred therapeutic strategy over percutaneous coronary intervention while both hyperglycemia and hypoglycemia should be avoided with closed monitoring of glycemic status during the acute phase of myocardial infraction. However, the best treatment strategy remains undefined. Non-insulin therapies, due to the low risk of hypoglycemia concurrently with the multifactorial CV protective effects, may be proved to be the best treatment option in the future. Nevertheless, evidence for the beneficial effects of glucagon like peptide-1 receptor agonists, dipeptidyl-peptidase 4 inhibitors and sodium glycose cotransporter 2 inhibitors, despite accumulating, is not robust and future randomized control trials may provide more definitive data.
Transcriptional profile of the rat cardiovascular system at single cell resolution
Arduini A, Fleming SJ, Xiao L, Hall AW, Akkad AD, Chaffin M, Bendinelli KJ, Tucker NR, Papangeli I, Mantineo H, Babadi M, Stegmann CM, García-Cardeña G, Lindsay ME, Klattenhoff C and Ellinor PT
Despite the critical role of the cardiovascular system, our understanding of its cellular and transcriptional diversity remains limited. We therefore sought to characterize the cellular composition, phenotypes, molecular pathways, and communication networks between cell types at the tissue and sub-tissue level across the cardiovascular system of the healthy Wistar rat, an important model in preclinical cardiovascular research. We obtained high quality tissue samples under controlled conditions that reveal a level of cellular detail so far inaccessible in human studies.
Deep Learning-Enabled Assessment of Left Heart Structure and Function Predicts Cardiovascular Outcomes
Lau ES, Di Achille P, Kopparapu K, Andrews CT, Singh P, Reeder C, Al-Alusi M, Khurshid S, Haimovich JS, Ellinor PT, Picard MH, Batra P, Lubitz SA and Ho JE
Deep learning interpretation of echocardiographic images may facilitate automated assessment of cardiac structure and function.
Heart Failure, Female Sex, and Atrial Fibrillation Are the Main Drivers of Human Atrial Cardiomyopathy: Results From the CATCH ME Consortium
Winters J, Isaacs A, Zeemering S, Kawczynski M, Maesen B, Maessen J, Bidar E, Boukens B, Hermans B, van Hunnik A, Casadei B, Fabritz L, Chua W, Sommerfeld L, Guasch E, Mont L, Batlle M, Hatem S, Kirchhof P, Wakili R, Sinner M, Stoll M, Goette A, Verheule S and Schotten U
Atrial cardiomyopathy (atCM) is an emerging prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been quantified. This study aimed to evaluate the association between histological features of atCM and the clinical phenotype.
Treatment of calcific arterial disease via enhancement of autophagy using GSK343
Lino Cardenas CL, Jiang W, Kajuluri LP, Singh K, Ostrom K, Li R, Cherbonneau F, Boerboom S, Birchenough C, Roh K, Chou EL, Shahrooz Z, Nicholson C, Johnson AL, Lee S, Ichinose F, Bloch DB, Nigwekar S, Ellinor PT, Musolino P, Lindsay ME, Dou Z, Miller CL and Malhotra R
Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large () and small () artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.
Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies
van der Voorn SM, van Drie E, Proost V, Dimitrova K, Netherlands Acm/Pln Registry , Ernst RF, James CA, Tichnell C, Murray B, Calkins H, Saguner AM, Duru F, Ellinor PT, Bezzina CR, Jurgens SJ, van Tintelen JP and van Veen TAB
Inherited forms of arrhythmogenic and dilated cardiomyopathy (ACM and DCM) are characterized by variable disease expression and age-related penetrance. Calcium (Ca) is crucially important for proper cardiac function, and dysregulation of Ca homeostasis seems to underly cardiomyopathy etiology. A polymorphism, c.286T>G p.(Ser96Ala), in the gene encoding the histidine-rich Ca binding (HRC) protein, relevant for sarcoplasmic reticulum Ca cycling, has previously been associated with a marked increased risk of life-threatening arrhythmias among idiopathic DCM patients. Following this finding, we investigated whether p.(Ser96Ala) affects major cardiac disease manifestations in carriers of the phospholamban () c.40_42delAGA; p.(Arg14del) pathogenic variant (cohort 1); patients diagnosed with, or predisposed to, ACM (cohort 2); and DCM patients (cohort 3). We found that the allele frequency of the p.(Ser96Ala) polymorphism was similar across the general European-American population (control cohort, 40.3-42.2%) and the different cardiomyopathy cohorts (cohorts 1-3, 40.9-43.9%). Furthermore, the p.(Ser96Ala) polymorphism was not associated with life-threatening arrhythmias or heart failure-related events across various patient cohorts. We therefore conclude that there is a lack of evidence supporting the important role of the p.(Ser96Ala) polymorphism as a modifier in cardiomyopathy, refuting previous findings. Further research is required to identify bona fide genomic predictors for the stratification of cardiomyopathy patients and their risk for life-threatening outcomes.
Clinical utility of polygenic scores for cardiometabolic disease in Arabs
Shim I, Kuwahara H, Chen N, Hashem MO, AlAbdi L, Abouelhoda M, Won HH, Natarajan P, Ellinor PT, Khera AV, Gao X, Alkuraya FS and Fahed AC
Arabs account for 5% of the world population and have a high burden of cardiometabolic disease, yet clinical utility of polygenic risk prediction in Arabs remains understudied. Among 5399 Arab patients, we optimize polygenic scores for 10 cardiometabolic traits, achieving a performance that is better than published scores and on par with performance in European-ancestry individuals. Odds ratio per standard deviation (OR per SD) for a type 2 diabetes score was 1.83 (95% CI 1.74-1.92), and each SD of body mass index (BMI) score was associated with 1.18 kg/m difference in BMI. Polygenic scores associated with disease independent of conventional risk factors, and also associated with disease severity-OR per SD for coronary artery disease (CAD) was 1.78 (95% CI 1.66-1.90) for three-vessel CAD and 1.41 (95% CI 1.29-1.53) for one-vessel CAD. We propose a pragmatic framework leveraging public data as one way to advance equitable clinical implementation of polygenic scores in non-European populations.
Edoxaban in patients with non-valvular atrial fibrillation after percutaneous coronary intervention: ENCOURAGE-AF design
Baldus S, Beyer-Westendorf J, Möllmann H, Rottbauer W, Beyerlein E and Goette A
Approximately one fifth of patients diagnosed with atrial fibrillation (AF) undergo a percutaneous coronary intervention (PCI). Current guidelines recommend different combinations and durations of triple or dual antithrombotic therapy for these patients but data on the implementation of these recommendations in clinical routine are scarce. ENCOURAGE-AF is a prospective, non-interventional, non-comparative, multicentre study. Approximately 720 patients will be consecutively enrolled from 70 participating sites across Germany. Patients with non-valvular AF treated with edoxaban, who have undergone successful PCI, have no planned elective cardiac intervention during the study period, have capability, availability, and willingness for follow-up by telephone interview during the study, are aged ≥ 18 years with life expectancy ≥ 1 year, and provide written informed consent, will be included. Eligible patients will be enrolled between 4- and 72-h after completing a successful PCI. Duration of exposure to and dosing regimens of edoxaban, antiplatelet agents and other concomitant medications of interest will be monitored in line with the clinical practice. Physician- and patient-reported clinical events, adverse drug reactions, patient quality of life (EQ-5D-5L) and health resource utilisation (HRU) parameters will be evaluated at 30 days and 1-year post-PCI. The ENCOURAGE-AF non-interventional study will provide insights into the patterns of edoxaban usage in combination with antiplatelet treatment and other concomitant medications in AF patients with a successful PCI over a 1-year time period during routine clinical practice in Germany. The effectiveness and safety of edoxaban in this patient population, as well as patients' quality of life and HRU will be evaluated.Trial registration: Clinicaltrial.gov NCT04519944, registered on 20 August 2020.
Decoding Genetics, Ancestry, and Geospatial Context for Precision Health
Koyama S, Wang Y, Paruchuri K, Uddin MM, Cho SMJ, Urbut SM, Haidermota S, Hornsby WE, Green RC, Daly MJ, Neale BM, Ellinor PT, Smoller JW, Lebo MS, Karlson EW, Martin AR and Natarajan P
Mass General Brigham, an integrated healthcare system based in the Greater Boston area of Massachusetts, annually serves 1.5 million patients. We established the Mass General Brigham Biobank (MGBB), encompassing 142,238 participants, to unravel the intricate relationships among genomic profiles, environmental context, and disease manifestations within clinical practice. In this study, we highlight the impact of ancestral diversity in the MGBB by employing population genetics, geospatial assessment, and association analyses of rare and common genetic variants. The population structures captured by the genetics mirror the sequential immigration to the Greater Boston area throughout American history, highlighting communities tied to shared genetic and environmental factors. Our investigation underscores the potency of unbiased, large-scale analyses in a healthcare-affiliated biobank, elucidating the dynamic interplay across genetics, immigration, structural geospatial factors, and health outcomes in one of the earliest American sites of European colonization.
Novel Biomarkers and Their Role in the Diagnosis and Prognosis of Acute Coronary Syndrome
Katsioupa M, Kourampi I, Oikonomou E, Tsigkou V, Theofilis P, Charalambous G, Marinos G, Gialamas I, Zisimos K, Anastasiou A, Katsianos E, Kalogeras K, Katsarou O, Vavuranakis M, Siasos G and Tousoulis D
The burden of cardiovascular diseases and the critical role of acute coronary syndrome (ACS) in their progression underscore the need for effective diagnostic and prognostic tools. Biomarkers have emerged as crucial instruments for ACS diagnosis, risk stratification, and prognosis assessment. Among these, high-sensitivity troponin (hs-cTn) has revolutionized ACS diagnosis due to its superior sensitivity and negative predictive value. However, challenges regarding specificity, standardization, and interpretation persist. Beyond troponins, various biomarkers reflecting myocardial injury, neurohormonal activation, inflammation, thrombosis, and other pathways are being explored to refine ACS management. This review article comprehensively explores the landscape of clinically used biomarkers intricately involved in the pathophysiology, diagnosis, and prognosis of ACS (i.e., troponins, creatine kinase MB (CK-MB), B-type natriuretic peptides (BNP), copeptin, C-reactive protein (CRP), interleukin-6 (IL-6), d-dimers, fibrinogen), especially focusing on the prognostic role of natriuretic peptides and of inflammatory indices. Research data on novel biomarkers (i.e., endocan, galectin, soluble suppression of tumorigenicity (sST2), microRNAs (miRNAs), soluble oxidized low-density lipoprotein receptor-1 (sLOX-1), F2 isoprostanes, and growth differentiation factor 15 (GDF-15)) are further analyzed, aiming to shed light on the multiplicity of pathophysiologic mechanisms implicated in the evolution of ACS. By elucidating the complex interplay of these biomarkers in ACS pathophysiology, diagnosis, and outcomes, this review aims to enhance our understanding of the evolving trajectory and advancements in ACS management. However, further research is necessary to establish the clinical utility and integration of these biomarkers into routine practice to improve patient outcomes.
Direct Oral Anticoagulants use in Patients with Stable Coronary Artery Disease, Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention
Sagris M, Theofilis P, Papanikolaou A, Antonopoulos AS, Tsioufis C and Tousoulis D
The investigation for the optimal anticoagulation strategy for patients with stable coronary artery disease, acute coronary syndromes, and undergoing percutaneous coronary intervention constitutes a great challenge for physicians and is a field of extensive research. Although aspirin is commonly recommended as a protective measure for all patients with coronary artery disease and dual antiplatelet therapy for those undergoing procedures, such as percutaneous coronary intervention or coronary artery bypass graft surgery, the risk of recurrent cardiovascular events remains significant. In this context, the shortcomings associated with the use of vitamin K antagonists have led to the assessment of direct oral anticoagulants as promising alternatives. This review will explore and provide a comprehensive analysis of the existing data regarding the use of direct oral anticoagulants in patients with stable coronary artery disease or acute coronary syndrome, as well as their effectiveness in those undergoing percutaneous coronary intervention or coronary artery bypass graft surgery.
Cardiorenal ketone metabolism: a positron emission tomography study in healthy humans
Cuenoud B, Croteau E, St-Pierre V, Richard G, Fortier M, Vandenberghe C, Carpentier AC and Cunnane SC
Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present double tracer positron emission tomography (PET) study evaluated the organ distribution and basal kinetic rates of the radiolabeled ketone, C-acetoacetate (C-AcAc), in the heart and kidney compared to C-acetate (C-Ac), which is a well-validated metabolic radiotracer. Both tracers were highly metabolized by the left ventricle and the renal cortex. In the heart, kinetic rates were similar for both tracers. But in the renal cortex, uptake of C-Ac was higher compared to C-AcAc, while the reverse was observed for the clearance. Interestingly, infusion of C-AcAc led to a significantly delayed release of radioactivity in the renal medulla and pelvis, a phenomenon not observed with C-Ac. This suggests an equilibrium of C-AcAc with the other ketone, C-D-beta-hydroxybutyrate, and a different clearance profile. Overall, this suggests that in the kidney, the absorption and metabolism of C-AcAc is different compared to C-Ac. This dual tracer PET protocol provides the opportunity to explore the relative importance of ketone metabolism in cardiac and renal diseases, and to improve our mechanistic understanding of new metabolic interventions targeting these two organs.
In Memoriam: Denis Richard 1953-2023
Caron A, Carpentier AC, Deshaies Y, Després JP, Picard F, Rivest S and Tchernof A
Contemporary Management of Risk Factors in Coronary Artery Disease (Part 2)
Tousoulis D and Theofilis P