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151. Sexual dimorphism in selenium deficiency is associated with metabolic syndrome and prevalence of heart disease

Author: Weening, Eerde H., Al-Mubarak, Ali A., Dokter, Martin M., Dickstein, Kenneth, Lang, Chim C., Ng, Leong L., Metra, Marco, van Veldhuisen, Dirk J., Touw, Daan J., de Boer, Rudolf A., Gansevoort, Ron T., Voors, Adriaan A., Bakker, Stephan J. L., van der Meer, Peter, Bomer, Nils, Cardiovascular Centre (CVC), Pharmaceutical Analysis, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Medicinal Chemistry and Bioanalysis (MCB), Groningen Research Institute for Asthma and COPD (GRIAC), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Groningen Kidney Center (GKC), Faculteit Medische Wetenschappen/UMCG, Groningen Institute for Organ Transplantation (GIOT), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
Subjects: Selenium, Sexual dimorphism, Interaction, Endocrinology, Diabetes and Metabolism, Heart failure, Metabolic syndrome, Cardiology and Cardiovascular Medicine
Abstract: Background Serum selenium levels have been associated with the incidence of heart failure (HF) and signs of the metabolic syndrome. In addition, notable differences have been reported between males and females in food intake and micronutrient metabolism, possibly explaining different health outcomes. Objective Our objective was to elucidate sex-specific, cross-sectional phenotypic differences in the association of serum selenium concentrations with parameters of metabolic syndrome and HF. Methods We investigated data from individuals from a community-based cohort (PREVEND; N = 4288) and heart failure cohort (BIOSTAT-CHF; N = 1994). In both populations, cross-sectional analyses were performed for potential interaction (p Results Baseline selenium levels of the total cohort were similar between PREVEND (85.7 μg/L) and BIOSTAT-CHF (89.1 μg/L). Females with lower selenium levels had a higher BMI and increased prevalence of diabetes than females with higher selenium, in both PREVEND (pinteraction interaction = 0.040, resp.) and BIOSTAT-CHF (pinteraction = 0.021; pinteraction = 0.024, resp.), while opposite associations were observed for males. Additionally, in females, but not in males, lower selenium was associated with a higher prevalence of myocardial infarction (MI) in PREVEND (pinteraction = 0.021) and BIOSTAT-CHF (pinteraction = 0.084). Conclusion Lower selenium was associated with a higher BMI and increased prevalence of diabetes in females, opposite to males, and was also associated with more MI in females. Interventional studies are needed to validate this observation.
Published: 2023

152. Multiple Prior Live Births Are Associated With Cardiac Remodeling and Heart Failure Risk in Women

Author: AMY A. Sarma, SAMANTHA M. PANIAGUA, EMILY S. LAU, DONGYU WANG, ELIZABETH E. LIU, MARTIN G. LARSON, NAOMI M. HAMBURG, GARY F. MITCHELL, JORGE KIZER, BRUCE M. PSATY, NORRINA B. ALLEN, A. TITIA LELY, RONALD T. GANSEVOORT, EMILY ROSENBERG, KENNETH MUKAMAL, EMELIA J. BENJAMIN, RAMACHANDRAN S. VASAN, SUSAN CHENG, DANIEL LEVY, RUDOLF A. DE BOER, JOHN S. GOTTDIENER, SANJIV J. SHAH, JENNIFER E. HO, Groningen Kidney Center (GKC), and Cardiovascular Centre (CVC)
Subjects: Pregnancy, echocardiography, heart failure, Cardiology and Cardiovascular Medicine
Abstract: Objective: Greater parity has been associated with cardiovascular disease risk. We sought to find whether the effects on cardiac remodeling and heart failure risk are clear.Methods: We examined the association of number of live births with echocardiographic measures of cardiac structure and function in participants of the Framingham Heart Study (FHS) using multivariable linear regression. We next examined the association of parity with incident heart failure with preserved (HFpEF) or reduced (HFrEF) ejection fraction using a Fine-Gray subdistribution hazards model in a pooled analysis of n = 12,635 participants in the FHS, the Cardiovascular Health Study, the Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular Endstage Disease. Secondary analyses included major cardiovascular disease, myocardia infarction and stroke.Results: Among n = 3931 FHS participants (mean age 48 ± 13 years), higher numbers of live births were associated with worse left ventricular fractional shortening (multivariable β -1.11 (0.31); P = 0.0005 in ≥ 5 live births vs nulliparous women) and worse cardiac mechanics, including global circumferential strain and longitudinal and radial dyssynchrony (P < 0.01 for all comparing ≥ 5 live births vs nulliparity). When examining HF subtypes, women with ≥ 5 live births were at higher risk of developing future HFrEF compared with nulliparous women (HR 1.93, 95% CI 1.19–3.12; P = 0.008); by contrast, a lower risk of HFpEF was observed (HR 0.58, 95% CI 0.37–0.91; P = 0.02).Conclusions: Greater numbers of live births are associated with worse cardiac structure and function. There was no association with overall HF, but a higher number of live births was associated with greater risk for incident HFrEF.
Published: 2023
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153. Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant

Author: Edgar T. Hoorntje, Charlotte Burns, Luisa Marsili, Ben Corden, Victoria N. Parikh, Gerard J. te Meerman, Belinda Gray, Ahmet Adiyaman, Richard D. Bagnall, Daniela Q.C.M. Barge-Schaapveld, Maarten P. van den Berg, Marianne Bootsma, Laurens P. Bosman, Gemma Correnti, Johan Duflou, Ruben N. Eppinga, Diane Fatkin, Michael Fietz, Eric Haan, Jan D.H. Jongbloed, Arnaud D. Hauer, Lien Lam, Freyja H.M. van Lint, Amrit Lota, Carlo Marcelis, Hugh J. McCarthy, Anneke M. van Mil, Rogier A. Oldenburg, Nicholas Pachter, R. Nils Planken, Chloe Reuter, Christopher Semsarian, Jasper J. van der Smagt, Tina Thompson, Jitendra Vohra, Paul G.A. Volders, Jaap I. van Waning, Nicola Whiffin, Arthur van den Wijngaard, Ahmad S. Amin, Arthur A.M. Wilde, Gijs van Woerden, Laura Yeates, Dominica Zentner, Euan A. Ashley, Matthew T. Wheeler, James S. Ware, J. Peter van Tintelen, Jodie Ingles, Cardiovascular Centre (CVC), Human Genetics, Graduate School, ACS - Heart failure & arrhythmias, AII - Cancer immunology, Amsterdam Reproduction & Development (AR&D), Radiology and Nuclear Medicine, ACS - Pulmonary hypertension & thrombosis, ACS - Atherosclerosis & ischemic syndromes, Cardiology, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, and Clinical Genetics
Subjects: cardiomyopathies, All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], sudden cardiac, death, death, sudden cardiac, primary, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], General Medicine, desmoplakins, genetic testing
Abstract: Background: Truncating variants in desmoplakin ( DSP tv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSP tv cardiomyopathy. Methods: Individuals with DSP tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSP tv performed. Results: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSP tv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSP tv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P Conclusions: In the largest series of individuals with DSP tv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.
Published: 2023

154. Hot spot imaging in cardiovascular diseases: an information statement from SNMMI, ASNC, and EANM

Author: Brett W. Sperry, Timothy M. Bateman, Esma A. Akin, Paco E. Bravo, Wengen Chen, Vasken Dilsizian, Fabien Hyafil, Yiu Ming Khor, Robert J.H. Miller, Riemer H.J.A. Slart, Piotr Slomka, Hein Verberne, Edward J. Miller, Chi Liu, Cardiovascular Centre (CVC), Translational Immunology Groningen (TRIGR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Radiology and Nuclear Medicine, and ACS - Amsterdam Cardiovascular Sciences
Subjects: modalities, STANDARDIZED UPTAKE VALUE, diseases/processes, MYOCARDIAL-PERFUSION, processes, Basic science, LOW-CARBOHYDRATE-DIET, 18F-SODIUM FLUORIDE UPTAKE, FDG-PET/CT, diseases, POSITRON-EMISSION-TOMOGRAPHY, GIANT-CELL ARTERITIS, HIGH-FAT, Radiology, Nuclear Medicine and imaging, F-18-FDG PET, Cardiology and Cardiovascular Medicine, CORONARY CT ANGIOGRAPHY
Abstract: This information statement from the Society of Nuclear Medicine and Molecular Imaging, American Society of Nuclear Cardiology, and European Association of Nuclear Medicine describes the performance, interpretation, and reporting of hot spot imaging in nuclear cardiology. The field of nuclear cardiology has historically focused on cold spot imaging for the interpretation of myocardial ischemia and infarction. Hot spot imaging has been an important part of nuclear medicine, particularly for oncology or infection indications, and the use of hot spot imaging in nuclear cardiology continues to expand. This document focuses on image acquisition and processing, methods of quantification, indications, protocols, and reporting of hot spot imaging. Indications discussed include myocardial viability, myocardial inflammation, device or valve infection, large vessel vasculitis, valve calcification and vulnerable plaques, and cardiac amyloidosis. This document contextualizes the foundations of image quantification and highlights reporting in each indication for the cardiac nuclear imager.
Published: 2023

155. Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

Author: William J. Young, Jeffrey Haessler, Jan-Walter Benjamins, Linda Repetto, Jie Yao, Aaron Isaacs, Andrew R. Harper, Julia Ramirez, Sophie Garnier, Stefan van Duijvenboden, Antoine R. Baldassari, Maria Pina Concas, ThuyVy Duong, Luisa Foco, Jonas L. Isaksen, Hao Mei, Raymond Noordam, Casia Nursyifa, Anne Richmond, Meddly L. Santolalla, Colleen M. Sitlani, Negin Soroush, Sébastien Thériault, Stella Trompet, Stefanie Aeschbacher, Fariba Ahmadizar, Alvaro Alonso, Jennifer A. Brody, Archie Campbell, Adolfo Correa, Dawood Darbar, Antonio De Luca, Jean-François Deleuze, Christina Ellervik, Christian Fuchsberger, Anuj Goel, Christopher Grace, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Rebecca D. Jackson, Jan A. Kors, Maria Fernanda Lima-Costa, Allan Linneberg, Peter W. Macfarlane, Alanna C. Morrison, Pau Navarro, David J. Porteous, Peter P. Pramstaller, Alexander P. Reiner, Lorenz Risch, Ulrich Schotten, Xia Shen, Gianfranco Sinagra, Elsayed Z. Soliman, Monika Stoll, Eduardo Tarazona-Santos, Andrew Tinker, Katerina Trajanoska, Eric Villard, Helen R. Warren, Eric A. Whitsel, Kerri L. Wiggins, Dan E. Arking, Christy L. Avery, David Conen, Giorgia Girotto, Niels Grarup, Caroline Hayward, J.Wouter Jukema, Dennis O. Mook-Kanamori, Morten Salling Olesen, Sandosh Padmanabhan, Bruce M. Psaty, Cristian Pattaro, Antonio Luiz P. Ribeiro, Jerome I. Rotter, Bruno H. Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James G. Wilson, Michele Orini, Philippe Charron, Hugh Watkins, Charles Kooperberg, Henry J. Lin, James F. Wilson, Jørgen K. Kanters, Nona Sotoodehnia, Borbala Mifsud, Pier D. Lambiase, Larisa G. Tereshchenko, Patricia B. Munroe, Epidemiology, Department of Finance, Medical Informatics, Internal Medicine, Erasmus MC other, Cardiovascular Centre (CVC), Young, William J, Haessler, Jeffrey, Benjamins, Jan-Walter, Repetto, Linda, Yao, Jie, Isaacs, Aaron, Harper, Andrew R, Ramirez, Julia, Garnier, Sophie, van Duijvenboden, Stefan, Baldassari, Antoine R, Concas, Maria Pina, Duong, Thuyvy, Foco, Luisa, Isaksen, Jonas L, Mei, Hao, Noordam, Raymond, Nursyifa, Casia, Richmond, Anne, Santolalla, Meddly L, Sitlani, Colleen M, Soroush, Negin, Thériault, Sébastien, Trompet, Stella, Aeschbacher, Stefanie, Ahmadizar, Fariba, Alonso, Alvaro, Brody, Jennifer A, Campbell, Archie, Correa, Adolfo, Darbar, Dawood, De Luca, Antonio, Deleuze, Jean-Françoi, Ellervik, Christina, Fuchsberger, Christian, Goel, Anuj, Grace, Christopher, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R, Jackson, Rebecca D, Kors, Jan A, Lima-Costa, Maria Fernanda, Linneberg, Allan, Macfarlane, Peter W, Morrison, Alanna C, Navarro, Pau, Porteous, David J, Pramstaller, Peter P, Reiner, Alexander P, Risch, Lorenz, Schotten, Ulrich, Shen, Xia, Sinagra, Gianfranco, Soliman, Elsayed Z, Stoll, Monika, Tarazona-Santos, Eduardo, Tinker, Andrew, Trajanoska, Katerina, Villard, Eric, Warren, Helen R, Whitsel, Eric A, Wiggins, Kerri L, Arking, Dan E, Avery, Christy L, Conen, David, Girotto, Giorgia, Grarup, Niel, Hayward, Caroline, Jukema, J Wouter, Mook-Kanamori, Dennis O, Olesen, Morten Salling, Padmanabhan, Sandosh, Psaty, Bruce M, Pattaro, Cristian, Ribeiro, Antonio Luiz P, Rotter, Jerome I, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Verweij, Niek, Wilson, James G, Orini, Michele, Charron, Philippe, Watkins, Hugh, Kooperberg, Charle, Lin, Henry J, Wilson, James F, Kanters, Jørgen K, Sotoodehnia, Nona, Mifsud, Borbala, Lambiase, Pier D, Tereshchenko, Larisa G, and Munroe, Patricia B
Subjects: Electrocardiography/methods, General Physics and Astronomy, 610 Medicine & health, Arrhythmias, Cardiovascular, General Biochemistry, Genetics and Molecular Biology, cardiac arrhythmia, Electrocardiography, SDG 3 - Good Health and Well-being, Risk Factors, Cardiovascular Diseases/genetics, Genetics, Humans, Arrhythmias, Cardiac/genetics, Atrioventricular Block, Multidisciplinary, Human Genome, General Chemistry, Heart Disease, Cardiovascular Diseases, Cardiac, Biomarkers, Genome-Wide Association Study
Abstract: The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.
Published: 2023
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156. Impact of immunosuppressive treatment and type of SARS-CoV-2 vaccine on antibody levels after three vaccinations in patients with chronic kidney disease or kidney replacement therapy

Author: Bouwmans, Pim, Messchendorp, A Lianne, Imhof, Céline, Sanders, Jan-Stephan F, Hilbrands, Luuk B, Reinders, Marlies E J, Vart, Priya, Bemelman, Frederike J, Abrahams, Alferso C, van den Dorpel, René M A, Ten Dam, Marc A G J, de Vries, Aiko P J, Rispens, Theo, Steenhuis, Maurice, Gansevoort, Ron T, Hemmelder, Marc H, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interne Geneeskunde, RS: Carim - V02 Hypertension and target organ damage, and MUMC+: MA Nefrologie (9)
Subjects: Transplantation, All institutes and research themes of the Radboud University Medical Center, Nephrology, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11]
Abstract: BackgroundPatients with chronic kidney disease (CKD) or kidney replacement therapy demonstrate lower antibody levels after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination compared with healthy controls. In a prospective cohort, we analysed the impact of immunosuppressive treatment and type of vaccine on antibody levels after three SARS-CoV-2 vaccinations.MethodsControl subjects (n = 186), patients with CKD G4/5 (n = 400), dialysis patients (n = 480) and kidney transplant recipients (KTR) (n = 2468) were vaccinated with either mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech) or AZD1222 (Oxford/AstraZeneca) in the Dutch SARS-CoV-2 vaccination programme. Third vaccination data were available in a subgroup of patients (n = 1829). Blood samples and questionnaires were obtained 1 month after the second and third vaccination. Primary endpoint was the antibody level in relation to immunosuppressive treatment and type of vaccine. Secondary endpoint was occurrence of adverse events after vaccination.ResultsAntibody levels after two and three vaccinations were lower in patients with CKD G4/5 and dialysis patients with immunosuppressive treatment compared with patients without immunosuppressive treatment. After two vaccinations, we observed lower antibody levels in KTR using mycophenolate mofetil (MMF) compared with KTR not using MMF [20 binding antibody unit (BAU)/mL (3–113) vs 340 BAU/mL (50–1492), P ConclusionsImmunosuppressive treatment adversely affects the antibody levels after SARS-CoV-2 vaccination in patients with CKD G4/5, dialysis patients and KTR. mRNA-1273 vaccine induces a higher antibody level and higher frequency of adverse events.
Published: 2023

157. Peroxisome proliferator-activated receptor ɣ agonist mediated inhibition of heparanase expression reduces proteinuria

Author: Marjolein Garsen, Baranca Buijsers, Marloes Sol, Lena Gockeln, Ramon Sonneveld, Toin H. van Kuppevelt, Mark de Graaf, Jacob van den Born, Jan A.A.M. Kamps, Daniël H. van Raalte, Rutger W. van der Meer, Hildo J. Lamb, Jan-Luuk Hillebrands, Ton J. Rabelink, Marissa L. Maciej-Hulme, Guido Krenning, Tom Nijenhuis, Johan van der Vlag, Internal medicine, ACS - Diabetes & metabolism, Amsterdam Gastroenterology Endocrinology Metabolism, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Nanotechnology and Biophysics in Medicine (NANOBIOMED), and Cardiovascular Centre (CVC)
Subjects: Proteinuria, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Podocytes, Glomerular endothelial cells, Thiazolidinediones, General Medicine, Peroxisome proliferator-activated receptor ɣ, Heparanase, General Biochemistry, Genetics and Molecular Biology
Abstract: BACKGROUND: Proteinuria is associated with many glomerular diseases and a risk factor for the progression to renal failure. We previously showed that heparanase (HPSE) is essential for the development of proteinuria, whereas peroxisome proliferator-activated receptor ɣ (PPARɣ) agonists can ameliorate proteinuria. Since a recent study showed that PPARɣ regulates HPSE expression in liver cancer cells, we hypothesized that PPARɣ agonists exert their reno-protective effect by inhibiting glomerular HPSE expression.METHODS: Regulation of HPSE by PPARɣ was assessed in the adriamycin nephropathy rat model, and cultured glomerular endothelial cells and podocytes. Analyses included immunofluorescence staining, real-time PCR, heparanase activity assay and transendothelial albumin passage assay. Direct binding of PPARɣ to the HPSE promoter was evaluated by the luciferase reporter assay and chromatin immunoprecipitation assay. Furthermore, HPSE activity was assessed in 38 type 2 diabetes mellitus (T2DM) patients before and after 16/24 weeks treatment with the PPARɣ agonist pioglitazone.FINDINGS: Adriamycin-exposed rats developed proteinuria, an increased cortical HPSE and decreased heparan sulfate (HS) expression, which was ameliorated by treatment with pioglitazone. In line, the PPARɣ antagonist GW9662 increased cortical HPSE and decreased HS expression, accompanied with proteinuria in healthy rats, as previously shown. In vitro, GW9662 induced HPSE expression in both endothelial cells and podocytes, and increased transendothelial albumin passage in a HPSE-dependent manner. Pioglitazone normalized HPSE expression in adriamycin-injured human endothelial cells and mouse podocytes, and adriamycin-induced transendothelial albumin passage was reduced as well. Importantly, we demonstrated a regulatory effect of PPARɣ on HPSE promoter activity and direct PPARy binding to the HPSE promoter region. Plasma HPSE activity of T2DM patients treated with pioglitazone for 16/24 weeks was related to their hemoglobin A1c and showed a moderate, near significant correlation with plasma creatinine levels.INTERPRETATION: PPARɣ-mediated regulation of HPSE expression appears an additional mechanism explaining the anti-proteinuric and renoprotective effects of thiazolidinediones in clinical practice.FUNDING: This study was financially supported by the Dutch Kidney Foundation, by grants 15OI36, 13OKS023 and 15OP13. Consortium grant LSHM16058-SGF (GLYCOTREAT; a collaboration project financed by the PPP allowance made available by Top Sector Life Sciences & Health to the Dutch Kidney Foundation to stimulate public-private partnerships).
Published: 2023
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158. Albuminuria as a marker of systemic congestion in patients with heart failure

Author: Eva M Boorsma, Jozine M ter Maaten, Kevin Damman, Bart J van Essen, Faiez Zannad, Dirk J van Veldhuisen, Nilesh J Samani, Kenneth Dickstein, Marco Metra, Gerasimos Filippatos, Chim C Lang, Leong Ng, Stefan D Anker, John G Cleland, Pierpaolo Pellicori, Ron T Gansevoort, Hiddo J L Heerspink, Adriaan A Voors, Johanna E Emmens, BOZEC, Erwan, University Medical Center Groningen [Groningen] (UMCG), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Department of Cardiovascular Sciences [Leicester], University of Leicester, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Stavanger University Hospital, Università degli Studi di Brescia = University of Brescia (UniBs), National and Kapodistrian University of Athens (NKUA), University of Athens, Attikon Hospital, University of Dundee, Ninewells Hospital and Medical School [Dundee], Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
Subjects: EXCRETION, SICKLE-CELL-DISEASE, MODELS, PROTEINURIA, PRESSURE, DIAGNOSIS, EJECTION FRACTION, PREVALENCE, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, PULMONARY-HYPERTENSION, Central venous pressure, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, HOSPITALIZATION, Cardiorenal interaction, Congestion, Albuminuria, Biomarkers, Cardiology and Cardiovascular Medicine
Abstract: Aims Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is still incompletely understood. The association of clinical characteristics and biomarker profile with albuminuria in patients with heart failure with both reduced and preserved ejection fractions were evaluated. Methods and results Two thousand three hundred and fifteen patients included in the index cohort of BIOSTAT-CHF were evaluated and findings were validated in the independent BIOSTAT-CHF validation cohort (1431 patients). Micro-albuminuria and macro-albuminuria were defined as urinary albumin–creatinine ratio (UACR) >30 mg/gCr and >300 mg/gCr in spot urines, respectively. The prevalence of micro- and macro-albuminuria was 35.4% and 10.0%, respectively. Patients with albuminuria had more severe heart failure, as indicated by inclusion during admission, higher New York Heart Association functional class, more clinical signs and symptoms of congestion, and higher concentrations of biomarkers related to congestion, such as biologically active adrenomedullin, cancer antigen 125, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (all P < 0.001). The presence of albuminuria was associated with increased risk of mortality and heart failure (re)hospitalization in both cohorts. The strongest independent association with log UACR was found for log NT-proBNP (standardized regression coefficient 0.438, 95% confidence interval 0.35–0.53, P < 0.001). Hierarchical clustering analysis demonstrated that UACR clusters with markers of congestion and less with indices of renal function. The validation cohort yielded similar findings. Conclusion In patients with new-onset or worsening heart failure, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion.
Published: 2023
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159. The Netherlands Heart Tissue Bank Strengthening the cardiovascular research infrastructure with an open access Cardiac Tissue Repository: Strengthening the cardiovascular research infrastructure with an open access Cardiac Tissue Repository

Author: Henkens, M. T. H. M., van Ast, J. F., te Riele, A. S. J. M., Houweling, A. C., Amin, A. S., Nijveldt, R., Antoni, M. L., Li, X., Wehrens, S. M. T., von der Thusen, J. H., Damman, K., ter Horst, E. N., Manintveld, O. C., Abma-Schouten, R. Y., Niessen, H. W. M., Sillje, H. H. W., Jukema, J. W., Doevendans, P. A., and Cardiovascular Centre (CVC)
Subjects: Biological specimen banks, Heart diseases, Tissue banks, Registries, Translational research
Abstract: Aim Cardiac diseases remain a leading cause of cardiovascular disease (CVD) related hospitalisation and mortality. That is why research to improve our understanding of pathophysiological processes underlying cardiac diseases is of great importance. There is a strong need for healthy and diseased human cardiac tissue and related clinical data to accomplish this, since currently used animal and in vitro disease models do not fully grasp the pathophysiological processes observed in humans. This design paper describes the initiative of the Netherlands Heart Tissue Bank (NHTB) that aims to boost CVD-related research by providing an open-access biobank. Methods The NHTB, founded in June 2020, is a non-profit biobank that collects and stores biomaterial (including but not limited to myocardial tissue and blood samples) and clinical data of individuals with and without previously known cardiac diseases. All individuals aged >= 18 years living in the Netherlands are eligible for inclusion as a potential future donor. The stored samples and clinical data will be available upon request for cardiovascular researchers. Conclusion To improve the availability of cardiac tissue for cardiovascular research, the NHTB will include extensive (cardiac) biosamples, medical images, and clinical data of donors with and without a previously known cardiac disease. As such, the NHTB will function as a translational bridge to boost a wide range of cardiac disease-related fundamental and translational studies.
Published: 2023

160. Comorbidities complicating heart failure: changes over the last 15 years

Author: Elles M. Screever, Martje H. L. van der Wal, Dirk J. van Veldhuisen, Tiny Jaarsma, Astrid Koops, Kuna S. van Dijk, Janke Warink-Riemersma, Jenifer E. Coster, B. Daan Westenbrink, Peter van der Meer, Rudolf A. de Boer, Wouter C. Meijers, Cardiovascular Centre (CVC), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
Subjects: Hospitalization, Comorbidities, Heart failure, Mortality, Obesity, Clinical Trials as Topic, Kardiologi, Heart Failure/therapy, Humans, Cardiac and Cardiovascular Systems, Stroke Volume, General Medicine, Comorbidity, Cardiology and Cardiovascular Medicine, Prognosis
Abstract: Aims Management of comorbidities represents a critical step in optimal treatment of heart failure (HF) patients. However, minimal attention has been paid whether comorbidity burden and their prognostic value changes over time. Therefore, we examined the association between comorbidities and clinical outcomes in HF patients between 2002 and 2017. Methods and results The 2002-HF cohort consisted of patients from The Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) trial (n = 1,032). The 2017-HF cohort were outpatient HF patients enrolled after hospitalization for HF in a tertiary referral academic hospital (n = 382). Kaplan meier and cox regression analyses were used to assess the association of comorbidities with HF hospitalization and all-cause mortality. Patients from the 2017-cohort were more likely to be classified as HF with preserved ejection fraction (24 vs 15%, p p for interaction 0.026). Conclusion Despite major advances in HF treatment over the past decades, comorbidity burden remains high in HF and influences outcome to a large extent. Obesity emerges as a prominent comorbidity, and efforts should be made for prevention and treatment. Graphical abstract Created with BioRender.com.
Published: 2023

161. Clonal haematopoiesis of indeterminate potential: associations with heart failure incidence, clinical parameters and biomarkers

Author: Canxia Shi, Joseph Pierre Aboumsallem, Navin Suthahar, Aniek O. de Graaf, Joop H. Jansen, Isabelle A. van Zeventer, Valentina Bracun, Sanne de Wit, Elles M. Screever, Pieter F. van den Berg, Wouter C. Meijers, Ron T. Gansevoort, Stephan J.L. Bakker, Pim van der Harst, Herman H.W. Silljé, Gerwin Huls, Rudolf A. de Boer, Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Stem Cell Aging Leukemia and Lymphoma (SALL), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Cardiology
Subjects: All institutes and research themes of the Radboud University Medical Center, Risk factors, CHIP, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Heart failure, Clonal haematopoiesis, Cardiology and Cardiovascular Medicine, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Biomarkers
Abstract: Contains fulltext : 291058.pdf (Publisher’s version ) (Open Access) AIM: We aimed to analyse the association of clonal haematopoiesis of indeterminate potential (CHIP) with incident heart failure (HF) in a European population cohort. METHODS AND RESULTS: From the prospective Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort, we included all 374 participants with incident HF and selected 1:1 age- and sex-matched control subjects. Peripheral blood samples of 705 individuals were successfully analysed by error-corrected next generation sequencing for acquired mutations at a variant allele frequency ≥2% in 27 CHIP driver genes. The median age of the study population was 65 years (interquartile range 58-70) and 35.6% were female. CHIP mutations positively correlated with age, smoking, hypertension and cardiovascular biomarkers including N-terminal pro-B-type natriuretic peptide and mid-regional pro-A-type natriuretic peptide, but the frequency of CHIP was comparable in individuals with incident HF and in control participants (18.4% vs. 17.3%; p = 0.69). In multivariable Cox regression models, CHIP was not significantly associated with incident HF (hazard ratio [HR] 1.24, 95% confidence interval [CI] 0.93-1.65; p = 0.144). This association, however, was modified by age (p for CHIP-age interaction = 0.002). Among people younger than 65 years, CHIP mutations were more frequently detected in the case cohort compared to the control cohort (14.2% vs. 5.8%; p = 0.009), and were significantly associated with new-onset HF (HR 2.07, 95% CI 1.30-3.29; p = 0.002). CONCLUSION: Clonal haematopoiesis of indeterminate potential correlates with HF risk factors and biomarkers, and is associated with incident HF in subjects
Published: 2023
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162. SEPT-GD: A decision tree to prioritise potential RNA splice variants in cardiomyopathy genes for functional splicing assays in diagnostics

Author: Mohamed Z. Alimohamed, Ludolf G. Boven, Krista K. van Dijk, Yvonne J. Vos, Yvonne M. Hoedemaekers, Paul A. van der Zwaag, Rolf H. Sijmons, Jan D.H. Jongbloed, Birgit Sikkema-Raddatz, Helga Westers, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Cardiovascular Centre (CVC)
Subjects: All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], RNA Splicing, Decision Trees, Genetics, Humans, Genetic Variation, RNA Splice Sites, General Medicine, Cardiomyopathies
Abstract: Background: Splice prediction algorithms currently used in routine DNA diagnostics have limited sensitivity and specificity, therefore many potential splice variants are classified as variants of uncertain significance (VUSs). However, functional assessment of VUSs to test splicing is labour-intensive and time-consuming. We developed a decision tree to prioritise potential splice variants for functional studies and functionally verified the outcome of the decision tree. Materials and methods: We built the decision tree, SEPT–GD, by setting thresholds for the splice prediction programs implemented in Alamut. A set of 343 variants with known effects on splicing was used as control for sensitivity and specificity. We tested SEPT–GD using variants from a Dutch cardiomyopathy cohort of 2002 patients that were previously classified as VUS and predicted to have a splice effect according to diagnostic rules. We then selected 12 VUSs ranked by SEPT–GD to functionally verify the predicted effect on splicing using a minigene assay: 10 variants predicted to have a strong effect and 2 with a weak effect. RT-PCR was performed for nine variants. Variant classification was re-evaluated based on the functional test outcome. Results: Compared to similar individually tested algorithms, SEPT–GD shows higher sensitivity (91 %) and comparable specificity (88 %) for both consensus (dinucleotides at the start and end of the intron, GT at the 5′ end and AG at the 3′ end) and non-consensus splice-site variants (excluding middle of exon variants). Using clinical diagnostic criteria, 1295 unique variants in our cardiomyopathy cohort had originally been classified as VUSs, with 57 predicted by Alamut to have an effect on splicing. Using SEPT–GD, we prioritised 31 variants in 40 patients. In the minigene assay, all 12 variants showed results concordant with SEPT-GD predictions. RT-PCR confirmed the minigene results for two variants, TMEM43 c.1000 + 5G > T and TTN c.25922–6 T > G. Based on all outcomes, the SGCD c.4-1G > A and CSRP3 c.282-5_285del variants were reclassified as likely pathogenic. Conclusion: SEPT–GD outperforms the tools commonly used for RNA splicing prediction and improves prioritisation of variants in cardiomyopathy genes for functional splicing analysis in a diagnostic setting.
Published: 2023

163. Proton Pump Inhibitor Use, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients: Results From the TransplantLines Biobank and Cohort Study

Author: Tim J. Knobbe, Daan Kremer, Rianne M. Douwes, Michele F. Eisenga, António W. Gomes-Neto, Coby Annema, J. Casper Swarte, Frank Klont, Gerjan Navis, Stefan P. Berger, Stephan J.L. Bakker, Hans Blokzijl, Frank A.J.A. Bodewes, Marieke T. de Boer, Kevin Damman, Martin H. de Borst, Arjan Diepstra, Gerard Dijkstra, Caecilia S.E. Doorenbos, Michiel E. Erasmus, C. Tji Gan, Eelko Hak, Bouke G. Hepkema, Henri G.D. Leuvenink, Willem S. Lexmond, Vincent E. de Meijer, Hubert G.M. Niesters, L. Joost van Pelt, Robert A. Pol, Robert J. Porte, Adelta V. Ranchor, Jan Stephan F. Sanders, Marion J. Siebelink, Riemer J.H.J.A. Slart, Daan J. Touw, Marius C. van den Heuvel, Coretta van Leer-Buter, Marco van Londen, Erik A.M. Verschuuren, Michel J. Vos, Rinse K. Weersma, Faculteit Medische Wetenschappen/UMCG, Department of Health and Life Sciences, University of Groningen, PharmacoTherapy, -Epidemiology and -Economics, Value, Affordability and Sustainability (VALUE), Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Cardiovascular Centre (CVC), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Microbes in Health and Disease (MHD), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Pharmaceutical Analysis, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Groningen Research Institute for Asthma and COPD (GRIAC), and Medicinal Chemistry and Bioanalysis (MCB)
Subjects: side effects, quality of life, Nephrology, kidney transplantation, Gut-brain interaction, patient-reported outcome measures, tiredness
Abstract: Rationale & Objective: Prior studies report that the use of proton pump inhibitors (PPIs) can adversely affect gut microbiota and gastrointestinal uptake of micronutrients, in particular iron and magnesium, and are used frequently by kidney transplant recipients. Altered gut microbiota, iron deficiency, and magnesium deficiency have been implicated in the pathogenesis of chronic fatigue. Therefore, we hypothesized that PPI use may be an important and underappreciated cause of fatigue and reduced health-related quality of life (HRQoL) in this population. Study Design: Cross-sectional study. Setting & Participants: Kidney transplant recipients (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Study. Exposure: PPI use, PPI type, PPI dosage, and duration of PPI use. Outcome: Fatigue and HRQoL, assessed using the validated Checklist Individual Strength 20 Revised questionnaire and Short Form-36 questionnaire. Analytical Approach: Logistic and linear regression. Results: We included 937 kidney transplant recipients (mean age 56 ± 13 years, 39% female) at a median of 3 (1-10) years after transplantation. PPI use was associated with fatigue severity (regression coefficient 4.02, 95% CI, 2.18 to 5.85, P < 0.001), a higher risk of severe fatigue (OR 2.05, 95% CI, 1.48 to 2.84, P < 0.001), lower physical HRQoL (regression coefficient −8.54, 95% CI, −11.54 to −5.54, P < 0.001), and lower mental HRQoL (regression coefficient −4.66, 95% CI, −7.15 to −2.17, P < 0.001). These associations were independent of potential confounders including age, time since transplantation, history of upper gastrointestinal disease, antiplatelet therapy, and the total number of medications. They were present among all individually assessed PPI types and were dose dependent. Duration of PPI exposure was only associated with fatigue severity. Limitations: Residual confounding and inability to assess causal relationships. Conclusions: PPI use is independently associated with fatigue and lower HRQoL among kidney transplant recipients. PPI use might be an easily accessible target for alleviating fatigue and improving HRQoL among kidney transplant recipients. Further studies examining the effect of PPI exposure in this population are warranted.
Published: 2023

164. Dietary butyrate ameliorates metabolic health associated with selective proliferation of gut Lachnospiraceae bacterium 28-4

Author: Zhuang Li, Enchen Zhou, Cong Liu, Hope Wicks, Sena Yildiz, Farhana Razack, Zhixiong Ying, Sander Kooijman, Debby P.Y. Koonen, Marieke Heijink, Sarantos Kostidis, Martin Giera, Ingrid M.J.G. Sanders, Ed J. Kuijper, Wiep Klaas Smits, Ko Willems van Dijk, Patrick C.N. Rensen, Yanan Wang, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Cardiovascular Centre (CVC)
Subjects: General Medicine
Abstract: Short-chain fatty acids, including butyrate, have multiple metabolic benefits in individuals who are lean but not in individuals with metabolic syndrome, with the underlying mechanisms still being unclear. We aimed to investigate the role of gut microbiota in the induction of metabolic benefits of dietary butyrate. We performed antibiotic-induced microbiota depletion of the gut and fecal microbiota transplantation (FMT) in APOE*3-Leiden.CETP mice, a well-established translational model for developing human-like metabolic syndrome, and revealed that dietary butyrate reduced appetite and ameliorated high-fat diet-induced (HFD-induced) weight gain dependent on the presence of gut microbiota. FMT from butyrate-treated lean donor mice, but not butyrate-treated obese donor mice, into gut microbiota-depleted recipient mice reduced food intake, attenuated HFD-induced weight gain, and improved insulin resistance. 16S rRNA and metagenomic sequencing on cecal bacterial DNA of recipient mice implied that these effects were accompanied by the selective proliferation of Lachnospiraceae bacterium 28-4 in the gut as induced by butyrate. Collectively, our findings reveal a crucial role of gut microbiota in the beneficial metabolic effects of dietary butyrate as strongly associated with the abundance of Lachnospiraceae bacterium 28-4.
Published: 2023

165. Infective endocarditis in adult patients with congenital heart disease

Author: Joost P. van Melle, Jolien W. Roos-Hesselink, Manish Bansal, Otto Kamp, Marwa Meshaal, Jiri Pudich, Vlatka Reskovic Luksic, Regino Rodriguez-Alvarez, Anita Sadeghpour, Jadranka Separovic Hanzevacki, Rouguiatou Sow, Ana Teresa Timóteo, Marisa Trabulo Morgado, Michele De Bonis, Cecile Laroche, Eric Boersma, Patrizio Lancellotti, Gilbert Habib, Cardiovascular Centre (CVC), Cardiology, ACS - Heart failure & arrhythmias, University of Groningen [Groningen], Faculty Of Medicine Kasr Al-Ainy Cairo University, European Infective Endocarditis Registry (Euro-Endo), European Society of Cardiology (ESC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre Hospitalier Universitaire de Liège (CHU-Liège), Maria Cecilia Hospital [Cotignola], Assistance Publique - Hôpitaux de Marseille (APHM), Microbes évolution phylogénie et infections (MEPHI), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Endocarditis, [SDV]Life Sciences [q-bio], Adult congenital heart disease, Cardiology and Cardiovascular Medicine
Abstract: Background: Congenital Heart Disease (CHD) predisposes to Infective Endocarditis (IE), but data about characterization and prognosis of IE in CHD patients is scarce.Methods: The ESC-EORP-EURO-ENDO study is a prospective international study in IE patients (n = 3111). In this pre-specified analysis, adult CHD patients (n = 365, 11.7%) are described and compared with patients without CHD (n = 2746) in terms of baseline characteristics and mortality.Results: CHD patients (73% men, age 44.8 ± 16.6 years) were younger and had fewer comorbidities. Of the CHD patients, 14% had a dental procedure before hospitalization versus 7% in non-CHD patients (p < 0.001) and more often had positive blood cultures for Streptococcus viridans (16.4% vs 8.8%, p < 0.001). As in non-CHD patients, IE most often affected the left-sided valves. For CHD patients, in-hospital mortality was 9.0% vs 18.1% in non-CHD patients (p < 0.001), and also, during the entire follow-up of 700 days, survival was more favorable (log-rank p < 0.0001), even after adjustment for age, gender and major comorbidities (Hazard Ratio (HR) 0.68; 95%CI 0.50–0.92). Within the CHD population, multivariable Cox regression revealed the following effects (HR and [95% CI]) on mortality: fistula (HR 6.97 [3.36–14.47]), cerebral embolus (HR 4.64 [2.08–10.35]), renal insufficiency (HR 3.44 [1.48–8.02]), Staphylococcus aureus as causative agent (HR 2.06 [1.11–3.81]) and failure to undertake surgery when indicated (HR 5.93 [3.15–11.18]).Conclusions: CHD patients with IE have a better outcome in terms of all-cause mortality. The observed high incidence of dental procedures prior to IE warrants further studies about the current use, need and efficacy of antibiotic prophylaxis in CHD patients.
Published: 2023
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166. Sex-based differences in nuclear medicine imaging and therapy

Author: Slart, Riemer H.J.A., de Geus-Oei, Lioe Fee, Stevens, Jasper, Elsinga, Philip A., Ivashchenko, Oleksandra, Erba, Paola A., Slart, R, de Geus-Oei, L, Stevens, J, Elsinga, P, Ivashchenko, O, Erba, P, Biomedical Photonic Imaging, TechMed Centre, Cardiovascular Centre (CVC), Translational Immunology Groningen (TRIGR), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Groningen Kidney Center (GKC), Molecular Neuroscience and Ageing Research (MOLAR), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Faculteit Medische Wetenschappen/UMCG
Subjects: 2023 OA procedure, Gender medicine, nuclear medicine, Radiology, Nuclear Medicine and imaging, General Medicine
Published: 2023

167. Ultra-low dose infection imaging of a newborn without sedation using long axial field-of-view PET/CT

Author: N. D. van Rijsewijk, B. van Leer, O. V. Ivashchenko, E. H. Schölvinck, F. van den Heuvel, J. H. van Snick, R. H. J. A. Slart, W. Noordzij, A. W. J. M. Glaudemans, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Translational Immunology Groningen (TRIGR), and Cardiovascular Centre (CVC)
Subjects: Radiology, Nuclear Medicine and imaging, General Medicine
Published: 2023

168. Nuclear medicine in the assessment and prevention of cancer therapy-related cardiotoxicity : Prospects and proposal of use by the European Association of Nuclear Medicine (EANM)

Author: Matthias Totzeck, Nicolas Aide, Johann Bauersachs, Jan Bucerius, Panagiotis Georgoulias, Ken Herrmann, Fabien Hyafil, Jolanta Kunikowska, Mark Lubberink, Carmela Nappi, Tienush Rassaf, Antti Saraste, Roberto Sciagra, Riemer H. J. A. Slart, Hein Verberne, Christoph Rischpler, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Translational Immunology Groningen (TRIGR), and Cardiovascular Centre (CVC)
Subjects: Medicin och hälsovetenskap, Cancer therapy-related cardiotoxicity, Cardio-oncology, PET, Radiotherapy, SPECT, Nuclear medicine, Medizin, Chemotherapy, Radiology, Nuclear Medicine and imaging, General Medicine, Immunotherapy, Medical and Health Sciences
Abstract: Cardiotoxicity may present as (pulmonary) hypertension, acute and chronic coronary syndromes, venous thromboembolism, cardiomyopathies/heart failure, arrhythmia, valvular heart disease, peripheral arterial disease, and myocarditis. Many of these disease entities can be diagnosed by established cardiovascular diagnostic pathways. Nuclear medicine, however, has proven promising in the diagnosis of cardiomyopathies/heart failure, and peri- and myocarditis as well as arterial inflammation. This article first outlines the spectrum of cardiotoxic cancer therapies and the potential side effects. This will be complemented by the definition of cardiotoxicity using non-nuclear cardiovascular imaging (echocardiography, CMR) and biomarkers. Available nuclear imaging techniques are then presented and specific suggestions are made for their application and potential role in the diagnosis of cardiotoxicity. Correction to: European Journal of Nuclear Medicine and Molecular Imaginghttps://doi.org/10.1007/s00259-022-05991-7The authors regret that their names in the original article are incorrect as the first and last names were interchanged. It is now corrected in erratum article.
Published: 2023

169. Patient-Reported Versus Physician-Assessed Health Status in Heart Failure With Reduced and Preserved Ejection Fraction From ASIAN-HF Registry

Author: Kanako Teramoto, Wan Ting Tay, Jasper Tromp, Tiew-Hwa Katherine Teng, Chanchal Chandramouli, Wouter Ouwerkerk, Claire A. Lawson, Weiting Huang, Chung-Lieh Hung, Vijay Chopra, Inder Anand, Arthur Mark Richards, Carolyn S.P. Lam, Epidemiology and Data Science, CCA - Cancer Treatment and Quality of Life, CCA - Imaging and biomarkers, CCA - Cancer biology and immunology, AII - Cancer immunology, and Cardiovascular Centre (CVC)
Subjects: Cardiology and Cardiovascular Medicine, patient-reported outcome, physician-assessed heart failure, cardiomyopathy, New York Heart Association class, Kansas City Cardiomyopathy Questionnaire
Abstract: Background: We aimed to assess if discordance between patient-reported Kansas City Cardiomyopathy Questionnaire (KCCQ)-overall summary (os) score and physician-assessed New York Heart Association (NYHA) class is common among patients with heart failure (HF) with reduced or preserved ejection fraction, and determine its association with outcomes. Methods: A total of 4818 patients with HF were classified according to KCCQ-os score (range 0–100, dichotomized by median value 71.9 into high [good] versus low [bad]) and NYHA class (I/II [good] or III/IV [bad]) as concordant good (low NYHA class, high KCCQ-os score), concordant bad (high NYHA class, low KCCQ-os score), discordant worse NYHA class (high NYHA class, high KCCQ-os score), and discordant worse KCCQ-os score (low NYHA class, low-KCCQ-os score). The composite of HF hospitalization or death at 1 year was compared across groups. Results: There were 2070 (43.0%) concordant good, 1099 (22.8%) concordant bad, 331 (6.9%) discordant worse NYHA class, and 1318 (27.4%) discordant worse KCCQ-os score patients. Compared with concordant good, adverse outcomes were the highest in concordant bad (HR, 2.7 [95% CI, 2.2–3.5]) followed by discordant worse KCCQ-os score (HR, 1.8 [95% CI, 1.4–2.2]) and discordant worse NYHA class (HR, 1.5 [95% CI, 1.0–2.3]); with no modification by HF phenotype (preserved versus reduced ejection fraction, P interaction =0.52). At 6 months, 1403 (48%) experienced clinically significant improvement in KCCQ-os score (≥5 points increase over 6 months). Patients with improved KCCQ-os at 6 months (HR, 0.65 [95% CI, 0.47–0.92]) had better outcomes and the association was not modified by HF phenotype ( P interaction =0.40). Conclusions: One-third of patients with HF had discordance between patient-reported and clinician-assessed health status, largely attributable to worse patient-reported outcomes. Such discordance, particularly in those with discordantly worse KCCQ, should alert physicians to an increased risk of HF hospitalization and death, and prompt further assessment for potential drivers of worse patient-reported outcomes relative to physicians’ assessment.
Published: 2023
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170. Atrial fibrillation and heart failure temporality: does it matter?

Author: Colinda Van Deutekom, Isabelle C Van Gelder, Michiel Rienstra, and Cardiovascular Centre (CVC)
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2022

171. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author: Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, Gina M. Peloso, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, HUSLAB, Epigenetics of Complex Diseases and Traits, Department of Medicine, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Faculty Common Matters (Faculty of Social Sciences), Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Tampere University, Primary Health Care, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Epidemiology and Data Science, APH - Aging & Later Life, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Lee Kong Chian School of Medicine (LKCMedicine), Peloso, Gina M [0000-0002-5355-8636], Apollo - University of Cambridge Repository, Epidemiology, Department of Marketing Management, Erasmus MC other, Radiology & Nuclear Medicine, Kanoni, Stavroula, Graham, Sarah E, Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L, Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Zajac, Greg J M, Wu, Kuan-Han H, Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T, Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Havulinna, Aki S, Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A, Lingren, Todd, Feng, Qiping, Kullo, Iftikhar J, Narita, Akira, Takayama, Jun, Martin, Hilary C, Hunt, Karen A, Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Rasheed, Asif, Hindy, George, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian'An, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achillea, Hottenga, Jouke Jan, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A, Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Flori, Mcdaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthia, Trompet, Stella, Sattar, Naveed, Møllehave, Line T, Munz, Matthia, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Luka, Scholz, Marku, Galesloot, Tessel E, Bradfield, Jonathan P, Ruotsalainen, Sanni E, Daw, Ewarwick, Zmuda, Joseph M, Mitchell, Jonathan S, Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A, Vazquez-Moreno, Miguel, Feitosa, Mary F, Wojczynski, Mary K, Wang, Zhe, Preuss, Michael H, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W, Engmann, Jorgen, Tsao, Noah L, Verma, Anurag, Slieker, Roderick C, Lo, Ken Sin, Zilhao, Nuno R, Le, Phuong, Kleber, Marcus E, Delgado, Graciela E, Huo, Shaofeng, Ikeda, Daisuke D, Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L, Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J, Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlo, Lyssenko, Valeriya, Nongmaithem, Suraj S, Bayyana, Swati, Stringham, Heather M, Irvin, Marguerite R, Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R H J, Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N, Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C, Wang, Ya Xing, Wei, Wen B, Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A, Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F, Smith, Jennifer A, Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J, Pitkänen, Niina, Cade, Brian E, van der Laan, Sander W, Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R, Doumatey, Ayo P, Adeyemo, Adebowale A, Lee, Jong Young, Petersen, Eva R B, Nielsen, Aneta A, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W, Wang, Carol A, Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O, van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D, Reiner, Alexander P, Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C, Launer, Lenore J, Li, Huaixing, Nalls, Mike A, Raitakari, Olli T, Ichihara, Sahoko, Wild, Sarah H, Nelson, Christopher P, Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S, Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J, Kim, Eung Kweon, Adams, Hieab H H, Ikram, M Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W, Kraaijeveld, Adriaan O, Beulens, Joline W J, Shu, Xiao-Ou, Rallidis, Loukianos S, Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W, Kähönen, Mika, Pérusse, Loui, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E, Mori, Trevor A, Lieb, Wolfgang, Franke, Andre, Ohlsson, Clae, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M, Stark, Klaus J, Zimmermann, Martina E, Völzke, Henry, Homuth, Georg, Evans, Michele K, Zonderman, Alan B, Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E, Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J, Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L R, Peyser, Patricia A, Kato, Norihiro, Schulze, Matthias B, Girotto, Giorgia, Böger, Carsten A, Jung, Bettina, Joshi, Peter K, Bennett, David A, De Jager, Philip L, Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morri, Caulfield, Mark J, Munroe, Patricia B, Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B, Samani, Nilesh J, Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A, Adair, Linda S, Bechayda, Sonny Augustin, de Silva, H Janaka, Wickremasinghe, Ananda R, Krauss, Ronald M, Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G, Lind, Lar, Heng, Chew-Kiat, Nelson, Amanda E, Golightly, Yvonne M, Wilson, James F, Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J, Rao, D C, Arnett, Donna K, Hunt, Steven C, Walker, Mark, Koistinen, Heikki A, Chandak, Giriraj R, Mercader, Josep M, Costanzo, Maria C, Jang, Dongkeun, Burtt, Noël P, Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, Eshyong, van Dam, Rob M, Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F, Mcknight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, Mccarthy, Mark I, Palmer, Colin N A, Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M, Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M 't, Elders, Petra J M, Damrauer, Scott M, Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D, Loos, Ruth J F, Province, Michael A, Parra, Esteban J, Cruz, Miguel, Psaty, Bruce M, Brandslund, Ivan, Pramstaller, Peter P, Rotimi, Charles N, Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F A, Kiemeney, Lambertus A L M, de Graaf, Jacqueline, Loeffler, Marku, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W, Linneberg, Allan, Jukema, J Wouter, Khera, Amit V, Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O, van Dijk, Ko Willem, Watkins, Hugh, Strachan, David P, Grarup, Niel, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I, Dantoft, Thomas M, Karpe, Fredrik, Neville, Matt J, Timpson, Nicholas J, Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T, Pedersen, Nancy L, Magnusson, Patrik K E, Boomsma, Dorret I, Willemsen, Allegonda H M, Cupples, Ladrienne, van Meurs, Joyce B J, Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J, Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C, Kooner, Jaspal S, de Vries, Paul S, Morrison, Alanna C, Hazelhurst, Scott, Ramsay, Michèle, North, Kari E, Daviglus, Martha, Kraft, Peter, Martin, Nicholas G, Whitfield, John B, Abbas, Shahid, Saleheen, Danish, Walters, Robin G, Holmes, Michael V, Black, Corri, Smith, Blair H, Baras, Ari, Justice, Anne E, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Kooperberg, Charle, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A, Trembath, Richard C, Wei, Wei-Qi, Jarvik, Gail P, Namjou, Bahram, Hayes, M Geoffrey, Ritchie, Marylyn D, Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, Yeugene, Ho, Yuk-Lam, Lynch, Julie A, Rader, Daniel J, Tsao, Philip S, Chang, Kyong-Mi, Cho, Kelly, O'Donnell, Christopher J, Gaziano, John M, Wilson, Peter W F, Frayling, Timothy M, Hirschhorn, Joel N, Kathiresan, Sekar, Mohlke, Karen L, Sun, Yan V, Morris, Andrew P, Boehnke, Michael, Brown, Christopher D, Natarajan, Pradeep, Deloukas, Pano, Willer, Cristen J, Assimes, Themistocles L, and Peloso, Gina M
Subjects: Genome-wide association study, Medizin, Polymorphism, Single Nucleotide, Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Sex Characteristics, Phenotype, Lipids/genetics, Genetic Pleiotropy, Cholesterol, GWAS, Genetics, Lipids, Genetic, SDG 3 - Good Health and Well-being, Medicine [Science], 112 Statistics and probability, Medicinsk genetik, Genome-wide Association Study, Gwas, 1184 Genetics, developmental biology, physiology, 3126 Surgery, anesthesiology, intensive care, radiology, 3142 Public health care science, environmental and occupational health, 3141 Health care science, FOS: Biological sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 3111 Biomedicine, Medical Genetics
Abstract: Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756
Published: 2022
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172. First Genotype-Phenotype Study in TBX4 Syndrome Gain-of-Function Mutations Causative for Lung Disease

Author: Prapa, M., Lago-Docampo, M., Swietlik, E.M., Montani, D., Eyries, M., Humbert, M., Welch, C.C.L., Chung, W., Berger, R.M.F., Bogaard, H.J., Danhaive, O., Escribano-Subías, P., Gall, H., Girerd, B., Hernandez-Gonzalez, I., Holden, S., Hunt, D., Jansen, S.M.A., Kerstjens-Frederikse, W., Kiely, D., Lapunzina, P., McDermott, J., Moledina, S., Pepke-Zaba, J., Polwarth, G.J., Schotte, G., Tenorio-Castaño, J., Thompson, A.A.R., Wharton, J., Wort, S.J., Megy, K., Mapeta, R., Treacy, C.M., Martin, J.M., Li, W., Swift, A.J., Upton, P.D., Morrell, N.W., Gräf, S., Valverde, D., Cardiovascular Centre (CVC), Pulmonary medicine, and ACS - Pulmonary hypertension & thrombosis
Subjects: interstitial lung disease, Pulmonary and Respiratory Medicine, gain-of-function, pulmonary arterial hypertension, TBX4, Critical Care and Intensive Care Medicine, lung developmental disease
Abstract: Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights.Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis.Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases.Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-functio effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P, 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups.Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.
Published: 2022
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173. Anterior Myocardial Infarction Complicated by Apical Thrombus and Purulent Pericarditis

Author: Simone C.M.D. Panman, Jan A. Krikken, Gianclaudio Mecozzi, Kevin Damman, and Cardiovascular Centre (CVC)
Subjects: left ventricular thrombus, purulent pericarditis, case report, intramyocardial hematoma, Cardiology and Cardiovascular Medicine
Abstract: We describe a man with cardiac tamponade after anterior myocardial infarction with a mass on echocardiography, complicated by a S. Milleri purulent pericarditis. This case is an example of how 2 cardiac conditions can interfere with the diagnosis and management of each individual disorder, resulting in an extremely complex disease course. (Level of Difficulty: Beginner.)
Published: 2022

174. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

Author: William J. Young, Najim Lahrouchi, Aaron Isaacs, ThuyVy Duong, Luisa Foco, Farah Ahmed, Jennifer A. Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E. van den Berg, Stefan Weiss, Antoine R. Baldassari, Traci M. Bartz, James P. Cook, Daniel S. Evans, Rebecca Freudling, Oliver Hines, Jonas L. Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A. Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan van Duijvenboden, Helen R. Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C. Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J. Cutler, Dawood Darbar, Alessandro De Grandi, Antonio De Luca, Jun Ding, Christina Ellervik, Patrick T. Ellinor, Stephan B. Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Paul L. Huang, Heikki V. Huikuri, Nina Hutri-Kähönen, M. Arfan Ikram, Rebecca D. Jackson, Juhani Junttila, Maryam Kavousi, Jan A. Kors, Thiago P. Leal, Rozenn N. Lemaitre, Henry J. Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W. MacFarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P. Mishra, Rebecca N. Mitchell, Nina Mononen, May E. Montasser, Alanna C. Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K. Patton, Giulia Pelliccione, Alan Pittman, David J. Porteous, Peter P. Pramstaller, Michael H. Preuss, Olli T. Raitakari, Alexander P. Reiner, Antonio Luiz P. Ribeiro, Kenneth M. Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M. Benjamin Shoemaker, Gianfranco Sinagra, Moritz F. Sinner, Elsayed Z. Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D. Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A. Whitsel, James G. Wilson, Christy L. Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A. Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J. Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J. F. Loos, Steven A. Lubitz, Dennis O. Mook-Kanamori, Andrew P. Morris, Jeffrey R. O’Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M. Psaty, Jerome I. Rotter, Bruno Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James F. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, Patricia B. Munroe, Cardiology, ACS - Heart failure & arrhythmias, Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Internal Medicine, Young, William J, Lahrouchi, Najim, Isaacs, Aaron, Duong, Thuyvy, Foco, Luisa, Ahmed, Farah, Brody, Jennifer A, Salman, Reem, Noordam, Raymond, Benjamins, Jan-Walter, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Repetto, Linda, Concas, Maria Pina, van den Berg, Marten E, Weiss, Stefan, Baldassari, Antoine R, Bartz, Traci M, Cook, James P, Evans, Daniel S, Freudling, Rebecca, Hines, Oliver, Isaksen, Jonas L, Lin, Honghuang, Mei, Hao, Moscati, Arden, Müller-Nurasyid, Martina, Nursyifa, Casia, Qian, Yong, Richmond, Anne, Roselli, Carolina, Ryan, Kathleen A, Tarazona-Santos, Eduardo, Thériault, Sébastien, van Duijvenboden, Stefan, Warren, Helen R, Yao, Jie, Raza, Dania, Aeschbacher, Stefanie, Ahlberg, Gustav, Alonso, Alvaro, Andreasen, Laura, Bis, Joshua C, Boerwinkle, Eric, Campbell, Archie, Catamo, Eulalia, Cocca, Massimiliano, Cutler, Michael J, Darbar, Dawood, De Grandi, Alessandro, De Luca, Antonio, Ding, Jun, Ellervik, Christina, Ellinor, Patrick T, Felix, Stephan B, Froguel, Philippe, Fuchsberger, Christian, Gögele, Martin, Graff, Clau, Graff, Mariaelisa, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R, Huang, Paul L, Huikuri, Heikki V, Hutri-Kähönen, Nina, Ikram, M Arfan, Jackson, Rebecca D, Junttila, Juhani, Kavousi, Maryam, Kors, Jan A, Leal, Thiago P, Lemaitre, Rozenn N, Lin, Henry J, Lind, Lar, Linneberg, Allan, Liu, Simin, Macfarlane, Peter W, Mangino, Massimo, Meitinger, Thoma, Mezzavilla, Massimo, Mishra, Pashupati P, Mitchell, Rebecca N, Mononen, Nina, Montasser, May E, Morrison, Alanna C, Nauck, Matthia, Nauffal, Victor, Navarro, Pau, Nikus, Kjell, Pare, Guillaume, Patton, Kristen K, Pelliccione, Giulia, Pittman, Alan, Porteous, David J, Pramstaller, Peter P, Preuss, Michael H, Raitakari, Olli T, Reiner, Alexander P, Ribeiro, Antonio Luiz P, Rice, Kenneth M, Risch, Lorenz, Schlessinger, David, Schotten, Ulrich, Schurmann, Claudia, Shen, Xia, Shoemaker, M Benjamin, Sinagra, Gianfranco, Sinner, Moritz F, Soliman, Elsayed Z, Stoll, Monika, Strauch, Konstantin, Tarasov, Kirill, Taylor, Kent D, Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Weng, Lu-Chen, Whitsel, Eric A, Wilson, James G, Avery, Christy L, Conen, David, Correa, Adolfo, Cucca, Francesco, Dörr, Marcu, Gharib, Sina A, Girotto, Giorgia, Grarup, Niel, Hayward, Caroline, Jamshidi, Yalda, Järvelin, Marjo-Riitta, Jukema, J Wouter, Kääb, Stefan, Kähönen, Mika, Kanters, Jørgen K, Kooperberg, Charle, Lehtimäki, Terho, Lima-Costa, Maria Fernanda, Liu, Yongmei, Loos, Ruth J F, Lubitz, Steven A, Mook-Kanamori, Dennis O, Morris, Andrew P, O'Connell, Jeffrey R, Olesen, Morten Salling, Orini, Michele, Padmanabhan, Sandosh, Pattaro, Cristian, Peters, Annette, Psaty, Bruce M, Rotter, Jerome I, Stricker, Bruno, van der Harst, Pim, van Duijn, Cornelia M, Verweij, Niek, Wilson, James F, Arking, Dan E, Ramirez, Julia, Lambiase, Pier D, Sotoodehnia, Nona, Mifsud, Borbala, Newton-Cheh, Christopher, Munroe, Patricia B, Cardiovascular Centre (CVC), Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Paediatrics, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Fysiologie, RS: Carim - B01 Blood proteins & engineering, RS: Carim - H08 Experimental atrial fibrillation, and Biochemie
Subjects: Male, Electrocardiography/methods, General Physics and Astronomy, 610 Medicine & health, Arrhythmias, 3121 Internal medicine, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Electrocardiography, Humans, Arrhythmias, Cardiac/genetics, Genetic Testing, Medicinsk genetik, Multidisciplinary, Death, Sudden, Cardiac, Arrhythmias, Cardiac, General Chemistry, Sudden, Electrocardiogram, Death, Genetic markers, 3111 Biomedicine, 610 Medizin und Gesundheit, Cardiac, Medical Genetics
Abstract: The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Published: 2022
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175. Right ventricular dysfunction in patients with new-onset heart failure: longitudinal follow-up during guideline-directed medical therapy

Author: Mohammad Mostafa Ansari Ramandi, Joost P. van Melle, Thomas M. Gorter, Elke S. Hoendermis, Dirk J. van Veldhuisen, Jan F. Nauta, Martje H.L. van der Wal, Janke Warink‐Riemersma, Adriaan A. Voors, Michael G. Dickinson, and Cardiovascular Centre (CVC)
Subjects: Ventricular Dysfunction, Right, Ventricular Function, Right, Guideline-directed medical therapy, Humans, Stroke Volume, Heart failure, Cardiology and Cardiovascular Medicine, Prognosis, Right ventricular function, Ventricular Function, Left, Follow-Up Studies
Abstract: Aims: Improvement in left ventricular ejection fraction (LVEF) after up-titration of guideline-directed medical therapy (GDMT) has been well described in heart failure (HF) patients. Less is known about the prevalence and clinical course of right ventricular dysfunction (RVD) in patients with new-onset HF.Methods and results: From 2012 to 2018, 625 patients with a recent (Conclusion: More than one-third of patients with new-onset HF have RVD. RVD is associated with a higher risk of all-cause mortality and HF hospitalization. Recovery of RVD regularly occurs during up-titration of GDMT and is associated with improved clinical outcomes.
Published: 2022

176. Hand dexterity, daily functioning and health-related quality of life in kidney transplant recipients

Author: Daan Kremer, Wim Timens, Jan Stephan Sanders, Erik Verschuuren, Tim Jacob Knobbe, Arjan Diepstra, Martin De Borst, Eva Corpeleijn, Daniel Touw, Cas Swarte, Henri Leuvenink, Reproductive Origins of Adult Health and Disease (ROAHD), Clinical Neuropsychology, Movement Disorder (MD), Molecular Neuroscience and Ageing Research (MOLAR), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Stem Cell Aging Leukemia and Lymphoma (SALL), Translational Immunology Groningen (TRIGR), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), PharmacoTherapy, -Epidemiology and -Economics, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Microbes in Health and Disease (MHD), Center for Liver, Digestive and Metabolic Diseases (CLDM), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Health Psychology Research (HPR), Groningen Research Institute for Asthma and COPD (GRIAC), Pharmaceutical Analysis, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Medicinal Chemistry and Bioanalysis (MCB), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), and Value, Affordability and Sustainability (VALUE)
Subjects: Adult, Cohort Studies, Male, Multidisciplinary, Activities of Daily Living, Quality of Life, Humans, Female, Middle Aged, Hand, Kidney Transplantation, Transplant Recipients, Aged
Abstract: Impaired interplay between sensory and motor function may be an important, often overlooked cause of the decreased daily functioning and impaired health-related quality of life (HRQoL) of kidney transplant recipients (KTR). We assessed this interplay using a hand dexterity test, and investigated its potential associations with daily functioning and HRQoL among KTR enrolled at the TransplantLines Biobank and Cohort Study. A total of 309 KTR (58% male, mean age 56 ± 13 years) at median 4 [IQR: 1–11] years after transplantation were included. Impaired hand dexterity, as defined by a test performance slower than the 95th percentile of an age- and sex-specific reference population, was observed in 71 (23%) KTR. Worse hand dexterity was independently associated with worse performance on almost all measures of physical capacity, activities of daily living and societal participation. Finally, hand dexterity was independently associated with physical HRQoL (standardized beta − 0.22, 95%CI − 0.34 to − 0.09, P
Published: 2022

177. Interpretation of pre-morbid cardiac 3T MRI findings in overweight and hypertensive young adults

Author: Gert J. H. Snel, Riemer H. J. A. Slart, Birgitta K. Velthuis, Maaike van den Boomen, Christopher T. Nguyen, David E. Sosnovik, Vincent M. van Deursen, Rudi A. J. O. Dierckx, Ronald J. H. Borra, Niek H. J. Prakken, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Translational Immunology Groningen (TRIGR), Cardiovascular Centre (CVC), Faculteit Medische Wetenschappen/UMCG, and Molecular Neuroscience and Ageing Research (MOLAR)
Subjects: Adult, Male, Young Adult, Multidisciplinary, Hypertension, Humans, Female, Heart, Overweight, Morbidity, Magnetic Resonance Imaging
Abstract: In young adults, overweight and hypertension possibly already trigger cardiac remodeling as seen in mature adults, potentially overlapping non-ischemic cardiomyopathy findings. To this end, in young overweight and hypertensive adults, we aimed to investigate changes in left ventricular mass (LVM) and cardiac volumes, and the impact of different body scales for indexation. We also aimed to explore the presence of myocardial fibrosis, fat and edema, and changes in cellular mass with extracellular volume (ECV), T1 and T2 tissue characteristics. We prospectively recruited 126 asymptomatic subjects (51% male) aged 27–41 years for 3T cardiac magnetic resonance imaging: 40 controls, 40 overweight, 17 hypertensive and 29 hypertensive overweight. Myocyte mass was calculated as (100%–ECV) * height2.7-indexed LVM. Absolute LVM was significantly increased in overweight, hypertensive and hypertensive overweight groups (104 ± 23, 109 ± 27, 112 ± 26 g) versus controls (87 ± 21 g), with similar volumes. Body surface area (BSA) indexation resulted in LVM normalization in overweights (48 ± 8 g/m2) versus controls (47 ± 9 g/m2), but not in hypertensives (55 ± 9 g/m2) and hypertensive overweights (52 ± 9 g/m2). BSA-indexation overly decreased volumes in overweight versus normal-weight (LV end-diastolic volume; 80 ± 14 versus 92 ± 13 ml/m2), where height2.7-indexation did not. All risk groups had lower ECV (23 ± 2%, 23 ± 2%, 23 ± 3%) than controls (25 ± 2%) (P = 0.006, P = 0.113, P = 0.039), indicating increased myocyte mass (16.9 ± 2.7, 16.5 ± 2.3, 18.1 ± 3.5 versus 14.0 ± 2.9 g/m2.7). Native T1 values were similar. Lower T2 values in the hypertensive overweight group related to heart rate. In conclusion, BSA-indexation masks hypertrophy and causes volume overcorrection in overweight subjects compared to controls, height2.7-indexation therefore seems advisable.
Published: 2022
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178. Shortened duration whole body 18F-FDG PET Patlak imaging on the Biograph Vision Quadra PET/CT using a population-averaged input function

Author: Joyce van Sluis, Johannes H. van Snick, Adrienne H. Brouwers, Walter Noordzij, Rudi A. J. O. Dierckx, Ronald J. H. Borra, Adriaan A. Lammertsma, Andor W. J. M. Glaudemans, Riemer H. J. A. Slart, Maqsood Yaqub, Charalampos Tsoumpas, Ronald Boellaard, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Molecular Neuroscience and Ageing Research (MOLAR), Translational Immunology Groningen (TRIGR), Cardiovascular Centre (CVC), Radiology and nuclear medicine, AMS - Tissue Function & Regeneration, Amsterdam Neuroscience - Brain Imaging, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and CCA - Imaging and biomarkers
Subjects: Radiation, Vision Quadra, Patlak, PET/CT, Dynamic imaging, Biomedical Engineering, Radiology, Nuclear Medicine and imaging, Scan duration, Instrumentation
Abstract: Background Excellent performance characteristics of the Vision Quadra PET/CT, e.g. a substantial increase in sensitivity, allow for precise measurements of image-derived input functions (IDIF) and tissue time activity curves. Previously we have proposed a method for a reduced 30 min (as opposed to 60 min) whole body 18F-FDG Patlak PET imaging procedure using a previously published population-averaged input function (PIF) scaled to IDIF values at 30–60 min post-injection (p.i.). The aim of the present study was to apply this method using the Vision Quadra PET/CT, including the use of a PIF to allow for shortened scan durations. Methods Twelve patients with suspected lung malignancy were included and received a weight-based injection of 18F-FDG. Patients underwent a 65-min dynamic PET acquisition which were reconstructed using European Association of Nuclear Medicine Research Ltd. (EARL) standards 2 reconstruction settings. A volume of interest (VOI) was placed in the ascending aorta (AA) to obtain the IDIF. An external PIF was scaled to IDIF values at 30–60, 40–60, and 50–60 min p.i., respectively, and parametric 18F-FDG influx rate constant (Ki) images were generated using a t* of 30, 40 or 50 min, respectively. Herein, tumour lesions as well as healthy tissues, i.e. liver, muscle tissue, spleen and grey matter, were segmented. Results Good agreement between the IDIF and corresponding PIF scaled to 30–60 min p.i. and 40–60 min p.i. was obtained with 7.38% deviation in Ki. Bland–Altman plots showed excellent agreement in Ki obtained using the PIF scaled to the IDIF at 30–60 min p.i. and at 40–60 min p.i. as all data points were within the limits of agreement (LOA) (− 0.004–0.002, bias: − 0.001); for the 50–60 min p.i. Ki, all except one data point fell in between the LOA (− 0.021–0.012, bias: − 0.005). Conclusions Parametric whole body 18F-FDG Patlak Ki images can be generated non-invasively on a Vision Quadra PET/CT system. In addition, using a scaled PIF allows for a substantial (factor 2 to 3) reduction in scan time without substantial loss of accuracy (7.38% bias) and precision (image quality and noise interference).
Published: 2022
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179. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author: Winkler, Thomas W., Rasheed, Humaira, Teumer, Alexander, Gorski, Mathias, Rowan, Bryce X., Stanzick, Kira J., Thomas, Laurent F., Tin, Adrienne, Hoppmann, Anselm, Chu, Audrey Y., Tayo, Bamidele, Thio, Chris H. L., Cusi, Daniele, Chai, Jin-Fang, Sieber, Karsten B., Horn, Katrin, Li, Man, Scholz, Markus, Cocca, Massimiliano, Wuttke, Matthias, van der Most, Peter J., Yang, Qiong, Ghasemi, Sahar, Nutile, Teresa, Li, Yong, Pontali, Giulia, Günther, Felix, Dehghan, Abbas, Correa, Adolfo, Parsa, Afshin, Feresin, Agnese, de Vries, Aiko P. J., Zonderman, Alan B., Smith, Albert V., Oldehinkel, Albertine J., De Grandi, Alessandro, Rosenkranz, Alexander R., Franke, Andre, Teren, Andrej, Metspalu, Andres, Hicks, Andrew A., Morris, Andrew P., Tönjes, Anke, Morgan, Anna, Podgornaia, Anna I., Peters, Annette, Körner, Antje, Mahajan, Anubha, Campbell, Archie, Freedman, Barry I., Spedicati, Beatrice, Ponte, Belen, Schöttker, Ben, Brumpton, Ben, Banas, Bernhard, Krämer, Bernhard K., Jung, Bettina, Åsvold, Bjørn Olav, Smith, Blair H., Ning, Boting, Penninx, Brenda W. J. H., Vanderwerff, Brett R., Psaty, Bruce M., Kammerer, Candace M., Langefeld, Carl D., Hayward, Caroline, Spracklen, Cassandra N., Robinson-Cohen, Cassianne, Hartman, Catharina A., Lindgren, Cecilia M., Wang, Chaolong, Sabanayagam, Charumathi, Heng, Chew-Kiat, Lanzani, Chiara, Khor, Chiea-Chuen, Cheng, Ching-Yu, Fuchsberger, Christian, Gieger, Christian, Shaffer, Christian M., Schulz, Christina-Alexandra, Willer, Cristen J., Chasman, Daniel I., Gudbjartsson, Daniel F., Ruggiero, Daniela, Toniolo, Daniela, Czamara, Darina, Porteous, David J., Waterworth, Dawn M., Mascalzoni, Deborah, Mook-Kanamori, Dennis O., Reilly, Dermot F., Daw, E. Warwick, Hofer, Edith, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Tai, E-Shyong, Catamo, Eulalia, Rizzi, Federica, Guo, Feng, Rivadeneira, Fernando, Guilianini, Franco, Sveinbjornsson, Gardar, Ehret, Georg, Waeber, Gerard, Biino, Ginevra, Girotto, Giorgia, Pistis, Giorgio, Nadkarni, Girish N., Delgado, Graciela E., Montgomery, Grant W., Snieder, Harold, Campbell, Harry, White, Harvey D., Gao, He, Stringham, Heather M., Schmidt, Helena, Li, Hengtong, Brenner, Hermann, Holm, Hilma, Kirsten, Holger, Kramer, Holly, Rudan, Igor, Nolte, Ilja M., Tzoulaki, Ioanna, Olafsson, Isleifur, Martins, Jade, Cook, James P., Wilson, James F., Halbritter, Jan, Felix, Janine F., Divers, Jasmin, Kooner, Jaspal S., Lee, Jeannette Jen-Mai, O’Connell, Jeffrey, Rotter, Jerome I., Liu, Jianjun, Xu, Jie, Thiery, Joachim, Ärnlöv, Johan, Kuusisto, Johanna, Jakobsdottir, Johanna, Tremblay, Johanne, Chambers, John C., Whitfield, John B., Gaziano, John M., Marten, Jonathan, Coresh, Josef, Jonas, Jost B., Mychaleckyj, Josyf C., Christensen, Kaare, Eckardt, Kai-Uwe, Mohlke, Karen L., Endlich, Karlhans, Dittrich, Katalin, Ryan, Kathleen A., Rice, Kenneth M., Taylor, Kent D., Ho, Kevin, Nikus, Kjell, Matsuda, Koichi, Strauch, Konstantin, Miliku, Kozeta, Hveem, Kristian, Lind, Lars, Wallentin, Lars, Yerges-Armstrong, Laura M., Raffield, Laura M., Phillips, Lawrence S., Launer, Lenore J., Lyytikäinen, Leo-Pekka, Lange, Leslie A., Citterio, Lorena, Klaric, Lucija, Ikram, M. Arfan, Ising, Marcus, Kleber, Marcus E., Francescatto, Margherita, Concas, Maria Pina, Ciullo, Marina, Piratsu, Mario, Orho-Melander, Marju, Laakso, Markku, Loeffler, Markus, Perola, Markus, de Borst, Martin H., Gögele, Martin, Bianca, Martina La, Lukas, Mary Ann, Feitosa, Mary F., Biggs, Mary L., Wojczynski, Mary K., Kavousi, Maryam, Kanai, Masahiro, Akiyama, Masato, Yasuda, Masayuki, Nauck, Matthias, Waldenberger, Melanie, Chee, Miao-Li, Chee, Miao-Ling, Boehnke, Michael, Preuss, Michael H., Stumvoll, Michael, Province, Michael A., Evans, Michele K., O’Donoghue, Michelle L., Kubo, Michiaki, Kähönen, Mika, Kastarinen, Mika, Nalls, Mike A., Kuokkanen, Mikko, Ghanbari, Mohsen, Bochud, Murielle, Josyula, Navya Shilpa, Martin, Nicholas G., Tan, Nicholas Y. Q., Palmer, Nicholette D., Pirastu, Nicola, Schupf, Nicole, Verweij, Niek, Hutri-Kähönen, Nina, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Melander, Olle, Raitakari, Olli T., Polasek, Ozren, Manunta, Paolo, Gasparini, Paolo, Mishra, Pashupati P., Sulem, Patrick, Magnusson, Patrik K. E., Elliott, Paul, Ridker, Paul M., Hamet, Pavel, Svensson, Per O., Joshi, Peter K., Kovacs, Peter, Pramstaller, Peter P., Rossing, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z. H., Burkhardt, Ralph, Tao, Ran, Noordam, Raymond, Mägi, Reedik, Schmidt, Reinhold, de Mutsert, Renée, Rueedi, Rico, van Dam, Rob M., Carroll, Robert J., Gansevoort, Ron T., Loos, Ruth J. F., Felicita, Sala Cinzia, Sedaghat, Sanaz, Padmanabhan, Sandosh, Freitag-Wolf, Sandra, Pendergrass, Sarah A., Graham, Sarah E., Gordon, Scott D., Hwang, Shih-Jen, Kerr, Shona M., Vaccargiu, Simona, Patil, Snehal B., Hallan, Stein, Bakker, Stephan J. L., Lim, Su-Chi, Lucae, Susanne, Vogelezang, Suzanne, Bergmann, Sven, Corre, Tanguy, Ahluwalia, Tarunveer S., Lehtimäki, Terho, Boutin, Thibaud S., Meitinger, Thomas, Wong, Tien-Yin, Bergler, Tobias, Rabelink, Ton J., Esko, Tõnu, Haller, Toomas, Thorsteinsdottir, Unnur, Völker, Uwe, Foo, Valencia Hui Xian, Salomaa, Veikko, Vitart, Veronique, Giedraitis, Vilmantas, Gudnason, Vilmundur, Jaddoe, Vincent W. V., Huang, Wei, Zhang, Weihua, Wei, Wen Bin, Kiess, Wieland, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Gao, Xin, Sim, Xueling, Wang, Ya Xing, Friedlander, Yechiel, Tham, Yih-Chung, Kamatani, Yoichiro, Okada, Yukinori, Milaneschi, Yuri, Yu, Zhi, Hung, Adriana M., Stark, Klaus J., Stefansson, Kari, Böger, Carsten A., Kronenberg, Florian, Köttgen, Anna, Pattaro, Cristian, Heid, Iris M., Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, Research Programs Unit, Tampere University, Clinical Medicine, TAYS Heart Centre, Department of Clinical Chemistry, Department of Clinical Physiology and Nuclear Medicine, Internal Medicine, Pediatrics, Epidemiology, Radiology & Nuclear Medicine, Erasmus MC other, Home Office, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), UK DRI Ltd, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Winkler, Thomas W, Rasheed, Humaira, Teumer, Alexander, Gorski, Mathia, Rowan, Bryce X, Stanzick, Kira J, Thomas, Laurent F, Tin, Adrienne, Hoppmann, Anselm, Chu, Audrey Y, Tayo, Bamidele, Thio, Chris H L, Cusi, Daniele, Chai, Jin-Fang, Sieber, Karsten B, Horn, Katrin, Li, Man, Scholz, Marku, Cocca, Massimiliano, Wuttke, Matthia, van der Most, Peter J, Yang, Qiong, Ghasemi, Sahar, Nutile, Teresa, Li, Yong, Pontali, Giulia, Günther, Felix, Dehghan, Abba, Correa, Adolfo, Parsa, Afshin, Feresin, Agnese, de Vries, Aiko P J, Zonderman, Alan B, Smith, Albert V, Oldehinkel, Albertine J, De Grandi, Alessandro, Rosenkranz, Alexander R, Franke, Andre, Teren, Andrej, Metspalu, Andre, Hicks, Andrew A, Morris, Andrew P, Tönjes, Anke, Morgan, Anna, Podgornaia, Anna I, Peters, Annette, Körner, Antje, Mahajan, Anubha, Campbell, Archie, Freedman, Barry I, Spedicati, Beatrice, Ponte, Belen, Schöttker, Ben, Brumpton, Ben, Banas, Bernhard, Krämer, Bernhard K, Jung, Bettina, Åsvold, Bjørn Olav, Smith, Blair H, Ning, Boting, Penninx, Brenda W J H, Vanderwerff, Brett R, Psaty, Bruce M, Kammerer, Candace M, Langefeld, Carl D, Hayward, Caroline, Spracklen, Cassandra N, Robinson-Cohen, Cassianne, Hartman, Catharina A, Lindgren, Cecilia M, Wang, Chaolong, Sabanayagam, Charumathi, Heng, Chew-Kiat, Lanzani, Chiara, Khor, Chiea-Chuen, Cheng, Ching-Yu, Fuchsberger, Christian, Gieger, Christian, Shaffer, Christian M, Schulz, Christina-Alexandra, Willer, Cristen J, Chasman, Daniel I, Gudbjartsson, Daniel F, Ruggiero, Daniela, Toniolo, Daniela, Czamara, Darina, Porteous, David J, Waterworth, Dawn M, Mascalzoni, Deborah, Mook-Kanamori, Dennis O, Reilly, Dermot F, Daw, E Warwick, Hofer, Edith, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P, Tai, E-Shyong, Catamo, Eulalia, Rizzi, Federica, Guo, Feng, Rivadeneira, Fernando, Guilianini, Franco, Sveinbjornsson, Gardar, Ehret, Georg, Waeber, Gerard, Biino, Ginevra, Girotto, Giorgia, Pistis, Giorgio, Nadkarni, Girish N, Delgado, Graciela E, Montgomery, Grant W, Snieder, Harold, Campbell, Harry, White, Harvey D, Gao, He, Stringham, Heather M, Schmidt, Helena, Li, Hengtong, Brenner, Hermann, Holm, Hilma, Kirsten, Holgen, Kramer, Holly, Rudan, Igor, Nolte, Ilja M, Tzoulaki, Ioanna, Olafsson, Isleifur, Martins, Jade, Cook, James P, Wilson, James F, Halbritter, Jan, Felix, Janine F, Divers, Jasmin, Kooner, Jaspal S, Lee, Jeannette Jen-Mai, O'Connell, Jeffrey, Rotter, Jerome I, Liu, Jianjun, Xu, Jie, Thiery, Joachim, Ärnlöv, Johan, Kuusisto, Johanna, Jakobsdottir, Johanna, Tremblay, Johanne, Chambers, John C, Whitfield, John B, Gaziano, John M, Marten, Jonathan, Coresh, Josef, Jonas, Jost B, Mychaleckyj, Josyf C, Christensen, Kaare, Eckardt, Kai-Uwe, Mohlke, Karen L, Endlich, Karlhan, Dittrich, Katalin, Ryan, Kathleen A, Rice, Kenneth M, Taylor, Kent D, Ho, Kevin, Nikus, Kjell, Matsuda, Koichi, Strauch, Konstantin, Miliku, Kozeta, Hveem, Kristian, Lind, Lar, Wallentin, Lar, Yerges-Armstrong, Laura M, Raffield, Laura M, Phillips, Lawrence S, Launer, Lenore J, Lyytikäinen, Leo-Pekka, Lange, Leslie A, Citterio, Lorena, Klaric, Lucija, Ikram, M Arfan, Ising, Marcu, Kleber, Marcus E, Francescatto, Margherita, Concas, Maria Pina, Ciullo, Marina, Piratsu, Mario, Orho-Melander, Marju, Laakso, Markku, Loeffler, Marku, Perola, Marku, de Borst, Martin H, Gögele, Martin, Bianca, Martina La, Lukas, Mary Ann, Feitosa, Mary F, Biggs, Mary L, Wojczynski, Mary K, Kavousi, Maryam, Kanai, Masahiro, Akiyama, Masato, Yasuda, Masayuki, Nauck, Matthia, Waldenberger, Melanie, Chee, Miao-Li, Chee, Miao-Ling, Boehnke, Michael, Preuss, Michael H, Stumvoll, Michael, Province, Michael A, Evans, Michele K, O'Donoghue, Michelle L, Kubo, Michiaki, Kähönen, Mika, Kastarinen, Mika, Nalls, Mike A, Kuokkanen, Mikko, Ghanbari, Mohsen, Bochud, Murielle, Josyula, Navya Shilpa, Martin, Nicholas G, Tan, Nicholas Y Q, Palmer, Nicholette D, Pirastu, Nicola, Schupf, Nicole, Verweij, Niek, Hutri-Kähönen, Nina, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Melander, Olle, Raitakari, Olli T, Polasek, Ozren, Manunta, Paolo, Gasparini, Paolo, Mishra, Pashupati P, Sulem, Patrick, Magnusson, Patrik K E, Elliott, Paul, Ridker, Paul M, Hamet, Pavel, Svensson, Per O, Joshi, Peter K, Kovacs, Peter, Pramstaller, Peter P, Rossing, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z H, Burkhardt, Ralph, Tao, Ran, Noordam, Raymond, Mägi, Reedik, Schmidt, Reinhold, de Mutsert, Renée, Rueedi, Rico, van Dam, Rob M, Carroll, Robert J, Gansevoort, Ron T, Loos, Ruth J F, Felicita, Sala Cinzia, Sedaghat, Sanaz, Padmanabhan, Sandosh, Freitag-Wolf, Sandra, Pendergrass, Sarah A, Graham, Sarah E, Gordon, Scott D, Hwang, Shih-Jen, Kerr, Shona M, Vaccargiu, Simona, Patil, Snehal B, Hallan, Stein, Bakker, Stephan J L, Lim, Su-Chi, Lucae, Susanne, Vogelezang, Suzanne, Bergmann, Sven, Corre, Tanguy, Ahluwalia, Tarunveer S, Lehtimäki, Terho, Boutin, Thibaud S, Meitinger, Thoma, Wong, Tien-Yin, Bergler, Tobia, Rabelink, Ton J, Esko, Tõnu, Haller, Tooma, Thorsteinsdottir, Unnur, Völker, Uwe, Foo, Valencia Hui Xian, Salomaa, Veikko, Vitart, Veronique, Giedraitis, Vilmanta, Gudnason, Vilmundur, Jaddoe, Vincent W V, Huang, Wei, Zhang, Weihua, Wei, Wen Bin, Kiess, Wieland, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Gao, Xin, Sim, Xueling, Wang, Ya Xing, Friedlander, Yechiel, Tham, Yih-Chung, Kamatani, Yoichiro, Okada, Yukinori, Milaneschi, Yuri, Yu, Zhi, Stark, Klaus J, Stefansson, Kari, Böger, Carsten A, Hung, Adriana M, Kronenberg, Florian, Köttgen, Anna, Pattaro, Cristian, Heid, Iris M, and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: Life Sciences & Biomedicine - Other Topics, EXPRESSION, Diabetic Nephropathies/genetics, 610 Medizin, LOCI, Medicine (miscellaneous), EFFICIENT, Lifelines cohort study, Kidney, General Biochemistry, Genetics and Molecular Biology, DISEASE, QUALITY-CONTROL, SDG 3 - Good Health and Well-being, Diabetic Nephropathy, Diabetes Mellitus, Humans, Medicine [Science], Diabetic Nephropathies, GENOME-WIDE ASSOCIATION, Biology, DiscovEHR/MyCode study, METAANALYSIS, Glomerular Filtration Rate/genetics, Medicinsk genetik, ddc:610, Science & Technology, genetic, effects, kidney, diabetic, JOINT, Klinisk medicin, Diabetes Mellitu, 3126 Surgery, anesthesiology, intensive care, radiology, Multidisciplinary Sciences, ENVIRONMENT INTERACTION, Creatinine, VA Million Veteran Program, Science & Technology - Other Topics, 3111 Biomedicine, Clinical Medicine, SMOKING, General Agricultural and Biological Sciences, Life Sciences & Biomedicine, Medical Genetics, Human, Genome-Wide Association Study, Glomerular Filtration Rate
Abstract: Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM. Published version The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supported the meta-analysis—Project-ID 387509280—SFB1350 (Subproject C6 to I.M.H.). A.M.H., B.R., and R.T. were supported by VACSR&D MVP grant CX001897. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by VACSR&D MVP grant CX001897 (A.M.H.). This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We conducted this research using the UK Biobank resource under the application number 20272.
Published: 2022
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180. A translation re-initiation variant in KLHL24 also causes epidermolysis bullosa simplex and dilated cardiomyopathy via intermediate filament degradation

Author: Mathilde C.S.C. Vermeer, Mohammad Al-Shinnag, Herman H.W. Silljé, Antonio Esquivel Gaytan, Dedee F. Murrell, Julie McGaughran, Wei Melbourne, Timothy Cowan, Peter C. van den Akker, Karin Y. van Spaendonck-Zwarts, Peter van der Meer, Maria C. Bolling, Human Genetics, ACS - Heart failure & arrhythmias, Cardiovascular Centre (CVC), Translational Immunology Groningen (TRIGR), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
Subjects: Cardiomyopathy, Dilated, Phenotype, Epidermolysis Bullosa Simplex, Mutation, Intermediate Filaments, Humans, Codon, Initiator, Dermatology
Abstract: This study shows that gain-of-function variants in KLHL24 causing EBS and DCM, do not only originate in the start-codon and suggest that any nonsense-inducing variant affecting nucleotides c.4_84 will likely cause the same effect on protein level and a similar potential lethal phenotype.
Published: 2022

181. Contained rupture of a sinus of Valsalva aneurysm

Author: Giorgio Vigano, Rozemarijn Vliegenthart, Daniël K. M. Pollack, Massimo A. Mariani, Cardiovascular Centre (CVC), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
Subjects: Male, Pulmonary and Respiratory Medicine, Contained aortic rupture, Bicuspid aortic valve, Aortic Rupture, General Medicine, Sinus of Valsalva, Aortic Aneurysm, Diabetes Mellitus, Type 2, Acute aortic syndrome, cardiovascular system, Humans, Aortic root replacement, Surgery, Cardiology and Cardiovascular Medicine, Aorta, Aged
Abstract: Background Contained rupture of the ascending aorta is a rare condition, but the severity of this complication enforces strict guidelines for its prevention and a prompt diagnosis, once already occurred. Case presentation A 66-year-old man with a history of type 2 diabetes, longstanding aortic valve stenosis and aortic root aneurysm of 47 mm was hospital admitted for elective surgery. A Bentall-De Bono procedure was performed in order to replace the stenotic bicuspid aortic valve and exclude the dilated portion of the aortic wall. Intraoperatively, a discontinuity of the aortic wall, just above the aortic annulus, at the non-coronary sinus of Valsalva was incidentally observed. The aortic wall discontinuity was none other than a contained aortic rupture. The preoperative CT-scan images were afterwards analyzed by the radiologist, in order to identify the contained aortic rupture. Indeed a false aneurysm of the non-coronary sinus of Valsalva of a maximum diameter of 15 mm was detected, thanks to a 3D reconstruction. Conclusions The diagnosis of contained aortic rupture is certainly demanding, particularly in absence of signs or symptoms of rupture in a chamber of the heart or in the pericardium. Although this case represents a consensus of experts’ opinion, the recognition of these specific cases in which the risk of dissection, rupture or death is at its highest, would allow to operate at the appropriate time, improving the outcomes.
Published: 2022
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182. Clinical significance of early Pulmonary Hypertension in Preterm Infants

Author: Sanne Arjaans, Marian W.F. Fries, Mirthe H. Schoots, Carine F.M. Schilte, Marc T.R. Roofthooft, Elianne J.L.E. Vrijlandt, Arie F. Bos, Elisabeth M.W. Kooi, Rolf M.F. Berger, Groningen Research Institute for Asthma and COPD (GRIAC), Reproductive Origins of Adult Health and Disease (ROAHD), and Cardiovascular Centre (CVC)
Subjects: Pregnancy, Hypertension, Pulmonary, Placenta, Pediatrics, Perinatology and Child Health, Infant, Newborn, Humans, Female, Gestational Age, Prospective Studies, Infant, Premature, Bronchopulmonary Dysplasia
Abstract: OBJECTIVE: To characterize different phenotypes of early pulmonary hypertension (PH) in preterm infants and their respective associations with bronchopulmonary dysplasia (BPD) and survival.STUDY DESIGN: A prospective cohort study in a tertiary University Medical Centre from June 2016 until March 2019. Infants with a gestational age RESULTS: Early-PH was identified in 55% of 104 included infants: 21% with persistent PH of the newborn (PPHN), 61% with flow-associated PH and 18% PH without-shunt. Only PPHN was associated with placental fetal vascular malperfusion, lower gestational age and low Apgar-scores. Both PPHN and flow-PH were associated with the development of BPD. Early-PH was associated with poorer survival, driven by PPHN.CONCLUSIONS: Early-PH is highly prevalent (55%) in preterm infants and associated with the development of BPD, independent of the phenotype of PH. Infants with PPHN had the poorest survival. Early-PH presents in various phenotypes that are characterized by different etiology, pathophysiology, and associated long-term sequelae.
Published: 2022

183. Heart failure medication

Author: Jasper Tromp, Adriaan A Voors, and Cardiovascular Centre (CVC)
Subjects: Heart Failure, Ventricular Dysfunction, Left, Humans, Stroke Volume, Cardiology and Cardiovascular Medicine
Published: 2022

184. Risk factors for the development of heart failure in patients with or without prior myocardial infarction COMMENT

Author: Bart J, van Essen, Adriaan A, Voors, Jasper, Tromp, and Cardiovascular Centre (CVC)
Subjects: Heart Failure, Risk Factors, Myocardial Infarction, Humans, EPIDEMIOLOGY, Cardiology and Cardiovascular Medicine
Published: 2022
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185. Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction

Author: Subodh Verma, Milton Packer, Stefan D. Anker, Carolyn S.P. Lam, Daniel Cotton, Stuart J. Pocock, Martina Brueckmann, David Sim, Janet Schnee, Javed Butler, Egon Pfarr, Gerasimos Filippatos, João Pedro Ferreira, Hiroyuki Tsutsui, Faiez Zannad, Naveed Sattar, Cardiovascular Centre (CVC), National Heart Centre Singapore (NHCS), University Medical Center Groningen [Groningen] (UMCG), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Boehringer Ingelheim International GmbH, Department of Cardiovascular Medicine, Kyushu University, Higashi-ku, Kyushu University [Fukuoka], Berlin-Brandenburg Center for Regenerative Therapies [Berlin, Germany], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Mississippi State University [Mississippi], Attikon University Hospital, National and Kapodistrian University of Athens (NKUA), London School of Hygiene and Tropical Medicine (LSHTM), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, St. Michael's Hospital, University of Toronto, University of Heidelberg, Medical Faculty, Boehringer Ingelheim Pharmaceuticals, Inc, Baylor University Medical Center, Baylor College of Medecine, Imperial College London, and The EMPEROR-Reduced trial was funded by Boehringer Ingelheim and Eli Lilly (EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977)
Subjects: Relative risk reduction, Ethnic group, Empagliflozin, Fast Track Clinical Research, Heart failure, 030204 cardiovascular system & hematology, Placebo, Racial differences, 03 medical and health sciences, 0302 clinical medicine, Primary outcome, Glucosides, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Ethnicity, Medicine, Humans, In patient, AcademicSubjects/MED00200, 030212 general & internal medicine, Benzhydryl Compounds, 10. No inequality, Heart Failure and Cardiomyopathies, Ejection fraction, business.industry, Geographic differences, Stroke Volume, medicine.disease, 3. Good health, Cardiology and Cardiovascular Medicine, business, Demography
Abstract: Aims The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial. Methods and results Of 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%. Conclusions There were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events., Graphical Abstract Effect of empagliflozin by region and race in EMPEROR-Reduced. Inclusion of outpatient events in the extended composite endpoint attenuated the between-region differences in the effect of empagliflozin seen in the primary outcome of EMPEROR-Reduced.
Published: 2021
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186. Heart rate increase and inappropriate sinus tachycardia after cryoballoon pulmonary vein isolation for atrial fibrillation

Author: Michiel Rienstra, Yuri Blaauw, Eng S. Tan, Ans C.P. Wiesfeld, C van Deutekom, Robert G. Tieleman, H F Groenveld, I. C. Van Gelder, Bart A. Mulder, and Cardiovascular Centre (CVC)
Subjects: medicine.medical_specialty, Heart rate, GANGLIONATED PLEXI, Cryoballoon, Pulmonary vein isolation, MECHANISMS, Pulmonary vein, Internal medicine, ABLATION, medicine, Sinus rhythm, Sinus (anatomy), RISK, business.industry, Atrial fibrillation, AUTONOMIC NERVOUS-SYSTEM, medicine.disease, Inappropriate sinus tachycardia, Autonomic nervous system, medicine.anatomical_structure, cardiovascular system, Cardiology, Cardiology and Cardiovascular Medicine, business, Holter monitoring, circulatory and respiratory physiology
Abstract: Background Cryoballoon pulmonary vein isolation (PVI) is a common therapy for atrial fibrillation (AF). While moderately increased sinus rhythm heart rate (HR) after PVI has been observed, inappropriate sinus tachycardia (IST) is a rare phenomenon. We aimed to investigate the prevalence and natural history of an abnormal sinus HR response after cryoballoon PVI. Methods We included 169/646 (26.2%) patients with AF undergoing PVI with available Holter recordings before and 3, 6 and 12 months after the procedure. Patients with AF on Holter monitoring were excluded. Mean HR increase ≥ 20 bpm or an IST-like pattern (mean HR > 90 bpm or > 80 bpm when beta-blocking agents were used) following PVI was categorised as abnormal sinus HR response. Results Following PVI, mean HR ± standard deviation increased in the entire group from 63.5 ± 8.4 to 69.1 ± 9.9 bpm at 3 months (p p p p = 0.033). However, in patients meeting IST-like pattern criteria, mean HR at 12 months was no longer significantly different from that pre-ablation. Conclusion Few patients had an abnormal sinus HR response after PVI. Peak HR was observed 3 months after PVI, but HR was still significantly increased 12 months post-ablation compared with pre-ablation. An IST-like pattern was rarely observed. In these patients, HR decreased to pre-ablation values within a year.
Published: 2021
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187. COVID-19-related mortality in kidney transplant and haemodialysis patients

Author: Goffin, Eric, Candellier, Alexandre, Vart, Priya, Noordzij, Marlies, Arnol, Miha, Covic, Adrian, Lentini, Paolo, Malik, Shafi, Reichert, Louis J., Sever, Mehmet S., Watschinger, Bruno, Jager, Kitty J., Gansevoort, Ron T., van der Net, Jeroen B., Essig, Marie, du Buf-Vereijken, Peggy W. G., van Ginneken, Betty, Vogt, Liffert, van Jaarsveld, Brigit C., Bemelman, Frederike J., Klingenberg-Salahova, Farah, Heenan-Vos, Frederiek, Vervloet, Marc G., Nurmohamed, Azam, Abramowicz, Daniel, Verhofstede, Sabine, Maoujoud, Omar, Malfait, Thomas, Avitum, B. Braun, Fialova, Jana, Melilli, Edoardo, Favà, Alexandre, Cruzado, Josep M., Perez, Nuria Montero, Lips, Joy, Krepel, Harmen, Adilovic, Harun, Hengst, Maaike, Rydzewski, Andrzej, Gellert, Ryszard, Oliveira, João, Alferes, Daniela G., Zakharova, Elena V., Ambuehl, Patrice Max, Walker, Andrea, Winzeler, Rebecca, Lepeytre, Fanny, Rabaté, Clémentine, Rostoker, Guy, Marques, Sofia, Azasevac, Tijana, Katicic, Dajana, ten Dam, Marc, Krüger, Thilo, Brzosko, Szymon, Zanen, Adriaan L., Logtenberg, Susan J. J., Fricke, Lutz, Slebe, Jeroen J. P., Kemlin, Delphine, van de Wetering, Jacqueline, Reinders, Marlies E. J., Eiselt, Jaromir, Kielberger, Lukas, el-Wakil, Hala S., Verhoeven, Martine A. M., Canal, Cristina, Facundo, Carme, Ramos, Ana M., Debska-Slizien, Alicja, Veldhuizen, Nicoline M. H., Tigka, Eirini, Konsta, Maria Anna Polyzou, Panagoutsos, Stylianos, Mallamaci, Francesca, Matceac, Irina, Nistor, Ionut, Cordos, Monica, Groeneveld, J. H. M., Jousma, Jolanda, van Buren, Marjolijn, Elhafeez, Samar Abd, Diekmann, Fritz, Pereira, Tiago Assis, Santos, Augusto Cesar S., Arias-Cabrales, Carlos, Crespo, Marta, Llinàs-Mallol, Laura, Buxeda, Anna, Tàrrega, Carla Burballa, Redondo-Pachon, Dolores, Jimenez, Maria Dolores Arenas, Hofstra, Julia M., Franco, Antonio, Arroyo, David, Rodríguez-Ferrero, Maria Luisa, Manzanos, Sagrario Balda, Barrios, R. Haridian Sosa, Ávila, Gonçalo, Laranjinha, Ivo, Mateus, Catarina, Lemahieu, Wim, Dirim, Ahmet Burak, Demir, Erol, Å afak, Seda, Turkmen, Aydin, Hollander, Daan A. M. J., Büttner, Stefan, de Vries, Aiko P. J., Meziyerh, Soufian, van der Helm, Danny, Mallat, Marko, Bouwsma, Hanneke, Sridharan, Sivakumar, Petruliene, Kristina, Maloney, Sharon-Rose, Verberk, Iris, van der Sande, Frank M., Christiaans, Maarten H. L., Hemmelder, Marc, Kumar, Mohan N., di Luca, Marina, Tuǧlular, Serhan Z., Kramer, Andrea, Beerenhout, Charles, Luik, Peter T., Kerschbaum, Julia, Tiefenthaler, Martin, Adema, Aaltje Y., Stepanov, Vadim A., Zulkarnaev, Alexey B., Turkmen, Kultigin, Fliedner, Anselm, Åsberg, Anders, Mjoen, Geir, Miyasato, Hitoshi, de Fijter, Carola W. H., Mongera, Nicola, Pini, Stefano, de Biase, Consuelo, Duivenvoorden, Raphaël, Hilbrands, Luuk, Kerckhoffs, Angele, Maas, Rutger, Lebedeva, Olga, Lopez, Veronica, Verhave, Jacobien, Titov, Denis, Parshina, Ekaterina V., Zanoli, Luca, Marcantoni, Carmelita, van Gils-Verrij, Liesbeth E. A., Harty, John C., Meurs, Marleen, Myslak, Marek, Battaglia, Yuri, den Deurwaarder, Edwin, Stendahl, Maria, Rahimzadeh, Hormat, Schouten, Marcel, Rychlik, Ivan, Cabezas-Reina, Carlos J., Roca, Ana Maria, Nauta, Ferdau, Kanaan, Nada, Labriola, Laura, Devresse, Arnaud, Diaz-Mareque, Anabel, Coca, Armando, Meijers, Björn K. I., Naesens, Maarten, Kuypers, Dirk, Desschans, Bruno, Tonnelier, Annelies, Wissing, Karl M., de Arriba, Gabriel, Dedinska, Ivana, Pessolano, Giuseppina, Gandolfini, Ilaria, Maggiore, Umberto, Papachristou, Evangelos, Franssen, Casper F. M., Berger, Stefan P., Meijer, Esther, Özyilmaz, Akin, Sanders, Jan Stephan F., Ponikvar, Jadranka Buturović, Pernat, Andreja Marn, Kovac, Damjan, Ekart, Robert, Abrahams, Alferso C., Molenaar, Femke M., van Zuilen, Arjan D., Meijvis, Sabine C. A., Dolmans, Helma, Tantisattamos, Ekamol, Esposito, Pasquale, Krzesinski, Jean-Marie, Barahira, Jean Damacène, Gallieni, Maurizio, Sabiu, Gianmarco, Martin-Moreno, Paloma Leticia, Guglielmetti, Gabriele, Guzzo, Gabriella, Toapanta, Nestor, Luik, Antinus J., van Kuijk, Willi H. M., Stikkelbroeck, Lonneke W. H., Hermans, Marc M. H., Rimsevicius, Laurynas, Righetti, Marco, Islam, Mahmud, Braak, Nicole Heitink-Ter, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Internal Medicine, Clinical sciences, Nephrology, ACS - Diabetes & metabolism, AII - Inflammatory diseases, AII - Infectious diseases, Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Medical Informatics, ACS - Pulmonary hypertension & thrombosis, APH - Aging & Later Life, APH - Quality of Care, ACS - Microcirculation, APH - Health Behaviors & Chronic Diseases, and APH - Global Health
Subjects: medicine.medical_specialty, kidney, Original Article - Dialysis, medicine.medical_treatment, infectious diseases, law.invention, Kidney Failure, SDG 3 - Good Health and Well-being, Renal Dialysis, Risk Factors, law, Internal medicine, medicine, Humans, COVID-19, dialysis, mortality, transplantation, Registries, Renal replacement therapy, Chronic, AcademicSubjects/MED00340, Kidney transplantation, Dialysis, Transplantation, SARS-CoV-2, business.industry, Kidney Transplantation/adverse effects, Hazard ratio, medicine.disease, Kidney Transplantation, Intensive care unit, Comorbidity, Transplant Recipients, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Kidney Failure, Chronic/therapy, Nephrology, Kidney Failure, Chronic, Hemodialysis, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], business
Abstract: BACKGROUND AND AIMS: Studies examining kidney failure patients with COVID-19 reported higher mortality in hemodialysis patients than in kidney transplant recipients. However, hemodialysis patients are often older and have more comorbidities. This study investigated the association of type of kidney replacement therapy with COVID-19 severity adjusting for differences in characteristics. METHOD: Data were retrieved from the European Renal Association COVID-19 Database (ERACODA), which includes kidney replacement therapy patients diagnosed with COVID-19 from all over Europe. We included all kidney transplant recipients and hemodialysis patients who presented between February 1st and December 1st 2020 and had complete information reason for COVID-19 screening and vital status at day 28. The diagnosis of COVID-19 was made based on a PCR of a nasal or pharyngeal swab specimens and/or COVID-19 compatible findings on a lung CT scan. The association of kidney transplantation or hemodialysis with 28-day mortality was examined using Cox proportional-hazards regression models adjusted for age, sex, frailty and comorbidities. Additionally, this association was investigated in the subsets of patients that were screened because of symptoms or have had routine screening. RESULTS: A total of 1,670 patients (496 functional kidney transplant recipients and 1,174 hemodialysis patients) were examined. 16.9% of kidney transplant recipients and 23.9% of hemodialysis patients died within 28 days of presentation. In an unadjusted model, the risk of 28-day mortality was 33% lower in kidney transplant recipients compared with hemodialysis patients (hazard ratio (HR): 0.67, 95% CI: 0.52, 0.85). However, in an age, sex and frailty adjusted model, the risk of 28-day mortality was 29% higher in kidney transplant recipients (HR=1.29, 95% CI: 1.00, 1.68), whereas in a fully adjusted model the risk was even 43% higher (HR=1.43, 95% CI: 1.06, 1.93). This association in patients who were screened because of symptoms (n=1,145) was similar (fully adjusted model HR=1.46, 95% CI: 1.05, 2.04). Results were similar when other endpoints were studied (e.g. risk for hospitalization, ICU admission or mortality beyond 28 days) as well as across subgroups. Only age was found to interact significantly, suggesting that the increased mortality risk associated with kidney transplantation was especially present in elderly subjects. CONCLUSION: In this study, kidney transplant recipients had a greater risk of a more severe course of COVID-19 compared with hemodialysis patients when adjusted for age, sex and comorbidities.
Published: 2021
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188. Clinical presentation, disease course, and outcome of COVID-19 in hospitalized patients with and without pre-existing cardiac disease: a cohort study across 18 countries

Author: Linschoten, M, Uijl, A, Schut, A, Jakob, CEM, Romao, LR, Bell, RM, McFarlane, E, Stecher, M, Zondag, AGM, van Iperen, EPA, Hermans-van Ast, JF, Lea, NC, Schaap, J, Jewbali, LS, Smits, PC, Patel, RS, Aujayeb, A, van Smeden, M, Siebelink, HJ, Williams, S, Pilgram, L, Tieleman, RG, Williams, B, Asselbergs, FW, Al-Ali, AK, Al-Muhanna, FA, Al-Rubaish, AM, Al-Windy, NYY, Alkhalil, M, Almubarak, YA, Al Nafie, AN, Al Shahrani, M, Al Shehri, AM, Anning, C, Anthonio, RL, Badings, EA, Ball, C, Van Beek, EA, Ten Berg, JM, Von Bergwelt-Baildon, M, Bianco, M, Blagova, O, Bleijendaal, H, Bor, WL, Borgmann, S, van Boxem, AJM, van den Brink, FS, Bucciarelli-Ducci, C, Van Bussel, BCT, Byrom-Goulthorp, R, Captur, G, Caputo, M, Charlotte, N, vom Dahl, J, Dark, P, De Sutter, J, Degenhardt, C, Delsing, CE, Dolff, S, Dorman, HGR, Drost, JT, Eberwein, L, Emans, ME, Er, AG, Ferreira, JB, Forner, MJ, Friedrichs, A, Gabriel, L, Groenemeijer, BE, Groenendijk, AL, Gruener, B, Guggemos, W, Haerkens-Arends, HE, Hanses, F, Hedayat, B, Heigener, D, van der Heijden, DJ, Hellou, E, Hellwig, K, Henkens, MTHM, Hermanides, RS, Hermans, WRM, van Hessen, MWJ, Heymans, SRB, Hilt, AD, van der Horst, ICC, Hower, M, van Ierssel, SH, Isberner, N, Jensen, B, Kearney, MT, Kielstein, JT, Kietselaer, BLJH, Kochanek, M, Kolk, MZH, Koning, AMH, Kopylov, PY, Kuijper, AFM, Kwakkel-van, ERPJM, Lanznaster, J, van der Linden, MMJM, van der Lingen, ACJ, Linssen, GCM, Lomas, D, Maarse, M, Magdelijns, FJH, Magro, M, Markart, P, Martens, FMAC, Mazzilli, SG, McCann, GP, van der Meer, P, Meijs, MFL, Merle, U, Messiaen, P, Milovanovic, M, Monraats, PS, Montagna, L, Moriarty, A, Moss, AJ, Mosterd, A, Nadalin, S, Nattermann, J, Neufang, M, Nierop, PR, Offerhaus, JA, Van Ofwegen-Hanekamp, CEE, Parker, E, Persoon, AM, Piepel, C, Pinto, YM, Poorhosseini, H, Prasad, S, Raafs, AG, Raichle, C, Rauschning, D, Redon, J, Reidinga, AC, Ribeiro, MIA, Riedel, C, Rieg, S, Ripley, DP, Rommele, C, Rothfuss, K, Ruddel, J, Ruthrich, MM, Salah, R, Saneei, E, Saxena, M, Schellings, DAAM, Scholte, NTB, Schubert, J, Seelig, J, Shafiee, A, Shore, AC, Spinner, C, Stieglitz, S, Strauss, R, Sturkenboom, NH, Tessitore, E, Thomson, RJ, Timmermans, PJR, Tio, RA, Tjong, FVY, Tometten, L, Trauth, J, Van Craenenbroeck, EM, van Veen, HPAA, den Uil, CA, Vehreschild, MJGT, Veldhuis, L, Veneman, T, Verschure, DO, Voigt, I, Walter, L, vande Watering, DJ, de Vries, JK, vande Wal, RMA, Westendorp, ICD, Westendorp, PHM, Westhoff, T, Weytjens, C, Wierda, E, Wille, K, de With, K, Worm, M, Woudstra, P, Wu, KW, Zaal, R, Zaman, AG, van der Zee, PM, Zijlstra, LE, Alling, TE, Ahmed, R, Bayraktar-Verver, ECE, van Aken, K, Jimenes, Bermudez FJ, Biole, CA, Den Boer-Penning, P, Bontje, M, Bos, M, Bosch, L, Broekman, M, Broeyer, FJF, de Bruijn, EAW, Bruinsma, S, Cardoso, NM, Cosyns, B, Len, van Da DH, Dekimpe, E, Domange, J, van Doorn, JL, van DOorn, P, Dormal, F, Drost, IMJ, Dunnink, A, van Eck, JWM, Elshinawy, K, Gevers, RMM, Gognieva, DG, van der Graaf, M, Grangeon, S, Guclu, A, Habib, A, Haenen, NA, Hamilton, K, Handgraaf, S, Heidbuchel, H, Hendriks-van Woerden, M, Hessels-Linnemeijer, BM, Hosseini, K, Huisman, J, Jacobs, TC, Jansen, SE, Janssen, A, Jourdan, K, ten Kate, GL, van Kempen, MJ, Kievit, CM, Kleikers, P, Knufman, N, van der Kooi, SE, Koole, BAS, Koole, MAC, Kui, KK, Kuipers-Elferink, L, Lemoine, I, Lensink, E, van Marrewijk, V, Meijer, EJ, Melein, AJ, Mesitskaya, DF, van Nes, CPM, Paris, FMA, Perrelli, MG, Pieterse-Rots, A, Pisters, R, Polkerman, BC, van Poppel, A, Reinders, S, Reitsma, MJ, Ruiter, AH, Selder, JL, van der Sluis, A, Sousa, AIC, Tajdini, M, Sanchez, Tercedor L, Van de Heyning, CM, Vial, H, Vlieghe, E, Vonkeman, HE, Vreugdenhil, P, de Vries, TAC, Willems, AM, Wils, AM, Zoet-Nugteren, SK, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Cardiology, Intensive Care, RS: CAPHRI - R5 - Optimising Patient Care, MUMC+: MA Medische Staf IC (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - V04 Surgical intervention, MUMC+: MA Intensive Care (3), UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de cardiologie, CAPACITY-COVID Collaborative Consortium, LEOSS Study Group, Rheumatology, AII - Infectious diseases, AII - Inflammatory diseases, AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, ACS - Heart failure & arrhythmias, General practice, Epidemiology and Data Science, Graduate School, Nuclear Medicine, and ACS - Atherosclerosis & ischemic syndromes
Subjects: Male, Cardiac & Cardiovascular Systems, Epidemiology, education, Medizin, Comorbidity, AMERICAN-COLLEGE, GUIDELINES, DIAGNOSIS, Cohort Studies, Risk Factors, MANAGEMENT, Humans, AcademicSubjects/MED00200, Hospital Mortality, Aged, Heart Failure, Science & Technology, SARS-CoV-2, COVID-19, ASSOCIATION, Cardiovascular disease, EUROPEAN-SOCIETY, Hospitalization, surgical procedures, operative, Editorial, Cardiovascular System & Cardiology, behavior and behavior mechanisms, HEART-FAILURE, Female, Patient registry, Human medicine, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, psychological phenomena and processes, TASK-FORCE
Abstract: Aims Patients with cardiac disease are considered high risk for poor outcomes following hospitalization with COVID-19. The primary aim of this study was to evaluate heterogeneity in associations between various heart disease subtypes and in-hospital mortality. Methods and results We used data from the CAPACITY-COVID registry and LEOSS study. Multivariable Poisson regression models were fitted to assess the association between different types of pre-existing heart disease and in-hospital mortality. A total of 16 511 patients with COVID-19 were included (21.1% aged 66–75 years; 40.2% female) and 31.5% had a history of heart disease. Patients with heart disease were older, predominantly male, and often had other comorbid conditions when compared with those without. Mortality was higher in patients with cardiac disease (29.7%; n = 1545 vs. 15.9%; n = 1797). However, following multivariable adjustment, this difference was not significant [adjusted risk ratio (aRR) 1.08, 95% confidence interval (CI) 1.02–1.15; P = 0.12 (corrected for multiple testing)]. Associations with in-hospital mortality by heart disease subtypes differed considerably, with the strongest association for heart failure (aRR 1.19, 95% CI 1.10–1.30; P Conclusion Considerable heterogeneity exists in the strength of association between heart disease subtypes and in-hospital mortality. Of all patients with heart disease, those with heart failure are at greatest risk of death when hospitalized with COVID-19. Serious cardiac complications are rare during hospitalization.
Published: 2021
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189. Hemoglobin and Clinical Outcomes in the Vericiguat Global Study in Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA)

Author: Javed Butler, Adrian F. Hernandez, Paul W. Armstrong, Justin A. Ezekowitz, Piotr Ponikowski, Cynthia M. Westerhout, Vojtěch Melenovský, Burkert Pieske, Ciaran McMullan, Yinggan Zheng, Adriaan A. Voors, Jorge Escobedo, Christopher DeFilippi, Lothar Roessig, Carolyn S.P. Lam, Christopher M. O'Connor, Alain Cohen-Solal, leboeuf, Christophe, University of Alberta, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institute of Clinical and Experimental Medicine [Prague, Czech Republic] (ICEM), Mexican Social Security Institute [Mexico City] (M2SI), University of Mississippi Medical Center (UMMC), Duke University Medical Center, Duke-National University of Singapore Graduate Medical School, Inova Heart and Vascular Institute [Falls Church, VA, USA] (IHVI), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Wrocław Medical University, University of Groningen [Groningen], Merck & Co., Inc. [Kenilworth, NJ, États-Unis], Bayer AG [Wuppertal, Germany], and Cardiovascular Centre (CVC)
Subjects: Male, medicine.medical_specialty, Anemia, vericiguat, heart failure, World Health Organization, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Internal medicine, medicine, Humans, In patient, hemoglobins, Aged, Ejection fraction, business.industry, Stroke Volume, medicine.disease, anemia, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Treatment Outcome, Heart failure, Cardiology, Vericiguat, Female, Hemoglobin, Cardiology and Cardiovascular Medicine, business
Abstract: Background: In the VICTORIA trial (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction), anemia occurred more often in patients treated with vericiguat (7.6%) than with placebo (5.7%). We explored the association between vericiguat, randomization hemoglobin, development of anemia, and whether the benefit of vericiguat related to baseline hemoglobin. Methods: Anemia was defined as hemoglobin Results: At baseline, 1719 (35.7%) patients had World Health Organization anemia; median hemoglobin was 13.4 g/L (25th, 75th percentile: 12.1, 14.7 g/dL). At 16 weeks from randomization, 1643 patients had World Health Organization anemia (284 new for vericiguat and 219 for placebo), which occurred more often with vericiguat than placebo ( P Conclusions: Anemia was common at randomization and lower hemoglobin was associated with a greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor was it related to the treatment benefit of vericiguat. Registration: URL: https://www.clinicaltrials.gov : Unique identifier: NCT02861534.
Published: 2021
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190. Prehospital risk stratification in patients with chest pain

Author: Robert van Barneveld, Vincent E. Hagens, Wybe Nieuwland, E Lipsic, Pim van der Harst, Edward Jorna, Louis Bartels, Carien van Well, Peter van der Meer, Thea van Asselt, YJ Gu, Dennis Sagel, Luis Juarez Orozco, Ryanne Addink, Roelof Lettinga, Antoon Oomen, Derk Drenth, Radboud van Roosmalen, Ingmar Waardenburg, Sjoerd Hofma, Roelof Kijlstra, Pieter J. Vlaar, Rutger L. Anthonio, Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
Subjects: Male, Acute coronary syndrome, medicine.medical_specialty, Chest Pain, Chest Pain/complications, Emergency Medical Services, Cost effectiveness, effectiveness, Netherlands/epidemiology, cardiac care, Critical Care and Intensive Care Medicine, Chest pain, Risk Assessment, Hospital/organization & administration, acute coronary syndrome, Risk Management/methods, Risk Factors, medicine, Humans, Myocardial infarction, Prospective Studies, Prospective cohort study, Risk Assessment/methods, Netherlands, Original Research, Aged, Risk Management, Emergency Service, cost effectiveness, business.industry, General Medicine, Emergency department, Middle Aged, medicine.disease, prehospital care, ROC Curve, emergency ambulance systems, Emergency Service, Hospital/organization & administration, Area Under Curve, Emergency medicine, Cohort, Emergency Medicine, Female, medicine.symptom, business, Emergency Service, Hospital, Mace
Abstract: ObjectivesThe History, ECG, Age, Risk Factors and Troponin (HEART) Score is a decision support tool applied by physicians in the emergency department developed to risk stratify low-risk patients presenting with chest pain. We assessed the potential value of this tool in prehospital setting, when applied by emergency medical services (EMS), and derived and validated a tool adapted to the prehospital setting in order to determine if it could assist with decisions regarding conveyance to a hospital.MethodsIn 2017, EMS personnel prospectively determined the HEART Score, including point-of-care (POC) troponin measurements, in patients presenting with chest pain, in the north of the Netherlands. The primary endpoint was a major adverse cardiac event (MACE), consisting of acute myocardial infarction or death, within 3 days. The components of the HEART Score were evaluated for their discriminatory value, cut-offs were calibrated for the prehospital setting and sex was substituted for cardiac risk factors to develop a prehospital HEART (preHEART) Score. This score was validated in an independent prospective cohort of 435 patients in 2018.ResultsAmong 1208 patients prospectively recruited in the first cohort, 123 patients (10.2%) developed a MACE. The HEART Score had a negative predictive value (NPV) of 98.4% (96.4–99.3), a positive predictive value (PPV) of 35.5% (31.8–39.3) and an area under the receiver operating characteristic curve (AUC) of 0.81 (0.78–0.85). The preHEART Score had an NPV of 99.3% (98.1–99.8), a PPV of 49.4% (42.0–56.9) and an AUC of 0.85 (0.82–0.88), outperforming the HEART Score or POC troponin measurements on their own. Similar results were found in a validation cohort.ConclusionsThe HEART Score can be used in the prehospital setting to assist with conveyance decisions and choice of hospitals; however, the preHEART Score outperforms both the HEART Score and single POC troponin measurements when applied by EMS personnel in the prehospital setting.
Published: 2021
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191. TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility

Author: Aafke Engwerda, Maarten P. van den Berg, Wilhelmina S. Kerstjens-Frederikse, Yvonne J. Vos, Bert B.A. de Vries, Tuula Rinne, Marc T R Roofthooft, Paulien A Terhal, Patrick Deelen, Conny M. A. van Ravenswaaij-Arts, Barbara Frentz, Katharina Löhner, Trijnie Dijkhuizen, Erika Leenders, Cardiovascular Centre (CVC), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: Joint Instability, CONGENITAL HEART-DEFECTS, Pathology, medicine.medical_specialty, TAK1, Heart Valve Diseases, Cardiomyopathy, GROWTH FAILURE, Dwarfism, Disease, Short stature, Article, Mitral valve, Genetics, medicine, Humans, MICRODELETION, DYSPLASIA, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, business.industry, Syndrome, medicine.disease, Phenotype, DELINEATION, medicine.anatomical_structure, Mitral Valve, Noonan syndrome, Chromosomes, Human, Pair 6, medicine.symptom, Cardiomyopathies, Haploinsufficiency, business, Gene Deletion
Abstract: Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.1 deletion that includes TAB2. To confirm if this phenotype is caused by haploinsufficiency of TAB2 and to delineate a TAB2-related phenotype, we subsequently sequenced TAB2 in patients with matching phenotypes and recruited patients with pathogenic TAB2 variants detected by exome sequencing. This identified 11 patients with a deletion containing TAB2 (size 1.68-14.31 Mb) and 14 patients from six families with novel truncating TAB2 variants. Twenty (80%) patients had cardiac disease, often mitral valve defects and/or cardiomyopathy, 18 (72%) had short stature and 18 (72%) had hypermobility. Twenty patients (80%) had facial features suggestive for Noonan syndrome. No substantial phenotypic differences were noted between patients with deletions and those with intragenic variants. We then compared our patients to 45 patients from the literature. All literature patients had cardiac diseases, but syndromic features were reported infrequently. Our study shows that the phenotype in 6q25.1 deletions is caused by haploinsufficiency of TAB2 and that TAB2 is associated not just with cardiac disease, but also with a distinct phenotype, with features overlapping with Noonan syndrome. We propose the name "TAB2-related syndrome".
Published: 2021
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192. Large Between-Patient Variability in eGFR Decline before Clinical Trial Enrollment and Impact on Atrasentan’s Efficacy

Author: Hans-Henrik Parving, José Luis Górriz, Sydney C.W. Tang, Michele Provenzano, Luca De Nicola, Simke W. Waijer, Dick de Zeeuw, Julio Pascual, Christoph Wanner, Robert S. Busch, Ron T. Gansevoort, Di Xie, Fan Fan Hou, Sieta T. de Vries, Pablo E. Pergola, Philippe Zaoui, Gozewijn D. Laverman, Hiddo J.L. Heerspink, Waijer, S. W., de Vries, S. T., Busch, R., Xie, D., Gansevoort, R. T., Hou, F. F., Gorriz, J. L., Laverman, G. D., de Nicola, L., Pascual, J., Provenzano, M., Pergola, P. E., Tang, S. C. W., Wanner, C., Zaoui, P., Parving, H. -H., de Zeeuw, D., Heerspink, H. J. L., Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Biomedical Signals and Systems
Subjects: Oncology, medicine.medical_specialty, MEDLINE, eGFR decline, Type 2 diabetes, Egfr decline, endothelin receptor antagonist, law.invention, Randomized controlled trial, law, Internal medicine, Post-hoc analysis, medicine, business.industry, Endothelin receptor antagonist, Atrasentan, 22/2 OA procedure, General Medicine, medicine.disease, Clinical trial, Nephrology, randomized controlled trial, type 2 diabetes, business, chronic kidney disease, medicine.drug
Abstract: n/a.
Published: 2021
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193. Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF)

Author: Jonathan M. Coutinho, Berber Zweedijk, Catharina J.M. Klijn, Floris H.B.M. Schreuder, Gert P Messchendorp, Ido R. van den Wijngaard, Isabelle C. Van Gelder, Apache-Af Trial Investigators, P. J. A. M. Brouwers, H. Paul Bienfait, Michel J M Remmers, Jeannette Hofmeijer, Henk Kerkhoff, Diederik W.J. Dippel, Koen M. van Nieuwenhuizen, Antonia H C M L Schreuder, Julie Staals, Gabriel J.E. Rinkel, L. Jaap Kappelle, Julia H. van Tuijl, Suzanne J Booij, Marieke J.H. Wermer, Jan Willem van Dalen, Sarah E. Vermeer, Ale Algra, H. Bart van der Worp, Gert-Jan Luijckx, Elles Zock, Roger E. G. Schutgens, Vincent I. H. Kwa, ANS - Neuroinfection & -inflammation, Neurology, ACS - Atherosclerosis & ischemic syndromes, ANS - Neurovascular Disorders, Cardiovascular Centre (CVC), Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and RS: Carim - B05 Cerebral small vessel disease
Subjects: Male, medicine.medical_specialty, INTRACRANIAL HEMORRHAGE, Pyridones, Population, Netherlands/epidemiology, SECONDARY PREVENTION, All institutes and research themes of the Radboud University Medical Center, Modified Rankin Scale, Internal medicine, Atrial Fibrillation, Medicine, Humans, Prospective Studies, Adverse effect, education, Stroke, Cerebral Hemorrhage, Netherlands, ORAL ANTICOAGULANTS, APACHE, Aged, education.field_of_study, VASCULAR EVENTS, business.industry, Proportional hazards model, Hazard ratio, Anticoagulants, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], Atrial fibrillation, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Cerebral Hemorrhage/chemically induced, Treatment Outcome, Pyrazoles, Apixaban, Female, Neurology (clinical), ANTITHROMBOTIC TREATMENT, business, Anticoagulants/adverse effects, Atrial Fibrillation/complications, Stroke/drug therapy, STROKE, medicine.drug
Abstract: Background: In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial. Methods: APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7–90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites. Findings: Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73–83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21–74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0–3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7–21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2–20·8]; adjusted hazard ratio 1·05 [95% CI 0·48–2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation. Interpretation: Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous. Funding: Dutch Heart Foundation (grant 2012T077).
Published: 2021

194. Association of Circulating Ketone Bodies With Functional Outcomes After ST-Segment Elevation Myocardial Infarction

Author: Erik Lipsic, B. Daan Westenbrink, Marie Sophie L.Y. de Koning, Pim van der Harst, Solmaz Assa, Dirk J. van Veldhuisen, Erwin Garcia, Robin P. F. Dullaart, Margery A. Connelly, and Cardiovascular Centre (CVC)
Subjects: Male, medicine.medical_specialty, Ischemia, Cardiac magnetic resonance imaging, Interquartile range, Internal medicine, Natriuretic Peptide, Brain, medicine, Humans, Hypoglycemic Agents, ST segment, Myocardial infarction, cardiovascular diseases, Aged, Ejection fraction, medicine.diagnostic_test, business.industry, Myocardium, Stroke Volume, Recovery of Function, Middle Aged, medicine.disease, ischemia/reperfusion, Peptide Fragments, Metformin, myocardial infarction, Heart failure, ketone bodies, Cardiology, ST Elevation Myocardial Infarction, Female, Cardiology and Cardiovascular Medicine, business, metformin, metabolism, Biomarkers, medicine.drug
Abstract: Background: Circulating ketone bodies (KBs) are increased in patients with heart failure (HF), corresponding with increased cardiac KB metabolism and HF severity. However, the role of circulating KBs in ischemia/reperfusion remains unknown. Objectives: This study sought to investigate longitudinal changes of KBs and their associations with functional outcomes in patients presenting with ST-segment elevation myocardial infarction (STEMI). Methods: KBs were measured in 369 participants from a randomized trial on early metformin therapy after STEMI. Nonfasting plasma concentrations of KBs (β-hydroxybutyrate, acetoacetate, and acetone) were measured by nuclear magnetic resonance spectroscopy at presentation, at 24 hours, and after 4 months. Myocardial infarct size and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging at 4 months. Associations of circulating KBs with infarct size and LVEF were determined using multivariable linear regression analyses. Results: Circulating KBs were high at presentation with STEMI (median total KBs: 520 μmol/L; interquartile range [IQR]: 315-997 μmol/L). At 24 hours after reperfusion, KBs were still high compared with levels at 4-month follow-up (206 μmol/L [IQR: 174-246] vs 166 μmol/L [IQR: 143-201], respectively; P < 0.001). Increased KB concentrations at 24 hours were independently associated with larger myocardial infarct size (total KBs, per 100 μmol/L: β = 1.56; 95% confidence interval: 0.29-2.83; P = 0.016) and lower LVEF (β = −1.78; 95% CI: (−3.17 to −0.39; P = 0.012). Conclusions: Circulating KBs are increased in patients presenting with STEMI. Higher KBs at 24 hours are associated with functional outcomes after STEMI, which suggests a potential role for ketone metabolism in response to myocardial ischemia. (Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III): a Randomized Controlled Trial; NCT01217307)
Published: 2021
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195. First-line treatment of persistent and long-standing persistent atrial fibrillation with single-stage hybrid ablation

Author: Isabelle C. Van Gelder, Federico T Magni, Michiel Rienstra, Yuri Blaauw, Massimo A. Mariani, Bart A. Mulder, Theo J. Klinkenberg, Meelad I H Al-Jazairi, and Cardiovascular Centre (CVC)
Subjects: Tachycardia, Male, medicine.medical_specialty, medicine.medical_treatment, Catheter ablation, Recurrence, Clinical Research, Physiology (medical), Internal medicine, medicine, Humans, Sinus rhythm, AcademicSubjects/MED00200, Prospective Studies, Prospective cohort study, medicine.diagnostic_test, business.industry, Surgical ablation, Atrial fibrillation, Hybrid atrial fibrillation ablation, medicine.disease, Ablation, Ablation for Atrial Fibrillation, Treatment Outcome, Cardiology, Catheter Ablation, Electrocardiography, Ambulatory, medicine.symptom, Persistent atrial fibrillation, Cardiology and Cardiovascular Medicine, business, Electrocardiography, Atrial flutter, Follow-Up Studies
Abstract: Aims This study evaluates the efficacy and safety of first-line single-stage hybrid ablation of (long-standing) persistent atrial fibrillation (AF), over a follow-up period of 2 years, and provides additional information on arrhythmia recurrences and electrophysiological findings at repeat ablation. Methods and results This is a prospective cohort study that included 49 patients (65% persistent AF; 35% long-standing persistent AF) who underwent hybrid ablation as first-line ablation treatment (no previous endocardial ablation). Patients were relatively young (57.0 ± 8.5 years) and predominantly male (89.8%). Median CHA2DS2-VASc score was 1.0 (0.5; 2.0) and mean left atrium volume index was 43.7 ± 10.9 mL/m2. Efficacy was assessed by 12-lead electrocardiography and 72-h Holter monitoring after 3, 6, 12, and 24 months. Recurrence was defined as AF/atrial flutter (AFL)/tachycardia (AT) recorded by electrocardiography or Holter monitoring lasting >30 s during 2-year follow-up. At 2-year follow-up, single and multiple procedure success rates were 67% and 82%, respectively. Two (4%) patients experienced a major complication (bleeding) requiring intervention following hybrid ablation. Among the 16 (33%) patients who experienced an AF/AFL/AT recurrence, 13 (81%) were ATs/AFLs and only 3 (19%) were AF. Repeat ablation was performed in 10 (20%) patients and resulted in sinus rhythm in 7 (70%) at 2-year follow-up. Conclusion First-line single-stage hybrid AF ablation is an effective treatment strategy for patients with persistent and long-standing persistent AF with an acceptable rate of major complications. Recurrences are predominantly AFL/AT that can be successfully ablated percutaneously. Hybrid ablation seems a feasible approach for first-line ablation of (long-standing) persistent AF.
Published: 2021
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196. Albuminuria Testing in Hypertension and Diabetes

Author: Jung-Im Shin, Alex R. Chang, Morgan E. Grams, Josef Coresh, Shoshana H. Ballew, Aditya Surapaneni, Kunihiro Matsushita, Henk J.G. Bilo, Juan J. Carrero, Gabriel Chodick, Kenn B. Daratha, Simerjot K. Jassal, Girish N. Nadkarni, Robert G. Nelson, Christoph Nowak, Nikita Stempniewicz, Keiichi Sumida, Jamie P. Traynor, Mark Woodward, Yingying Sang, Ron T. Gansevoort, John Chalmers, Katherine Tuttle, Radica Alicic, Sterling McPherson, Cami Jones, Gurmukteshwar Singh, Jamie Green, H. Lester Kirchner, Varda Shalev, Erwin P. Bottinger, Ruth J.F. Loos, Stephen B. Ellis, John Cuddeback, Elizabeth Ciemins, Emily Carbonara, Stephan Dunning, William C. Knowler, Helen C. Looker, Lyane M. Kieneker, Stephan J.L. Bakker, Hans L. Hillege, Pim van der Harst, Jacklyn Bergstrom, Joachim Ix, Csaba P. Kovesdy, Praveen Potukuchi, Marco Trevisan, Carl Gustaf Elinder, Björn Wettermark, Johan Ärnlöv, Patrick B. Mark, Peter C. Thomson, Colin C. Geddes, Gijs W.D. Landman, Kornelis J.J. van Hateren, Nanne Kleefstra, Orlando Gutierrez, Tsuneo Konta, Andrew S. Levey, Kevan Polkinghorne, Elke Schäffner, Jingsha Chen, Aditya Surapeneni, Groningen Kidney Center (GKC), and Cardiovascular Centre (CVC)
Subjects: Adult, medicine.medical_specialty, Article, Diabetes mellitus, Internal medicine, Internal Medicine, Diabetes Mellitus, Medicine, Albuminuria, Humans, Renal Insufficiency, Chronic, Aged, business.industry, Incidence (epidemiology), Odds ratio, Middle Aged, medicine.disease, Blood pressure, Meta-analysis, Creatinine, Cohort, Hypertension, medicine.symptom, business, Kidney disease, Glomerular Filtration Rate
Abstract: Albuminuria is an under-recognized component of chronic kidney disease definition, staging, and prognosis. Guidelines, particularly for hypertension, conflict on recommendations for urine albumin-to-creatinine ratio (ACR) measurement. Separately among 1 344 594 adults with diabetes and 2 334 461 nondiabetic adults with hypertension from the chronic kidney disease Prognosis Consortium, we assessed ACR testing, estimated the prevalence and incidence of ACR ≥30 mg/g and developed risk models for ACR ≥30 mg/g. The ACR screening rate (cohort range) was 35.1% (12.3%–74.5%) in diabetes and 4.1% (1.3%–20.7%) in hypertension. Screening was largely unrelated to the predicted risk of prevalent albuminuria. The median prevalence of ACR ≥30 mg/g across cohorts was 32.1% in diabetes and 21.8% in hypertension. Higher systolic blood pressure was associated with a higher prevalence of albuminuria (odds ratio [95% CI] per 20 mm Hg in diabetes, 1.50 [1.42–1.60]; in hypertension, 1.36 [1.28–1.45]). The ratio of undetected (due to lack of screening) to detected ACR ≥30 mg/g was estimated at 1.8 in diabetes and 19.5 in hypertension. Among those with ACR
Published: 2021

197. Identification of sex‐specific biomarkers predicting new‐onset heart failure

Author: Anne G. Raafs, Christian Delles, Andrew L. Clark, Arantxa González, Nicolas Vodovar, Timothy Collier, Michiel T H M Henkens, Jan A. Staessen, Javier Díez, Alessandro Boccanelli, João Pedro Ferreira, Florence Pinet, Ping Wang, Patrick Rossignol, Mark R. Hazebroek, Vanessa P. M. van Empel, John G.F. Cleland, Faiez Zannad, J. Wouter Jukema, Rudolf A. de Boer, Jens Björkman, Nicolas Girerd, Thomas Thum, Stephane Heymans, Job Verdonschot, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Cardiovascular Research Institute Maastricht (CARIM), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), London School of Hygiene and Tropical Medicine (LSHTM), TATAA Biocenter AB, Casa di Cura Quisisana, University of Hull [United Kingdom], Castle Hill Hospital, Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, CIBERCV, Carlos III Institute of Health, Instituto de Investigacion Sanitaria de Navarra (IdiSNA), Universidad de Navarra [Pamplona] (UNAV), Clínica Universidad de Navarra [Pamplona], Netherlands Heart Institute, Partenaires INRAE, Leiden University Medical Center (LUMC), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris (UP), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, University Medical Center Groningen [Groningen] (UMCG), Non-Profit Research Institute Alliance for the Promotion of Preventive Medicine, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Robertson Centre for Biostatistics and Clinical Trials, Institute of Health and Wellbeing, Royal Brompton and Harefield NHS Foundation Trust, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, The research leading to these results has received funding from the European Union Commission's Seventh Framework Programme under grant agreement 305507 [HOMAGE (Heart Omics in Ageing consortium)]. We acknowledge the support from the Netherlands Cardiovascular Research Initiative, an initiative with the support of the Dutch Heart Foundation CVON2016-Early HFPEF, and CVON 2017-21, SHE-PREDICTS-HF. JPF, NG, PR, and FZ are supported by the Contrat de Plan Etat-Lorraine and FEDER Lorraine, and a public grant overseen by the French National Research Agency (ANR) as part of the second 'Investissements d'Avenir' programme FIGHT-HF (reference: ANR-15-RHU-0004) and by the French PIA project 'Lorraine Université d'Excellence', reference ANR-15-IDEX-04-LUE. They thank the CRB lorrain for biobaking activities. JAS is supported by the Non-Profit Research Institute Alliance for the Promotion of Preventive Medicine (URL: http://www.appremed.org), Mechelen, Belgium received a non-binding research grant from OMRON Healthcare Co., Ltd., Kyoto, Japan., ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), European Project: 305507, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universiteit Leiden, Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Cardiologie, RS: Carim - H02 Cardiomyopathy, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: MA Med Staf Spec Cardiologie (9), MUMC+: MA Med Staf Artsass Cardiologie (9), Cardiovascular Centre (CVC), BOZEC, Erwan, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, HOMAGE (Heart Omics in Ageing consortium) - 305507 - INCOMING, and Publica
Subjects: Male, Proteomics, Cardiac & Cardiovascular Systems, Disease, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, DESIGN, Original Research Articles, Medicine, Original Research Article, 030212 general & internal medicine, ASSOCIATIONS, RISK, Sex Characteristics, WOMEN, Pathophysiology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Cohort, Biomarker (medicine), Female, ADIPOSITY, HORMONES, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, medicine.medical_specialty, Incident heart failure, New onset, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Sex differences, Humans, Diseases of the circulatory (Cardiovascular) system, ANTAGONIST, Heart Failure, Science & Technology, business.industry, INTERLEUKIN-17, medicine.disease, GENE, Interleukin 1 receptor antagonist, Case-Control Studies, Heart failure, RC666-701, Cardiovascular System & Cardiology, IL17A, business, Biomarkers
Abstract: AIMS: Heart failure (HF) is common in both men and women, yet disease pathophysiology, presentation, and progression differ between sexes. Studies addressing whether biomarkers predict new onset HF sex-specifically are scarce. This study therefore aims to test the sex-specificity of 252 protein biomarkers for new-onset HF. METHODS AND RESULTS: A matched case-control design in patients selected from cohorts within the HOMAGE consortium was used. Cases (new-onset HF, n = 562) and controls (n = 780) were matched for cohort (PREDICTOR, HEALTH-ABC, & PROSPER), follow-up time (defined as time from entry to incident HF), and age. Incident HF was defined as first hospitalization for HF. Targeted plasma proteins (n = 252) were measured using Proximity Extension Assay technology from O-link. To look for sex differences for new onset HF, we adjusted for cohort, age, and baseline clinical parameters. At baseline, women had a biomarker profile reflecting activated metabolism and immune responses. However, none of the biomarkers had a significant interaction with sex in predicting new onset HF, but four biomarkers had a trend towards sex-specificity (P
Published: 2021
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198. Classification of moving coronary calcified plaques based on motion artifacts using convolutional neural networks: a robotic simulating study on influential factors

Author: Magdalena Dobrolinska, Beibei Jiang, Marcel J. W. Greuter, Niels R van der Werf, Riemer H. J. A. Slart, Xueqian Xie, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Translational Immunology Groningen (TRIGR), Cardiovascular Centre (CVC), and Radiology & Nuclear Medicine
Subjects: Artificial intelligence, Computer science, Coronary Artery Disease, Iterative reconstruction, Radiation Dosage, Convolutional neural network, Imaging phantom, Motion, Motion artifacts, medicine, Medical technology, Radiology, Nuclear Medicine and imaging, Imaging phantoms, R855-855.5, X-ray computed tomography, Radon transform, Phantoms, Imaging, business.industry, Ranging, Pattern recognition, Robotics, Plaque, Atherosclerotic, Coronary arteries, medicine.anatomical_structure, Radiographic Image Interpretation, Computer-Assisted, Neural Networks, Computer, Tomography, X-Ray Computed, business, Artifacts, Robotic arm, Research Article
Abstract: Background Motion artifacts affect the images of coronary calcified plaques. This study utilized convolutional neural networks (CNNs) to classify the motion-contaminated images of moving coronary calcified plaques and to determine the influential factors for the classification performance. Methods Two artificial coronary arteries containing four artificial plaques of different densities were placed on a robotic arm in an anthropomorphic thorax phantom. Each artery moved linearly at velocities ranging from 0 to 60 mm/s. CT examinations were performed with four state-of-the-art CT systems. All images were reconstructed with filtered back projection and at least three levels of iterative reconstruction. Each examination was performed at 100%, 80% and 40% radiation dose. Three deep CNN architectures were used for training the classification models. A five-fold cross-validation procedure was applied to validate the models. Results The accuracy of the CNN classification was 90.2 ± 3.1%, 90.6 ± 3.5%, and 90.1 ± 3.2% for the artificial plaques using Inception v3, ResNet101 and DenseNet201 CNN architectures, respectively. In the multivariate analysis, higher density and increasing velocity were significantly associated with higher classification accuracy (all P P > 0.05). Conclusions The CNN achieved a high accuracy of 90% when classifying the motion-contaminated images into the actual category, regardless of different vendors, velocities, radiation doses, and reconstruction algorithms, which indicates the potential value of using a CNN to correct calcium scores.
Published: 2021

199. Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure

Author: Karl Wegscheider, Christina Magnussen, Paulus Kirchhof, Anna Suling, Ann-Kathrin Ozga, Isabelle C. Van Gelder, Harry J.G.M. Crijns, Andreas Goette, Günter Breithardt, Karl-Heinz Kuck, Michele Massimo Gulizia, Axel Brandes, Lukasz Szumowski, Andreas Rillig, Arif Elvan, A. John Camm, Hein Heidbuchel, Andre Ng, Laurent M. Haegeli, Lars Eckardt, Cardiovascular Centre (CVC), RS: Carim - H01 Clinical atrial fibrillation, Cardiologie, and MUMC+: MA Cardiologie (9)
Subjects: Adult, Male, Acute coronary syndrome, medicine.medical_specialty, medicine.medical_treatment, heart failure, Catheter ablation, Rhythm control, 030204 cardiovascular system & hematology, Ventricular Function, Left, acute coronary syndrome, Ventricular Dysfunction, Left, 03 medical and health sciences, anti-arrhythmia agents, 0302 clinical medicine, Original Research Articles, death, Physiology (medical), Internal medicine, Secondary Prevention, medicine, Humans, atrial fibrillation, In patient, cardiovascular diseases, 030212 general & internal medicine, Stroke, Aged, Aged, 80 and over, CATHETER ABLATION, controlled clinical trial, business.industry, Stroke Volume, Atrial fibrillation, ASSOCIATION, medicine.disease, stroke, Heart failure, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, cardiovascular system, Cardiology, atrial fibrillation ablation, Female, Human medicine, Cardiology and Cardiovascular Medicine, business, DAPA-HF, Anti-Arrhythmia Agents
Abstract: Supplemental Digital Content is available in the text., Background: Even on optimal therapy, many patients with heart failure and atrial fibrillation experience cardiovascular complications. Additional treatments are needed to reduce these events, especially in patients with heart failure and preserved left ventricular ejection fraction. Methods: This prespecified subanalysis of the randomized EAST-AFNET4 trial (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) assessed the effect of systematic, early rhythm control therapy (ERC; using antiarrhythmic drugs or catheter ablation) compared with usual care (allowing rhythm control therapy to improve symptoms) on the 2 primary outcomes of the trial and on selected secondary outcomes in patients with heart failure, defined as heart failure symptoms New York Heart Association II to III or left ventricular ejection fraction [LVEF]
Published: 2021
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200. Clinical Outcome Predictions for the VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction (VICTORIA) Trial

Author: Adrian F. Hernandez, Nancy K. Sweitzer, Javed Butler, Hillary Mulder, Arend Mosterd, Piotr Ponikowski, Adriaan A. Voors, Justin A. Ezekowitz, Robert J. Mentz, Kevin J. Anstrom, Paul W. Armstrong, Michele Senni, Burkert Pieske, Christopher M. O'Connor, Carolyn S.P. Lam, and Cardiovascular Centre (CVC)
Subjects: medicine.medical_specialty, education.field_of_study, Ejection fraction, business.industry, Proportional hazards model, Population, Heart failure with reduced ejection fraction, outcomes, predictive models, medicine.disease, Clinical trial, Internal medicine, Heart failure, Cohort, Clinical endpoint, Cardiology, Medicine, prognosis, Myocardial infarction, Cardiology and Cardiovascular Medicine, business, education
Abstract: Background: The prediction of outcomes in patients with heart failure (HF) may inform prognosis, clinical decisions regarding treatment selection, and new trial planning. The VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction included high-risk patients with HF with reduced ejection fraction and a recent worsening HF event. The study participants had a high event rate despite the use of contemporary guideline-based therapies. To provide generalizable predictive data for a broad population with a recent worsening HF event, we focused on risk prognostication in the placebo group.Methods and Results: Data from 2524 participants randomized to placebo with chronic HF (New York Heart Association functional class II–IV) and an ejection fraction of less than 45% were studied and backward variable selection was used to create Cox proportional hazards models for clinical end points, selecting from 66 candidate predictors. Final model results were produced, accounting for missing data, and nonlinearities. Optimism-corrected c-indices were calculated using 200 bootstrap samples. Over a median follow-up of 10.4 months, the primary outcome of HF hospitalization or cardiovascular death occurred in 972 patients (38.5%). Independent predictors of increased risk for the primary end point included HF characteristics (longer HF duration and worse New York Heart Association functional class), medical history (prior myocardial infarction), and laboratory values (higher N-terminal pro-hormone B-type natriuretic peptide, bilirubin, urate; lower chloride and albumin). Optimism-corrected c-indices were 0.68 for the HF hospitalization/cardiovascular death model, 0.68 for HF hospitalization/all-cause death, 0.72 for cardiovascular death, and 0.73 for all-cause death.Conclusions: Predictive models developed in a large diverse clinical trial with comprehensive clinical and laboratory baseline data—including novel measures—performed well in high-risk patients with HF who were receiving excellent guideline-based clinical care.Clinical Trial Registration: Clinicaltrials.gov identifier, NCT02861534.Lay Summary: Patients with heart failure may benefit from tools that help clinicians to better understand a patient's risk for future events like hospitalization. Relatively few risk models have been created after the worsening of heart failure in a contemporary cohort. We provide insights on the risk factors for clinical events from a recent, large, global trial of patients with worsening heart failure to help clinicians better understand and communicate prognosis and select treatment options.
Published: 2021
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