156 results on '"David R. Van Wagoner"'
Search Results
2. Sleep‐Disordered Breathing, Hypoxia, and Pulmonary Physiologic Influences in Atrial Fibrillation
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Catherine M. Heinzinger, Nicolas R. Thompson, Alex Milinovich, Matheus Lima Diniz Araujo, Cinthya Pena Orbea, Nancy Foldvary‐Schaefer, Philippe Haouzi, Michael Faulx, David R. Van Wagoner, Mina K. Chung, and Reena Mehra
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cardiac arrhythmias ,lung volume measurements ,plethysmography ,sleep apnea ,spirometry ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background We leverage a large clinical cohort to elucidate sleep‐disordered breathing and sleep‐related hypoxia in incident atrial fibrillation (AF) development given the yet unclear contributions of sleep‐related hypoxia and pulmonary physiology in sleep‐disordered breathing and AF. Methods and Results Patients who underwent sleep studies at Cleveland Clinic January 2, 2000, to December 30, 2015, comprised this retrospective cohort. Cox proportional hazards models were used to examine apnea hypopnea index, percentage time oxygen saturation
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- 2023
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3. The association between eicosanoids and incident atrial fibrillation in the Framingham Heart Study
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Jelena Kornej, Maha A. Qadan, Mona Alotaibi, David R. Van Wagoner, Jeramie D. Watrous, Ludovic Trinquart, Sarah R. Preis, Darae Ko, Mohit Jain, Emelia J. Benjamin, Susan Cheng, and Honghuang Lin
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Medicine ,Science - Abstract
Abstract Chronic inflammation is a continuous low-grade activation of the systemic immune response. Whereas downstream inflammatory markers are associated with atrial fibrillation (AF), upstream inflammatory effectors including eicosanoids are less studied. To examine the association between eicosanoids and incident AF. We used a liquid chromatography-mass spectrometry for the non-targeted measurement of 161 eicosanoids and eicosanoid-related metabolites in the Framingham Heart Study. The association of each eicosanoid and incident AF was assessed using Cox proportional hazards models and adjusted for AF risk factors, including age, sex, height, weight, systolic/diastolic blood pressure, current smoking, antihypertensive medication, diabetes, history of myocardial infarction and heart failure. False discovery rate (FDR) was used to adjust for multiple testing. Eicosanoids with FDR
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- 2022
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4. New Radiomic Markers of Pulmonary Vein Morphology Associated With Post-Ablation Recurrence of Atrial Fibrillation
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Michael A. Labarbera, Thomas Atta-Fosu, Albert K. Feeny, Marjan Firouznia, Meghan Mchale, Catherine Cantlay, Tyler Roach, Alexis Axtell, Paul Schoenhagen, John Barnard, Jonathan D. Smith, David R. Van Wagoner, Anant Madabhushi, and Mina K. Chung
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Cardiology ,electrophysiology ,biomedical imaging ,machine learning ,biomarkers ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Medical technology ,R855-855.5 - Abstract
Objective: To identify radiomic and clinical features associated with post-ablation recurrence of AF, given that cardiac morphologic changes are associated with persistent atrial fibrillation (AF), and initiating triggers of AF often arise from the pulmonary veins which are targeted in ablation. Methods: Subjects with pre-ablation contrast CT scans prior to first-time catheter ablation for AF between 2014–2016 were retrospectively identified. A training dataset (D1) was constructed from left atrial and pulmonary vein morphometric features extracted from equal numbers of consecutively included subjects with and without AF recurrence determined at 1 year. The top-performing combination of feature selection and classifier methods based on C-statistic was evaluated on a validation dataset (D2), composed of subjects retrospectively identified between 2005–2010. Clinical models ( $\text{M}_{\mathrm {C}}$ ) were similarly evaluated and compared to radiomic ( $\text{M}_{\mathrm {R}}$ ) and radiomic-clinical models ( $\text{M}_{\mathrm {RC}}$ ), each independently validated on D2. Results: Of 150 subjects in D1, 108 received radiofrequency ablation and 42 received cryoballoon. Radiomic features of recurrence included greater right carina angle, reduced anterior-posterior atrial diameter, greater atrial volume normalized to height, and steeper right inferior pulmonary vein angle. Clinical features predicting recurrence included older age, greater BMI, hypertension, and warfarin use; apixaban use was associated with reduced recurrence. AF recurrence was predicted with radio-frequency ablation models on D2 subjects with C-statistics of 0.68, 0.63, and 0.70 for radiomic, clinical, and combined feature models, though these were not prognostic in patients treated with cryoballoon. Conclusions: Pulmonary vein morphology associated with increased likelihood of AF recurrence within 1 year of catheter ablation was identified on cardiac CT. Significance: Radiomic and clinical features-based predictive models may assist in identifying atrial fibrillation ablation candidates with greatest likelihood of successful outcome.
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- 2022
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5. What is the impact of endothelin receptor blockade on atrial remodeling in a hypertensive model?
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David R. Van Wagoner
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Published
- 2022
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6. Research Priorities in the Secondary Prevention of Atrial Fibrillation: A National Heart, Lung, and Blood Institute Virtual Workshop Report
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Emelia J. Benjamin, Sana M. Al‐Khatib, Patrice Desvigne‐Nickens, Alvaro Alonso, Luc Djoussé, Daniel E. Forman, Anne M. Gillis, Jeroen M. L. Hendriks, Mellanie True Hills, Paulus Kirchhof, Mark S. Link, Gregory M. Marcus, Reena Mehra, Katherine T. Murray, Ratika Parkash, Ileana L. Piña, Susan Redline, Michiel Rienstra, Prashanthan Sanders, Virend K. Somers, David R. Van Wagoner, Paul J. Wang, Lawton S. Cooper, and Alan S. Go
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atrial fibrillation ,cardiac rehabilitation ,prevention ,research ,risk factors ,sleep ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF‐related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced‐based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF‐related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team‐based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.
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- 2021
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7. Right atrial blood supply and complexity of induced atrial fibrillation: What’s left?
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David R. Van Wagoner
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Published
- 2021
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8. Sleep apnea screening instrument evaluation and novel model development and validation in the paroxysmal atrial fibrillation population
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Anna M. May, Lu Wang, Deborah H. Kwon, David R. Van Wagoner, Mina K. Chung, Jarrod E. Dalton, and Reena Mehra
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Obstructive sleep apnea ,Atrial fibrillation ,Screening ,STOP-BANG ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Standard sleep apnea (SA) screening instruments perform suboptimally in the atrial fibrillation (AF) population. We evaluated and optimized common OSA screening tools in the AF population. Participants of the Sleep Apnea and Atrial Fibrillation Biomarkers and Electrophysiologic Atrial Triggers (SAFEBEAT, NCT02576587) age (±5 years)-, sex-, body mass index (BMI ± 5 kg/m2)-matched case control study (n = 150 each group) completed concurrent questionnaires and overnight polysomnography. Models based on STOP, STOP-BANG, Berlin, NoSAS and Epworth Sleepiness Scale and also models with STOP-BANG predictors with resting heart rate or left atrial volume were constructed. “Best subset” analysis was used to select a predictor subset for evaluation. We assessed test performance for two outcome thresholds: apnea-hypopnea index (AHI) ≥ 5 and AHI ≥ 15. Paroxysmal AF participants were: 61.3 ± 12.1 years, BMI = 31.2 ± 6.6 kg/m2 with median AHI = 11.8(IQR: 3.8, 24.5); 65 (43.3%) with AHI ≥ 15. Only STOP and STOP-BANG did not perform worse in AF relative to controls. For AHI ≥ 15, STOP-BANG (AUC 0.71, 95%CI:0.55–0.85) did not perform as well as NABS – a composite of neck circumference, age, and BMI as continuous variables and snoring (AUC 0.88, 95%CI:0.76–0.96). Optimal model for AHI ≥ 15 was NABS (sensitivity = 45%, specificity = 97%). For AHI ≥ 5, NABS was also the best performing (AUC 0.82, 95%CI:0.68–0.92, sensitivity = 78%, specificity = 67%). We identify a novel, short-item SA screening instrument for use in paroxysmal AF, i.e. NABS, with improved discriminative ability compared to commonly-used instruments. Further validation studies are needed to assess utility in other AF subtypes.Trial registration: clinicaltrials.gov NCT02576587.
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- 2020
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9. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
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Jessica van Setten, Jennifer A. Brody, Yalda Jamshidi, Brenton R. Swenson, Anne M. Butler, Harry Campbell, Fabiola M. Del Greco, Daniel S. Evans, Quince Gibson, Daniel F. Gudbjartsson, Kathleen F. Kerr, Bouwe P. Krijthe, Leo-Pekka Lyytikäinen, Christian Müller, Martina Müller-Nurasyid, Ilja M. Nolte, Sandosh Padmanabhan, Marylyn D. Ritchie, Antonietta Robino, Albert V. Smith, Maristella Steri, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sheila Ulivi, Niek Verweij, Xiaoyan Yin, David O. Arnar, Folkert W. Asselbergs, Joel S. Bader, John Barnard, Josh Bis, Stefan Blankenberg, Eric Boerwinkle, Yuki Bradford, Brendan M. Buckley, Mina K. Chung, Dana Crawford, Marcel den Hoed, Josh C. Denny, Anna F. Dominiczak, Georg B. Ehret, Mark Eijgelsheim, Patrick T. Ellinor, Stephan B. Felix, Oscar H. Franco, Lude Franke, Tamara B. Harris, Hilma Holm, Gandin Ilaria, Annamaria Iorio, Mika Kähönen, Ivana Kolcic, Jan A. Kors, Edward G. Lakatta, Lenore J. Launer, Honghuang Lin, Henry J. Lin, Ruth J. F. Loos, Steven A. Lubitz, Peter W. Macfarlane, Jared W. Magnani, Irene Mateo Leach, Thomas Meitinger, Braxton D. Mitchell, Thomas Munzel, George J. Papanicolaou, Annette Peters, Arne Pfeufer, Peter P. Pramstaller, Olli T. Raitakari, Jerome I. Rotter, Igor Rudan, Nilesh J. Samani, David Schlessinger, Claudia T. Silva Aldana, Moritz F. Sinner, Jonathan D. Smith, Harold Snieder, Elsayed Z. Soliman, Timothy D. Spector, David J. Stott, Konstantin Strauch, Kirill V. Tarasov, Unnur Thorsteinsdottir, Andre G. Uitterlinden, David R. Van Wagoner, Uwe Völker, Henry Völzke, Melanie Waldenberger, Harm Jan Westra, Philipp S. Wild, Tanja Zeller, Alvaro Alonso, Christy L. Avery, Stefania Bandinelli, Emelia J. Benjamin, Francesco Cucca, Marcus Dörr, Luigi Ferrucci, Paolo Gasparini, Vilmundur Gudnason, Caroline Hayward, Susan R. Heckbert, Andrew A. Hicks, J. Wouter Jukema, Stefan Kääb, Terho Lehtimäki, Yongmei Liu, Patricia B. Munroe, Afshin Parsa, Ozren Polasek, Bruce M. Psaty, Dan M. Roden, Renate B. Schnabel, Gianfranco Sinagra, Kari Stefansson, Bruno H. Stricker, Pim van der Harst, Cornelia M. van Duijn, James F. Wilson, Sina A. Gharib, Paul I. W. de Bakker, Aaron Isaacs, Dan E. Arking, and Nona Sotoodehnia
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Science - Abstract
Abnormal PR interval duration is associated with risk for atrial fibrillation and heart block. Here, van Setten et al. identify 44 PR interval loci in a genome-wide association study of over 92,000 individuals and find genetic overlap with QRS duration, heart rate and atrial fibrillation.
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- 2018
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10. EHRA/HRS/APHRS/SOLAECE expert consensus on Atrial cardiomyopathies: Definition, characterisation, and clinical implication
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Andreas Goette, Jonathan M. Kalman, Luis Aguinaga, Joseph Akar, Jose Angel Cabrera, Shih Ann Chen, Sumeet S. Chugh, Domenico Corradi, Andre D׳Avila, Dobromir Dobrev, Guilherme Fenelon, Mario Gonzalez, Stephane N. Hatem, Robert Helm, Gerhard Hindricks, Siew Yen Ho, Brian Hoit, Jose Jalife, Young-Hoon Kim, Gregory Y.H. Lip, Chang-Sheng Ma, Gregory M. Marcus, Katherine Murray, Akihiko Nogami, Prashanthan Sanders, William Uribe, David R. Van Wagoner, and Stanley Nattel
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Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Published
- 2016
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11. Dysregulated Ca2+ cycling in atrial fibrillation
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Julie H Rennison and David R Van Wagoner
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Cardiology and Cardiovascular Medicine - Published
- 2023
12. Gut Microbiota-Generated Phenylacetylglutamine and Heart Failure
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Kymberleigh A. Romano, Ina Nemet, Prasenjit Prasad Saha, Arash Haghikia, Xinmin S. Li, Maradumane L. Mohan, Beth Lovano, Laurie Castel, Marco Witkowski, Jennifer A. Buffa, Yu Sun, Lin Li, Christopher M. Menge, Ilja Demuth, Maximilian König, Elisabeth Steinhagen-Thiessen, Joseph A. DiDonato, Arjun Deb, Fredrik Bäckhed, W.H. Wilson Tang, Sathyamangla Venkata Naga Prasad, Ulf Landmesser, David R. Van Wagoner, and Stanley L. Hazen
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Cardiology and Cardiovascular Medicine - Abstract
Background: The gut microbiota-dependent metabolite phenylacetylgutamine (PAGln) is both associated with atherothrombotic heart disease in humans, and mechanistically linked to cardiovascular disease pathogenesis in animal models via modulation of adrenergic receptor signaling. Methods: Here we examined both clinical and mechanistic relationships between PAGln and heart failure (HF). First, we examined associations among plasma levels of PAGln and HF, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide in 2 independent clinical cohorts of subjects undergoing coronary angiography in tertiary referral centers (an initial discovery US Cohort, n=3256; and a validation European Cohort, n=829). Then, the impact of PAGln on cardiovascular phenotypes relevant to HF in cultured cardiomyoblasts, and in vivo were also examined. Results: Circulating PAGln levels were dose-dependently associated with HF presence and indices of severity (reduced ventricular ejection fraction, elevated N-terminal pro-B-type natriuretic peptide) independent of traditional risk factors and renal function in both cohorts. Beyond these clinical associations, mechanistic studies showed both PAGln and its murine counterpart, phenylacetylglycine, directly fostered HF-relevant phenotypes, including decreased cardiomyocyte sarcomere contraction, and B-type natriuretic peptide gene expression in both cultured cardiomyoblasts and murine atrial tissue. Conclusions: The present study reveals the gut microbial metabolite PAGln is clinically and mechanistically linked to HF presence and severity. Modulating the gut microbiome, in general, and PAGln production, in particular, may represent a potential therapeutic target for modulating HF. Registration: URL: https://clinicaltrials.gov/ ; Unique identifier: NCT00590200 and URL: https://drks.de/drks_web/ ; Unique identifier: DRKS00020915.
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- 2023
13. Genome-first approach to rare EYA4 variants and cardio-auditory phenotypes in adults
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Ian D. Krantz, Jason A. Brant, W.H. Wilson Tang, Yi-An Ko, Marylyn D. Ritchie, Batsal Devkota, Shadi Ahmadmehrabi, Michael J. Ruckenstein, Douglas J. Epstein, Marijana Vujkovic, David R. Van Wagoner, Binglan Li, Joseph Park, and Daniel J. Rader
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0303 health sciences ,education.field_of_study ,medicine.diagnostic_test ,Hearing loss ,030305 genetics & heredity ,Population ,Biology ,Bioinformatics ,Phenotype ,Human genetics ,03 medical and health sciences ,Cardiac conduction ,Genetics ,medicine ,medicine.symptom ,education ,Gene ,Genetics (clinical) ,030304 developmental biology ,Genetic association ,Genetic testing - Abstract
While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue. The pleiotropic effects of rare EYA4 variants are poorly understood and their prevalence in a large cohort has not been previously reported. We investigated cardio-auditory phenotypes in 11,451 individuals in a large biobank using a rare variant, genome-first approach to EYA4. We filtered 256 EYA4 variants carried by 6737 participants to 26 rare and predicted deleterious variants carried by 42 heterozygotes. We aggregated predicted deleterious EYA4 gene variants into a combined variable (i.e. “gene burden”) and performed association studies across phenotypes compared to wildtype controls. We validated findings with replication in three independent cohorts and human tissue expression data. EYA4 gene burden was significantly associated with audiometric-proven HL (p = $${5.43\times 10}^{-5})$$ , Mobitz Type II AV block (p = $${2.16\times 10}^{-5}$$ ) and the syndromic presentation of HL and primary cardiomyopathy (p = 0.0194). Analyses on audiogram, echocardiogram, and electrocardiogram data validated these associations. Prior reports have focused on identifying variants in families with severe or syndromic phenotypes. In contrast, we found, using a genotype-first approach, that gene burden in EYA4 is associated with more subtle cardio-auditory phenotypes in an adult medical biobank population, including cardiac conduction disorders which have not been previously reported. We show the value of using a focused approach to uncover human disease related to pleiotropic gene variants and suggest a role for genetic testing in adults presenting with hearing loss.
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- 2021
14. Activated intestinal muscle cells promote preadipocyte migration: a novel mechanism for creeping fat formation in Crohn’s disease
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David R. Van Wagoner, Thi Hong Nga Le, Ren Mao, Jiannan Li, Michael Elias, Shuai Zhao, Sinan Lin, Jie Wang, Brian D. Southern, Florian Rieder, Jyotsna Chandra, Gail West, Satya Kurada, Pranab K. Mukherjee, Ilyssa O. Gordon, Claudio Fiocchi, Mitchell A. Olman, Genevieve Doyon, Dina Dejanovic, and Minhu Chen
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Integrin ,Matrix (biology) ,Article ,Extracellular matrix ,Crohn Disease ,Cell Movement ,Fibrosis ,Adipocytes ,medicine ,Humans ,Myocyte ,Cells, Cultured ,Adipogenesis ,Tissue Scaffolds ,biology ,Cell growth ,Chemistry ,Gastroenterology ,Cell Differentiation ,Muscle, Smooth ,Cell migration ,medicine.disease ,Extracellular Matrix ,Fibronectins ,Cell biology ,Intestines ,Fibronectin ,Adipose Tissue ,biology.protein - Abstract
ObjectiveCreeping fat, the wrapping of mesenteric fat around the bowel wall, is a typical feature of Crohn’s disease, and is associated with stricture formation and bowel obstruction. How creeping fat forms is unknown, and we interrogated potential mechanisms using novel intestinal tissue and cell interaction systems.DesignTissues from normal, UC, non-strictured and strictured Crohn’s disease intestinal specimens were obtained. The muscularis propria matrisome was determined via proteomics. Mesenteric fat explants, primary human preadipocytes and adipocytes were used in multiple ex vivo and in vitro cell migration systems on muscularis propria muscle cell derived or native extracellular matrix. Functional experiments included integrin characterisation via flow cytometry and their inhibition with specific blocking antibodies and chemicals.ResultsCrohn’s disease muscularis propria cells produced an extracellular matrix scaffold which is in direct spatial and functional contact with the immediately overlaid creeping fat. The scaffold contained multiple proteins, but only fibronectin production was singularly upregulated by transforming growth factor-β1. The muscle cell-derived matrix triggered migration of preadipocytes out of mesenteric fat, fibronectin being the dominant factor responsible for their migration. Blockade of α5β1 on the preadipocyte surface inhibited their migration out of mesenteric fat and on 3D decellularised intestinal tissue extracellular matrix.ConclusionCrohn’s disease creeping fat appears to result from the migration of preadipocytes out of mesenteric fat and differentiation into adipocytes in response to an increased production of fibronectin by activated muscularis propria cells. These new mechanistic insights may lead to novel approaches for prevention of creeping fat-associated stricture formation.
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- 2021
15. Abstract 11214: Ibrutinib Decreases Mitochondrial Oxidative Phosphorylation and Metabolic Gene Expression in Atrial-Like Engineered Heart Tissue
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Julie H Rennison, Beth Lovano, Laurie Castel, Cheryl R Lin, Feixong Cheng, Rohit Moudgil, Jonathan D Smith, John Barnard, Mina K Chung, and David R Van Wagoner
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Ibrutinib is a Bruton kinase inhibitor which treats many hematological malignancies, but also precipitates atrial fibrillation (AF). The precise mechanism(s) remain to be elucidated. Hypothesis: We hypothesized ibrutinib treatment would decrease mitochondrial function and metabolic gene expression in human inducible pluripotent stem cell-derived atrial cardiomyocytes grown as atrial-like engineered heart tissues (aEHTs). Methods: aEHTs were treated with vehicle or 1 μM ibrutinib daily, for 72 hours. Oxidative phosphorylation was assessed (n=5/group) using an Oroboros Oxygraph. Gene expression was evaluated by RNAseq (n=3/group). Results: Oxidative phosphorylation in the presence of complex I and complex II substrates, and maximal oxidative capacity, was decreased in ibrutinib-treated aEHTs compared to vehicle (Panel A). Subunit expression of complex I (NDUFA6, NDUFA9, NDUFS1, NDUFS2, NDUFS4, ND3, ND4, ND5, ND4L), complex II (SDHA, SDHB, SDHD), complex III (UQCR10, UQCRB, UQCRC1, UQCRC2, UQCRFS1), and complex IV (CO2, COX10, COX7A2, CYCS) was decreased. Ingenuity Pathway Analysis of genes differentially expressed identified TCA Cycle and Glycolysis I (Panel B), pathways that provide reducing equivalents to the electron transport chain, as pathways that were decreased by ibrutinib. These changes were accompanied by decreased AMPK Signaling, including key metabolic regulators (PRKAA2, PRKAB2, PRKAG2, SIRT1, and PPARGC1A), and Calcium Signaling. Tumor protein (TP53), nuclear protein 1 (NUPR1), and erb-B2 receptor tyrosine kinase (ERBB2) were identified as top upstream regulators. Conclusions: Ibrutinib treatment decreased oxidative phosphorylation and gene expression of electron transport chain subunits and key modulators of atrial metabolism. Together, these data identify metabolic pathways that are altered by ibrutinib in aEHTs and metabolic regulators that could be targeted for AF therapeutic intervention.
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- 2021
16. Abstract 11237: Expression of Mitochondrial, Contractile, and Calcium Regulatory Proteins is Altered in Patients with Atrial Fibrillation
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Julie H Rennison, Catherine C Cantlay, Ling Li, Cheryl R Lin, Beth S Lovano, Laurie Castel, Paul J Cantlay, A M Gillinov, Christine S Moravec, Belinda B Willard, Jonathan D Smith, Mina K Chung, John Barnard, and David R Van Wagoner
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Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Introduction: Atrial fibrillation (AF) increases energy demand for contractile and electrical activity. Changes in left atrial (LA) protein expression of AF patients are poorly characterized. Hypothesis: Mitochondrial protein expression in patients with AF is altered in an attempt to meet increased energy demand. Methods: LA appendage tissue was obtained from 198 patients undergoing Maze surgery. At the time of surgery, 80 were in sinus rhythm (SR) (50 paroxysmal AF, 30 persistent AF) and 118 in AF (65 persistent AF, 53 permanent AF). Protein content was assessed by mass spectrometry and 2539 proteins were identified. Results: In AF compared to SR, 257 proteins were differentially expressed (q Conclusions: In one of the largest proteomic datasets in human LA to date, we find that expression of proteins in metabolic, myofibrillar, and calcium regulation pathways is altered in patients with AF. Additional metabolic changes were detected with progression to permanent AF. These data identify proteins that are altered in patients with AF providing insight into cellular pathways that may be targeted for AF prevention and therapy.
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- 2021
17. Statin Therapy in Patients Undergoing Thoracic Aorta Replacement for Aortic Aneurysms
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Ashley M. Lowry, Kyle G. Miletic, Eric E. Roselli, Eugene H. Blackstone, Bogdan A. Kindzelski, David R. Van Wagoner, and Andrea Hanick
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medicine.medical_specialty ,Statin ,medicine.drug_class ,thoracic aortic aneurysm surgery ,medicine.medical_treatment ,Thoracic aortic aneurysm ,statins ,medicine.artery ,medicine ,Thoracic aorta ,Radiology, Nuclear Medicine and imaging ,cardiovascular diseases ,Original Research Article ,Stroke ,Dialysis ,business.industry ,Perioperative ,medicine.disease ,Comorbidity ,Surgery ,postoperative renal failure ,Propensity score matching ,cardiovascular system ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Patients undergoing surgery for thoracic aortic aneurysms receive statin therapy out of proportion to cardiovascular comorbidity. We sought to determine the prevalence of statin use among patients presenting for thoracic aortic aneurysm surgery and investigate its effect on outcomes. Methods From January 1, 2005 to January 1, 2011, 1,839 consecutive patients underwent aortic replacement for degenerative thoracic aortic aneurysm at Cleveland Clinic. Of these, 771 (42%) were on statins preoperatively. Statin users (vs. nonstatin users) were older (65 ± 11 vs. 56 ± 16 years) and had more hypertension (78 vs. 59%). Propensity matching based on 56 preoperative variables other than lipid levels was used to compare outcomes among 570 matched patient pairs (74% of possible pairs). Results Propensity-matched statin and nonstatin users were aged 64 ± 11 years, 394 (69%) versus 387 (68%) were male, and 437 (77%) versus 442 (78%) had ascending aortic aneurysms, respectively. Overall, 25% of patients were followed for more than 8.2 years and 10% for more than 10 years. Perioperative outcomes were similar, including hospital mortality (11 [1.9%] vs. 5 [0.88%]) and stroke (22 [3.9%] vs. 13 [2.3%]), but 16 statin users (2.8%) versus 5 nonstatin users (0.88%) required temporary dialysis after surgery (p = 0.02). At 6 years, 3.7% of statin users versus 5.1% of nonstatin users (p[log-rank] = 0.5) underwent further aortic surgery, and at 10 years, mortality was 25% in both groups (p > 0.5). Conclusion Patients presenting for thoracic aortic aneurysm surgery frequently receive unnecessary statins. Additionally, statin use was associated with more postoperative renal failure, but not less intermediate-term risk for aortic reintervention or all-cause mortality after surgery. Therefore, presence of a thoracic aortic aneurysm should not be considered an indication for statin therapy in the absence of well-established indications.
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- 2021
18. Transcriptomics-based network medicine approach identifies metformin as a repurposable drug for atrial fibrillation
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Jessica C. Lal, Chengsheng Mao, Yadi Zhou, Shamone R. Gore-Panter, Julie H. Rennison, Beth S. Lovano, Laurie Castel, Jiyoung Shin, A. Marc Gillinov, Jonathan D. Smith, John Barnard, David R. Van Wagoner, Yuan Luo, Feixiong Cheng, and Mina K. Chung
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Atrial Fibrillation ,Humans ,Heart Atria ,Transcriptome ,Metformin ,General Biochemistry, Genetics and Molecular Biology - Abstract
Effective drugs for atrial fibrillation (AF) are lacking, resulting in significant morbidity and mortality. This study demonstrates that network proximity analysis of differentially expressed genes from atrial tissue to drug targets can help prioritize repurposed drugs for AF. Using enrichment analysis of drug-gene signatures and functional testing in human inducible pluripotent stem cell (iPSC)-derived atrial-like cardiomyocytes, we identify metformin as a top repurposed drug candidate for AF. Using the active compactor, a new design analysis of large-scale longitudinal electronic health record (EHR) data, we determine that metformin use is significantly associated with a reduced risk of AF (odds ratio = 0.48, 95%, confidence interval [CI] 0.36-0.64, p 0.001) compared with standard treatments for diabetes. This study utilizes network medicine methodologies to identify repurposed drugs for AF treatment and identifies metformin as a candidate drug.
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- 2022
19. Network-based prediction and functional validation of metformin for potential treatment of atrial fibrillation using human inducible pluripotent stem cell-derived atrial-like cardiomyocytes
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Feixiong Cheng, Julie H. Rennison, Mina K. Chung, John Barnard, Yadi Zhou, Shamone R. Gore-Panter, Jessica Castrillon Lal, and David R. Van Wagoner
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Drug ,Network medicine ,business.industry ,media_common.quotation_subject ,Atrial fibrillation ,medicine.disease ,Bioinformatics ,Metformin ,Transcriptome ,Immune system ,medicine ,Induced pluripotent stem cell ,business ,Repurposing ,media_common ,medicine.drug - Abstract
Atrial fibrillation (AF) is a significant cause of morbidity and mortality, and effective therapeutic interventions are lacking. Here, we harness an integrative, network medicine approach to repurpose FDA-approved drugs for AF. We hypothesize that the use of an unbiased method for prioritizing AF drugs using patient transcriptomics data can help to identify alternative therapeutic strategies and mechanism-of-action for these drugs. To achieve this, we first characterized the molecular networks specific to AF by incorporating transcriptomic data of left atrial tissue. We quantified the network proximity of genes differentially expressed in AF to drug targets to identify putative drugs for repurposing. We identified nine high-confidence drug candidates that were validated using enrichment analysis of drug-gene signatures in human cell lines. We identified metformin for the potential treatment of AF and validated its use in human inducible pluripotent stem cell-derived atrial-like cardiomyocytes. We identified AF-specific dysregulated networks enriched in cardiac metabolism, ion transport, and immune pathways that were improved following metformin treatment. In summary, this study utilized network-based approaches for rapid identification of drugs that may be repurposed for AF treatment and validated metformin as a candidate drug using a robust human atrial cell model.
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- 2021
20. Abstract P382: Transcriptomic Analysis Of Human Left Atrial Tissue Reveals Mitochondrial Gene Co-expression
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Julie H. Rennison, A. Gillinov, John Barnard, Jeffrey Hsu, Sojin Y Wass, Han Sun, Mina K. Chung, Jonathan D. Smith, David R. Van Wagoner, Cheryl R Lin, Catherine Cantlay, Laurie Castel, Christine S. Moravec, Meghan McHale, and Beth Lovano
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Transcriptome ,Mitochondrial DNA ,Physiology ,Left atrial ,Biology ,Cardiology and Cardiovascular Medicine ,Cell biology - Abstract
Atrial fibrillation (AF) risk is heritable. High rate electrical activity in AF requires increased energy. Atrial mitochondrial structure and function are altered in AF patients in an effort to generate adequate ATP through oxidative phosphorylation. Genomic studies have identified putative AF risk genes, but the association of AF risk genes with expression of mitochondrial genes is unclear. We tested the hypothesis that putative AF risk genes are co-expressed with mitochondrial genes that play a role in atrial energy production. RNA-seq was performed on left atrial appendage (LAA) tissues obtained from 251 cardiac surgery patients. RNA coexpression profiles were evaluated for 222 putative AF risk genes. Genes encoding proteins that localize to the mitochondria were identified using MitoCarta 2.0. Changes in metabolic pathways were detected using Ingenuity Pathway Analysis (IPA). Our analysis identified 128 AF risk genes that coexpressed with at least one mitochondrial gene. The highest level of mitochondrial gene coexpression was evident with PCCB, in which 30% (253 of 848) of coexpressed genes were mitochondrial. CASQ2 (24%, 104 of 431) and ASAH1 (20%, 37 of 182) also showed high levels of mitochondrial gene coexpression. The IPA Oxidative Phosphorylation Pathway was significantly altered (p
- Published
- 2021
21. Research Priorities in the Secondary Prevention of Atrial Fibrillation: A National Heart, Lung, and Blood Institute Virtual Workshop Report
- Author
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Patrice Desvigne-Nickens, Ileana L. Piña, Ratika Parkash, Mark S. Link, Paul J. Wang, Sana M. Al-Khatib, Mellanie True Hills, Anne M. Gillis, Daniel E. Forman, Paulus Kirchhof, David R. Van Wagoner, Emelia J. Benjamin, Jeroen M.L. Hendriks, Katherine T. Murray, Michiel Rienstra, Gregory M. Marcus, Luc Djoussé, Alan S. Go, Reena Mehra, Prashanthan Sanders, Alvaro Alonso, Susan Redline, Lawton S. Cooper, Virend K. Somers, and Cardiovascular Centre (CVC)
- Subjects
Comparative Effectiveness Research ,Biomedical Research ,Anti-Arrhythmia Agents/therapeutic use ,medicine.medical_treatment ,Psychological intervention ,Comorbidity ,Cardiorespiratory Medicine and Haematology ,Cardiovascular ,law.invention ,prevention ,Randomized controlled trial ,Recurrence ,Risk Factors ,law ,and Blood Institute (U.S.) ,Atrial Fibrillation ,Secondary Prevention ,risk factors ,Medicine ,atrial fibrillation ,Lung ,Atrial fibrillation ,Stroke ,Treatment Outcome ,Heart Disease ,Research Design ,Body Composition ,Disease Progression ,Cardiology and Cardiovascular Medicine ,Anti-Arrhythmia Agents ,Needs Assessment ,Cohort study ,medicine.medical_specialty ,Clinical Trials and Supportive Activities ,Risk Assessment ,Pharmacotherapy ,Clinical Research ,Weight Loss ,Atrial Fibrillation/diagnosis ,Animals ,Humans ,Healthy Lifestyle ,Obesity ,sleep ,Intensive care medicine ,Special Report ,Health Services Needs and Demand ,research ,Health Priorities ,business.industry ,Prevention ,National Heart ,medicine.disease ,United States ,cardiac rehabilitation ,Heart failure ,Smoking cessation ,Observational study ,National Heart, Lung, and Blood Institute (U.S.) ,business - Abstract
There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF‐related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced‐based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF‐related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team‐based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.
- Published
- 2021
22. Identifying Sex‐dependent Markers of Heart Failure and Atrial Myopathy
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Iyad Manserh, Kamila Bledzka, Walter J. Koch, David R. Van Wagoner, and Sarah M. Schumacher
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medicine.medical_specialty ,business.industry ,medicine.disease ,Biochemistry ,Internal medicine ,Heart failure ,Genetics ,Cardiology ,Medicine ,medicine.symptom ,business ,Myopathy ,Molecular Biology ,Biotechnology - Published
- 2021
23. Novel mechanisms and clinical trial endpoints in intestinal fibrosis
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David R. Van Wagoner, Florian Rieder, Claudio Fiocchi, Jonathan Mark Brown, Sinan Lin, and Jie Wang
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,Disease ,Constriction, Pathologic ,Biology ,Bioinformatics ,Inflammatory bowel disease ,Article ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Crohn Disease ,Fibrosis ,medicine ,Immunology and Allergy ,Humans ,medicine.disease ,Inflammatory Bowel Diseases ,Clinical trial ,Bowel obstruction ,Intestines ,030104 developmental biology ,Cytokine ,030215 immunology - Abstract
The incidence of inflammatory bowel diseases (IBD) worldwide has resulted in a global public health challenge. Intestinal fibrosis leading to stricture formation and bowel obstruction is a frequent complication in Crohn's disease (CD), and the lack of anti-fibrotic therapies makes elucidation of fibrosis mechanisms a priority. Progress has shown that mesenchymal cells, cytokines, microbial products, and mesenteric adipocytes are jointly implicated in the pathogenesis of intestinal fibrosis. This recent information puts prevention or reversal of intestinal strictures within reach through innovative therapies validated by reliable clinical trial endpoints. Here, we review the role of immune and non-immune components of the pathogenesis of intestinal fibrosis, including new cell clusters, cytokine networks, host-microbiome interactions, creeping fat, and their translation for endpoint development in anti-fibrotic clinical trials.
- Published
- 2021
24. Inflammation, Inflammasome Activation, and Atrial Fibrillation
- Author
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David R. Van Wagoner and Mina K. Chung
- Subjects
0301 basic medicine ,biology ,business.industry ,Extramural ,C-reactive protein ,Interleukin ,Inflammation ,Atrial fibrillation ,Inflammasome ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Physiology (medical) ,medicine ,biology.protein ,Myocyte ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Published
- 2018
25. Cardiac Pressure Overload Decreases ETV1 Expression in the Left Atrium, Contributing to Atrial Electrical and Structural Remodeling
- Author
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David S. Park, Sojin Y Wass, David R. Van Wagoner, Alireza Khodadadi-Jamayran, Xianming Lin, Mina K. Chung, Naoko Yamaguchi, Erik Offerman, Akshay Shekhar, Junhua Xiao, Devin Shaheen, Deven Narke, and Alex Choy
- Subjects
Male ,Left atrium ,Receptor, Transforming Growth Factor-beta Type I ,030204 cardiovascular system & hematology ,ETV1 ,Mice ,0302 clinical medicine ,Aged, 80 and over ,Mice, Knockout ,0303 health sciences ,Ventricular Remodeling ,Angiotensin II ,Atrial fibrillation ,Middle Aged ,DNA-Binding Proteins ,medicine.anatomical_structure ,Cardiology ,cardiovascular system ,Female ,Signal transduction ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Adult ,medicine.medical_specialty ,Adolescent ,Neuregulin-1 ,Down-Regulation ,Intracardiac pressure ,Article ,03 medical and health sciences ,Young Adult ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Heart Atria ,Myopathy ,030304 developmental biology ,Aged ,Pressure overload ,Heart Failure ,business.industry ,Arrhythmias, Cardiac ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Heart failure ,business ,Transcription Factors - Abstract
Background: Elevated intracardiac pressure attributable to heart failure induces electrical and structural remodeling in the left atrium (LA) that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The purpose of this study is to characterize the response of the ETV1 (ETS translocation variant 1) signaling axis in the LA during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling. Methods: We performed gene expression profiling in 265 left atrial samples from patients who underwent cardiac surgery. Comparative gene expression profiling was performed between 2 murine models of cardiac pressure overload, transverse aortic constriction banding and angiotensin II infusion, and a genetic model of Etv1 cardiomyocyte-selective knockout ( Etv1 f/f Mlc2a Cre /+ ). Results: Using the Cleveland Clinic biobank of human LA specimens, we found that ETV1 expression is decreased in patients with reduced ejection fraction. Consistent with its role as an important mediator of the NRG1 (Neuregulin 1) signaling pathway and activator of rapid conduction gene programming, we identified a direct correlation between ETV1 expression level and NRG1 , ERBB4 , SCN5A , and GJA5 levels in human LA samples. In a similar fashion to patients with heart failure, we showed that left atrial ETV1 expression is downregulated at the RNA and protein levels in murine pressure overload models. Comparative analysis of LA RNA sequencing datasets from transverse aortic constriction and angiotensin II–treated mice showed a high Pearson correlation, reflecting a highly ordered process by which the LA undergoes electrical and structural remodeling. Cardiac pressure overload produced a consistent downregulation of ErbB4 , Etv1 , Scn5a , and Gja5 and upregulation of profibrotic gene programming, which includes Tgfbr1/2, Igf1 , and numerous collagen genes. Etv1 f/f Mlc2a Cre /+ mice displayed atrial conduction disease and arrhythmias. Correspondingly, the LA from Etv1 f/f Mlc2a Cre /+ mice showed downregulation of rapid conduction genes and upregulation of profibrotic gene programming, whereas analysis of a gain-of-function ETV1 RNA sequencing dataset from neonatal rat ventricular myocytes transduced with Etv1 showed reciprocal changes. Conclusions: ETV1 is downregulated in the LA during cardiac pressure overload, contributing to both electrical and structural remodeling.
- Published
- 2020
26. Abstract 15509: SYNE2 Expression Regulates Calcium Cycling and Mitochondria Function in Cardiomyocytes: Implications for Association With Atrial Fibrillation
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John Barnard, Conner P Witherow, Mina K. Chung, Sathyamangla V. Naga Prasad, David R. Van Wagoner, Nana Liu, and Jonathan D. Smith
- Subjects
business.industry ,Endoplasmic reticulum ,Atrial fibrillation ,Mitochondrion ,medicine.disease ,Cell biology ,medicine.anatomical_structure ,Physiology (medical) ,Gene expression ,Medicine ,Nuclear membrane ,Cardiology and Cardiovascular Medicine ,business ,Cytoskeleton ,Nucleus ,SYNE2 Gene - Abstract
Introduction: SYNE2 encodes a nuclear membrane protein that connects the nucleus with the cytoskeleton. rs1152591 is a common SNP in the SYNE2 gene that is associated with atrial fibrillation (AF) and with reduced expression of SYNE2α1 , a short isoform, in human left atrial appendage tissue. We previously found that SYNE2α1 over expression (OE) acts as a dominant negative for the nuclear phenotype, similar to the SYNE2 knockdown (KD), leading to enlarged nuclear size and decreased nuclear stiffness. Objectives: To determine if GFP- SYNE2α1 (OE) and KD of all SYNE2 isoforms show similar effects on gene expression and cell physiology in human induced pluripotent stem cell-derived cardiomyocytes (iCMs). Methods and Results: RNAseq after SYNE2α1 OE or SYNE2 KD revealed both congruent changes in expression of specific genes, supporting the dominant negative role of SYNE2α1 , but also divergent changes in expression of some genes, showing specific effects of the SYNE2α1 short isoform. We identified both mitochondrial function and sarcoplasmic reticulum (SR) function as differentially expressed pathways comparing OE vs. KD iCMs. Fura-2 photometry was used to study Ca 2+ cycling in beating iCMs, and revealed delayed calcium reuptake in the SYNE2 KD cells (15.9% increase in reuptake time as % of each contraction, pSYNE2α1 OE cells (not significant). Flow cytometry showed significantly lower SERCA2 expression in the SYNE2 KD cells but not in the SYNE2α1 OE cells (12% decrease, p=0.029). Immunofluorescence microscopy revealed that GFP-SYNE2α1 not only localized to the nuclear membrane but also to the SR, stained with anti-SERCA2. Flow cytometry after MitoTracker Orange staining, to monitor the cellular volume of functional mitochondria, was significantly increased in both the SYNE2α1 OE and SYNE2 KD iCMs vs. their respective controls. Thus, despite differential expression of mitochondrial pathway genes, SYNE2α1 mimics the KD of all SYNE2 isoforms in regard to mitochondrial function. Conclusions: SYNE2α1 OE, unlike KD of all SYNE2 isoforms, preserves SR Ca 2+ reuptake activity, and this may contribute to the mechanism by which the AF risk allele in the SYNE2 gene, associated with decreased expression of SYNE2α1, predisposes carriers to AF.
- Published
- 2020
27. Abstract 17259: Identification of Biological Pathways of Candidate Atrial Fibrillation Risk Genes Through the Use of Weighted Gene Coexpression Network Analysis
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Meghan McHale, David R. Van Wagoner, Jonathan D. Smith, Christine S. Moravec, Jeffery Hsu, Erik Offerman, A. Gillinov, Sojin Y Wass, Han Sun, John Barnard, Mina K. Chung, Catherine Cantlay, and Julie H. Rennison
- Subjects
Biological pathway ,business.industry ,Physiology (medical) ,medicine ,Atrial fibrillation ,Identification (biology) ,Computational biology ,Cardiology and Cardiovascular Medicine ,Gene coexpression ,medicine.disease ,business ,Gene ,Network analysis - Abstract
Introduction: Over 135 genetic loci have been linked to atrial fibrillation (AF), yet the biological pathways of AF pathophysiology remain elusive. Weighted gene coexpression network analysis (WGCNA) constructs gene modules within a network based on correlations in gene expression, and identifies mechanisms related to AF risk. Objective: To identify biological pathways of candidate AF risk genes that will advance our understanding of AF mechanisms. Methods: RNA-sequencing was performed on left atrial appendage tissue from 265 patients. RNA-seq data were adjusted for differences in AF rhythm state and other known AF risk factors. Correlations from adjusted data were further adjusted for latent factors then spatial quantile normalized to correct for mean-variance bias. WGCNA was applied to the resulting adjusted and normalized gene-gene correlations to identify gene modules. Ingenuity Pathway Analysis and gene set over representation analysis (GSOR) were applied to each module. Results: WGCNA identified 63 modules from 17,434 genes; 47 of these contained at least one candidate AF risk gene. AF risk genes were overrepresented in 7 modules (Table 1). Notable top pathways of AF overrepresented modules include apelin signaling, heme metabolism, intracellular ion homeostasis, and the unfolded protein response. These are known to be involved in calcium signaling, iron homeostasis, glucose regulation, heat shock response, and protein ubiquitination during states of high energy demand and stress. These pathways coincide with larger cellular processes of myocyte remodeling, apoptosis, and cell survival, which were also prominent. Conclusions: Biological pathways identified through WGCNA and GSOR suggest that sustained increases in energy demand during AF promotes stress-induced cellular remodeling. Changes in calcium signaling, iron homeostasis, the unfolded protein response and glucose regulation are likely primary mechanisms of AF pathophysiology.
- Published
- 2020
28. Atrial fibrillation rhythm is associated with marked changes in metabolic and myofibrillar protein expression in left atrial appendage
- Author
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David R. Van Wagoner, Laurie Castel, John Barnard, Mina K. Chung, Belinda Willard, Sojin Y Wass, Julie H. Rennison, Catherine Cantlay, Reena Mehra, A. Marc Gillinov, Jonathan D. Smith, Meghan McHale, Cheryl R Lin, Ling Li, and Beth Lovano
- Subjects
0301 basic medicine ,Male ,Proteomics ,medicine.medical_specialty ,Physiology ,Clinical Biochemistry ,Oxidative phosphorylation ,Mitochondrion ,Article ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Atrial Fibrillation ,medicine ,Humans ,Sinus rhythm ,Atrial Appendage ,Receptor ,Stroke ,Aged ,biology ,business.industry ,Atrial fibrillation ,Middle Aged ,medicine.disease ,030104 developmental biology ,Heart failure ,Sirtuin ,Cardiology ,biology.protein ,Female ,business ,030217 neurology & neurosurgery - Abstract
Atrial fibrillation (AF) is strongly associated with risk of stroke and heart failure. AF promotes atrial remodeling that increases risk of stroke due to left atrial thrombogenesis, and increases energy demand to support high rate electrical activity and muscle contraction. While many transcriptomic studies have assessed AF-related changes in mRNA abundance, fewer studies have assessed proteomic changes. We performed a proteomic analysis on left atrial appendage (LAA) tissues from 12 patients with a history of AF undergoing elective surgery; atrial rhythm was documented at time of surgery. Proteomic analysis was performed using liquid chromatography with mass spectrometry (LC/MS-MS). Data-dependent analysis identified 3090 unique proteins, with 408 differentially expressed between sinus rhythm and AF. Ingenuity Pathway Analysis of differentially expressed proteins identified mitochondrial dysfunction, oxidative phosphorylation, and sirtuin signaling among the most affected pathways. Increased abundance of electron transport chain (ETC) proteins in AF was accompanied by decreased expression of ETC complex assembly factors, tricarboxylic acid cycle proteins, and other key metabolic modulators. Discordant changes were also evident in the contractile unit with both up- and down-regulation of key components. Similar pathways were affected in a comparison of patients with a history of persistent vs. paroxysmal AF, presenting for surgery in sinus rhythm. Together, these data suggest that while the LAA attempts to meet the energetic demands of AF, an uncoordinated response may reduce ATP availability, contribute to tissue contractile and electrophysiologic heterogeneity, and promote a progression of AF from paroxysmal episodes to development of a substrate amenable to persistent arrhythmia.
- Published
- 2020
29. Circulating Neuropeptide Y as a Biomarker for Neuromodulation in Atrial Fibrillation
- Author
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David R. Van Wagoner, Lynsie Morris, Stavros Stavrakis, Olujimi A. Ajijola, Ayahiro D Takashima, and Khaled Elkholey
- Subjects
business.industry ,Atrial fibrillation ,medicine.disease ,Neuropeptide Y receptor ,Bioinformatics ,Neuromodulation (medicine) ,Article ,Atrial Fibrillation ,medicine ,Biomarker (medicine) ,Humans ,Neuropeptide Y ,business ,Biomarkers - Published
- 2020
30. Atrial fibrillation after rheumatic heart valve surgery: Incidence, predictors and outcomes
- Author
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David R. Van Wagoner, Nabil A Al-Zoubi, Khalid S. Ibrahim, Nizar R. AlWaqfi, Fadia Mayyas, and Khalid A. Kheirallah
- Subjects
medicine.medical_specialty ,Ejection fraction ,business.industry ,medicine.medical_treatment ,Mitral valve replacement ,Diastole ,Atrial fibrillation ,medicine.disease ,Cardiac surgery ,medicine.anatomical_structure ,Aortic valve replacement ,Internal medicine ,medicine ,Cardiology ,business ,Stroke ,Artery - Abstract
Introduction: Atrial fibrillation after cardiac surgery (AFACS) impacts 10-65% of patients, depending on the complexity and trauma associated with the surgery. AFACS is associated with stroke and other systemic embolic manifestations. Methods: Patients at our hospital who underwent valve surgery procedures including aortic valve replacement (AVR), mitral valve replacement (MVR), AVR with coronary artery bypass grafting (CABG), MVR with CABG, or AVR and MVR with/without CABG were included in this study. Results: 346 patients were included in the current analysis, with a mean age of 51.6±16.1 years; 51% of patients were males. Univariate predictors of AF included age, gender, body mass index (BMI), operation type, ejection fraction (EF), left atrial (LA) diameter, previous history of AF, use of aldosterone antagonists > a month before surgery, use of loop diuretics > a month before surgery, length of ICU stay, total length of stay, cross clamp time > 90 minutes, pump time > 120 minutes, postoperative acute kidney injury, left ventricular systolic and diastolic end dimensions. By multivariate analysis, only age (P=0.028, AOR=10.6), male gender (P=0.021, AOR=3.398), type of surgery (P=0.034, AOR=7.12), history of AF (P=0.018, AOR=2.317), BMI (P
- Published
- 2020
31. Abstract 262: Regional Transcriptomics of Left Atrial Cardiac Tissue in a Patient With Atrial Fibrillation
- Author
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John Barnard, Mina K. Chung, David R. Van Wagoner, Kenneth R. McCurry, Jonathan D. Smith, Toshihiro Okamoto, Han Sun, and Samuel Harwood
- Subjects
medicine.medical_specialty ,Physiology ,business.industry ,Left atrial ,Internal medicine ,Cardiology ,medicine ,Atrial fibrillation ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business - Abstract
Background: Common genetic variants and inflammatory factors are associated with atrial fibrillation (AF) risk. Although the top AF risk locus is near PITX2 (associated with pulmonary vein (PV) development), regional differential expression (DE) of AF risk genes in the left atrium (LA) and PVs is not well studied. While LAA and PV gene expression have been compared, transcriptome mapping of the entire LA has not been done. We tested the hypothesis that there is significant regional DE in LA structures. Methods: RNAseq was performed in 25 regions within the PVs (n=12), LA body (LAB) (n=10), and LA appendage (LAA) (n=3) from a 75 year old male with hypertension and AF who died of a stroke. DE analysis of regional clusters (R 3.6 Limma package) and gene set enrichment analysis (GSEA) (Broad Institute) were performed. Results: In full transcriptome (n=20664) sequencing, 118 genes were significantly (q < 0.05) upregulated in the LAA, including FOSB (fold change [FC] 67.0), IL6 (FC 15.4), TNF (FC 2.4) and NLRP3 (FC 2.4), and 56 downregulated, including developmental genes such as SHOX2 (FC -12.9) and HOXA4 (FC -4.1). LAA GSEA showed enrichment (FDR < 0.05) of inflammatory response genes and TNF-α, IL-2, IL-6, and IgG signaling pathways. 2454 genes were significantly upregulated and 3737 downregulated in the PVs while 4021 genes were upregulated and 2998 were downregulated in the LAB. In an AF implicated gene set (n=190), 28 genes were upregulated in the PVs, including SIRT1 (FC 1.7), and 31 downregulated, including PMNT (FC -2.1) and CGA (FC -3.2). NEURL1 was significantly upregulated in the inferior PV (n=4) compared to the superior PV (n=8) (FC 3.6). In the LAB, 33 genes were upregulated, including MYH7 (FC 2.2) and PMNT (FC 2.1) , and 38 downregulated including SIRT1 (FC -1.9). PITX2 did not show any significant DE in any gene set. Conclusions: This data shows that genes involved in AF pathogenesis can have substantial regional expression difference, particularly when comparing the LA body, PVs, and LAA. Inflammatory activation in the LAA may contribute to increased stroke risk.
- Published
- 2020
32. Paracrine Signals Modulate Atrial Epicardial Progenitor Cells and Development of Subepicardial Adiposity and Fibrosis Implications for Atrial Fibrillation
- Author
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David R. Van Wagoner
- Subjects
medicine.medical_specialty ,Physiology ,business.industry ,Stem Cells ,Atrial fibrillation ,Paracrine signals ,medicine.disease ,Fibrosis ,Internal medicine ,Atrial Fibrillation ,medicine ,Cardiology ,Humans ,Heart Atria ,Progenitor cell ,Cardiology and Cardiovascular Medicine ,business ,Cardiomyopathies ,Pericardium ,Adiposity - Published
- 2020
33. Genetic Susceptibility for Atrial Fibrillation in Patients Undergoing Atrial Fibrillation Ablation
- Author
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Moritz F. Sinner, Lauren Lee Rinke, Steffen Blum, M. Benjamin Shoemaker, Victoria Jacobs, Carolina Roselli, Omeed Zardkoohi, Mina K. Chung, Joylene E. Siland, Han Sun, Diane M. Crawford, Jay A. Montgomery, Michiel Rienstra, Gerhard Hindricks, Sanghamitra Mohanty, Benjamin Neumann, Tariq Z Issa, John Barnard, Isabelle C. Van Gelder, Dan M. Roden, Hugh Calkins, Petra Büttner, Rebecca Freudling, David Conen, Peter Weeke, Sébastien Thériault, Christian M. Shaffer, Andreas Bollmann, Steven A. Lubitz, Michael Kühne, Greg Michaud, Bastiaan Geelhoed, Stefan Kääb, Andrea Natale, Michael J. Cutler, Laura Ueberham, Quinn S. Wells, Stefanie Aeschbacher, Stacey Knight, Patrick T. Ellinor, Dawood Darbar, Martina Müller-Nurasyid, Jonathan D. Smith, Saman Nazarian, Jonathan Chrispin, Zachary T. Yoneda, Meelad Al Jazairi, Daniela Husser, David R. Van Wagoner, and Cardiovascular Centre (CVC)
- Subjects
Male ,Multifactorial Inheritance ,medicine.medical_specialty ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Physiology (medical) ,Internal medicine ,Atrial Fibrillation ,Genetic variation ,Genetic predisposition ,medicine ,Humans ,Genetic Predisposition to Disease ,In patient ,Prospective Studies ,Aged ,030304 developmental biology ,0303 health sciences ,business.industry ,Body Surface Potential Mapping ,Atrial fibrillation ,Middle Aged ,Prognosis ,medicine.disease ,Ablation ,Preoperative Period ,Catheter Ablation ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,Genetic Variation ,Genetics ,Phenotype ,Pulmonary Veins ,Follow-Up Studies - Abstract
Background: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. Methods: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. Results: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger ( P P =0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22–1.58]; P P P =0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99–1.18]; P =0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98–1.15]; P =0.13). Conclusions: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.
- Published
- 2020
34. B-PO05-002 DIFFERENTIAL GENE EXPRESSION BY AGE AND ATRIAL FIBRILLATION IN THE HUMAN LEFT ATRIUM
- Author
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John Barnard, David R. Van Wagoner, A. Marc Gillinov, Jonathan D. Smith, Christine S. Moravec, Mina K. Chung, Julie H. Rennison, Samuel Harwood, Han Sun, and Sojin Y Wass
- Subjects
medicine.medical_specialty ,business.industry ,Left atrium ,Atrial fibrillation ,medicine.disease ,medicine.anatomical_structure ,Physiology (medical) ,Internal medicine ,Gene expression ,medicine ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Differential (mathematics) - Published
- 2021
35. Su480 ACTIVATED INTESTINAL MUSCLE PROMOTES PREADIPOCYTE MIGRATION: A NOVEL MECHANISM OF CREEPING FAT FORMATION IN CROHN'S DISEASE
- Author
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Jie Wang, David R. Van Wagoner, Mitch Olman, Ilyssa O. Gordon, Thi Hong Nga Le, Brian D. Southern, Jyotsna Chandra, Satya Kurada, Dina Dejanovic, Claudio Fiocchi, Michael Elias, Shuai Zhao, Pranab K. Mukherjee, Florian Rieder, Gail West, Genevieve Doyon, Sinan Lin, Jiannan Li, and Ren Mao
- Subjects
Crohn's disease ,Hepatology ,Chemistry ,Mechanism (biology) ,Intestinal muscle ,Gastroenterology ,medicine ,medicine.disease ,Cell biology - Published
- 2021
36. The burden of proof: The current state of atrial fibrillation prevention and treatment trials
- Author
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David R. Van Wagoner, E. Kevin Heist, Cecilia Linde, Hugh Calkins, Timothy E. Meyer, Robert J. Mentz, Faiez Zannad, Bertram Pitt, John G.F. Cleland, Tom Wong, Heather M. Ross, Rosita Zakeri, and Peter R. Kowey
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Alternative medicine ,Catheter ablation ,030204 cardiovascular system & hematology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Physiology (medical) ,Atrial Fibrillation ,Humans ,Medicine ,030212 general & internal medicine ,Intensive care medicine ,Clinical Trials as Topic ,business.industry ,Burden of proof ,Atrial fibrillation ,medicine.disease ,R1 ,Clinical trial ,Informatics ,Personalized medicine ,Cardiology and Cardiovascular Medicine ,business - Abstract
Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3-5, 2015.
- Published
- 2017
37. OSA and Cardiac Arrhythmogenesis
- Author
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David R. Van Wagoner, Anna May, and Reena Mehra
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Atrial enlargement ,030204 cardiovascular system & hematology ,Critical Care and Intensive Care Medicine ,QT interval ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Ventricular hypertrophy ,Internal medicine ,Cardiac conduction ,medicine ,cardiovascular diseases ,business.industry ,Effective refractory period ,Cardiac arrhythmia ,Atrial fibrillation ,medicine.disease ,respiratory tract diseases ,cardiovascular system ,Cardiology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery - Abstract
A surge of data has reproducibly identified strong associations of OSA with cardiac arrhythmias. As an extension of epidemiologic and clinic-based findings, experimental investigations have made strides in advancing our understanding of the putative OSA and cardiac arrhythmogenesis mechanistic underpinnings. Although most studies have focused on the links between OSA and atrial fibrillation (AF), relationships with ventricular arrhythmias have also been characterized. Key findings implicate OSA-related autonomic nervous system fluctuations typified by enhanced parasympathetic activation during respiratory events and sympathetic surges subsequent to respiratory events, which contribute to augmented arrhythmic propensity. Other more immediate pathophysiologic influences of OSA-enhancing arrhythmogenesis include intermittent hypoxia, intrathoracic pressure swings leading to atrial stretch, and hypercapnia. Intermediate pathways by which OSA may trigger arrhythmia include increased systemic inflammation, oxidative stress, enhanced prothrombotic state, and vascular dysfunction. Long-term OSA-associated sequelae such as hypertension, atrial enlargement and fibrosis, ventricular hypertrophy, and coronary artery disease also predispose to cardiac arrhythmia. These factors can lead to a reduction in atrial effective refractory period, triggered and abnormal automaticity, and promote slowed and heterogeneous conduction; all of these mechanisms increase the persistence of reentrant arrhythmias and prolong the QT interval. Cardiac electrical and structural remodeling observed in OSA animal models can progress the arrhythmogenic substrate to further enhance arrhythmia generation. Future investigations clarifying the contribution of specific OSA-related mechanistic pathways to arrhythmia generation may allow targeted preventative therapies to mitigate OSA-induced arrhythmogenicity. Furthermore, interventional studies are needed to clarify the impact of OSA pathophysiology reversal on cardiac arrhythmogenesis and related adverse outcomes.
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- 2017
38. Pitfalls and potential for the use of computational modelling to guide the treatment of atrial fibrillation
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David R. Van Wagoner
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medicine.medical_specialty ,Physiology ,business.industry ,medicine.medical_treatment ,MEDLINE ,Atrial fibrillation ,Catheter ablation ,medicine.disease ,Pulmonary Veins ,Internal medicine ,Atrial Fibrillation ,Catheter Ablation ,medicine ,Cardiology ,Humans ,Personalized medicine ,business - Published
- 2020
39. Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress
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Takhar Kasumov, David R. Van Wagoner, Yana Sandlers, Allawy Allawy, Avinash Kumar, Samjhana Thapaliya, Julie H. Rennison, Dharmvir Singh, Christopher A Flask, Charles L. Hoppel, Gangarao Davuluri, and Srinivasan Dasarathy
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0301 basic medicine ,Mitochondrial ROS ,medicine.medical_specialty ,Physiology ,Cellular respiration ,Skeletal muscle ,Metabolism ,Oxidative phosphorylation ,Mitochondrion ,Biology ,medicine.disease_cause ,Citric acid cycle ,03 medical and health sciences ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Biochemistry ,Internal medicine ,medicine ,Oxidative stress - Abstract
Key points Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia. We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD+/NADH ratio and ATP content. During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids. Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell-permeable ester of αKG reversed the lower TCA cycle intermediate concentrations and increased ATP content. Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS. Abstract Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonaemia occurs in advanced hepatic, cardiac and pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non-hepatic ammonia disposal. Non-hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from α-ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonaemia in a comprehensive array of human, rodent and cellular models. ATP synthesis, oxygen consumption, generation of reactive oxygen species with oxidative stress, and tricarboxylic acid (TCA) cycle intermediates were quantified. ATP content was lower in the skeletal muscle from cirrhotic patients, hyperammonaemic portacaval anastomosis rat, and C2C12 myotubes compared to appropriate controls. Hyperammonaemia in C2C12 myotubes resulted in impaired intact cell respiration, reduced complex I/NADH oxidase activity and electron leak occurring at complex III of the electron transport chain. Consistently, lower NAD+/NADH ratio was observed during hyperammonaemia with reduced TCA cycle intermediates compared to controls. Generation of reactive oxygen species resulted in increased content of skeletal muscle carbonylated proteins and thiobarbituric acid reactive substances during hyperammonaemia. A cell-permeable ester of α-ketoglutarate reversed the low TCA cycle intermediates and ATP content in myotubes during hyperammonaemia. However, the mitochondrial antioxidant MitoTEMPO did not reverse the lower ATP content during hyperammonaemia. We provide for the first time evidence that skeletal muscle hyperammonaemia results in mitochondrial dysfunction and oxidative stress. Use of anaplerotic substrates to reverse ammonia-induced mitochondrial dysfunction is a novel therapeutic approach.
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- 2016
40. Causal SNP regulating FAM13B expression identified for the Chr. 5q31 atrial fibrillation susceptibility locus
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Fang Liu, David R. Van Wagoner, Jonathan D. Smith, Nana Liu, Christine S. Moravec, Jeffrey Hsu, Shamone R. Gore-Panter, Mina K. Chung, John Barnard, and Gregory Tchou
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Genetics ,0303 health sciences ,Gene knockdown ,Linkage disequilibrium ,Single-nucleotide polymorphism ,Transfection ,030204 cardiovascular system & hematology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Allele ,Enhancer ,Gene ,030304 developmental biology - Abstract
RationaleOur prior RNA sequencing study found that FAM13B gene expression in human left atrial appendages was strongly associated with an atrial fibrillation (AF) susceptibility-associated variant on chr. 5q31.ObjectiveTo identify the common genetic variant responsible for regulating FAM13B expression and the effect of FAM13B expression on cardiomyocyte gene expression in order to gain insight into the functional mechanism of the chr. 5q31 AF susceptibility locus.Methods and ResultsBy taking advantage of a smaller linkage disequilibrium block in African descent subjects and available chromatin conformation data, we identified the common single nucleotide polymorphism (SNP) rs17171731 as a candidate genetic variant controlling FAM13B gene expression in the left atrium. Functional analysis demonstrated that the AF risk allele of rs17171731 had less enhancer activity than the protective allele. Gel mobility shift studies determined that the risk allele bound to an additional protein that may function as a transcriptional repressor. Knockdown of FAM13B expression in stem cell-derived human cardiomyocytes (iCM) altered the expression of >1000 genes and modified the sodium current, consistent with increased susceptibility to atrial fibrillation. Transfection of GFP tagged FAM13B into iCMs demonstrated expression on the plasma membrane and at the Z-disk.ConclusionsThe chr. 5q31 AF risk variant was identified as rs17171731, with the risk allele having less enhancer activity, leading to decreased expression of FAM13B, which resides on the plasma membrane and the Z-disk, and appears to play a role in the regulation of cardiomyocyte gene expression and the late sodium current.
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- 2019
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41. Atrial fibrillation associated common risk variants in SYNE2 lead to lower expression of nesprin-2α1 and increased nuclear stiffness
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Gautam Mahajan, Chandrasekhar R. Kothapalli, Han Sun, David R. Van Wagoner, John Barnard, Jonathan D. Smith, Nana Liu, Mina K. Chung, and Jeffrey Hsu
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Gene isoform ,0303 health sciences ,Messenger RNA ,Reporter gene ,medicine.diagnostic_test ,RNA ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Molecular biology ,03 medical and health sciences ,0302 clinical medicine ,Western blot ,medicine ,Enhancer ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
RationaleAtrial fibrillation (AF) genome-wide association studies (GWAS) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding the nesprin-2 protein that connects the nuclear membrane with the cytoskeletonObjectiveDetermine the effects of the AF-associated rs1152591 and rs1152595, two linked intronic single nucleotide polymorphisms (SNPs), on SYNE2 expression and investigate the mechanisms for their association with AF.Methods and ResultsRNA sequencing of human left atrial appendage (LAA) tissues indicated that rs1152591 and rs1152595 were significantly associated with the expressions of SYNE2α1, a short mRNA isoform, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 mRNA uses an alternative transcription start site and encodes an N-terminal deleted 62 kDa nesprin-2α1 isoform, which can act as a dominant-negative on nuclear-cytoskeleton connectivity. Western blot and qPCR assays confirmed that AF risk alleles of both SNPs were associated with lower expression of nesprin-2α1 in human LAA tissues. Reporter gene transfections demonstrated that the risk vs. reference alleles of rs1152591 and rs1152595 had decreased enhancer activity. SYNE2 siRNA knockdown (KD) or nesprin-2α1 overexpression studies in human stem cell-derived induced cardiomyocytes (iCMs) resulted in ~12.5 % increases in the nuclear area compared to controls (pConclusionsAF-associated SNPs rs1152591 and rs1152595 downregulate the expression of SYNE2α1, increasing nuclear-cytoskeletal connectivity and nuclear stiffness. The resulting increase in mechanical stress may play a role in the development of AF.
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- 2019
42. Editorial commentary: A CRISPR approach to the study and treatment of cardiovascular disease
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Shamone R. Gore-Panter and David R. Van Wagoner
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business.industry ,Extramural ,Cardiovascular Diseases ,MEDLINE ,CRISPR ,Medicine ,Humans ,Clustered Regularly Interspaced Short Palindromic Repeats ,Disease ,CRISPR-Cas Systems ,Cardiology and Cardiovascular Medicine ,Bioinformatics ,business - Published
- 2019
43. Inflammation, Inflammasome Activation and AF: Evidence for Causation and New Therapeutic Targets
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David R, Van Wagoner and Mina K, Chung
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Inflammation ,integumentary system ,Inflammasomes ,Atrial Fibrillation ,NLR Family, Pyrin Domain-Containing 3 Protein ,Humans ,Myocytes, Cardiac ,Article - Abstract
BACKGROUND: Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The “NACHT, LRR and PYD domain containing protein 3” (NLRP3)-inflammasome mediates caspase-1 activation and interleukin-1β release in immune cells, but is not known to play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3-inflammasome in AF. METHODS: NLRP3-inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal (pAF) or long-standing persistent (chronic) AF (cAF). To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knock-in mouse model expressing constitutively active NLRP3 (CM-KI) was established. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To evaluate the mechanism of AF, electrical activation pattern, Ca(2+) spark frequency (CaSF), atrial effective refractory period (AERP), and morphology of atria were evaluated in CM-KI mice and WT littermates. RESULTS: NLRP3-inflammasome activity was increased in atrial CMs of pAF and cAF patients. CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which was attenuated by a specific NLRP3-inflammasome inhibitor, MCC950. CM-KI mice exhibited ectopic activity, abnormal sarcoplasmic-reticulum Ca(2+)-release, AERP shortening and atrial hypertrophy. Adeno-associated virus subtype-9 mediated CM-specific knockdown of Nlrp3 suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AF development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF. CONCLUSIONS: Our study establishes a novel pathophysiological role for CM NLRP3-inflammasome signaling with a mechanistic link to the pathogenesis of AF, and establishes inhibition of NLRP3 as a potential novel AF-therapy approach.
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- 2018
44. Oxidant and Inflammatory Mechanisms and Targeted Therapy in Atrial Fibrillation
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David R. Van Wagoner and Alejandra Gutierrez
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medicine.medical_specialty ,medicine.medical_treatment ,Anti-Inflammatory Agents ,Inflammation ,medicine.disease_cause ,Antioxidants ,Article ,Targeted therapy ,Drug Delivery Systems ,Fibrosis ,Internal medicine ,Atrial Fibrillation ,medicine ,Animals ,Humans ,cardiovascular diseases ,Risk factor ,Stroke ,Pharmacology ,business.industry ,Atrial fibrillation ,Oxidants ,medicine.disease ,Oxidative Stress ,Heart failure ,Cardiology ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Oxidative stress - Abstract
Atrial fibrillation (AF) is an important cause of stroke and risk factor for heart failure and death. Current pharmacologic treatments for AF have limited efficacy, and treatments that more directly target the underlying causes of AF are needed. Oxidant stress and inflammatory activation are inter-related pathways that promote atrial electrical and structural remodeling, leading to atrial ectopy, interstitial fibrosis and increased stroke risk. This review evaluates the impact of common stressors on atrial oxidant stress and inflammatory activation, and the contribution of these pathways to atrial remodeling. Recent studies suggest that integrated efforts to target the underlying risk factors, rather than the AF per se, may have a greater impact on health and outcomes than isolated efforts focused on the electrical abnormalities.
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- 2015
45. Plasma endothelin-1 levels are increased in atrial fibrillation patients with hyperthyroidism
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Fadia Mayyas, Nesreen A. Saadeh, David R. Van Wagoner, and Kusai M. Al-Muqbel
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0301 basic medicine ,Male ,endocrine system diseases ,Carbimazole ,Physiology ,Peptide Hormones ,030204 cardiovascular system & hematology ,Hyperthyroidism ,Vascular Medicine ,Biochemistry ,0302 clinical medicine ,Animal Cells ,Blood plasma ,Atrial Fibrillation ,Medicine and Health Sciences ,Coronary Heart Disease ,Euthyroid ,Enzyme-Linked Immunoassays ,Thyroid ,Multidisciplinary ,Endothelin-1 ,Atrial fibrillation ,Body Fluids ,medicine.anatomical_structure ,C-Reactive Protein ,Blood ,Medicine ,Female ,Anatomy ,Cellular Types ,hormones, hormone substitutes, and hormone antagonists ,Arrhythmia ,Research Article ,Adult ,medicine.medical_specialty ,endocrine system ,Thyroid Hormones ,Science ,Adrenergic beta-Antagonists ,Cardiology ,Muscle Tissue ,Endocrine System ,Research and Analysis Methods ,Blood Plasma ,03 medical and health sciences ,Thyroid-stimulating hormone ,Internal medicine ,medicine ,Humans ,Thyroid-Stimulating Hormone ,Immunoassays ,Muscle Cells ,business.industry ,Biology and Life Sciences ,Cell Biology ,medicine.disease ,Endothelin 1 ,Coronary heart disease ,Hormones ,030104 developmental biology ,Endocrinology ,Biological Tissue ,Multivariate Analysis ,Immunologic Techniques ,business ,Hormone - Abstract
BackgroundEndothelin-1 (ET-1) is a potent vasoconstrictor, mitogen and inflammatory factor that may contribute to development of atrial fibrillation (AF). Plasma ET-1 levels are increased in hyperthyroid patients, but studies evaluating its relation to AF development in hyperthyroid patients are lacking.ObjectiveThe present study seeks to evaluate the relation of plasma ET-1 to AF development as a function of thyroid status.MethodsBlood samples from euthyroid patients (n = 41), hypothyroid (n = 61), hyperthyroid (n = 41), AF with hyperthyroidism (n = 9), and euthyroid AF (n = 10) patients were collected. Plasma ET-1, CRP, and thyroid hormone levels were measured and compared between groups.ResultsPlasma ET-1 levels were higher in hyperthyroid and euthyroid AF patients> hyperthyroid-non-AF > hypo and euthyroid non-AF patients. Plasma ET-1 levels positively correlated with free T3 and T4 levels, and negatively with TSH levels. By multivariate analysis, plasma ET-1 was positively associated with AF, hyperthyroidism, and age. Plasma CRP did not vary by study group in either univariate or multivariate analyses.ConclusionPlasma ET-1 is associated with AF, elevated in hyperthyroid patients and positively correlated with thyroid hormone levels, suggesting that hyperthyroidism may increase ET-1 expression and release. This study may guide development of novel predictors of AF associated with hyperthyroidism, and may help to personalize therapy in hyperthyroid patients.
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- 2018
46. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
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Bruno H. Stricker, Antonietta Robino, Gandin Ilaria, Marylyn D. Ritchie, Mark Eijgelsheim, Hilma Holm, Marcus Dörr, Philipp S. Wild, Jessica van Setten, Stephan B. Felix, Maristella Steri, Jared W. Magnani, Brendan M. Buckley, Peter P. Pramstaller, Claudia T. Silva Aldana, Niek Verweij, Tim D. Spector, Ruth J. F. Loos, Dan M. Roden, Martina Müller-Nurasyid, Mina K. Chung, Sandosh Padmanabhan, Stefania Bandinelli, Harm-Jan Westra, James F. Wilson, Honghuang Lin, Braxton D. Mitchell, Patrick T. Ellinor, Patricia B. Munroe, Harold Snieder, Thomas Münzel, Sheila Ulivi, Andrew A. Hicks, Nona Sotoodehnia, Daniel S. Evans, Annamaria Iorio, Peter W. Macfarlane, Vilmundur Gudnason, Christy L. Avery, Caroline Hayward, Cornelia M. van Duijn, John Barnard, Alvaro Alonso, Dana C. Crawford, Uwe Völker, David R. Van Wagoner, Tamara B. Harris, Harry Campbell, Ozren Polasek, Daniel F. Gudbjartsson, Ilja M. Nolte, Bouwe P. Krijthe, Eric Boerwinkle, Moritz F. Sinner, Elsayed Z. Soliman, Mika Kähönen, Christian Müller, Renate B. Schnabel, Unnur Thorsteinsdottir, Leo-Pekka Lyytikäinen, George J. Papanicolaou, Ivana Kolcic, Stella Trompet, Jerome I. Rotter, Dan E. Arking, Kirill V. Tarasov, Igor Rudan, Bruce M. Psaty, Gianfranco Sinagra, Alexander Teumer, Yalda Jamshidi, David O. Arnar, Toshiko Tanaka, Melanie Waldenberger, Henry J. Lin, Luigi Ferrucci, Susan R. Heckbert, Jan A. Kors, Irene Mateo Leach, Joel S. Bader, Konstantin Strauch, Albert V. Smith, Paul I.W. de Bakker, Stefan Blankenberg, J. C. Bis, Edward G. Lakatta, Lenore J. Launer, Thomas Meitinger, Anna F. Dominiczak, Marcel den Hoed, Steven A. Lubitz, Stefan Kääb, David J. Stott, Francesco Cucca, Olli T. Raitakari, Afshin Parsa, Nilesh J. Samani, Josh C. Denny, Lude Franke, Oscar H. Franco, Yongmei Liu, Folkert W. Asselbergs, Henry Völzke, Terho Lehtimäki, Arne Pfeufer, Annette Peters, David Schlessinger, Xiaoyan Yin, Jennifer A. Brody, J. Wouter Jukema, Paolo Gasparini, Tanja Zeller, Aaron Isaacs, Anne M. Butler, Sina A. Gharib, Kathleen F. Kerr, Jonathan D. Smith, Pim van der Harst, André G. Uitterlinden, Quince Gibson, Yuki Bradford, Brenton R. Swenson, Emelia J. Benjamin, Georg Ehret, Kari Stefansson, Fabiola M. Del Greco, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Gandin, Ilaria, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth J F, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thoma, Mitchell, Braxton D, Munzel, Thoma, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcu, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R, Hicks, Andrew A, Jukema, J Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B, Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M, Roden, Dan M, Schnabel, Renate B, Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Wilson, James F, Gharib, Sina A, de Bakker, Paul I W, Isaacs, Aaron, Arking, Dan E, Sotoodehnia, Nona, Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Epidemiology, Medical Informatics, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), and Stem Cell Aging Leukemia and Lymphoma (SALL)
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Male ,QRS duration ,Epidemiology ,Genome-wide association study ,Biochemistry ,Linkage Disequilibrium ,Electrocardiography ,0302 clinical medicine ,Atrioventricular Conduction ,lcsh:Science ,COMMON VARIANTS ,Heart Depolarization ,Canal de iones ,Cardiovascular system ,Gene Locus ,Blood ,cardiovascular system ,Qrs Interval ,FIBRILLATION ,Enfermedades cardiovasculares ,Human ,Missense Mutation ,Heart block ,Science ,HEART-RATE ,Single-nucleotide polymorphism ,Missense/genetics ,Physics and Astronomy(all) ,Factor de transcripción ,European ,General Biochemistry, Genetics and Molecular Biology ,Article ,PR interval genome ,atrial electrical activity ,atrioventricular electrical activity ,03 medical and health sciences ,CARDIAC CONDUCTION ,Cardiac conduction ,Humans ,Sistema cardiovascular ,Common variants ,Sangre ,Cardiovascular genetics ,medicine.disease ,Heart-rate ,Enfermedades ,Electrophysiological Phenomena ,030104 developmental biology ,Heart Block ,Electric Activity ,Mutation ,lcsh:Q ,Cell Junction ,Cohorts ,Meta-Analysis ,0301 basic medicine ,Chemistry(all) ,Transcription Factor ,General Physics and Astronomy ,030204 cardiovascular system & hematology ,Fibrilación auricular ,Electrophysiological Phenomena/genetics ,RARE ,Ion Channel ,Heart Rate ,Risk Factors ,Atrial Fibrillation ,EPIDEMIOLOGY ,Bloqueo cardíaco ,SNPS ,Genetics ,RISK ,Multidisciplinary ,Genome ,Atrial fibrillation ,Genetic Analysis ,Atrioventricular Node/physiology ,Atrial Function ,Phenotype ,Heart Disease ,Rare ,Atrioventricular Node ,Female ,medicine.symptom ,QRS DURATION ,Atrial Function/physiology ,Medical Genetics ,SNPs ,Signal Transduction ,Risk ,Heart Diseases ,Mutation, Missense ,macromolecular substances ,Biology ,QRS complex ,medicine ,Disequilibrium ,Linkage Disequilibrium/genetics ,cardiovascular diseases ,PR interval ,Medicinsk genetik ,Fibrillation ,Biochemistry, Genetics and Molecular Biology(all) ,Risk Factor ,African ,General Chemistry ,COHORTS ,Pr Interval ,Gene Linkage Disequilibrium ,Genetics and Molecular Biology(all) ,Genome-Wide Association Study - Abstract
Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.
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- 2018
47. Common Coding Variants in SCN10A Are Associated With the Nav1.8 Late Current and Cardiac Conduction
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Alvaro Alonso, Donna M. Muzny, Moritz F. Sinner, Ching-Ti Liu, John Barnard, Eric Boerwinkle, David J. Milan, Thomas P. Cappola, Robert W. Mills, Alanna C. Morrison, Thomas Lumley, Colleen M. Sitlani, Dan E. Arking, Michael Morley, L. Adrienne Cupples, Nona Sotoodehnia, Rebecca D. Jackson, Mina K. Chung, Paul M.L. Janssen, Ning Li, Stephen S. Rich, Jerome I. Rotter, Christopher J. O'Donnell, David R. Van Wagoner, Kenneth B. Margulies, Xiaoyan Yin, Gus J. Vlahakes, Sara L. Pulit, Caroline N. Herndon, Vadim V. Fedorov, Joshua C. Bis, Susan R. Heckbert, Jared W. Magnani, Bruce M. Psaty, Steven A. Lubitz, Christopher Newton-Cheh, Honghuang Lin, Peter J. Mohler, Patrick T. Ellinor, Elena Dolmatova, Jonathan D. Smith, Vincenzo Macri, William J. Hucker, Emelia J. Benjamin, Richard A. Gibbs, and Jennifer A. Brody
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0301 basic medicine ,medicine.medical_specialty ,education.field_of_study ,Haplotype ,Population ,Single-nucleotide polymorphism ,Locus (genetics) ,General Medicine ,030204 cardiovascular system & hematology ,Biology ,03 medical and health sciences ,QRS complex ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Cardiac conduction ,medicine ,Missense mutation ,PR interval ,education - Abstract
Background: Genetic variants at the SCN5A / SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. Methods: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. Results: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( r 2 =0.86) with each other to be the strongest signals for PR (rs10428132, β=−4.74, P =1.52×10 −14 ) and QRS intervals (rs6599251, QRS β=−0.73; P =1.2×10 −4 ), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( r 2 ≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P =0.03, and I962V+V1073A, 22.4±0.8%, P =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P =0.03). Conclusions: Our findings suggest an association between genetic variation in SCN10A , the late sodium current, and alterations in cardiac conduction.
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- 2018
48. Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity
- Author
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Aaron Isaacs, Sina A. Gharib, Kathleen F. Kerr, Lenore J. Launer, Yuki Bradford, J. Wouter Jukema, Stefan Kääb, Ruth J. F. Loos, Philipp S. Wild, Igor Rudan, Moritz F. Sinner, Annamaria Iorio, David J. Stott, Sheila Ulivi, Martina Müller-Nurasyid, Jerome I. Rotter, Andrew A. Hicks, Leo-Pekka Lyytikäinen, Vilmundur Gudnason, Dan M. Roden, Dana C. Crawford, James F. Wilson, Renate B. Schnabel, Eric Boerwinkle, Mina K. Chung, M. Fabiola Del Greco, Jan A. Kors, Honghuang Lin, Dan E. Arking, Annette Peters, Daniel S. Evans, Kari Stefansson, Francesco Cucca, Harold Snieder, Nona Sotoodehnia, Claudia T. Silva Aldana, Paul I.W. de Bakker, David Schlessinger, Pim van der Harst, Irene Mateo Leach, Kirill V. Tarasov, Marylyn D. Ritchie, Xiaoyan Yin, Marcus Dörr, Jennifer A. Brody, Patrick T. Ellinor, Olli T. Raitakari, Christy L. Avery, Peter W. Macfarlane, Paolo Gasparini, Susan R. Heckbert, John Barnard, Jessica van Setten, Anna F. Dominiczak, Henry Völzke, Edward G. Lakatta, Nilesh J. Samani, Tamara B. Harris, Brenton R. Swenson, Joel S. Bader, Thomas Münzel, Patricia B. Munroe, Hilma Holm, Stefania Bandinelli, Christian Müller, Bruno H. Stricker, Oscar H. Franco, Yongmei Liu, Ivana Kolcic, Peter P. Pramstaller, Josh C. Denny, Maristella Steri, Henry J. Lin, Luigi Ferrucci, Arne Pfeufer, Antonietta Robino, Bruce M. Psaty, Niek Verweij, Lude Franke, Mark Eijgelsheim, Afshin Parsa, Toshiko Tanaka, Folkert W. Asselbergs, Terho Lehtimäki, Stella Trompet, Alvaro Alonso, Harm-Jan Westra, David O. Arnar, Jared W. Magnani, Bouwe P. Krijthe, Cornelia M. van Duijn, Brendan M. Buckley, Jonathan D. Smith, Tim D. Spector, George J. Papanicolaou, Anne M. Butler, Emelia J. Benjamin, Tanja Zeller, Quince Gibson, David R. Van Wagoner, André G. Uitterlinden, Albert V. Smith, Stephan B. Felix, Uwe Völker, Yalda Jamshidi, Ozren Polasek, Daniel F. Gudbjartsson, Harry Campbell, Caroline Hayward, Ilja M. Nolte, Elsayed Z. Soliman, Georg Ehret, Mika Kähönen, Konstantin Strauch, Steven A. Lubitz, Melanie Waldenberger, Alexander Teumer, Sandosh Padmanabhan, Braxton D. Mitchell, Gianfranco Sinagra, Gandin Ilaria, Thomas Meitinger, Marcel den Hoed, Stefan Blankenberg, and J. C. Bis
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Genetics ,QRS complex ,Heart block ,medicine ,cardiovascular system ,Missense mutation ,Genome-wide association study ,Atrial fibrillation ,PR interval ,Biology ,medicine.disease ,Genome ,Gene - Abstract
Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.
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- 2018
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49. Multi-ethnic genome-wide association study for atrial fibrillation
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Marcus E. Kleber, Raji P. Grewal, Yingchang Lu, Sanghamitra Mohanty, Harry J.G.M. Crijns, Han Sun, Ilkka Seppälä, Jonathan D. Smith, Albert Hofman, Yii-Der Ida Chen, Diane Fatkin, Patrik K. E. Magnusson, Pil Sung Yang, Jari Laurikka, Saman Nazarian, Peter W. Macfarlane, Natalia S. Rost, Sekar Kathiresan, Heribert Schunkert, Sandosh Padmanabhan, Tõnu Esko, Bruno H. Stricker, Rebecca Gutmann, Alfredo José Mansur, Jonathan Rosand, Jesper Hastrup Svendsen, Alvaro Alonso, J. Gustav Smith, Benjamin Neumann, John Barnard, Christopher D. Anderson, Joanna Pera, Samir Saba, Lynne J. Hocking, Siew-Kee Low, Daniel I. Chasman, Patrick T. Ellinor, Nancy L. Pedersen, Stephan B. Felix, Vilmundur Gudnason, Kjell Nikus, Kahraman Tanriverdi, David J. Porteous, Samuel C. Dudley, Clive R. Pullinger, Tamara B. Harris, Barry London, Lorenz Risch, Ruth J. F. Loos, Rainer Malik, Isabelle C. Van Gelder, John F. Carlquist, Lena Refsgaard, Carolina Roselli, Albert Y. Sun, Man Li, Lenore J. Launer, Anders Hamsten, Svati H. Shah, Lin Y. Chen, Martina Müller-Nurasyid, Michiel Rienstra, Kent D. Taylor, Katharina Schramm, Jennifer A. Brody, Honghuang Lin, Eric Boerwinkle, Rozenn N. Lemaitre, Olle Melander, Hugh Calkins, Elsayed Z. Soliman, Moritz F. Sinner, Heather L. Bloom, Nicholas L. Smith, Nada Esa, John W. Cole, Maartje N. Niemeijer, David R. Van Wagoner, Anubha Mahajan, Roopinder K. Sandhu, Henry J. Lin, Jordi Jimenez-Conde, Ian Ford, Eue Keun Choi, Stacey Knight, Scott M. Damrauer, Markku Eskola, Claudia Schurman, Stuart A. Scott, Sara L. Pulit, Raymond Noordam, Mika Kähönen, Jay A. Montgomery, Agnieszka Slowik, Esra Gucuk Ipek, Joylene E. Siland, Lingyao Zeng, Andrew P. Morris, Oscar H. Franco, Bas L.J.H. Kietselaer, Adnan Kastrati, Dan E. Arking, José Eduardo Krieger, J. Wouter Jukema, Stefan Gustafsson, Nathan R. Tucker, Zachary T. Yoneda, Daniel Woo, Winfried März, Lauren Margolin, Uwe Völker, Stefan Kääb, Marju Orho-Melander, Lars Lind, Yoichiro Kamatani, Maris Teder-Laving, Paul M. Ridker, Bradford B. Worrall, Jaemin Shim, Bob Weijs, Ingrid E. Christophersen, Kenneth B. Margulies, James P. Cook, Graciela Delgado, Andrea Natale, Stefan Weiss, Gustav Ahlberg, Jie Huang, Guillaume Paré, M. Benjamin Shoemaker, Marcus Dörr, Arnljot Tveit, Elton A. M. P. Dudink, Thomas P. Cappola, Bruce M. Psaty, Alaa Shalaby, Gregory M. Marcus, Sébastien Thériault, Niek Verweij, Traci M. Bartz, Thorsten Kessler, Michael Morley, Xiuqing Guo, Alexandre C. Pereira, Efthymia Vlachopoulou, Albert V. Smith, Andrea R. V. R. Horimoto, David Conen, Erik Ingelsson, Jie Yao, Raul Weiss, David D. McManus, Michiaki Kubo, Lu-Chen Weng, Michael A. Rosenberg, Nona Sotoodehnia, Jennifer E. Huffman, Hui Nam Pak, Dan M. Roden, Peter Weeke, Joshua C. Bis, Archie Campbell, Marta Ribasés, Renee Johnson, Renate B. Schnabel, Christian M. Shaffer, Krishna G. Aragam, Seung Hoan Choi, André G. Uitterlinden, Morten S. Olesen, Toshihiro Tanaka, Daniel J. Rader, Mina K. Chung, Stella Trompet, Steven A. Lubitz, Martin Dichgans, Peter Almgren, Christine M. Albert, Blair H. Smith, Petra Katschnig-Winter, Joshua C. Denny, Christopher Newton-Cheh, Paulus Kirchhof, Namrata Gupta, Emelia J. Benjamin, Stefanie Aeschbacher, Marja-Liisa Lokki, Jorge A. Wong, Quinn S. Wells, Jussi Hernesniemi, Cecilia M. Lindgren, Mark Chaffin, Kaoru Ito, Jerome I. Rotter, Michael J. Cutler, Kerri L. Wiggins, Maryam Kavousi, Nathan A. Bihlmeyer, Bastiaan Geelhoed, Susan R. Heckbert, Caroline Hayward, Alexander Teumer, Paul L. Huang, Terho Lehtimäki, Juha Sinisalo, John P. Kane, Kirsten Leineweber, Tanja Zeller, Hong Euy Lim, Kathryn L. Lunetta, Brian R. Daniels, Heidi Oellers, Biqi Wang, Pim van der Harst, Peter M. Nilsson, Dawood Darbar, Erwin B. Bottinger, Leo-Pekka Lyytikäinen, Epidemiology, Internal Medicine, RS: Carim - H01 Clinical atrial fibrillation, Cardiologie, MUMC+: MA Cardiologie (3), RS: CARIM - R2.01 - Clinical atrial fibrillation, RS: CARIM - R3.11 - Imaging, MUMC+: MA Med Staf Spec Cardiologie (9), MUMC+: MA Med Staf Artsass Cardiologie (9), Cardiovascular Centre (CVC), and MUMC+: MA Cardiologie (9)
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0301 basic medicine ,medicine.medical_specialty ,Identification ,Annotation ,Quantitative Trait Loci ,Genome-wide association study ,030204 cardiovascular system & hematology ,Quantitative trait locus ,Biology ,methods [Genome-Wide Association Study] ,Gene ,genetics [Ethnic Groups] ,Article ,DISEASE ,03 medical and health sciences ,COMPONENTS-ANALYSIS ,0302 clinical medicine ,ddc:570 ,Atrial Fibrillation ,Cardiac conduction ,Ethnicity ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,genetics [Atrial Fibrillation] ,Genetic association ,Imputation ,ethnology [Atrial Fibrillation] ,Loci ,Case-control study ,Variants ,METANÁLISE ,Polymorphic ventricular-tachycardia ,030104 developmental biology ,GWAS CATALOG ,Susceptibility ,Case-Control Studies ,Expression quantitative trait loci ,genetics [Ethnicity] ,Medical genetics ,Transcriptome ,Imputation (genetics) ,Mutations ,Genome-Wide Association Study - Abstract
Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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- 2018
50. Role of Inflammation in Atrial Fibrillation Pathophysiology and Management
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Masahide Harada, Christodoulos Stefanadis, Stanley Nattel, and David R. Van Wagoner
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Apoptosis ,Inflammation ,Article ,Pathogenesis ,Fibrosis ,Atrial Fibrillation ,medicine ,Animals ,Humans ,Platelet activation ,Endothelial dysfunction ,Blood Coagulation ,Pathological ,business.industry ,Atrial fibrillation ,General Medicine ,medicine.disease ,Pathophysiology ,Oxidative Stress ,Immunology ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Atrial fibrillation (AF) is the most common clinically relevant arrhythmia, but the methods available for treating AF and its complications (of which the most important is thrombogenesis), as well as for assessing AF risk and underlying pathophysiology, are largely limited. Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF. That evidence includes elevated serum levels of inflammatory biomarkers in AF subjects, the expression of inflammatory markers in cardiac tissues of AF patients and animal models of AF, and beneficial effects of anti-inflammatory drugs in experimental AF paradigms. Inflammation is suggested to be linked to various pathological processes, such as oxidative stress, apoptosis, and fibrosis, that promote AF substrate formation. Inflammation has also been associated with endothelial dysfunction, platelet activation, and coagulation cascade activation, leading to thrombogenesis. Thus, inflammation may contribute to both the occurrence/maintenance of AF and its thromboembolic complications. Here, we review the evidence for a role of inflammation and inflammatory biomarkers in the risk management and treatment of AF. We also summarize the current knowledge of inflammation-dependent cellular and molecular mechanisms in AF pathophysiology and their potential as therapeutic targets.
- Published
- 2015
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