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Sanghvi MM, Young WJ, Naderi H, Burns R, Ramírez J, Bell CG, Munroe PB. Using Genomics to Develop Personalized Cardiovascular Treatments. Arterioscler Thromb Vasc Biol 2025; 45:866-881. [PMID: 40244646 DOI: 10.1161/atvbaha.125.319221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 04/07/2025] [Indexed: 04/18/2025]
Abstract
Advances in genomic technologies have significantly enhanced our understanding of both monogenic and polygenic etiologies of cardiovascular disease. In this review, we explore how the utilization of genomic information is bringing personalized medicine approaches to the forefront of cardiovascular disease management. We describe how genomic data can resolve diagnostic uncertainty, support cascade screening, and inform treatment strategies. We discuss how genome-wide association studies have identified thousands of genetic variants associated with polygenic cardiovascular diseases, and how integrating these insights into polygenic risk scores can enhance personalized risk prediction beyond traditional clinical algorithms. We detail how pharmacogenomics approaches leverage genotype information to guide drug selection and mitigate adverse events. Finally, we present the paradigm-shifting approach of gene therapy, which holds the promise of being a curative intervention for cardiovascular conditions.
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Affiliation(s)
- Mihir M Sanghvi
- William Harvey Research Institute (M.M.S., W.J.Y., H.N., R.B., J.R., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- NIHR Barts Biomedical Research Centre (M.M.S., W.J.Y., H.N., R.B., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom (M.M.S., W.J.Y., H.N.)
| | - William J Young
- William Harvey Research Institute (M.M.S., W.J.Y., H.N., R.B., J.R., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- NIHR Barts Biomedical Research Centre (M.M.S., W.J.Y., H.N., R.B., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom (M.M.S., W.J.Y., H.N.)
| | - Hafiz Naderi
- William Harvey Research Institute (M.M.S., W.J.Y., H.N., R.B., J.R., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- NIHR Barts Biomedical Research Centre (M.M.S., W.J.Y., H.N., R.B., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom (M.M.S., W.J.Y., H.N.)
| | - Richard Burns
- William Harvey Research Institute (M.M.S., W.J.Y., H.N., R.B., J.R., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- NIHR Barts Biomedical Research Centre (M.M.S., W.J.Y., H.N., R.B., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
| | - Julia Ramírez
- William Harvey Research Institute (M.M.S., W.J.Y., H.N., R.B., J.R., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- Aragon Institute of Engineering Research, University of Zaragoza, Spain (J.R.)
- Centro de Investigación Biomédica en Red, Biomedicina, Bioingeniería y Nanomedicina, Zaragoza, Spain (J.R.)
| | - Christopher G Bell
- William Harvey Research Institute (M.M.S., W.J.Y., H.N., R.B., J.R., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- NIHR Barts Biomedical Research Centre (M.M.S., W.J.Y., H.N., R.B., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
| | - Patricia B Munroe
- William Harvey Research Institute (M.M.S., W.J.Y., H.N., R.B., J.R., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
- NIHR Barts Biomedical Research Centre (M.M.S., W.J.Y., H.N., R.B., C.G.B., P.B.M.), Queen Mary University of London, United Kingdom
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Khorgami M, Naderi F, Kalayinia S. Primary diagnosis of atrioventricular pseudo-block in a neonate with definitive diagnosis of long QT syndrome: diagnostic considerations and therapeutic approaches. Int J Emerg Med 2025; 18:22. [PMID: 39930402 PMCID: PMC11812141 DOI: 10.1186/s12245-025-00827-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 02/04/2025] [Indexed: 02/13/2025] Open
Abstract
INTRODUCTION Long QT syndrome (LQTS) is a potentially lethal medical condition that might never be diagnosed and cause sudden cardiac death. It is mainly caused by mutation in electrolyte transporter genes. Due to the significant difference in the treatment approach of heart block and other rhythm disorders that mimic this condition, it is necessary to discriminate these conditions. The occurrence of pseudo-block in electrocardiography features but without disturbance in the function of the conduction system can mask the definite diagnosis of the real underlying disorder, and this issue leads to the selection of an unfavorable treatment protocol and sometimes the sudden death of the patient. CASE PRESENTATION We described an infant who showed evidence of atrioventricular (AV) block in initial electrocardiography (ECG) on his first day, but in further evaluations, the final diagnosis of LQTS was raised. The patient recovered after performing the treatment protocol, which included Mexiletine and beta-blockers. After the genetic test of the parents and the patient, it was determined that a defective allele of the gene had caused the condition. CONCLUSION Our report shows the importance of timely differentiation between heart block and LQTS in neonates and choosing the correct treatment approach to faster patient recovery and prevent sudden death. CLINICAL KEY MESSAGE Primary diagnosis of LQTS in neonates might not be a straightforward process due to resembling AV pseudo-block and can cause misleading diagnosis and treatment. Long QT syndrome has several nonspecific presentations. They might be asymptomatic until adulthood and be diagnosed after sudden cardiac death. Preventive measures such as timely initiation of medications, ICD or PPM implantation, and continuous observation by caregivers are the mainstay of survival and quality of life improvement.
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Affiliation(s)
| | - Fatemeh Naderi
- Rajaie Cardiovascular Medical and Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, 1995614331, Iran.
| | - Samira Kalayinia
- Cardiogenetic Research Center, Rajaie Cardiovascular Institute, Tehran, Iran
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Mondéjar-Parreño G, Moreno-Manuel AI, Ruiz-Robles JM, Jalife J. Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome. Cell Discov 2025; 11:3. [PMID: 39788950 PMCID: PMC11717978 DOI: 10.1038/s41421-024-00738-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 09/10/2024] [Indexed: 01/12/2025] Open
Abstract
A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of "interactome mapping" and illustrate by example the multiple protein-protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.
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Affiliation(s)
| | | | | | - José Jalife
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
- Departments of Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
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Tomidokoro D, Nakamura T, Oka S, Miyazaki Y, Wakamiya A, Ueda N, Nakajima K, Kamakura T, Wada M, Ishibashi K, Inoue Y, Miyamoto K, Nagase S, Kitada S, Sakaue Y, Shiraishi H, Kabutoya T, Takami K, Miyoshi M, Takahashi N, Soeki T, Hiroi Y, Asano Y, Ohno S, Kusano K, Aiba T. Yield of Genetic Testing for Long-QT Syndrome in Elderly Patients With Torsades de Pointes. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2024; 17:e004671. [PMID: 39469765 DOI: 10.1161/circgen.124.004671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Affiliation(s)
- Daiki Tomidokoro
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
- Department of Cardiology, National Center for Global Health and Medicine, Tokyo, Japan (D.T., Y.H.)
| | - Toshihiro Nakamura
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Satoshi Oka
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Yuichiro Miyazaki
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Akionori Wakamiya
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Nobuhiko Ueda
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Kenzaburo Nakajima
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Tsukasa Kamakura
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Mitsuru Wada
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Kohei Ishibashi
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Yuko Inoue
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Koji Miyamoto
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Satoshi Nagase
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Shuichi Kitada
- Department of Cardiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan (S.K.)
| | - Yu Sakaue
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan (Y.S., H.S.)
| | - Hirokazu Shiraishi
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan (Y.S., H.S.)
| | - Tomoyuki Kabutoya
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Japan (T. Kabutoya)
| | - Kaoru Takami
- Department of Cardiology, Kita-Harima Medical Center, Ono, Japan (K.T.)
| | - Miwa Miyoshi
- Department of Cardiology, Japan Community Heath Care Organization Osaka Hospital, Osaka, Japan (M.M.)
| | - Naohiko Takahashi
- Department of Cardiology and Clinical Diagnostics, Oita University Hospital, Oita, Japan (N.T.)
| | - Takeshi Soeki
- Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan (T.S.)
| | - Yukio Hiroi
- Department of Cardiology, National Center for Global Health and Medicine, Tokyo, Japan (D.T., Y.H.)
| | - Yoshihiro Asano
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Seiko Ohno
- Department of Medical Genome Center (S. Ohno). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Kengo Kusano
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
| | - Takeshi Aiba
- Department of Cardiovascular Medicine (D.T., T.N., S. Oka, Y.M., A.W., N.U., K.N., T. Kamakura, M.W., K.I., Y.I., K.M., S.N., Y.A., K.K., T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
- Department of Clinical Laboratory Medicine and Genetics (T.A.). National Cerebral and Cardiovascular Center, Suita, Japan
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Jiang J, Thi Vy HM, Charney A, Kovatch P, Reddy V, Jayaraman P, Do R, Khera R, Chugh S, Bhatt DL, Vaid A, Lampert J, Nadkarni GN. Multimodal fusion learning for long QT syndrome pathogenic genotypes in a racially diverse population. NPJ Digit Med 2024; 7:226. [PMID: 39181999 PMCID: PMC11344778 DOI: 10.1038/s41746-024-01218-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 08/07/2024] [Indexed: 08/27/2024] Open
Abstract
Congenital long QT syndrome (LQTS) diagnosis is complicated by limited genetic testing at scale, low prevalence, and normal QT corrected interval in patients with high-risk genotypes. We developed a deep learning approach combining electrocardiogram (ECG) waveform and electronic health record data to assess whether patients had pathogenic variants causing LQTS. We defined patients with high-risk genotypes as having ≥1 pathogenic variant in one of the LQTS-susceptibility genes. We trained the model using data from United Kingdom Biobank (UKBB) and then fine-tuned in a racially/ethnically diverse cohort using Mount Sinai BioMe Biobank. Following group-stratified 5-fold splitting, the fine-tuned model achieved area under the precision-recall curve of 0.29 (95% confidence interval [CI] 0.28-0.29) and area under the receiver operating curve of 0.83 (0.82-0.83) on independent testing data from BioMe. Multimodal fusion learning has promise to identify individuals with pathogenic genetic mutations to enable patient prioritization for further work up.
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Affiliation(s)
- Joy Jiang
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Ha My Thi Vy
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexander Charney
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Patricia Kovatch
- Department of Scientific Computing, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vivek Reddy
- Helmsley Center for Electrophysiology at The Mount Sinai Hospital, New York, NY, USA
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Pushkala Jayaraman
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ron Do
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rohan Khera
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Section of Health Informatics, Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
| | - Sumeet Chugh
- Center for Cardiac Arrest Prevention, Smidt Heart Institute, Cedars-Sinai Health System, Los Angeles, CA, USA
| | - Deepak L Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Akhil Vaid
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joshua Lampert
- Helmsley Center for Electrophysiology at The Mount Sinai Hospital, New York, NY, USA
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Girish Nitin Nadkarni
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Division of Data Driven and Digital Medicine (D3M), Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Schwartz PJ, Crotti L, Nyegaard M, Overgaard MT. Calmodulin, sudden death, and the Folbigg case: genes in court. Eur Heart J 2024; 45:1801-1803. [PMID: 38591620 DOI: 10.1093/eurheartj/ehae152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/10/2024] Open
Affiliation(s)
- Peter J Schwartz
- Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano, IRCCS, Via Pier Lombardo, 22, Milano 20135, Italy
| | - Lia Crotti
- Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano, IRCCS, Via Pier Lombardo, 22, Milano 20135, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
| | - Mette Nyegaard
- Department of Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
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Nenadic I, Loring Z. Casting a Wide (QT) Net to Prevent Torsades de Pointes. JACC Clin Electrophysiol 2024; 10:967-969. [PMID: 38811071 DOI: 10.1016/j.jacep.2024.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/08/2024] [Accepted: 03/09/2024] [Indexed: 05/31/2024]
Affiliation(s)
- Ivan Nenadic
- Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Zak Loring
- Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina, USA.
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Hughes G, Young WJ, Bern H, Crook A, Lambiase PD, Goodall RL, Nunn AJ, Meredith SK. T-wave morphology abnormalities in the STREAM stage 1 trial. Expert Opin Drug Saf 2024; 23:469-476. [PMID: 38462751 PMCID: PMC11761056 DOI: 10.1080/14740338.2024.2322116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 12/15/2023] [Indexed: 03/12/2024]
Abstract
BACKGROUND Shorter regimens for drug-resistant tuberculosis (DR-TB) have non-inferior efficacy compared with longer regimens, but QT prolongation is a concern. T-wave morphology abnormalities may be a predictor of QT prolongation. RESEARCH DESIGN AND METHODS STREAM Stage 1 was a randomized controlled trial in rifampicin-resistant TB, comparing short and long regimens. All participants had regular ECGs. QT/QTcF prolongation (≥500 ms or increase in ≥60 ms from baseline) was more common on the short regimen which contained high-dose moxifloxacin and clofazimine. Blinded ECGs were selected from the baseline, early (weeks 1-4), and late (weeks 12-36) time points. T-wave morphology was categorized as normal or abnormal (notched, asymmetric, flat-wave, flat peak, or broad). Differences between groups were assessed using Chi-Square tests (paired/unpaired, as appropriate). RESULTS Two-hundred participants with available ECGs at relevant times were analyzed (QT prolongation group n = 82; non-prolongation group n = 118). At baseline, 23% (45/200) of participants displayed abnormal T-waves, increasing to 45% (90/200, p < 0.001) at the late time point. Abnormalities were more common in participants allocated the Short regimen (75/117, 64%) than the Long (14/38, 36.8%, p = 0.003); these occurred prior to QT/QTcF ≥500 ms in 53% of the participants (Long 2/5; Short 14/25). CONCLUSIONS T-wave abnormalities may help identify patients at risk of QT prolongation on DR-TB treatment. TRIAL REGISTRATION The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02409290). Current Controlled Trial number, ISRCTN78372190.
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Affiliation(s)
- Gareth Hughes
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, UK
| | - William J. Young
- Centre for Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK
- Barts Heart Centre, St Bartholomews Hospital, Barts Health NHS Trust, London, UK
| | - Henry Bern
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, UK
| | - Angela Crook
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, UK
| | - Pier D. Lambiase
- Institute of Cardiovascular Science, University College London, London, UK
- NIHR Barts Biomedical Research Centre, London, UK
| | - Ruth L. Goodall
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, UK
| | - Andrew J. Nunn
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, UK
| | - Sarah K. Meredith
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, UK
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Marchand M, Erickson AC, Gillman L, Haywood R, Morrison J, Jaworsky D, Drouin O, Laksman Z, Krahn AD, Arbour L. The Impact of Chronic Disease on the Corrected QT (QTc) Value in Women in a British Columbia First Nations Population. Can J Cardiol 2024; 40:89-97. [PMID: 37852605 DOI: 10.1016/j.cjca.2023.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 09/27/2023] [Accepted: 10/12/2023] [Indexed: 10/20/2023] Open
Abstract
BACKGROUND Indigenous women have higher rates of chronic disease than Indigenous men and non-Indigenous women. Long QT syndrome (LQTS) can be inherited or acquired; the latter may occur with chronic disease. A prolonged corrected QT value (QTc) is an independent risk factor for ventricular arrhythmias and sudden death, but few studies have quantified the impact of chronic disease on the QTc. We assessed the association between chronic disease and QTc prolongation in a population of First Nations women previously ascertained to study a high rate of inherited LQTS due to a unique genetic (founder) variant in their community. METHODS This substudy focusing on women expands on the original research where patients with clinical features of LQTS and their relatives were assessed for genetic variants discovered to affect the QTc. Medical records were retrospectively reviewed and chronic diseases documented. Using multivariate linear regression, adjusting for the effect of genetic variants, age, and QTc-prolonging medications, we evaluated the association between chronic disease and the QTc. RESULTS In total, 275 women were included. After adjustments, a prolonged QTc was associated with coronary artery disease (26.5 ms, 95% confidence interval [CI] 9.0-44.1 ms; P = 0.003), conduction system disease (26.8 ms, 95% CI 2.2-51.4 ms; P = 0.033), rheumatoid arthritis (28.9 ms, 95% CI 12.7-45.1 ms; P = 0.001), and type 2 diabetes mellitus (17.9 ms, 95% CI 3.6-32.3 ms; P = 0.015). CONCLUSIONS This quantification of the association between chronic disease and QTc prolongation in an Indigenous cohort provides insight into the nongenetic determinants of QTc prolongation. Corroboration in other populations will provide evidence for generalisability of these results.
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Affiliation(s)
- Miles Marchand
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada; Syilx Okanagan Nation, British Columbia, Canada
| | - Anders C Erickson
- Population and Public Health Division, British Columbia Ministry of Health, Victoria, British Columbia, Canada(‡)
| | - Lawrence Gillman
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; Community Genetics Research Program, University of British Columbia, Island Medical Program, Victoria, British Columbia, Canada
| | - Rachel Haywood
- Community Genetics Research Program, University of British Columbia, Island Medical Program, Victoria, British Columbia, Canada
| | - Julie Morrison
- Community Member, Gitxsan Nation, British Columbia, Canada
| | - Denise Jaworsky
- Northern Health Authority, Terrace, British Columbia, Canada; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Olivier Drouin
- Northern Health Authority, Terrace, British Columbia, Canada
| | - Zachary Laksman
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Cardiovascular Innovation, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrew D Krahn
- Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Cardiovascular Innovation, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Laura Arbour
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; Community Genetics Research Program, University of British Columbia, Island Medical Program, Victoria, British Columbia, Canada.
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10
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Venkateshappa R, Hunter DV, Muralidharan P, Nagalingam RS, Huen G, Faizi S, Luthra S, Lin E, Cheng YM, Hughes J, Khelifi R, Dhunna DP, Johal R, Sergeev V, Shafaattalab S, Julian LM, Poburko DT, Laksman Z, Tibbits GF, Claydon TW. Targeted activation of human ether-à-go-go-related gene channels rescues electrical instability induced by the R56Q+/- long QT syndrome variant. Cardiovasc Res 2023; 119:2522-2535. [PMID: 37739930 PMCID: PMC10676460 DOI: 10.1093/cvr/cvad155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 06/22/2023] [Accepted: 07/10/2023] [Indexed: 09/24/2023] Open
Abstract
AIMS Long QT syndrome type 2 (LQTS2) is associated with inherited variants in the cardiac human ether-à-go-go-related gene (hERG) K+ channel. However, the pathogenicity of hERG channel gene variants is often uncertain. Using CRISPR-Cas9 gene-edited hiPSC-derived cardiomyocytes (hiPSC-CMs), we investigated the pathogenic mechanism underlying the LQTS-associated hERG R56Q variant and its phenotypic rescue by using the Type 1 hERG activator, RPR260243. METHODS AND RESULTS The above approaches enable characterization of the unclear causative mechanism of arrhythmia in the R56Q variant (an N-terminal PAS domain mutation that primarily accelerates channel deactivation) and translational investigation of the potential for targeted pharmacologic manipulation of hERG deactivation. Using perforated patch clamp electrophysiology of single hiPSC-CMs, programmed electrical stimulation showed that the hERG R56Q variant does not significantly alter the mean action potential duration (APD90). However, the R56Q variant increases the beat-to-beat variability in APD90 during pacing at constant cycle lengths, enhances the variance of APD90 during rate transitions, and increases the incidence of 2:1 block. During paired S1-S2 stimulations measuring electrical restitution properties, the R56Q variant was also found to increase the variability in rise time and duration of the response to premature stimulations. Application of the hERG channel activator, RPR260243, reduces the APD variance in hERG R56Q hiPSC-CMs, reduces the variability in responses to premature stimulations, and increases the post-repolarization refractoriness. CONCLUSION Based on our findings, we propose that the hERG R56Q variant leads to heterogeneous APD dynamics, which could result in spatial dispersion of repolarization and increased risk for re-entry without significantly affecting the average APD90. Furthermore, our data highlight the antiarrhythmic potential of targeted slowing of hERG deactivation gating, which we demonstrate increases protection against premature action potentials and reduces electrical heterogeneity in hiPSC-CMs.
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Affiliation(s)
- Ravichandra Venkateshappa
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Diana V Hunter
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Priya Muralidharan
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Raghu S Nagalingam
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
- Cellular and Regenerative Medicine Centre, British Columbia Children’s Hospital Research Institute, 938 W 28th Ave, Vancouver, BC, Canada V5Z 4H4
| | - Galvin Huen
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Shoaib Faizi
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Shreya Luthra
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Eric Lin
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Yen May Cheng
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Julia Hughes
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Rania Khelifi
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Daman Parduman Dhunna
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Raj Johal
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Valentine Sergeev
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Sanam Shafaattalab
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Lisa M Julian
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Damon T Poburko
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Zachary Laksman
- Department of Medicine, School of Biomedical Engineering, University of British Columbia, 2194 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3
| | - Glen F Tibbits
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
- Cellular and Regenerative Medicine Centre, British Columbia Children’s Hospital Research Institute, 938 W 28th Ave, Vancouver, BC, Canada V5Z 4H4
- Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
| | - Tom W Claydon
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6
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11
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Pandit M, Finn C, Tahir UA, Frishman WH. Congenital Long QT Syndrome: A Review of Genetic and Pathophysiologic Etiologies, Phenotypic Subtypes, and Clinical Management. Cardiol Rev 2023; 31:318-324. [PMID: 35576393 DOI: 10.1097/crd.0000000000000459] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Congenital Long QT Syndrome (CLQTS) is the most common inherited arrhythmia. The QT interval, which marks the duration of ventricular depolarization and repolarization in the myocardium, can be prolonged due to mutations in genes coding for the ion channel proteins that govern the cardiac action potential. The lengthening of the QT interval can lead to a wide range of clinical symptoms, including seizures, torsades de pointes, and fatal arrhythmias. There is a growing body of evidence that has revealed the genetic mutations responsible for the pathophysiology of CLQTS, and this has led to hypotheses regarding unique triggers and clinical features associated with specific gene mutations. Epidemiologic evidence has revealed a 1-year mortality rate of approximately 20% in untreated CLQTS patients, and a <1% of 1-year mortality rate in treated patients, underscoring the importance of timely diagnosis and effective clinical management. There are many phenotypic syndromes that constitute CLQTS, including but not limited to, Jervell and Lange-Nielsen syndrome, Romano and Ward syndrome, Andersen-Tawil syndrome, and Timothy syndrome. In this review, we aim to (1) summarize the genetic, epidemiologic, and pathophysiological basis of CLQTS and (2) outline the unique features of the phenotypic subtypes and their clinical management.
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Affiliation(s)
- Maya Pandit
- From the New York Medical College, Valhalla, NY
| | - Caitlin Finn
- Department of Medicine, Division of Cardiology, Harvard Medical School/Beth Israel Deaconess Medical Center, Boston, MA
| | - Usman A Tahir
- Department of Medicine, Division of Cardiology, Harvard Medical School/Beth Israel Deaconess Medical Center, Boston, MA
| | - William H Frishman
- Departments of Medicine and Cardiology, New York Medical College/Westchester Medical Center, Valhalla, NY
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12
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Huse S, Acharya S, Agrawal S, J H, Sachdev A, Ghulaxe Y, Sarda P, Chavada J. Recent Advances in Inherited Cardiac Arrhythmias and Their Genetic Testing. Cureus 2023; 15:e47653. [PMID: 38021622 PMCID: PMC10668889 DOI: 10.7759/cureus.47653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
Inherited arrhythmias, encompassing conditions such as cardiomyopathies, cardiac ion channel disorders, and coronary heart disease, represent the common causes that elevate the threat of sudden cardiac death among adults. Researchers have pinpointed the genes responsible for these hereditary arrhythmias in the last 30 years. Concurrently, it has become clear that the genetic makeup underlying these conditions is more intricate than previously understood. Evolution in DNA sequencing techniques, particularly next-generation sequencing, has empowered us to learn these intricate hereditary characteristics. Genetic testing is crucial in diagnosing, assessing risk, and determining treatment for individuals with these conditions and their family members. The need for collaborative endeavors to comprehend and address these uncommon yet potentially life-threatening disorders is becoming more evident. This review aims to inform readers of the latest advances in understanding hereditary arrhythmias and provide the groundwork for collaborative genetic testing initiatives to characterize these disorders in the general population.
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Affiliation(s)
- Shreyash Huse
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sourya Acharya
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Shashank Agrawal
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Harshita J
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Ankita Sachdev
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Yash Ghulaxe
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Prayas Sarda
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Jay Chavada
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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13
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Crotti L, Spazzolini C, Nyegaard M, Overgaard MT, Kotta MC, Dagradi F, Sala L, Aiba T, Ayers MD, Baban A, Barc J, Beach CM, Behr ER, Bos JM, Cerrone M, Covi P, Cuneo B, Denjoy I, Donner B, Elbert A, Eliasson H, Etheridge SP, Fukuyama M, Girolami F, Hamilton R, Horie M, Iascone M, Jaimez JJ, Jensen HK, Kannankeril PJ, Kaski JP, Makita N, Muñoz-Esparza C, Odland HH, Ohno S, Papagiannis J, Porretta AP, Prandstetter C, Probst V, Robyns T, Rosenthal E, Rosés-Noguer F, Sekarski N, Singh A, Spentzou G, Stute F, Tfelt-Hansen J, Till J, Tobert KE, Vinocur JM, Webster G, Wilde AAM, Wolf CM, Ackerman MJ, Schwartz PJ. Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry. Eur Heart J 2023; 44:3357-3370. [PMID: 37528649 PMCID: PMC10499544 DOI: 10.1093/eurheartj/ehad418] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/14/2023] [Accepted: 06/13/2023] [Indexed: 08/03/2023] Open
Abstract
AIMS Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.
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Affiliation(s)
- Lia Crotti
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22, 20135 Milan, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milan, Italy
| | - Carla Spazzolini
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22, 20135 Milan, Italy
| | - Mette Nyegaard
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Michael T Overgaard
- Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark
| | - Maria-Christina Kotta
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22, 20135 Milan, Italy
| | - Federica Dagradi
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22, 20135 Milan, Italy
| | - Luca Sala
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22, 20135 Milan, Italy
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Takeshi Aiba
- Division of Arrhythmia, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Mark D Ayers
- Department of Pediatrics, Division of Pediatric Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Anwar Baban
- Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart
- Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Julien Barc
- Université de Nantes, CHU Nantes, CNRS, INSERM, L’institut du Thorax, Nantes, France
| | - Cheyenne M Beach
- Pediatric Cardiology, Yale School of Medicine, New Haven, CT, USA
| | - Elijah R Behr
- Cardiology Section, Institute of Molecular and Clinical Sciences, St George’s University of London and Cardiovascular Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, UK
| | - J Martijn Bos
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Division of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Marina Cerrone
- Inherited Arrhythmias Clinic, Leon H. Charney Division of Cardiology, NYU Grossmann School of Medicine, New York, NY, USA
| | - Peter Covi
- Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - Bettina Cuneo
- Department of Pediatrics, Section of Cardiology, University of Denver School of Medicine, Aurora, CO, USA
| | - Isabelle Denjoy
- Centre de Référence Maladies Cardiaques Héréditaires Filière Cardiogen, Département de Rythmologie, Groupe Hospitalier Bichat-Claude Bernard, Paris, France
| | - Birgit Donner
- Kardiologie, Universitäts-Kinderspital beider Basel (UKBB), Basel, Switzerland
| | - Adrienne Elbert
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Håkan Eliasson
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
- Pediatric Cardiology C8:34, Karolinska University Hospital, Stockholm, Sweden
| | - Susan P Etheridge
- Department of Pediatrics, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, UT, USA
| | - Megumi Fukuyama
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan
| | | | - Robert Hamilton
- Division of Cardiology, The Hospital for Sick Children (SickKids), Toronto, ON, Canada
| | - Minoru Horie
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Maria Iascone
- Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Juan Jiménez Jaimez
- Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitario IBS Granada, Spain
| | - Henrik Kjærulf Jensen
- Department of Cardiology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus University, K-8200 Aarhus N, Denmark
| | - Prince J Kannankeril
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Juan P Kaski
- Centre for Paediatric Inherited and Rare Cardiovascular Disease, Institute of Cardiovascular Science, University College London, Zayed Centre for Research into Rare Disease in Childhood, London, UK
- Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, UK
| | - Naomasa Makita
- National Cerebral and Cardiovascular Center, Suita, Japan
- Sapporo Teishinkai Hospital, Sapporo, Japan
| | - Carmen Muñoz-Esparza
- Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart
- Inherited Cardiac Disease Unit, Hospital Universitario Virgen Arrixaca, Murcia, Spain
| | - Hans H Odland
- Department of Cardiology and Pediatric Cardiology, Section for Arrhythmias, Oslo University Hospital, Oslo, Norway
| | - Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - John Papagiannis
- Pediatric and Adult Congenital Heart Disease, Onassis Cardiac Surgery Center, Athens, Greece
| | - Alessandra Pia Porretta
- Unité des Troubles du Rythme, Service de Cardiologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Christopher Prandstetter
- Medical Faculty, Johannes Kepler University Linz, Linz, Austria
- Department of Pediatric Cardiology, Kepler University Hospital, Linz, Austria
| | - Vincent Probst
- Service de Cardiologie, L’institut du Thorax, CHU Nantes, Nantes, France
| | - Tomas Robyns
- Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart
- Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Eric Rosenthal
- Evelina London Children’s Hospital, St Thomas’ Hospital, London, UK
| | - Ferran Rosés-Noguer
- Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart
- Lead Paediatric Cardiology Department, Vall d’Hebron University Hospital, Barcelona, Spain
- Royal Brompton Hospital NHS Guy’s and St Thomas Foundation Trust, London, UK
| | - Nicole Sekarski
- Unité de Cardiologie Pédiatrique, Département Médico-Chirurgical de Pédiatrie, CHUV | Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Anoop Singh
- Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, WI, USA
| | | | - Fridrike Stute
- Department of Pediatric Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany
| | - Jacob Tfelt-Hansen
- Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart
- Section of Genetics, Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark
- Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Jan Till
- Royal Brompton Hospital NHS Guy’s and St Thomas Foundation Trust, London, UK
| | - Kathryn E Tobert
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Division of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | | | - Gregory Webster
- Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Arthur A M Wilde
- Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart
- Department of Cardiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, The Netherlands
| | - Cordula M Wolf
- Center for Rare Congenital Heart Diseases, Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, Technical University Munich, School of Medicine & Health, Munich, Germany
| | - Michael J Ackerman
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Division of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Peter J Schwartz
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22, 20135 Milan, Italy
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14
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Cui S, Hayashi K, Kobayashi I, Hosomichi K, Nomura A, Teramoto R, Usuda K, Okada H, Deng Y, Kobayashi-Sun J, Nishikawa T, Furusho H, Saito T, Hirase H, Ohta K, Fujimoto M, Horita Y, Kusayama T, Tsuda T, Tada H, Kato T, Usui S, Sakata K, Fujino N, Tajima A, Yamagishi M, Takamura M. The utility of zebrafish cardiac arrhythmia model to predict the pathogenicity of KCNQ1 variants. J Mol Cell Cardiol 2023; 177:50-61. [PMID: 36898499 DOI: 10.1016/j.yjmcc.2023.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/11/2023]
Abstract
Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are classified as VUS. We studied the role of zebrafish cardiac arrhythmia model in determining the clinical significance of KCNQ1 variants. We generated homozygous kcnq1 deletion zebrafish (kcnq1del/del) using the CRISPR/Cas9 and expressed human Kv7.1/MinK channels in kcnq1del/del embryos. We dissected the hearts from the thorax at 48 h post-fertilization and measured the transmembrane potential of the ventricle in the zebrafish heart. Action potential duration was calculated as the time interval between peak maximum upstroke velocity and 90% repolarization (APD90). The APD90 of kcnq1del/del embryos was 280 ± 47 ms, which was significantly shortened by injecting KCNQ1 wild-type (WT) cRNA and KCNE1 cRNA (168 ± 26 ms, P < 0.01 vs. kcnq1del/del). A study of two pathogenic variants (S277L and T587M) and one VUS (R451Q) associated with clinically definite LQTS showed that the APD90 of kcnq1del/del embryos with these mutant Kv7.1/MinK channels was significantly longer than that of Kv7.1 WT/MinK channels. Given the functional results of the zebrafish model, R451Q could be reevaluated physiologically from VUS to likely pathogenic. In conclusion, functional analysis using in vivo zebrafish cardiac arrhythmia model can be useful for determining the pathogenicity of loss-of-function variants in patients with LQTS.
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Affiliation(s)
- Shihe Cui
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Kenshi Hayashi
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
| | - Isao Kobayashi
- Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kanazawa, Japan
| | - Kazuyoshi Hosomichi
- Laboratory of Computational Genomics, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Akihiro Nomura
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Ryota Teramoto
- Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Keisuke Usuda
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hirofumi Okada
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Yaowen Deng
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Jingjing Kobayashi-Sun
- Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kanazawa, Japan; Department of Clinical Engineering, Faculty of Health Sciences, Komatsu University, Komatsu, Japan
| | - Tetsuo Nishikawa
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hiroshi Furusho
- Department of Cardiology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Takekatsu Saito
- Department of Pediatrics, Minamigaoka Hospital, Kanazawa, Japan
| | - Hiroaki Hirase
- Department of Cardiology, Takaoka Minami Heart Center, Takaoka, Japan
| | - Kunio Ohta
- Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan; Medical Education Research Center, Graduate School of Medical Sciences, Kanazawa University, Japan
| | - Manabu Fujimoto
- Department of Cardiology, Kouseiren Takaoka Hospital, Takaoka, Japan
| | - Yuki Horita
- Department of Cardiology, Kanazawa Cardiovascular Hospital, Kanazawa, Japan
| | - Takashi Kusayama
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Toyonobu Tsuda
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hayato Tada
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Takeshi Kato
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Soichiro Usui
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Kenji Sakata
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Noboru Fujino
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Atsushi Tajima
- Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | | | - Masayuki Takamura
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
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15
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O'Neill MJ, Sala L, Denjoy I, Wada Y, Kozek K, Crotti L, Dagradi F, Kotta MC, Spazzolini C, Leenhardt A, Salem JE, Kashiwa A, Ohno S, Tao R, Roden DM, Horie M, Extramiana F, Schwartz PJ, Kroncke BM. Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies. Genet Med 2023; 25:100355. [PMID: 36496179 PMCID: PMC9992222 DOI: 10.1016/j.gim.2022.12.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/05/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
PURPOSE The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon. METHODS We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure. RESULTS Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain. CONCLUSIONS Bayesian penetrance estimates provide a continuous framework for variant interpretation.
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Affiliation(s)
- Matthew J O'Neill
- Vanderbilt University School of Medicine, Medical Scientist Training Program, Vanderbilt University, Nashville, TN
| | - Luca Sala
- IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milano, Italy
| | - Isabelle Denjoy
- Department of Cardiovascular Medicine, Hôpital Bichat, APHP, Université de Paris Cité, Paris, France
| | - Yuko Wada
- Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Krystian Kozek
- Vanderbilt University School of Medicine, Medical Scientist Training Program, Vanderbilt University, Nashville, TN
| | - Lia Crotti
- IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milano, Italy
| | - Federica Dagradi
- IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milano, Italy
| | - Maria-Christina Kotta
- IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milano, Italy
| | - Carla Spazzolini
- IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milano, Italy
| | - Antoine Leenhardt
- Department of Cardiovascular Medicine, Hôpital Bichat, APHP, Université de Paris Cité, Paris, France
| | - Joe-Elie Salem
- Department of Cardiovascular Medicine, Hôpital Bichat, APHP, Université de Paris Cité, Paris, France
| | - Asami Kashiwa
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine Kyoto, Japan
| | - Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Ran Tao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Dan M Roden
- Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN
| | - Minoru Horie
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Fabrice Extramiana
- Department of Cardiovascular Medicine, Hôpital Bichat, APHP, Université de Paris Cité, Paris, France
| | - Peter J Schwartz
- IRCCS, Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milano, Italy
| | - Brett M Kroncke
- Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
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16
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Abstract
PURPOSE OF REVIEW To summarize and critically assess the contribution of genetics to the Long QT Syndrome (LQTS), with specific reference to the unraveling of its underlying mechanisms and to its impact on clinical practice. RECENT FINDINGS The evolution towards our current approach to therapy for LQTS patients is examined in terms of risk stratification, gene-specific management, and assessment of the clinical impact that genetic modifiers may have in modulating the natural history of the patients. Glimpses are provided on the newest multidisciplinary approaches to study disease mechanisms, test new candidate drugs and identify precision treatments. SUMMARY It is undeniable that genetics has revolutionized our mechanistic understanding of cardiac channelopathies. Its impact has been enormous but, curiously, the way LQTS patients are being treated today is largely the same that was used in the pregenetic era, even though management has been refined and gene-specific differences allow a more individually tailored antiarrhythmic protection. The synergy of genetic findings with modern in vitro and in silico tools may expand precision treatments; however, they will need to prove more effective than the current therapeutic approaches and equally safe.
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Affiliation(s)
- Peter J Schwartz
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics
| | - Luca Sala
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics.,Department of Biotechnology and Biosciences, University of Milano - Bicocca, Milan, Italy
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17
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Abstract
Long QT syndrome (LQTS) is a detrimental arrhythmia syndrome mainly caused by dysregulated expression or aberrant function of ion channels. The major clinical symptoms of ventricular arrhythmia, palpitations and syncope vary among LQTS subtypes. Susceptibility to malignant arrhythmia is a result of delayed repolarisation of the cardiomyocyte action potential (AP). There are 17 distinct subtypes of LQTS linked to 15 autosomal dominant genes with monogenic mutations. However, due to the presence of modifier genes, the identical mutation may result in completely different clinical manifestations in different carriers. In this review, we describe the roles of various ion channels in orchestrating APs and discuss molecular aetiologies of various types of LQTS. We highlight the usage of patient-specific induced pluripotent stem cell (iPSC) models in characterising fundamental mechanisms associated with LQTS. To mitigate the outcomes of LQTS, treatment strategies are initially focused on small molecules targeting ion channel activities. Next-generation treatments will reap the benefits from development of LQTS patient-specific iPSC platform, which is bolstered by the state-of-the-art technologies including whole-genome sequencing, CRISPR genome editing and machine learning. Deep phenotyping and high-throughput drug testing using LQTS patient-specific cardiomyocytes herald the upcoming precision medicine in LQTS.
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18
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Krijger Juárez C, Amin AS, Offerhaus JA, Bezzina CR, Boukens BJ. Cardiac Repolarization in Health and Disease. JACC Clin Electrophysiol 2023; 9:124-138. [PMID: 36697193 DOI: 10.1016/j.jacep.2022.09.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 09/16/2022] [Accepted: 09/21/2022] [Indexed: 12/03/2022]
Abstract
Abnormal cardiac repolarization is at the basis of life-threatening arrhythmias in various congenital and acquired cardiac diseases. Dysfunction of ion channels involved in repolarization at the cellular level are often the underlying cause of the repolarization abnormality. The expression pattern of the gene encoding the affected ion channel dictates its impact on the shape of the T-wave and duration of the QT interval, thereby setting the stage for both the occurrence of the trigger and the substrate for maintenance of the arrhythmia. Here we discuss how research into the genetic and electrophysiological basis of repolarization has provided us with insights into cardiac repolarization in health and disease and how this in turn may provide the basis for future improved patient-specific management.
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Affiliation(s)
- Christian Krijger Juárez
- Department of Experimental Cardiology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Ahmad S Amin
- Department of Cardiology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Joost A Offerhaus
- Department of Experimental Cardiology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Connie R Bezzina
- Department of Experimental Cardiology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Bastiaan J Boukens
- Department of Medical Biology, Amsterdam University Medical Center, Amsterdam, the Netherlands; Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
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19
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A Possible Explanation for the Low Penetrance of Pathogenic KCNE1 Variants in Long QT Syndrome Type 5. Pharmaceuticals (Basel) 2022; 15:ph15121550. [PMID: 36559002 PMCID: PMC9782992 DOI: 10.3390/ph15121550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/07/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Long QT syndrome (LQTS) is an inherited cardiac rhythm disorder associated with increased incidence of cardiac arrhythmias and sudden death. LQTS type 5 (LQT5) is caused by dominant mutant variants of KCNE1, a regulatory subunit of the voltage-gated ion channels generating the cardiac potassium current IKs. While mutant LQT5 KCNE1 variants are known to inhibit IKs amplitudes in heterologous expression systems, cardiomyocytes from a transgenic rabbit LQT5 model displayed unchanged IKs amplitudes, pointing towards the critical role of additional factors in the development of the LQT5 phenotype in vivo. In this study, we demonstrate that KCNE3, a candidate regulatory subunit of IKs channels minimizes the inhibitory effects of LQT5 KCNE1 variants on IKs amplitudes, while current deactivation is accelerated. Such changes recapitulate IKs properties observed in LQT5 transgenic rabbits. We show that KCNE3 accomplishes this by displacing the KCNE1 subunit within the IKs ion channel complex, as evidenced by a dedicated biophysical assay. These findings depict KCNE3 as an integral part of the IKs channel complex that regulates IKs function in cardiomyocytes and modifies the development of the LQT5 phenotype.
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20
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Harris CS, Froelicher VF, Hadley D, Wheeler MT. Guide to the Female Student Athlete ECG: A Comprehensive Study of 3466 Young, Racially Diverse Athletes. Am J Med 2022; 135:1478-1487.e4. [PMID: 35981651 DOI: 10.1016/j.amjmed.2022.07.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 07/16/2022] [Accepted: 07/18/2022] [Indexed: 11/01/2022]
Abstract
OBJECTIVES The 12-lead electrocardiogram (ECG) is used in the preparticipation screening examination for athletes. Despite known differences in ECG findings by sex, only QTc prolongation is given a sex-specific threshold. We hypothesize that our large dataset-with diversity in age, race, and sport participation-can be utilized to improve ECG screening in female student athletes. METHODS Computerized 12-lead ECGs were recorded and analyzed in female athletes who underwent preparticipation screening examination between June 2010 and September 2021. The quantitative, empirical 2017 international criteria for electrocardiographic interpretation were compared with either the 99th percentile in our cohort or the percentile that corresponded to the known disease prevalence. RESULTS Of 3466 female athletes with ECGs as part of preparticipation screening examination, the 2017 international criteria classified 2.1% of athletes with at least one ECG abnormality requiring cardiological evaluation. Rates were similar across age, race/ethnicity, and sporting discipline. Using ranges based on our population, 2.7% of athletes would require additional workup. Surprisingly, ST depression up to 0.03 mV was a normal finding in this cohort. If RS voltage extremes were considered findings requiring follow-up, an additional 9.6% of the athlete population would be flagged using current definitions. This number decreases to 2.7% if using the 99th percentile in this cohort. CONCLUSION These results highlight a difference in the reported prevalence of ECG abnormalities when comparing empirically derived thresholds to statistically derived ranges. Consideration of new metrics specific to the female athlete population has the potential to further refine athlete ECG screening.
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21
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Nafissi NA, Abdulrahim JW, Kwee LC, Coniglio AC, Kraus WE, Piccini JP, Daubert JP, Sun AY, Shah SH. Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2022; 15:e003675. [PMID: 36136372 PMCID: PMC9588708 DOI: 10.1161/circgen.121.003675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 06/22/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Inherited primary arrhythmia syndromes and arrhythmogenic cardiomyopathies can lead to sudden cardiac arrest in otherwise healthy individuals. The burden and expression of these diseases in a real-world, well-phenotyped cardiovascular population is not well understood. METHODS Whole exome sequencing was performed on 8574 individuals from the CATHGEN cohort (Catheterization Genetics). Variants in 55 arrhythmia-related genes (associated with 8 disorders) were identified and assessed for pathogenicity based on American College of Genetics and Genomics/Association for Molecular Pathology criteria. Individuals carrying pathogenic/likely pathogenic (P/LP) variants were grouped by arrhythmogenic disorder and matched 1:5 to noncarrier controls based on age, sex, and genetic ancestry. Long-term phenotypic data were annotated through deep electronic health record review. RESULTS Fifty-eight P/LP variants were found in 79 individuals in 12 genes associated with 5 arrhythmogenic disorders (arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, hypertrophic cardiomyopathy, LMNA-related cardiomyopathy, and long QT syndrome). The penetrance of these P/LP variants in this cardiovascular cohort was 33%, 0%, 28%, 83%, and 4%, respectively. Carriers of P/LP variants associated with arrhythmogenic disorders showed significant differences in ECG, imaging, and clinical phenotypes compared with noncarriers, but displayed no difference in survival. Carriers of novel truncating variants in FLNC, MYBPC3, and MYH7 also developed relevant arrhythmogenic cardiomyopathy phenotypes. CONCLUSIONS In a real-world cardiovascular cohort, P/LP variants in arrhythmia-related genes were relatively common (1:108 prevalence) and most penetrant in LMNA. While hypertrophic cardiomyopathy P/LP variant carriers showed significant differences in clinical outcomes compared with noncarriers, carriers of P/LP variants associated with other arrhythmogenic disorders displayed only ECG differences.
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Affiliation(s)
- Navid A. Nafissi
- Division of Cardiology, Dept of Medicine, Duke University School of Medicine, Durham, NC
| | | | - Lydia Coulter Kwee
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC
| | - Amanda C. Coniglio
- Division of Cardiology, Dept of Medicine, Duke University School of Medicine, Durham, NC
| | - William E. Kraus
- Division of Cardiology, Dept of Medicine, Duke University School of Medicine, Durham, NC
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC
| | - Jonathan P. Piccini
- Division of Cardiology, Dept of Medicine, Duke University School of Medicine, Durham, NC
- Duke Clinical Research Institute, Durham, NC
| | - James P. Daubert
- Division of Cardiology, Dept of Medicine, Duke University School of Medicine, Durham, NC
| | - Albert Y. Sun
- Division of Cardiology, Dept of Medicine, Duke University School of Medicine, Durham, NC
| | - Svati H. Shah
- Division of Cardiology, Dept of Medicine, Duke University School of Medicine, Durham, NC
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC
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22
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Yee LA, Han H, Davies B, Pearman CM, Laksman ZWM, Roberts JD, Steinberg C, Tadros R, Cadrin‐Tourigny J, Simpson CS, Gardner M, MacIntyre C, Arbour L, Leather R, Fournier A, Green MS, Kimber S, Angaran P, Sanatani S, Joza J, Khan H, Healey JS, Atallah J, Seifer C, Krahn AD. Sex Differences and Utility of Treadmill Testing in Long‐QT Syndrome. J Am Heart Assoc 2022; 11:e025108. [DOI: 10.1161/jaha.121.025108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background
Diagnosis of congenital long‐QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal‐to‐borderline resting QT interval. A 3‐step algorithm based on exercise response of the corrected QT interval (QTc) was previously developed to diagnose patients with LQTS and predict subtype. This study evaluated the 3‐step algorithm in a population that is more representative of the general population with LQTS with milder phenotypes and establishes sex‐specific cutoffs beyond the resting QTc.
Methods and Results
We identified 208 LQTS likely pathogenic or pathogenic
KCNQ1
or
KCNH2
variant carriers in the Canadian NLQTS (National Long‐QT Syndrome) Registry and 215 unaffected controls from the HiRO (Hearts in Rhythm Organization) Registry. Exercise treadmill tests were analyzed across the 5 stages of the Bruce protocol. The predictive value of exercise ECG characteristics was analyzed using receiver operating characteristic curve analysis to identify optimal cutoff values. A total of 78% of male carriers and 74% of female carriers had a resting QTc value in the normal‐to‐borderline range. The 4‐minute recovery QTc demonstrated the best predictive value for carrier status in both sexes, with better LQTS ascertainment in female patients (area under the curve, 0.90 versus 0.82), with greater sensitivity and specificity. The optimal cutoff value for the 4‐minute recovery period was 440 milliseconds for male patients and 450 milliseconds for female patients. The 1‐minute recovery QTc had the best predictive value in female patients for differentiating LQTS1 versus LQTS2 (area under the curve, 0.82), and the peak exercise QTc had a marginally better predictive value in male patients for subtype with (area under the curve, 0.71). The optimal cutoff value for the 1‐minute recovery period was 435 milliseconds for male patients and 455 milliseconds for femal patients.
Conclusions
The 3‐step QT exercise algorithm is a valid tool for the diagnosis of LQTS in a general population with more frequent ambiguity in phenotype. The algorithm is a simple and reliable method for the identification and prediction of the 2 major genotypes of LQTS.
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Affiliation(s)
- Lauren A. Yee
- Center for Cardiovascular Innovation, Heart Rhythm Services, Division of Cardiology, Department of Medicine University of British Columbia Vancouver British Columbia Canada
| | - Hui‐Chen Han
- Center for Cardiovascular Innovation, Heart Rhythm Services, Division of Cardiology, Department of Medicine University of British Columbia Vancouver British Columbia Canada
| | - Brianna Davies
- Center for Cardiovascular Innovation, Heart Rhythm Services, Division of Cardiology, Department of Medicine University of British Columbia Vancouver British Columbia Canada
| | - Charles M. Pearman
- Center for Cardiovascular Innovation, Heart Rhythm Services, Division of Cardiology, Department of Medicine University of British Columbia Vancouver British Columbia Canada
| | - Zachary W. M. Laksman
- Center for Cardiovascular Innovation, Heart Rhythm Services, Division of Cardiology, Department of Medicine University of British Columbia Vancouver British Columbia Canada
| | - Jason D. Roberts
- Population Health Research Institute, McMaster University, and Hamilton Health Sciences Hamilton Ontario Canada
| | - Christian Steinberg
- Institut Universitaire de Cardiologie et Pneumologie de Québec, Laval University Quebec City Quebec Canada
| | - Rafik Tadros
- Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal Montreal Quebec Canada
| | - Julia Cadrin‐Tourigny
- Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal Montreal Quebec Canada
| | | | - Martin Gardner
- Queen Elizabeth II Health Sciences Center Halifax Nova Scotia Canada
| | - Ciorsti MacIntyre
- Queen Elizabeth II Health Sciences Center Halifax Nova Scotia Canada
| | - Laura Arbour
- Department of Medical Genetics University of British Columbia, and Island Health Victoria British Columbia Canada
| | | | - Anne Fournier
- Centre Hospitalier Universitaire Sainte‐Justine Montréal Quebec Canada
| | | | | | - Paul Angaran
- St. Michael’s Hospital, University of Toronto Toronto Ontario Canada
| | | | - Jacqueline Joza
- McGill University Health Sciences Center Montreal Quebec Canada
| | - Habib Khan
- London Health Sciences Center London Ontario Canada
| | | | | | | | - Andrew D. Krahn
- Center for Cardiovascular Innovation, Heart Rhythm Services, Division of Cardiology, Department of Medicine University of British Columbia Vancouver British Columbia Canada
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23
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Homma K. The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants. Biomedicines 2022; 10:biomedicines10092254. [PMID: 36140355 PMCID: PMC9496569 DOI: 10.3390/biomedicines10092254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 11/29/2022] Open
Abstract
Deafness-associated genes KCNQ1 (also associated with heart diseases) and KCNQ4 (only associated with hearing loss) encode the homotetrameric voltage-gated potassium ion channels Kv7.1 and Kv7.4, respectively. To date, over 700 KCNQ1 and over 70 KCNQ4 variants have been identified in patients. The vast majority of these variants are inherited dominantly, and their pathogenicity is often explained by dominant-negative inhibition or haploinsufficiency. Our recent study unexpectedly identified cell-death-inducing cytotoxicity in several Kv7.1 and Kv7.4 variants. Elucidation of this cytotoxicity mechanism and identification of its modifiers (drugs) have great potential for aiding the development of a novel pharmacological strategy against many pathogenic KCNQ variants. The purpose of this review is to disseminate this emerging pathological role of Kv7 variants and to underscore the importance of experimentally characterizing disease-associated variants.
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Affiliation(s)
- Kazuaki Homma
- Department of Otolaryngology-Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; ; Tel.: +1-312-503-5344
- The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University, Evanston, IL 60608, USA
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24
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Wilde AAM, Semsarian C, Márquez MF, Shamloo AS, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace 2022; 24:1307-1367. [PMID: 35373836 PMCID: PMC9435643 DOI: 10.1093/europace/euac030] [Citation(s) in RCA: 188] [Impact Index Per Article: 62.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Affiliation(s)
- Arthur A M Wilde
- Heart Centre, Department of Cardiology, Amsterdam Universitair Medische
Centra, Amsterdam, location AMC, The Netherlands
| | - Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute,
University of Sydney, Sydney, Australia
| | - Manlio F Márquez
- Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de
México, Mexico
- Member of the Latin American Heart Rhythm Society (LAHRS)
| | | | - Michael J Ackerman
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine,
and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm
Services and Pediatric Cardiology; Windland Smith Rice Genetic Heart Rhythm Clinic and
Windland Smith Rice Sudden Death Genomics Laboratory, Mayo
Clinic, Rochester, MN, USA
| | - Euan A Ashley
- Department of Cardiovascular Medicine, Stanford University,
Stanford, California, USA
| | - Eduardo Back Sternick
- Arrhythmia and Electrophysiology Unit, Biocor Institute,
Minas Gerais, Brazil; and
Member of the Latin American Heart Rhythm Society (LAHRS)
| | - Héctor Barajas-Martinez
- Cardiovascular Research, Lankenau Institute of Medical
Research, Wynnewood, PA, USA; and Member of the Latin American Heart Rhythm Society (LAHRS)
| | - Elijah R Behr
- Cardiovascular Clinical Academic Group, Institute of Molecular and Clinical
Sciences, St. George’s, University of London; St. George’s University Hospitals NHS
Foundation Trust, London, UK; Mayo Clinic Healthcare, London
| | - Connie R Bezzina
- Amsterdam UMC Heart Center, Department of Experimental
Cardiology, Amsterdam, The
Netherlands
| | - Jeroen Breckpot
- Center for Human Genetics, University Hospitals Leuven,
Leuven, Belgium
| | - Philippe Charron
- Sorbonne Université, APHP, Centre de Référence des Maladies Cardiaques
Héréditaires, ICAN, Inserm UMR1166, Hôpital
Pitié-Salpêtrière, Paris, France
| | | | - Lia Crotti
- Center for Cardiac Arrhythmias of Genetic Origin,
Istituto Auxologico Italiano, IRCCS, Milan, Italy
- Cardiomyopathy Unit and Cardiac Rehabilitation Unit, San Luca Hospital,
Istituto Auxologico Italiano, IRCCS, Milan,
Italy
- Department of Medicine and Surgery, University of
Milano-Bicocca, Milan, Italy
| | - Michael H Gollob
- Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology,
University of Toronto, Toronto, ON, Canada
| | - Steven Lubitz
- Cardiac Arrhythmia Service, Massachusetts General Hospital and Harvard
Medical School, Boston, MA, USA
| | - Naomasa Makita
- National Cerebral and Cardiovascular Center, Research
Institute, Suita, Japan
| | - Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular
Center, Suita, Japan
| | - Martín Ortiz-Genga
- Clinical Department, Health in Code, A
Coruña, Spain; and Member of the Latin
American Heart Rhythm Society (LAHRS)
| | - Luciana Sacilotto
- Arrhythmia Unit, Instituto do Coracao, Hospital das Clinicas HCFMUSP,
Faculdade de Medicina, Universidade de Sao Paulo, Sao
Paulo, Brazil; and Member of the Latin
American Heart Rhythm Society (LAHRS)
| | - Eric Schulze-Bahr
- Institute for Genetics of Heart Diseases, University Hospital
Münster, Münster, Germany
| | - Wataru Shimizu
- Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon
Medical School, Bunkyo-ku, Tokyo, Japan
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, Department of
Medicine, University of Washington, Seattle, WA,
USA
| | - Rafik Tadros
- Cardiovascular Genetics Center, Department of Medicine, Montreal Heart
Institute, Université de Montréal, Montreal,
Canada
| | - James S Ware
- National Heart and Lung Institute and MRC London Institute of Medical
Sciences, Imperial College London, London,
UK
- Royal Brompton & Harefield Hospitals, Guy’s
and St. Thomas’ NHS Foundation Trust, London, UK
| | - David S Winlaw
- Cincinnati Children's Hospital Medical Centre, University of
Cincinnati, Cincinnati, OH, USA
| | - Elizabeth S Kaufman
- Metrohealth Medical Center, Case Western Reserve University,
Cleveland, OH, USA
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Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick Eduardo B, Barajas‐Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz‐Genga M, Sacilotto L, Schulze‐Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Aiba T, Bollmann A, Choi J, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn AD, Mac Intyre C, Mackall JA, Mont L, Napolitano C, Ochoa Juan P, Peichl P, Pereira AC, Schwartz PJ, Skinner J, Stellbrink C, Tfelt‐Hansen J, Deneke T. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. J Arrhythm 2022; 38:491-553. [PMID: 35936045 PMCID: PMC9347209 DOI: 10.1002/joa3.12717] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Arthur A. M. Wilde
- Heart Centre, Department of Cardiology, Amsterdam Universitair Medische CentraAmsterdamThe Netherlands
| | - Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary InstituteUniversity of SydneySydneyAustralia
| | - Manlio F. Márquez
- Instituto Nacional de Cardiología Ignacio ChávezCiudad de MéxicoMexico
| | | | - Michael J. Ackerman
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology; Windland Smith Rice Genetic Heart Rhythm Clinic and Windland Smith Rice Sudden Death Genomics Laboratory, Mayo ClinicRochesterMNUSA
| | - Euan A. Ashley
- Department of Cardiovascular MedicineStanford UniversityStanfordCAUSA
| | | | | | - Elijah R. Behr
- Cardiovascular Clinical Academic Group, Institute of Molecular and Clinical Sciences, St. George’sUniversity of London; St. George’s University Hospitals NHS Foundation TrustLondonUKMayo Clinic HealthcareLondon
| | - Connie R. Bezzina
- Amsterdam UMC Heart Center, Department of Experimental CardiologyAmsterdamThe Netherlands
| | - Jeroen Breckpot
- Center for Human GeneticsUniversity Hospitals LeuvenLeuvenBelgium
| | | | | | - Lia Crotti
- Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano, IRCCSMilanItaly
- Cardiomyopathy Unit and Cardiac Rehabilitation Unit, San Luca Hospital, Istituto Auxologico Italiano, IRCCSMilanItaly
- Department of Medicine and SurgeryUniversity of Milano‐BicoccaMilanItaly
| | - Michael H. Gollob
- Inherited Arrhythmia and Cardiomyopathy Program, Division of CardiologyUniversity of TorontoTorontoONCanada
| | - Steven Lubitz
- Cardiac Arrhythmia ServiceMassachusetts General Hospital and Harvard Medical SchoolBostonMAUSA
| | - Naomasa Makita
- National Cerebral and Cardiovascular CenterResearch InstituteSuitaJapan
| | - Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular CenterSuitaJapan
| | | | - Luciana Sacilotto
- Arrhythmia Unit, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao PauloBrazil
| | - Eric Schulze‐Bahr
- Institute for Genetics of Heart DiseasesUniversity Hospital MünsterMünsterGermany
| | - Wataru Shimizu
- Department of Cardiovascular MedicineGraduate School of MedicineTokyoJapan
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, Department of MedicineUniversity of WashingtonSeattleWAUSA
| | - Rafik Tadros
- Cardiovascular Genetics Center, Department of Medicine, Montreal Heart InstituteUniversité de MontréalMontrealCanada
| | - James S. Ware
- National Heart and Lung Institute and MRC London Institute of Medical SciencesImperial College LondonLondonUK
- Royal Brompton & Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation TrustLondonUK
| | - David S. Winlaw
- Cincinnati Children's Hospital Medical CentreUniversity of CincinnatiCincinnatiOHUSA
| | | | - Takeshi Aiba
- Department of Clinical Laboratory Medicine and Genetics, National Cerebral and Cardiovascular Center, SuitaOsakaJapan
| | - Andreas Bollmann
- Department of ElectrophysiologyHeart Center Leipzig at University of LeipzigLeipzigGermany
- Leipzig Heart InstituteLeipzigGermany
| | - Jong‐Il Choi
- Division of Cardiology, Department of Internal Medicine, Korea University Anam HospitalKorea University College of MedicineSeoulRepublic of Korea
| | - Aarti Dalal
- Department of Pediatrics, Division of CardiologyVanderbilt University School of MedicineNashvilleTNUSA
| | - Francisco Darrieux
- Arrhythmia Unit, Instituto do Coração, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São PauloSão PauloBrazil
| | - John Giudicessi
- Department of Cardiovascular Medicine (Divisions of Heart Rhythm Services and Circulatory Failure and the Windland Smith Rice Genetic Heart Rhythm Clinic), Mayo ClinicRochesterMNUSA
| | - Mariana Guerchicoff
- Division of Pediatric Arrhythmia and Electrophysiology, Italian Hospital of Buenos AiresBuenos AiresArgentina
| | - Kui Hong
- Department of Cardiovascular MedicineThe Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Andrew D. Krahn
- Division of CardiologyUniversity of British ColumbiaVancouverCanada
| | - Ciorsti Mac Intyre
- Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo ClinicRochesterMNUSA
| | - Judith A. Mackall
- Center for Cardiac Electrophysiology and Pacing, University Hospitals Cleveland Medical CenterCase Western Reserve University School of MedicineClevelandOHUSA
| | - Lluís Mont
- Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS). Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), MadridSpain
| | - Carlo Napolitano
- Molecular Cardiology, Istituti Clinici Scientifici Maugeri, IRCCSPaviaItaly
- Department of Molecular MedicineUniversity of PaviaPaviaItaly
| | - Pablo Ochoa Juan
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), MadridSpain
- Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de HierroMadridSpain
- Centro de Investigacion Biomedica en Red en Enfermedades Cariovasculares (CIBERCV), MadridSpain
| | - Petr Peichl
- Department of CardiologyInstitute for Clinical and Experimental MedicinePragueCzech Republic
| | - Alexandre C. Pereira
- Laboratory of Genetics and Molecular Cardiology, Heart InstituteUniversity of São Paulo Medical SchoolSão PauloBrazil
- Hipercol Brasil ProgramSão PauloBrazil
| | - Peter J. Schwartz
- Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano, IRCCSMilanItaly
| | - Jon Skinner
- Sydney Childrens Hospital NetworkUniversity of SydneySydneyAustralia
| | - Christoph Stellbrink
- Department of Cardiology and Intensive Care MedicineUniversity Hospital Campus Klinikum BielefeldBielefeldGermany
| | - Jacob Tfelt‐Hansen
- The Department of Cardiology, the Heart Centre, Copenhagen University Hospital, Rigshopitalet, Copenhagen, Denmark; Section of genetics, Department of Forensic Medicine, Faculty of Medical SciencesUniversity of CopenhagenDenmark
| | - Thomas Deneke
- Heart Center Bad NeustadtBad Neustadt a.d. SaaleGermany
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Rieder M, Kreifels P, Stuplich J, Ziupa D, Servatius H, Nicolai L, Castiglione A, Zweier C, Asatryan B, Odening KE. Genotype-Specific ECG-Based Risk Stratification Approaches in Patients With Long-QT Syndrome. Front Cardiovasc Med 2022; 9:916036. [PMID: 35911527 PMCID: PMC9329832 DOI: 10.3389/fcvm.2022.916036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Background Congenital long-QT syndrome (LQTS) is a major cause of sudden cardiac death (SCD) in young individuals, calling for sophisticated risk assessment. Risk stratification, however, is challenging as the individual arrhythmic risk varies pronouncedly, even in individuals carrying the same variant. Materials and Methods In this study, we aimed to assess the association of different electrical parameters with the genotype and the symptoms in patients with LQTS. In addition to the heart-rate corrected QT interval (QTc), markers for regional electrical heterogeneity, such as QT dispersion (QTmax-QTmin in all ECG leads) and delta Tpeak/end (Tpeak/end V5 – Tpeak/end V2), were assessed in the 12-lead ECG at rest and during exercise testing. Results QTc at rest was significantly longer in symptomatic than asymptomatic patients with LQT2 (493.4 ms ± 46.5 ms vs. 419.5 ms ± 28.6 ms, p = 0.004), but surprisingly not associated with symptoms in LQT1. In contrast, post-exercise QTc (minute 4 of recovery) was significantly longer in symptomatic than asymptomatic patients with LQT1 (486.5 ms ± 7.0 ms vs. 463.3 ms ± 16.3 ms, p = 0.04), while no such difference was observed in patients with LQT2. Enhanced delta Tpeak/end and QT dispersion were only associated with symptoms in LQT1 (delta Tpeak/end 19.0 ms ± 18.1 ms vs. −4.0 ms ± 4.4 ms, p = 0.02; QT-dispersion: 54.3 ms ± 10.2 ms vs. 31.4 ms ± 10.4 ms, p = 0.01), but not in LQT2. Delta Tpeak/end was particularly discriminative after exercise, where all symptomatic patients with LQT1 had positive and all asymptomatic LQT1 patients had negative values (11.8 ± 7.9 ms vs. −7.5 ± 1.7 ms, p = 0.003). Conclusion Different electrical parameters can distinguish between symptomatic and asymptomatic patients in different genetic forms of LQTS. While the classical “QTc at rest” was only associated with symptoms in LQT2, post-exercise QTc helped distinguish between symptomatic and asymptomatic patients with LQT1. Enhanced regional electrical heterogeneity was only associated with symptoms in LQT1, but not in LQT2. Our findings indicate that genotype-specific risk stratification approaches based on electrical parameters could help to optimize risk assessment in LQTS.
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Affiliation(s)
- Marina Rieder
- Translational Cardiology, Department of Cardiology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
| | - Paul Kreifels
- Department of Cardiology and Angiology I, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, Germany
| | - Judith Stuplich
- Department of Cardiology and Angiology I, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, Germany
| | - David Ziupa
- Department of Cardiology and Angiology I, Faculty of Medicine, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Freiburg, Germany
| | - Helge Servatius
- Translational Cardiology, Department of Cardiology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
| | - Luisa Nicolai
- Translational Cardiology, Department of Cardiology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
| | - Alessandro Castiglione
- Translational Cardiology, Department of Cardiology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
| | - Christiane Zweier
- Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Babken Asatryan
- Translational Cardiology, Department of Cardiology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
| | - Katja E Odening
- Translational Cardiology, Department of Cardiology, Inselspital, University Hospital Bern, University of Bern, Bern, Switzerland
- Department of Physiology, University of Bern, Bern, Switzerland
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27
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Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Aiba T, Bollmann A, Choi JI, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn AD, MacIntyre C, Mackall JA, Mont L, Napolitano C, Ochoa JP, Peichl P, Pereira AC, Schwartz PJ, Skinner J, Stellbrink C, Tfelt-Hansen J, Deneke T. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases. Heart Rhythm 2022; 19:e1-e60. [PMID: 35390533 DOI: 10.1016/j.hrthm.2022.03.1225] [Citation(s) in RCA: 115] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 12/12/2022]
Affiliation(s)
- Arthur A M Wilde
- Heart Centre, Department of Cardiology, Amsterdam Universitair Medische Centra, Amsterdam, location AMC, The Netherlands.
| | - Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Sydney, Australia.
| | - Manlio F Márquez
- Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México, Mexico; and Member of the Latin American Heart Rhythm Society (LAHRS).
| | | | - Michael J Ackerman
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology; Windland Smith Rice Genetic Heart Rhythm Clinic and Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA
| | - Euan A Ashley
- Department of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
| | - Eduardo Back Sternick
- Arrhythmia and Electrophysiology Unit, Biocor Institute, Minas Gerais, Brazil; and Member of the Latin American Heart Rhythm Society (LAHRS)
| | | | - Elijah R Behr
- Cardiovascular Clinical Academic Group, Institute of Molecular and Clinical Sciences, St. George's, University of London; St. George's University Hospitals NHS Foundation Trust, London, UK; Mayo Clinic Healthcare, London
| | - Connie R Bezzina
- Amsterdam UMC Heart Center, Department of Experimental Cardiology, Amsterdam, The Netherlands
| | - Jeroen Breckpot
- Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | - Philippe Charron
- Sorbonne Université, APHP, Centre de Référence des Maladies Cardiaques Héréditaires, ICAN, Inserm UMR1166, Hôpital Pitié-Salpêtrière, Paris, France
| | | | - Lia Crotti
- Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Cardiomyopathy Unit and Cardiac Rehabilitation Unit, San Luca Hospital, Istituto Auxologico Italiano, IRCCS, Milan, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Michael H Gollob
- Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, University of Toronto, Toronto, ON, Canada
| | - Steven Lubitz
- Cardiac Arrhythmia Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Naomasa Makita
- National Cerebral and Cardiovascular Center, Research Institute, Suita, Japan
| | - Seiko Ohno
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Martín Ortiz-Genga
- Clinical Department, Health in Code, A Coruña, Spain; and Member of the Latin American Heart Rhythm Society (LAHRS)
| | - Luciana Sacilotto
- Arrhythmia Unit, Instituto do Coracao, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil; and Member of the Latin American Heart Rhythm Society (LAHRS)
| | - Eric Schulze-Bahr
- Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany
| | - Wataru Shimizu
- Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Rafik Tadros
- Cardiovascular Genetics Center, Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Canada
| | - James S Ware
- National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - David S Winlaw
- Cincinnati Children's Hospital Medical Centre, University of Cincinnati, Cincinnati, OH, USA
| | - Elizabeth S Kaufman
- Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, USA.
| | - Takeshi Aiba
- Department of Clinical Laboratory Medicine and Genetics, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
| | - Andreas Bollmann
- Department of Electrophysiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany; Leipzig Heart Institute, Leipzig Heart Digital, Leipzig, Germany
| | - Jong-Il Choi
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Aarti Dalal
- Department of Pediatrics, Division of Cardiology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Francisco Darrieux
- Arrhythmia Unit, Instituto do Coração, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - John Giudicessi
- Department of Cardiovascular Medicine (Divisions of Heart Rhythm Services and Circulatory Failure and the Windland Smith Rice Genetic Heart Rhythm Clinic), Mayo Clinic, Rochester, MN, USA
| | - Mariana Guerchicoff
- Division of Pediatric Arrhythmia and Electrophysiology, Italian Hospital of Buenos Aires, Buenos Aires, Argentina
| | - Kui Hong
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Andrew D Krahn
- Division of Cardiology, University of British Columbia, Vancouver, Canada
| | - Ciorsti MacIntyre
- Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, MN, USA
| | - Judith A Mackall
- Center for Cardiac Electrophysiology and Pacing, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Lluís Mont
- Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Carlo Napolitano
- Molecular Cardiology, Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Juan Pablo Ochoa
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Cariovasculares (CIBERCV), Madrid, Spain
| | - Petr Peichl
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Alexandre C Pereira
- Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, São Paulo 05403-000, Brazil; Hipercol Brasil Program, São Paulo, Brazil
| | - Peter J Schwartz
- Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano, IRCCS, Milan, Italy
| | - Jon Skinner
- Sydney Childrens Hospital Network, University of Sydney, Sydney, Australia
| | - Christoph Stellbrink
- Department of Cardiology and Intensive Care Medicine, University Hospital Campus Klinikum Bielefeld, Bielefeld, Germany
| | - Jacob Tfelt-Hansen
- The Department of Cardiology, the Heart Centre, Copenhagen University Hospital, Rigshopitalet, Copenhagen, Denmark; Section of Genetics, Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark
| | - Thomas Deneke
- Heart Center Bad Neustadt, Bad Neustadt a.d. Saale, Germany
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28
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Wang M, Tu X. The Genetics and Epigenetics of Ventricular Arrhythmias in Patients Without Structural Heart Disease. Front Cardiovasc Med 2022; 9:891399. [PMID: 35783865 PMCID: PMC9240357 DOI: 10.3389/fcvm.2022.891399] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/25/2022] [Indexed: 12/19/2022] Open
Abstract
Ventricular arrhythmia without structural heart disease is an arrhythmic disorder that occurs in structurally normal heart and no transient or reversible arrhythmia factors, such as electrolyte disorders and myocardial ischemia. Ventricular arrhythmias without structural heart disease can be induced by multiple factors, including genetics and environment, which involve different genetic and epigenetic regulation. Familial genetic analysis reveals that cardiac ion-channel disorder and dysfunctional calcium handling are two major causes of this type of heart disease. Genome-wide association studies have identified some genetic susceptibility loci associated with ventricular tachycardia and ventricular fibrillation, yet relatively few loci associated with no structural heart disease. The effects of epigenetics on the ventricular arrhythmias susceptibility genes, involving non-coding RNAs, DNA methylation and other regulatory mechanisms, are gradually being revealed. This article aims to review the knowledge of ventricular arrhythmia without structural heart disease in genetics, and summarizes the current state of epigenetic regulation.
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29
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Lorca R, Junco-Vicente A, Pérez-Pérez A, Pascual I, Persia-Paulino YR, González-Urbistondo F, Cuesta-Llavona E, Fernández-Barrio BC, Morís C, Rubín JM, Coto E, Gómez J, Reguero JJR. KCNH2 p.Gly262AlafsTer98: A New Threatening Variant Associated with Long QT Syndrome in a Spanish Cohort. Life (Basel) 2022; 12:life12040556. [PMID: 35455047 PMCID: PMC9024605 DOI: 10.3390/life12040556] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/27/2022] [Accepted: 04/05/2022] [Indexed: 11/16/2022] Open
Abstract
Long QT syndrome (LQTS) is an inherited (autosomal dominant) channelopathy associated with susceptibility to ventricular arrhythmias due to malfunction of ion channels in cardiomyocytes, that could lead to sudden death (SD). Most pathogenic variants are in the main 3 genes: KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3). Efforts to improve the understanding of the genotype-phenotype relationship are essential to improve the medical clinical practice. In this study, we identified all index patients referred for NGS genetic sequencing due to LQTS, in a Spanish cohort, who were carriers of a new pathogenic variant (KCNH2 p.Gly262AlafsTer98). Genetic and clinical family screening was performed in order to describe its phenotypic characteristics. We identified 22 relatives of Romani ethnicity, who were carriers of the variant. Penetrance reached a 100% and adherence to medical treatment was low. There was a high rate of clinical events, particularly arrhythmic events and SD (1 in every 4 patients presented syncope, 1 presented an aborted SD, 2 obligated carriers suffered SD before the age of 40 and 4 out of 6 carriers of an implantable cardioverter-defibrillator (ICD) had appropriate ICD therapies. Correct adherence to medical treatment in all carriers should be specially encouraged in this population. ICD implantation decision in non-compliant patients, and refusing left cardiac sympathetic denervation, should be carefully outweighed.
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Affiliation(s)
- Rebeca Lorca
- Unidad de Referencia de Cardiopatías Familiares-HUCA, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (R.L.); (E.C.-L.); (C.M.); (J.M.R.); (E.C.); (J.G.); (J.J.R.R.)
- Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (A.J.-V.); (Y.R.P.-P.); (F.G.-U.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Alejandro Junco-Vicente
- Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (A.J.-V.); (Y.R.P.-P.); (F.G.-U.)
| | - Alicia Pérez-Pérez
- Pediatric Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (A.P.-P.); (B.C.F.-B.)
| | - Isaac Pascual
- Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (A.J.-V.); (Y.R.P.-P.); (F.G.-U.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Correspondence:
| | - Yvan Rafael Persia-Paulino
- Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (A.J.-V.); (Y.R.P.-P.); (F.G.-U.)
| | | | - Elías Cuesta-Llavona
- Unidad de Referencia de Cardiopatías Familiares-HUCA, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (R.L.); (E.C.-L.); (C.M.); (J.M.R.); (E.C.); (J.G.); (J.J.R.R.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | | | - César Morís
- Unidad de Referencia de Cardiopatías Familiares-HUCA, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (R.L.); (E.C.-L.); (C.M.); (J.M.R.); (E.C.); (J.G.); (J.J.R.R.)
- Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (A.J.-V.); (Y.R.P.-P.); (F.G.-U.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - José Manuel Rubín
- Unidad de Referencia de Cardiopatías Familiares-HUCA, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (R.L.); (E.C.-L.); (C.M.); (J.M.R.); (E.C.); (J.G.); (J.J.R.R.)
- Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (A.J.-V.); (Y.R.P.-P.); (F.G.-U.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Eliecer Coto
- Unidad de Referencia de Cardiopatías Familiares-HUCA, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (R.L.); (E.C.-L.); (C.M.); (J.M.R.); (E.C.); (J.G.); (J.J.R.R.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
| | - Juan Gómez
- Unidad de Referencia de Cardiopatías Familiares-HUCA, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (R.L.); (E.C.-L.); (C.M.); (J.M.R.); (E.C.); (J.G.); (J.J.R.R.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- CIBER-Enfermedades Respiratorias, 28029 Madrid, Spain
| | - José Julián Rodríguez Reguero
- Unidad de Referencia de Cardiopatías Familiares-HUCA, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (R.L.); (E.C.-L.); (C.M.); (J.M.R.); (E.C.); (J.G.); (J.J.R.R.)
- Heart Area, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; (A.J.-V.); (Y.R.P.-P.); (F.G.-U.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
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30
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Yazdanpanah MH, Naghizadeh MM, Sayyadipoor S, Farjam M. The best QT correction formula in a non-hospitalized population: the Fasa PERSIAN cohort study. BMC Cardiovasc Disord 2022; 22:52. [PMID: 35172723 PMCID: PMC8851728 DOI: 10.1186/s12872-022-02502-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 02/08/2022] [Indexed: 01/08/2023] Open
Abstract
Background QT interval as an indicator of ventricular repolarization is a clinically important parameter on an electrocardiogram (ECG). QT prolongation predisposes individuals to different ventricular arrhythmias and sudden cardiac death. The current study aimed to identify the best heart rate corrected QT interval for a non-hospitalized Iranian population based on cardiovascular mortality.
Methods Using Fasa PERSIAN cohort study data, this study enrolled 7071 subjects aged 35–70 years. Corrected QT intervals (QTc) were calculated by the QT interval measured by Cardiax® software from ECGs and 6 different correction formulas (Bazett, Fridericia, Dmitrienko, Framingham, Hodges, and Rautaharju). Mortality status was checked using an annual telephone-based follow-up and a minimum 3-year follow-up for each participant. Bland–Altman, QTc/RR regression, sensitivity analysis, and Cox regression were performed in IBM SPSS Statistics v23 to find the best QT. Also, for calculating the upper and lower limits of normal of different QT correction formulas, 3952 healthy subjects were selected. Results In this study, 56.4% of participants were female, and the mean age was 48.60 ± 9.35 years. Age, heart rate in females, and QT interval in males were significantly higher. The smallest slopes of QTc/RR analysis were related to Fridericia in males and Rautaharju followed by Fridericia in females. Thus, Fridericia’s formula was identified as the best mathematical formula and Bazett’s as the worst in males. In the sensitivity analysis, however, Bazett’s formula had the highest sensitivity (23.07%) among all others in cardiac mortality. Also, in the Cox regression analysis, Bazett’s formula was better than Fridericia’s and was identified as the best significant cardiac mortality predictor (Hazard ratio: 4.31, 95% CI 1.73–10.74, p value = 0.002). Conclusion Fridericia was the best correction formula based on mathematical methods. Bazett’s formula despite its poorest performance in mathematical methods, was the best one for cardiac mortality prediction. Practically, it is suggested that physicians use QTcB for a better evaluation of cardiac mortality risk. However, in population-based studies, QTcFri might be the one to be used by researchers. Supplementary Information The online version contains supplementary material available at 10.1186/s12872-022-02502-2.
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Affiliation(s)
- Mohammad Hosein Yazdanpanah
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Ibn-Sina Square, P.O. Box: 74616-86688, Fasa, Fars, Iran.,Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mehdi Naghizadeh
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Ibn-Sina Square, P.O. Box: 74616-86688, Fasa, Fars, Iran
| | | | - Mojtaba Farjam
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Ibn-Sina Square, P.O. Box: 74616-86688, Fasa, Fars, Iran.
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31
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Diagnostic Accuracy of the 12-Lead Electrocardiogram in the First 48 Hours of Life for Newborns of a Parent with Congenital Long QT Syndrome. Heart Rhythm 2022; 19:969-974. [PMID: 35144017 DOI: 10.1016/j.hrthm.2022.01.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/20/2022] [Accepted: 01/27/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Long QT syndrome (LQTS) is an autosomal dominant disorder characterized by a prolonged QT interval. ECG screening in the first 48 hours of life may be misleading, even in newborns with a genotype-positive LQTS parent. OBJECTIVE To determine the ECG's diagnostic accuracy in the first 48 hours of life for neonates born to a parent with LQTS. METHODS Retrospective review of all neonates born at Mayo Clinic to a parent with ≥1 pathogenic variant in a LQTS-causative gene who had least 1 ECG in the first 48 hours and genetic test results were available. Sensitivity and specificity of the diagnostic ECG were calculated using QTc thresholds of 440, 450, 460, and 470 ms. RESULTS Overall, 74 infants (36 [49%] females) were included (mean QTc on first ECG 489 ± 54 ms; 68% LQTS genotype-positive). Mean QTc in the first 48 hours for neonates that ultimately were genotype-positive was greater (506 ± 52 ms) compared to genotype-negative neonates (455 ± 41 ms; p=0.0004). When using a recommended threshold QTc of ≥ 440 ms, 6/50 (12%) genotype-positive neonates were missed (underdiagnosed) and 17/24 (71%) genotype-negative neonates were overdiagnosed (sensitivity: 88%, specificity: 29%). CONCLUSIONS The newborn ECG should not be used in isolation to make the diagnosis of LQTS since it will result in many misclassifications. Genetic testing must be initiated prior to discharge, and proper anticipatory guidance is vital while awaiting test results.
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32
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Tinker A. Does knowledge of the mutation in hereditary long QT syndrome aid risk stratification? Eur Heart J 2021; 42:4756-4758. [PMID: 34542608 DOI: 10.1093/eurheartj/ehab668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Andrew Tinker
- Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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33
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Kojima T, Wasano K, Takahashi S, Homma K. Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss. Dis Model Mech 2021; 14:272416. [PMID: 34622280 PMCID: PMC8628632 DOI: 10.1242/dmm.049015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 09/22/2021] [Indexed: 01/30/2023] Open
Abstract
KCNQ4 encodes the homotetrameric voltage-dependent potassium ion channel Kv7.4, and is the causative gene for autosomal dominant nonsyndromic sensorineural hearing loss, DFNA2. Dominant-negative inhibition accounts for the observed dominant inheritance of many DFNA2-associated KCNQ4 variants. In addition, haploinsufficiency has been presumed as the pathological mechanism for truncated Kv7.4 variants lacking the C-terminal tetramerization region, as they are unlikely to exert a dominant-negative inhibitory effect. Such truncated Kv7.4 variants should result in relatively mild hearing loss when heterozygous; however, this is not always the case. In this study, we characterized Kv7.4Q71fs (c.211delC), Kv7.4W242X (c.725G>A) and Kv7.4A349fs (c.1044_1051del8) in heterologous expression systems and found that expression of these truncated Kv7.4 variants induced cell death. We also found similar cell death-inducing cytotoxic effects in truncated Kv7.1 (KCNQ1) variants, suggesting that the generality of our findings could account for the dominant inheritance of many, if not most, truncated Kv7 variants. Moreover, we found that the application of autophagy inducers can ameliorate the cytotoxicity, providing a novel insight for the development of alternative therapeutic strategies for Kv7.4 variants. Summary: Expression of truncated KCNQ4 variants lacking the C-terminal tetramerization domain results in cell-death inducing cytotoxicity, providing novel insight into the development of alternative therapeutic strategies for DFNA2 hearing loss.
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Affiliation(s)
- Takashi Kojima
- Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.,Department of Otolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Koichiro Wasano
- Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.,Laboratory of Auditory Disorders, Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8902, Japan
| | - Satoe Takahashi
- Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Kazuaki Homma
- Department of Otolaryngology - Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.,The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University, Evanston, IL 60608, USA
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34
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Scrocco C, Bezzina CR, Ackerman MJ, Behr ER. Genetics and genomics of arrhythmic risk: current and future strategies to prevent sudden cardiac death. Nat Rev Cardiol 2021; 18:774-784. [PMID: 34031597 DOI: 10.1038/s41569-021-00555-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/12/2021] [Indexed: 02/04/2023]
Abstract
A genetic risk of sudden cardiac arrest and sudden death due to an arrhythmic cause, known as sudden cardiac death (SCD), has become apparent from epidemiological studies in the general population and in patients with ischaemic heart disease. However, genetic susceptibility to sudden death is greatest in young people and is associated with uncommon, monogenic forms of heart disease. Despite comprehensive pathology and genetic evaluations, SCD remains unexplained in a proportion of young people and is termed sudden arrhythmic death syndrome, which poses challenges to the identification of relatives from affected families who might be at risk of SCD. In this Review, we assess the current understanding of the epidemiology and causes of SCD and evaluate both the monogenic and the polygenic contributions to the risk of SCD in the young and SCD associated with drug therapy. Finally, we analyse the potential clinical role of genomic testing in the prevention of SCD in the general population.
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Affiliation(s)
- Chiara Scrocco
- Cardiovascular Clinical Academic Group, Molecular and Clinical Sciences Institute, St George's University of London and St George's University Hospitals NHS Foundation Trust, London, UK
| | - Connie R Bezzina
- Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Michael J Ackerman
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA.,Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA
| | - Elijah R Behr
- Cardiovascular Clinical Academic Group, Molecular and Clinical Sciences Institute, St George's University of London and St George's University Hospitals NHS Foundation Trust, London, UK.
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35
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Yin J, Zhou J, Chen J, Xu T, Zhang Z, Zhang H, Yuan C, Cheng X, Qin Y, Zheng B, Wang C, Yang S, Jia Z. Case Report: A Novel Variant c.2262+3A>T of the SCN5A Gene Results in Intron Retention Associated With Incessant Ventricular Tachycardias. Front Med (Lausanne) 2021; 8:659119. [PMID: 34422849 PMCID: PMC8371685 DOI: 10.3389/fmed.2021.659119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 06/30/2021] [Indexed: 11/18/2022] Open
Abstract
Objective: Voltage-gated sodium channel Nav1.5 encoded by the SCN5A gene plays crucial roles in cardiac electrophysiology. Previous genetic studies have shown that mutations in SCN5A are associated with multiple inherited cardiac arrhythmias. Here, we investigated the molecular defect in a Chinese boy with clinical manifestations of arrhythmias. Methods: Gene variations were screened using whole-exome sequencing and validated by direct Sanger sequencing. A minigene assay and reverse transcription PCR (RT-PCR) were performed to confirm the effects of splice variants in vitro. Western blot analysis was carried out to determine whether the c.2262+3A>T variant produced a truncated protein. Results: By genetic analysis, we identified a novel splice variant c.2262+3A>T in SCN5A gene in a Chinese boy with incessant ventricular tachycardias (VT). This variant was predicted to activate a new cryptic splice donor site and was identified by in silico analysis. The variant retained 79 bp at the 5′ end of intron 14 in the mature mRNA. Furthermore, the mutant transcript that created a premature stop codon at 818 amino acids [p.(R818*)] could be produced as a truncated protein. Conclusion: We verified the pathogenic effect of splicing variant c.2262+3A>T, which disturbed the normal mRNA splicing and caused a truncated protein, suggesting that splice variants play an important role in the molecular basis of early onset incessant ventricular tachycardias, and careful molecular profiling of these patients will be essential for future effective personalized treatment options.
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Affiliation(s)
- Jie Yin
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jia Zhou
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jinlong Chen
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Ting Xu
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhongman Zhang
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Han Zhang
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Chang Yuan
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Xueying Cheng
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Yuming Qin
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Bixia Zheng
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Chunli Wang
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Shiwei Yang
- Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
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36
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Trachsel DS, Calloe K, Mykkänen AK, Raistakka P, Anttila M, Fredholm M, Tala M, Lamminpää K, Klaerke DA, Buhl R. Exercise-Associated Sudden Death in Finnish Standardbred and Coldblooded Trotters - A Case Series With Pedigree Analysis. J Equine Vet Sci 2021; 104:103694. [PMID: 34416991 DOI: 10.1016/j.jevs.2021.103694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/30/2021] [Accepted: 06/19/2021] [Indexed: 10/21/2022]
Abstract
Exercise-associated sudden deaths (EASDs) are deaths occurring unexpectedly during or immediately after exercise. Sudden cardiac death (SCD) is one cause of EASD. Cardiac arrhythmias caused by genetic variants have been linked to SCD in humans. We hypothesize that genetic variants may be associated with SCD in animals, including horses. Genetic variants are transmitted to offspring and their frequency might increase within a family. Therefore, the frequency of such variants might increase with the inbreeding factor. Higher inbreeding could have a negative impact on racing performance. Pedigree data and career earnings from racehorses diagnosed with SCD between 2002 and 2017 were compared using non-parametric tests with 1) control horses that died due to catastrophic musculoskeletal injuries and 2) horses that raced during the same period without reported problems. Diagnosis of SCD was based on necropsy reports, including macroscopic and microscopic examinations. Death was registered in the study period for 61 horses. Eleven of these horses were excluded due to missing autopsy reports. In 25 cases, the diagnosis remained unknown and death was possibly caused by cardiac arrhythmia, in two cases cardiac disease was identified, in seven cases a rupture of a major vessel had occurred. In addition, 16 horses died or were euthanized due to severe musculoskeletal injuries. No significant differences in inbreeding coefficients or in career earnings were found between the groups or between horses with EASD compared with other horses racing during the same period. The study provides no evidence for increased inbreeding factor in Finnish racehorses with SCD.
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Affiliation(s)
- Dagmar S Trachsel
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark; Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.
| | - Kirstine Calloe
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Anna K Mykkänen
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - Pia Raistakka
- Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - Marjukka Anttila
- Veterinary Bacteriology and Pathology Research Unit, Finnish Food Authority, Helsinki
| | - Merete Fredholm
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Martti Tala
- Suomen Hippos, the Finnish Trotting and Breeding Association
| | | | - Dan A Klaerke
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Rikke Buhl
- Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark
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37
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Choi SH, Jurgens SJ, Haggerty CM, Hall AW, Halford JL, Morrill VN, Weng LC, Lagerman B, Mirshahi T, Pettinger M, Guo X, Lin HJ, Alonso A, Soliman EZ, Kornej J, Lin H, Moscati A, Nadkarni GN, Brody JA, Wiggins KL, Cade BE, Lee J, Austin-Tse C, Blackwell T, Chaffin MD, Lee CJY, Rehm HL, Roselli C, Redline S, Mitchell BD, Sotoodehnia N, Psaty BM, Heckbert SR, Loos RJ, Vasan RS, Benjamin EJ, Correa A, Boerwinkle E, Arking DE, Rotter JI, Rich SS, Whitsel EA, Perez M, Kooperberg C, Fornwalt BK, Lunetta KL, Ellinor PT, Lubitz SA, Lubitz SA. Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2021; 14:e003300. [PMID: 34319147 PMCID: PMC8373440 DOI: 10.1161/circgen.120.003300] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. METHODS Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). RESULTS We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. CONCLUSIONS Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.
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Affiliation(s)
- Seung Hoan Choi
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.)
| | - Sean J. Jurgens
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.)
| | - Christopher M. Haggerty
- Department of Translational Data Science and Informatics (C.M.H., B.K.F.), Geisinger, Danville, PA.,Heart Institute (C.M.H., B.K.F.), Geisinger, Danville, PA
| | - Amelia W. Hall
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).,Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA
| | - Jennifer L. Halford
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).,Harvard Medical School (J.L.H., C.A.-T., H.L.R.), Boston, MA
| | - Valerie N. Morrill
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).,Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA
| | - Lu-Chen Weng
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).,Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA
| | - Braxton Lagerman
- Phenomic Analytics and Clinical Data Core (B.L.), Geisinger, Danville, PA
| | - Tooraj Mirshahi
- Department of Molecular and Functional Genomics (T.M.), Geisinger, Danville, PA
| | - Mary Pettinger
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (M.P., C.K.)
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Insti for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., H.J.L., J.I.R.)
| | - Henry J. Lin
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Insti for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., H.J.L., J.I.R.)
| | - Alvaro Alonso
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA (A.A.)
| | - Elsayed Z. Soliman
- Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC (E.Z.S.)
| | - Jelena Kornej
- NHLBI and Boston University’s Framingham Heart Study (J.K., E.J.B., R.S.V).,Sections of Cardiovascular Medicine and Preventive Medicine, Boston Medical Center (J.K., R.S.V), Boston University School of Medicine, MA
| | - Honghuang Lin
- Section of Computational Biomedicine, Department of Medicine (H.L.), Boston University School of Medicine, MA
| | - Arden Moscati
- The Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY
| | - Girish N. Nadkarni
- The Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY.,Division of Nephrology, Department of Medicine (G.N.), Icahn School of Medicine, Mount Sinai, New York, NY
| | - Jennifer A. Brody
- Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle
| | - Kerri L. Wiggins
- Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle
| | - Brian E. Cade
- Massachusetts General Hospital. Division of Sleep Medicine, Department of Medicine (B.E.C.), Boston, MA.,Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology (B.E.C.), Harvard Medical School, Brigham and Women’s Hospital, Boston
| | - Jiwon Lee
- Division of Sleep and Circadian Disorders (J.L.), Harvard Medical School, Brigham and Women’s Hospital, Boston
| | - Christina Austin-Tse
- Center for Genomic Medicine (C.A.-T., H.L.R.), Boston, MA.,Harvard Medical School (J.L.H., C.A.-T., H.L.R.), Boston, MA.,Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA (C.A.-T.)
| | - Tom Blackwell
- Department of Biostatistics, University of Michigan, Ann Arbor (T.B.)
| | - Mark D. Chaffin
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.)
| | - Christina J.-Y. Lee
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.)
| | - Heidi L. Rehm
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).,Center for Genomic Medicine (C.A.-T., H.L.R.), Boston, MA.,Harvard Medical School (J.L.H., C.A.-T., H.L.R.), Boston, MA
| | - Carolina Roselli
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.)
| | - Susan Redline
- Regeneron Genetics Center, Tarrytown, NY. Departments of Medicine, Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (S.R.)
| | - Braxton D. Mitchell
- University of Maryland School of Medicine (B.D.M.).,Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.)
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.,Division of Cardiology, Department of Epidemiology (N.S.), University of Washington, Seattle
| | - Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.,Department of Epidemiology (B.M.P., S.R.H.), University of Washington, Seattle.,Department of Health Services (B.M.P.), University of Washington, Seattle.,Kaiser Permanente Washington Health Research Institute, Seattle (B.M.P.)
| | - Susan R. Heckbert
- Cardiovascular Health Research Unit, Department of Medicine (J.A.B., K.L.W., N.S., B.M.P., S.R.H.), University of Washington, Seattle.,Department of Epidemiology (B.M.P., S.R.H.), University of Washington, Seattle
| | - Ruth J.F. Loos
- The Charles Bronfman Institute for Personalized Medicine (A.M., G.N., R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY.,The Mindich Child Health and Development Institute (R.J.F.L.), Icahn School of Medicine, Mount Sinai, New York, NY
| | - Ramachandran S. Vasan
- NHLBI and Boston University’s Framingham Heart Study (J.K., E.J.B., R.S.V).,Sections of Cardiovascular Medicine and Preventive Medicine, Boston Medical Center (J.K., R.S.V), Boston University School of Medicine, MA.,Department of Medicine (E.J.B., R.S.V), Boston University School of Medicine, MA
| | - Emelia J. Benjamin
- NHLBI and Boston University’s Framingham Heart Study (J.K., E.J.B., R.S.V).,Department of Medicine (E.J.B., R.S.V), Boston University School of Medicine, MA.,Department of Epidemiology (E.J.B.), Boston University School of Public Health, MA
| | - Adolfo Correa
- Departments of Medicine, Pediatrics, and Population Health Science, University of Mississippi Medical Center, Jackson (A.C.)
| | - Eric Boerwinkle
- Human Genetics Center, University of Texas Health Science Center, Houston (E.B.)
| | - Dan E. Arking
- McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (D.E.A.)
| | - Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Insti for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., H.J.L., J.I.R.)
| | - Stephen S. Rich
- Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville (S.S.R.)
| | - Eric A. Whitsel
- Department of Epidemiology, Gillings School of Global Public Health (E.A.W.), School of Medicine, University of North Carolina, Chapel Hill.,Department of Medicine (E.A.W.), School of Medicine, University of North Carolina, Chapel Hill
| | - Marco Perez
- Division of Cardiovascular Medicine, Stanford University, CA (M.P.). Dr Sotoodehnia is supported by NIH grant R01HL141989, by AHA grant 19SFRN34830063, and by the Laughlin Family
| | - Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (M.P., C.K.)
| | - Brandon K. Fornwalt
- Department of Translational Data Science and Informatics (C.M.H., B.K.F.), Geisinger, Danville, PA.,Heart Institute (C.M.H., B.K.F.), Geisinger, Danville, PA.,Department of Radiology (B.K.F.), Geisinger, Danville, PA
| | - Kathryn L. Lunetta
- Department of Biostatistics (K.L.L.), Boston University School of Public Health, MA
| | - Patrick T. Ellinor
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).,Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA.,Cardiac Arrhythmia Service (P.T.E., S.A.L.), Boston, MA
| | - Steven A. Lubitz
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).,Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA.,Cardiac Arrhythmia Service (P.T.E., S.A.L.), Boston, MA
| | - Steven A Lubitz
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.).,Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA.,Cardiac Arrhythmia Service (P.T.E., S.A.L.), Boston, MA
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Heidbuchel H, Arbelo E, D'Ascenzi F, Borjesson M, Boveda S, Castelletti S, Miljoen H, Mont L, Niebauer J, Papadakis M, Pelliccia A, Saenen J, Sanz de la Garza M, Schwartz PJ, Sharma S, Zeppenfeld K, Corrado D. Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions. Part 2: ventricular arrhythmias, channelopathies, and implantable defibrillators. Europace 2021; 23:147-148. [PMID: 32596731 DOI: 10.1093/europace/euaa106] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
This paper belongs to a series of recommendation documents for participation in leisure-time physical activity and competitive sports by the European Association of Preventive Cardiology (EAPC). Together with an accompanying paper on supraventricular arrhythmias, this second text deals specifically with those participants in whom some form of ventricular rhythm disorder is documented, who are diagnosed with an inherited arrhythmogenic condition, and/or who have an implanted pacemaker or cardioverter defibrillator. A companion text on recommendations in athletes with supraventricular arrhythmias is published in the European Journal of Preventive Cardiology. Since both texts focus on arrhythmias, they are the result of a collaboration between EAPC and the European Heart Rhythm Association (EHRA). The documents provide a framework for evaluating eligibility to perform sports, based on three elements, i.e. the prognostic risk of the arrhythmias when performing sports, the symptomatic impact of arrhythmias while performing sports, and the potential progression of underlying structural problems as the result of sports.
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Affiliation(s)
- Hein Heidbuchel
- Department of Cardiology, University Hospital Antwerp, University Antwerp, Wilrijkstraat 10, 2650 Antwerp, Belgium
| | - Elena Arbelo
- Arrhythmia Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigació August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Flavio D'Ascenzi
- Division of Cardiology, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Mats Borjesson
- Centre for Health and Performance (CHP), Department of Food, Nutrition and Sport Sciences, Gothenburg University, Sweden.,Department of Neuroscience and Physiology, Gothenburg University, Gothenburg, Sweden
| | - Serge Boveda
- Cardiology Department, Clinique Pasteur, 45 Avenue de Lombez, 31076 Toulouse, France
| | - Silvia Castelletti
- Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Laboratory of Cardiovascular Genetics, Milan, Italy
| | - Hielko Miljoen
- Department of Cardiology, University Hospital Antwerp, University Antwerp, Wilrijkstraat 10, 2650 Antwerp, Belgium
| | - Lluis Mont
- Arrhythmia Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigació August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Josef Niebauer
- Institute of Sports Medicine, Prevention and Rehabilitation, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Michael Papadakis
- Cardiology Clinical Academic Group, St. George's University of London, London, UK.,St. George's University Hospitals NHS Foundation Trust, London, UK
| | - Antonio Pelliccia
- National Institute of Sports Medicine, Italian National Olympic Committee, Via dei Campi Sportivi 46, Rome, Italy
| | - Johan Saenen
- Department of Cardiology, University Hospital Antwerp, University Antwerp, Wilrijkstraat 10, 2650 Antwerp, Belgium
| | | | - Peter J Schwartz
- Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Laboratory of Cardiovascular Genetics, Milan, Italy
| | - Sanjay Sharma
- Cardiology Clinical Academic Group, St. George's University of London, London, UK.,St. George's University Hospitals NHS Foundation Trust, London, UK
| | - Katja Zeppenfeld
- Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Domenico Corrado
- Department of Cardiology, University of Padova, Padova, Italy.,Department of Pathology, University of Padova, Padova, Italy
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Gnecchi M, Sala L, Schwartz PJ. Precision Medicine and cardiac channelopathies: when dreams meet reality. Eur Heart J 2021; 42:1661-1675. [PMID: 33686390 PMCID: PMC8088342 DOI: 10.1093/eurheartj/ehab007] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/10/2020] [Accepted: 01/12/2021] [Indexed: 12/17/2022] Open
Abstract
Precision Medicine (PM) is an innovative approach that, by relying on large populations’ datasets, patients’ genetics and characteristics, and advanced technologies, aims at improving risk stratification and at identifying patient-specific management through targeted diagnostic and therapeutic strategies. Cardiac channelopathies are being progressively involved in the evolution brought by PM and some of them are benefiting from these novel approaches, especially the long QT syndrome. Here, we have explored the main layers that should be considered when developing a PM approach for cardiac channelopathies, with a focus on modern in vitro strategies based on patient-specific human-induced pluripotent stem cells and on in silico models. PM is where scientists and clinicians must meet and integrate their expertise to improve medical care in an innovative way but without losing common sense. We have indeed tried to provide the cardiologist’s point of view by comparing state-of-the-art techniques and approaches, including revolutionary discoveries, to current practice. This point matters because the new approaches may, or may not, exceed the efficacy and safety of established therapies. Thus, our own eagerness to implement the most recent translational strategies for cardiac channelopathies must be tempered by an objective assessment to verify whether the PM approaches are indeed making a difference for the patients. We believe that PM may shape the diagnosis and treatment of cardiac channelopathies for years to come. Nonetheless, its potential superiority over standard therapies should be constantly monitored and assessed before translating intellectually rewarding new discoveries into clinical practice.
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Affiliation(s)
- Massimiliano Gnecchi
- Department of Cardiothoracic and Vascular Sciences-Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy.,Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy.,Department of Medicine, University of Cape Town, J-Floor, Old Main Building, Groote Schuur Hospital, Observatory, 7925 Cape Town, South Africa
| | - Luca Sala
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22 - 20135 Milan, Italy
| | - Peter J Schwartz
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22 - 20135 Milan, Italy
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40
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Schwartz PJ. 1970-2020: 50 years of research on the long QT syndrome-from almost zero knowledge to precision medicine. Eur Heart J 2021; 42:1063-1072. [PMID: 33057695 DOI: 10.1093/eurheartj/ehaa769] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/13/2020] [Accepted: 09/07/2020] [Indexed: 12/17/2022] Open
Abstract
To those of us involved in clinical research it seldom happens to begin working on a rather obscure disease, still largely unexplored, and to follow its ripening into a medical entity of large interest to clinicians and basic scientists alike, and moreover to do so for exactly 50 years. This is what has been my privilege in the relentless pursuit of the intriguing disease known as the long QT syndrome (LQTS). This essay begins with the encounter with my first patient affected by LQTS when just a handful of cardiologists had seen similar cases and continues with the series of efforts, some sound some amateurish, which eventually led-together with many brilliant partners and associates-to describe and understand the natural history of the disease and the most effective therapies. It then touches on how our International Registry for LQTS, with its well-documented family trees, constituted the necessary springboard for the major genetic discoveries of the 1990s. From the explosion of genetic data, my own interest focused first on the intriguing genotype-phenotype correlation and then on 'modifier genes', in the attempt of understanding why family members with the same disease-causing mutation could have an opposite clinical history. And from there on to iPS-derived cardiomyocytes, used to unravelling the specific mechanisms of action of modifier genes and to exploring novel therapeutic strategies. This long, and highly rewarding, journey continues because the fascination and the attraction of the unknown are irresistible.
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Affiliation(s)
- Peter J Schwartz
- Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo, 22, Milan 20135, Italy
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41
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Functional testing for variant prioritization in a family with long QT syndrome. Mol Genet Genomics 2021; 296:823-836. [PMID: 33876311 DOI: 10.1007/s00438-021-01780-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 03/29/2021] [Indexed: 01/08/2023]
Abstract
Next-generation sequencing platforms are being increasingly applied in clinical genetic settings for evaluation of families with suspected heritable disease. These platforms potentially improve the diagnostic yield beyond that of disease-specific targeted gene panels, but also increase the number of rare or novel genetic variants that may confound precise diagnostics. Here, we describe a functional testing approach used to interpret the results of whole exome sequencing (WES) in a family presenting with syncope and sudden death. One individual had a prolonged QT interval on electrocardiogram (ECG) and carried a diagnosis of long QT syndrome (LQTS), but a second individual did not meet criteria for LQTS. Filtering WES results for uncommon variants with arrhythmia association identified four for further analyses. In silico analyses indicated that two of these variants, KCNH2 p.(Cys555Arg) and KCNQ1 p.(Arg293Cys), were likely to be causal in this family's LQTS. We subsequently performed functional characterization of these variants in a heterologous expression system. The expression of KCNQ1-Arg293Cys did not show a deleterious phenotype but KCNH2-Cys555Arg demonstrated a loss-of-function phenotype that was partially dominant. Our stepwise approach identified a precise genetic etiology in this family, which resulted in the establishment of a LQTS diagnosis in the second individual as well as an additional asymptomatic family member, enabling personalized clinical management. Given its ability to aid in the diagnosis, the application of functional characterization should be considered as a value adjunct to in silico analyses of WES.
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Abstract
Long QT syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval and T-wave irregularities on the surface electrocardiogram. It is commonly associated with syncope, seizures, susceptibility to torsades de pointes, and risk for sudden death. LQTS is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. The availability of therapy for this lethal disease emphasizes the importance of early and accurate diagnosis. Additionally, understanding of the molecular mechanisms underlying LQTS could help to optimize genotype-specific treatments to prevent deaths in LQTS patients. In this review, we briefly summarize current knowledge regarding molecular underpinning of LQTS, in particular focusing on LQT1, LQT2, and LQT3, and discuss novel strategies to study ion channel dysfunction and drug-specific therapies in LQT1, LQT2, and LQT3 syndromes.
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Affiliation(s)
| | - Isabelle Deschênes
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio
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43
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A computational model of induced pluripotent stem-cell derived cardiomyocytes for high throughput risk stratification of KCNQ1 genetic variants. PLoS Comput Biol 2020; 16:e1008109. [PMID: 32797034 PMCID: PMC7449496 DOI: 10.1371/journal.pcbi.1008109] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 08/26/2020] [Accepted: 06/30/2020] [Indexed: 01/01/2023] Open
Abstract
In the last decade, there has been tremendous progress in identifying genetic anomalies linked to clinical disease. New experimental platforms have connected genetic variants to mechanisms underlying disruption of cellular and organ behavior and the emergence of proarrhythmic cardiac phenotypes. The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) signifies an important advance in the study of genetic disease in a patient-specific context. However, considerable limitations of iPSC-CM technologies have not been addressed: 1) phenotypic variability in apparently identical genotype perturbations, 2) low-throughput electrophysiological measurements, and 3) an immature phenotype which may impact translation to adult cardiac response. We have developed a computational approach intended to address these problems. We applied our recent iPSC-CM computational model to predict the proarrhythmic risk of 40 KCNQ1 genetic variants. An IKs computational model was fit to experimental data for each mutation, and the impact of each mutation was simulated in a population of iPSC-CM models. Using a test set of 15 KCNQ1 mutations with known clinical long QT phenotypes, we developed a method to stratify the effects of KCNQ1 mutations based on proarrhythmic markers. We utilized this method to predict the severity of the remaining 25 KCNQ1 mutations with unknown clinical significance. Tremendous phenotypic variability was observed in the iPSC-CM model population following mutant perturbations. A key novelty is our reporting of the impact of individual KCNQ1 mutant models on adult ventricular cardiomyocyte electrophysiology, allowing for prediction of mutant impact across the continuum of aging. This serves as a first step toward translating predicted response in the iPSC-CM model to predicted response of the adult ventricular myocyte given the same genetic mutation. As a whole, this study presents a new computational framework that serves as a high throughput method to evaluate risk of genetic mutations based-on proarrhythmic behavior in phenotypically variable populations. In the last decade, there has been tremendous progress in identifying genetic mutations linked to clinical diseases, such as cardiac arrhythmia. Many experimental platforms have been developed to study this link, including induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). IPSC-CMs are patient-derived cardiac cells which allow for the study of genetic variants within a patient-specific context. However, experimentally iPSC-CMs have certain limitations, including: (1) they exhibit variability in behavior within cells that are apparently genetically identical, and (2) they are immature compared to adult cardiac cells. In our study, we have developed a computational approach to model 40 genetic variants in the KCNQ1 gene and predict the proarrhythmic risk of each variant. To do this, we modeled the ionic current determined by KCNQ1, IKs, to fit experimental data for each mutation. We then simulated the impact of each mutation in a population of iPSC-CMs, incorporating variability across the population. We also simulated each variant in an adult cardiac cell model, providing a link between iPSC-CM response to mutants and adult cardiac cell response to the same mutants. Overall, this study provides a new computational framework to evaluate risk of genetic mutations based-on proarrhythmic behavior diverse populations of iPSC-CM models.
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Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, et alLahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MW, Bezzina CR. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. Circulation 2020; 142:324-338. [PMID: 32429735 PMCID: PMC7382531 DOI: 10.1161/circulationaha.120.045956] [Show More Authors] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 06/22/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). CONCLUSIONS This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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Affiliation(s)
- Najim Lahrouchi
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
| | - Rafik Tadros
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Canada (R.T.)
| | - Lia Crotti
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Center for Cardiac Arrhythmias of Genetic Origin (L.C., F.D., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy
- Laboratory of Cardiovascular Genetics (L.C., M.P., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy
- Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital (L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy (L.C.)
| | - Yuka Mizusawa
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
| | - Pieter G. Postema
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
| | - Leander Beekman
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
| | - Roddy Walsh
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
| | - Kanae Hasegawa
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan (K.H., S.O., H.I., M.H.)
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Japan (K.H.)
| | - Julien Barc
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- L’Institut du Thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., V.P.)
| | - Marko Ernsting
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Muenster, Germany (M.E., B.S., S.Z., E.S.-B.)
| | - Kari L. Turkowski
- Departments of Cardiovascular Medicine (Division of Heart Rhythm Services and the Windland Smith Rice Genetic Heart Rhythm Clinic), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (K.L.T., D.J.T., J.M.B., M.J.A.)
| | - Andrea Mazzanti
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Molecular Cardiology, ICS Maugeri, IRCCS and Department of Molecular Medicine, University of Pavia, Italy (A.M., C.N., S.G.P.)
| | - Britt M. Beckmann
- Department of Internal Medicine I, University Hospital of the Ludwig Maximilians University, Munich, Germany (B.M.B., M.M.-N., S.K.)
| | - Keiko Shimamoto
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (K.S., W.S., T.A.)
| | - Ulla-Britt Diamant
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Department of Clinical Sciences, Unit of Paediatrics, Umeå University, Sweden (U.-B.D., A.R.)
| | - Yanushi D. Wijeyeratne
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Molecular and Clinical Sciences Research Institute, St George’s University of London and Cardiology Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, United Kingdom (Y.D.W., A.A., E.R.B.)
| | - Yu Kucho
- National Hospital Organization Kagoshima Medical Center, Japan (Y.K., M.Y.)
| | - Tomas Robyns
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Department of Cardiovascular Diseases, University Hospitals Leuven, Belgium (T.R.)
- Department of Cardiovascular Sciences, KU Leuven, Belgium (T.R.)
| | - Taisuke Ishikawa
- Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan (T.I.)
| | - Elena Arbelo
- Cardiovascular Institute, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d’Investigació August Pi i Sunyer (IDIBAPS), and Centro de Investigacion Biomedica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain (E.A.)
| | - Michael Christiansen
- Department of Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark (M.C.)
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark (M.C.)
- Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Denmark (M.C.)
| | - Annika Winbo
- Department of Physiology, The University of Auckland, New Zealand (A.W.)
| | - Reza Jabbari
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark (R.J., P.E.W., J.T.-H.)
| | - Steven A. Lubitz
- Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston (S.A.L., P.T.E.)
- Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (S.A.L., P.T.E.)
| | - Johannes Steinfurt
- Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty, Germany (J.S., K.E.O.)
| | - Boris Rudic
- Department of Medicine, University Medical Center Mannheim, and German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany (B.R., M.B.)
| | - Bart Loeys
- Department of Clinical Genetics, Antwerp University Hospital, Belgium (B.L.)
| | - M. Ben Shoemaker
- Department of Medicine (M.B.S., P.E.W., D.M.R.), Vanderbilt University Medical Center, Nashville, TN
| | - Peter E. Weeke
- The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark (R.J., P.E.W., J.T.-H.)
- Department of Medicine (M.B.S., P.E.W., D.M.R.), Vanderbilt University Medical Center, Nashville, TN
| | - Ryan Pfeiffer
- Masonic Medical Research Institute, Utica, NY (R.P.)
| | - Brianna Davies
- Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, Canada (B.D., A.D.K.)
| | - Antoine Andorin
- Molecular and Clinical Sciences Research Institute, St George’s University of London and Cardiology Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, United Kingdom (Y.D.W., A.A., E.R.B.)
- L’Institut du Thorax, CHU Nantes, Service de Cardiologie, France (A.A., J.-J.S., J.-B.G.)
| | - Nynke Hofman
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
| | - Federica Dagradi
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Center for Cardiac Arrhythmias of Genetic Origin (L.C., F.D., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy
| | - Matteo Pedrazzini
- Laboratory of Cardiovascular Genetics (L.C., M.P., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy
| | - David J. Tester
- Departments of Cardiovascular Medicine (Division of Heart Rhythm Services and the Windland Smith Rice Genetic Heart Rhythm Clinic), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (K.L.T., D.J.T., J.M.B., M.J.A.)
| | - J. Martijn Bos
- Departments of Cardiovascular Medicine (Division of Heart Rhythm Services and the Windland Smith Rice Genetic Heart Rhythm Clinic), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (K.L.T., D.J.T., J.M.B., M.J.A.)
| | - Georgia Sarquella-Brugada
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Arrhythmia, Inherited Heart Disease and Sudden Death Unit, Hospital Sant Joan de Déu, European Reference Center at the ERN GUARD-Heart Reference Network for Rare Cardiac Diseases, Barcelona, Spain (G.S.-B.)
- Medical Science Department, School of Medicine, University of Girona, Spain (G.S.-B.)
- Cardiovascular Program, Research Institute of Sant Joan de Déu (IRSJD), Barcelona, Spain (G.S.-B., O.C.)
| | - Óscar Campuzano
- Cardiovascular Program, Research Institute of Sant Joan de Déu (IRSJD), Barcelona, Spain (G.S.-B., O.C.)
- Center for Biomedical Diagnosis, Hospital Clinic de Barcelona, Universitat de Barcelona; Institut d’Investigació August Pi i Sunyer (IDIBAPS); Cardiovascular Genetics Center, University of Girona-IDIBGI; and Medical Science Department, School of Medicine, University of Girona, Spain (O.C., R.B.)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (O.C.)
| | - Pyotr G. Platonov
- Center for Integrative Electrocardiology (CIEL), Department of Cardiology, Clinical Sciences, Lund University, Sweden (P.G.P.)
| | - Birgit Stallmeyer
- Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Muenster, Germany (M.E., B.S., S.Z., E.S.-B.)
| | - Sven Zumhagen
- Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Muenster, Germany (M.E., B.S., S.Z., E.S.-B.)
| | - Eline A. Nannenberg
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, The Netherlands (E.A.N., J.P.v.T.)
| | - Jan H. Veldink
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, The Netherlands (J.H.V., L.H.v.d.B.)
| | - Leonard H. van den Berg
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, The Netherlands (J.H.V., L.H.v.d.B.)
| | - Ammar Al-Chalabi
- King’s College Hospital, Bessemer Road, London, United Kingdom (A.A.-C.)
- Department of Basic and Clinical Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience Institute, United Kingdom (A.A.-C., C.E.S.)
| | - Christopher E. Shaw
- Department of Basic and Clinical Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience Institute, United Kingdom (A.A.-C., C.E.S.)
- UK Dementia Research Institute, King’s College London, United Kingdom (C.E.S.)
| | - Pamela J. Shaw
- Center for Cardiac Arrhythmias of Genetic Origin (L.C., F.D., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy
- Laboratory of Cardiovascular Genetics (L.C., M.P., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy
- Sheffield Institute for Translational Neuroscience, University of Sheffield, United Kingdom (P.J.S.)
| | - Karen E. Morrison
- Faculty of Medicine, University of Southampton, University Hospital Southampton, United Kingdom (K.E.M.)
| | - Peter M. Andersen
- Department of Neurology, Ulm University, Germany (P.M.A.)
- Department of Pharmacology and Clinical Neuroscience, Umeå University, Sweden (P.M.A.)
| | - Martina Müller-Nurasyid
- Department of Internal Medicine I, University Hospital of the Ludwig Maximilians University, Munich, Germany (B.M.B., M.M.-N., S.K.)
- Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany (M.M.-N.)
- Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany (M.M.-N.)
| | - Daniele Cusi
- Department of Health Sciences, University of Milan, Italy (D.C., C.B.)
- Bio4Dreams - Business Nursery for Life Sciences, Milan, Italy (D.C., C.B.)
| | - Cristina Barlassina
- Department of Health Sciences, University of Milan, Italy (D.C., C.B.)
- Bio4Dreams - Business Nursery for Life Sciences, Milan, Italy (D.C., C.B.)
| | - Pilar Galan
- Equipe de Recherche en Epidémiologie Nutritionnelle, Centre d’Epidémiologie et Statistiques Paris Cité, Université Paris 13, Inserm (U1153), Inra (U1125), COMUE Sorbonne-Paris-Cité, Bobigny, France (P.G.)
| | - Mark Lathrop
- McGill University and Génome Québec Innovation Centre, Montréal, Canada (M.L., M.M.)
| | - Markus Munter
- McGill University and Génome Québec Innovation Centre, Montréal, Canada (M.L., M.M.)
| | - Thomas Werge
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark (T.W.)
- Institute of Biological Psychiatry, Mental Health Centre Sct Hans, Copenhagen University Hospital, Roskilde, Denmark (T.W.)
- Department of Clinical Medicine, University of Copenhagen, Denmark (T.W.)
| | - Marta Ribasés
- Psychiatric Genetics Unit, Institute Vall d’Hebron Research (VHIR), Universitat Autònoma de Barcelona, Spain (M.R.)
| | - Tin Aung
- Singapore Eye Research Institute (T.A.)
| | | | | | - Peter Lichtner
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (P.L., T.M.)
| | - Thomas Meitinger
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (P.L., T.M.)
| | - J. Peter van Tintelen
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, The Netherlands (E.A.N., J.P.v.T.)
- Department of Clinical Genetics, University Medical Centre Groningen, The Netherlands (J.P.v.T., Y.H.)
- Department of Clinical Genetics, University Medical Centre Utrecht, University of Utrecht, The Netherlands (J.P.v.T.)
| | - Yvonne Hoedemaekers
- Department of Clinical Genetics, University Medical Centre Groningen, The Netherlands (J.P.v.T., Y.H.)
| | - Isabelle Denjoy
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- AP-HP, Hôpital Bichat, Département de Cardiologie et Centre de Référence des Maladies Cardiaques Héréditaires, F-75018 Paris, France, Université de Paris INSERM U1166, F-75013 France (I.D., A.L.)
| | - Antoine Leenhardt
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- AP-HP, Hôpital Bichat, Département de Cardiologie et Centre de Référence des Maladies Cardiaques Héréditaires, F-75018 Paris, France, Université de Paris INSERM U1166, F-75013 France (I.D., A.L.)
| | - Carlo Napolitano
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Molecular Cardiology, ICS Maugeri, IRCCS and Department of Molecular Medicine, University of Pavia, Italy (A.M., C.N., S.G.P.)
| | - Wataru Shimizu
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (K.S., W.S., T.A.)
- Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan (W.S., V.P.)
| | - Jean-Jacques Schott
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- L’Institut du Thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., V.P.)
- L’Institut du Thorax, CHU Nantes, Service de Cardiologie, France (A.A., J.-J.S., J.-B.G.)
| | - Jean-Baptiste Gourraud
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- L’Institut du Thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., V.P.)
- L’Institut du Thorax, CHU Nantes, Service de Cardiologie, France (A.A., J.-J.S., J.-B.G.)
| | - Takeru Makiyama
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan (T.M.)
| | - Seiko Ohno
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan (K.H., S.O., H.I., M.H.)
- Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan (S.O., H.I., M.H.)
- Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan (S.O.)
| | - Hideki Itoh
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan (K.H., S.O., H.I., M.H.)
- Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan (S.O., H.I., M.H.)
| | - Andrew D. Krahn
- Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, Canada (B.D., A.D.K.)
| | - Charles Antzelevitch
- Lankenau Institute for Medical Research and Lankenau Heart Institute, Wynnewood, PA (C.A.)
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA (C.A.)
| | - Dan M. Roden
- Department of Biomedical Informatics (D.M.R.), Vanderbilt University Medical Center, Nashville, TN
- Department of Medicine (M.B.S., P.E.W., D.M.R.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, TN
| | - Johan Saenen
- Department of Cardiology, Antwerp University Hospital, Belgium (J.S.)
| | - Martin Borggrefe
- Department of Medicine, University Medical Center Mannheim, and German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany (B.R., M.B.)
| | - Katja E. Odening
- Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty, Germany (J.S., K.E.O.)
| | - Patrick T. Ellinor
- Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston (S.A.L., P.T.E.)
- Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (S.A.L., P.T.E.)
| | - Jacob Tfelt-Hansen
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark (R.J., P.E.W., J.T.-H.)
- Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Denmark (J.T.-H.)
| | - Jonathan R. Skinner
- Cardiac Inherited Disease Group, Starship Children’s Hospital, Auckland, New Zealand (J.R.S.)
| | - Maarten P. van den Berg
- Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (M.P.v.d.B.)
| | - Morten Salling Olesen
- Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet (Copenhagen University Hospital), Denmark (M.S.O.)
- Department of Biomedical Sciences, University of Copenhagen, Denmark (M.S.O.)
| | - Josep Brugada
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Arrhythmia Unit, Hospital Sant Joan de Déu, Institut d’Investigació August Pi i Sunyer (IDIBAPS), Cardiovascular Institute, and Hospital Clinic de Barcelona, Universitat de Barcelona, Spain (J.B.)
| | - Ramón Brugada
- Center for Biomedical Diagnosis, Hospital Clinic de Barcelona, Universitat de Barcelona; Institut d’Investigació August Pi i Sunyer (IDIBAPS); Cardiovascular Genetics Center, University of Girona-IDIBGI; and Medical Science Department, School of Medicine, University of Girona, Spain (O.C., R.B.)
- Cardiovascular Genetics Center, University of Girona-IDIBGI, and Medical Science Department, School of Medicine, University of Girona, Spain (R.B.)
- Cardiology Service, Hospital Josep Trueta, Girona, Spain (R.B.)
| | - Naomasa Makita
- National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (N.M.)
| | - Jeroen Breckpot
- Centre for Human Genetics, University Hospitals Leuven, Belgium (J.B.)
| | - Masao Yoshinaga
- National Hospital Organization Kagoshima Medical Center, Japan (Y.K., M.Y.)
| | - Elijah R. Behr
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Molecular and Clinical Sciences Research Institute, St George’s University of London and Cardiology Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, United Kingdom (Y.D.W., A.A., E.R.B.)
| | - Annika Rydberg
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Department of Clinical Sciences, Unit of Paediatrics, Umeå University, Sweden (U.-B.D., A.R.)
| | - Takeshi Aiba
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (K.S., W.S., T.A.)
| | - Stefan Kääb
- Department of Internal Medicine I, University Hospital of the Ludwig Maximilians University, Munich, Germany (B.M.B., M.M.-N., S.K.)
| | - Silvia G. Priori
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Molecular Cardiology, ICS Maugeri, IRCCS and Department of Molecular Medicine, University of Pavia, Italy (A.M., C.N., S.G.P.)
| | - Pascale Guicheney
- INSERM, Sorbonne University, UMRS 1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France (P.G.)
| | - Hanno L. Tan
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Netherlands Heart Institute, Utrecht (H.L.T.)
| | - Christopher Newton-Cheh
- Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston (C.N.-C.)
| | - Michael J. Ackerman
- Departments of Cardiovascular Medicine (Division of Heart Rhythm Services and the Windland Smith Rice Genetic Heart Rhythm Clinic), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (K.L.T., D.J.T., J.M.B., M.J.A.)
| | - Peter J. Schwartz
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
| | - Eric Schulze-Bahr
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Muenster, Germany (M.E., B.S., S.Z., E.S.-B.)
| | - Vincent Probst
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
- L’Institut du Thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., V.P.)
- Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan (W.S., V.P.)
| | - Minoru Horie
- Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan (K.H., S.O., H.I., M.H.)
- Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan (S.O., H.I., M.H.)
| | - Arthur A. Wilde
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
| | - Michael W.T. Tanck
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, The Netherlands (M.W.T.T.)
| | - Connie R. Bezzina
- Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)
- Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)
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Villar D, Frost S, Deloukas P, Tinker A. The contribution of non-coding regulatory elements to cardiovascular disease. Open Biol 2020; 10:200088. [PMID: 32603637 PMCID: PMC7574544 DOI: 10.1098/rsob.200088] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/08/2020] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular disease collectively accounts for a quarter of deaths worldwide. Genome-wide association studies across a range of cardiovascular traits and pathologies have highlighted the prevalence of common non-coding genetic variants within candidate loci. Here, we review genetic, epigenomic and molecular approaches to investigate the contribution of non-coding regulatory elements in cardiovascular biology. We then discuss recent insights on the emerging role of non-coding variation in predisposition to cardiovascular disease, with a focus on novel mechanistic examples from functional genomics studies. Lastly, we consider the clinical significance of these findings at present, and some of the current challenges facing the field.
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Affiliation(s)
- Diego Villar
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
| | - Stephanie Frost
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
| | - Panos Deloukas
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Andrew Tinker
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
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Roden DM. A current understanding of drug-induced QT prolongation and its implications for anticancer therapy. Cardiovasc Res 2020; 115:895-903. [PMID: 30689740 DOI: 10.1093/cvr/cvz013] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/18/2018] [Accepted: 01/16/2019] [Indexed: 01/08/2023] Open
Abstract
The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but reproducible effect on QT interval but in rare instances this is exaggerated and marked QT prolongation can provoke the polymorphic ventricular tachycardia 'torsades de pointes', which can cause syncope or sudden cardiac death. The generally accepted common mechanism whereby drugs prolong QT is block of a key repolarizing potassium current in heart, IKr, generated by expression of KCNH2, also known as HERG. Thus, evaluation of the potential that a new drug entity may cause torsades de pointes has relied on exposure of normal volunteers or patients to drug at usual and high concentrations, and on assessment of IKr block in vitro. More recent work, focusing on anticancer drugs with QT prolonging liability, is defining new pathways whereby drugs can prolong QT. Notably, the in vitro effects of some tyrosine kinase inhibitors to prolong cardiac action potentials (the cellular correlate of QT) can be rescued by intracellular phosphatidylinositol 3,4,5-trisphosphate, the downstream effector of phosphoinositide 3-kinase. This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward 'late' sodium current during the plateau of the action potential. The definition of non-IKr-dependent pathways to QT prolongation will be important for assessing risk, not only with anticancer therapies but also with other QT prolonging drugs and for generating a refined understanding how variable activity of intracellular signalling systems can modulate QT and associated arrhythmia risk.
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Affiliation(s)
- Dan M Roden
- Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Avenue, Room 1285B, Nashville, TN, USA.,Department of Pharmacology, Vanderbilt University Medical Center, 2215B Garland Avenue, Room 1285B, Nashville, TN, USA.,Department of Biomedical Informatics, Vanderbilt University Medical Center, 2215B Garland Avenue, Room 1285B, Nashville, TN, USA
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47
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Sharma N, Cortez D, Disori K, Imundo JR, Beck M. A Review of Long QT Syndrome: Everything a Hospitalist Should Know. Hosp Pediatr 2020; 10:369-375. [PMID: 32144177 DOI: 10.1542/hpeds.2019-0139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In this article, we will review various aspects of long QT syndrome (LQTS) necessary for hospitalists who care for children, adolescents, and young adults who have known LQTS and also review presenting features that should make one consider LQTS as a cause of hospitalization. Pediatric hospitalists care for patients who have suffered near-drowning, unexplained motor vehicular accidents, brief resolved unexpected events, sudden infant death syndrome, recurrent miscarriages, syncope, or seizures. These common conditions can be clinical clues in patients harboring 1 of 16 LQTS genetic mutations. LQTS is commonly caused by a channelopathy that can cause sudden cardiac death. Over the years, guidelines on management and recommendations for sports participation have evolved with our understanding of the disease and the burden of arrhythmias manifested in the pediatric age group. This review will include the genetic causes of LQTS, clinical features, and important historical information to obtain when these presentations are encountered. We will review medical and surgical treatments available to patients with LQTS and long-term care recommendations and prognosis for those diagnosed with LQTS.
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Affiliation(s)
| | - Daniel Cortez
- Division of Adult Electrophysiology, Department of Cardiology, Penn State Medical Center, Hershey, Pennsylvania; and.,Department of Cardiology, University of Lund, Lund, Sweden
| | - Kristin Disori
- Pediatric Hospital Medicine, Department of Pediatrics, Penn State Children's Hospital, Hershey, Pennsylvania
| | | | - Michael Beck
- Pediatric Hospital Medicine, Department of Pediatrics, Penn State Children's Hospital, Hershey, Pennsylvania;
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48
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Reynisson B, Tanghöj G, Naumburg E. QTc interval-dependent body posture in pediatrics. BMC Pediatr 2020; 20:107. [PMID: 32138709 PMCID: PMC7059365 DOI: 10.1186/s12887-020-1959-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 02/04/2020] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Syncope is a common and often benign disorder presenting at the pediatric emergency department. Long-QT syndrome may be presented with syncope, ventricular arrhythmias or sudden death and is vital to exclude as an underlying cause in children presented with syncope. Few studies have assessed QTc in relation to body posture in children. In this study, we assessed the QTc interval while laying down and during active standing in children with known long-QT syndrome compared to healthy controls. METHODS Children aged 1-18 years with long-QT syndrome (N = 17) matched to two healthy controls (N = 34) were included in this case-control study. The ECG standing was performed immediately after the ECG in the supine position. The QTc interval and QTc-difference by changing the body position were calculated. RESULTS All children with long-QT syndrome were treated with propranolol. QTc was prolonged among long-QT syndrome children while lying down and when standing up, compared to controls. A prolongation of QTc appeared when standing up for both cases and controls. There was no significant difference in QTc increase between the groups. A QTc over 440 ms was observed among four cases lying down and in eight cases while standing, but not in any of the controls. The standing test with a cut-off of 440 ms showed a sensitivity of 47% and a specificity of 100% for case-status in our study. CONCLUSION QTc measured on ECG when rapidly rising up is prolonged in both healthy and LQTS children. More importantly, it prolongs more in children with LQTS and increases in pathological levels.
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Affiliation(s)
- Björn Reynisson
- Institution of Clinical Science, Pediatrics, Umeå University, Umeå, Sweden
| | - Gustaf Tanghöj
- Institution of Clinical Science, Pediatrics, Umeå University, Umeå, Sweden
| | - Estelle Naumburg
- Institution of Clinical Science, Pediatrics, Umeå University, Umeå, Sweden.
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49
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Rowe MK, Roberts JD. The evolution of gene-guided management of inherited arrhythmia syndromes: Peering beyond monogenic paradigms towards comprehensive genomic risk scores. J Cardiovasc Electrophysiol 2020; 31:2998-3008. [PMID: 32107815 DOI: 10.1111/jce.14415] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/06/2020] [Accepted: 02/21/2020] [Indexed: 12/19/2022]
Abstract
Inherited arrhythmia syndromes have traditionally been viewed as monogenic forms of disease whose pathophysiology is driven by a single highly penetrant rare genetic variant. Although an accurate depiction of a proportion of genetic variants, the variable penetrance frequently noted in genotype positive families and the presence of sporadic genotype negative cases have long highlighted a more nuanced truth being operative. Coupled with our more recent recognition that many rare variants implicated in inherited arrhythmia syndromes possess unexpectedly high allele frequencies within the general population, these observations have contributed to the realization that a spectrum of pathogenicity exists among clinically relevant genetic variants. Notably, variable mutation pathogenicity and corresponding variable degrees of penetrance emphasize a limitation of contemporary guidelines, which attempt to dichotomize genetic variants as pathogenic or benign. Recognition of the existence of low and intermediate penetrant variants insufficient to be causative for disease in isolation has served to emphasize the importance of additional genetic, clinical, and environmental factors in the pathogenesis of rare inherited arrhythmia syndromes. Despite being rare, it has also become increasingly evident that common genetic variants play critical roles in both heritable channelopathies and cardiomyopathies and in aggregate may even be the primary drivers in certain instances, such as genotype negative Brugada syndrome. Our growing realization that the genetic substrates of inherited arrhythmia syndromes have intricacies that extend beyond traditionally perceived monogenic paradigms has highlighted a potential value of leveraging more comprehensive genomic risk scores for predicting disease development and arrhythmic risk.
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Affiliation(s)
- Matthew K Rowe
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
| | - Jason D Roberts
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
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50
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Lakušić N, Slivnjak V, Ciglenečki N, Cerovec D. TORSADES DE POINTES IN ELDERLY PATIENT WITH PAROXYSMAL ATRIAL FIBRILLATION TREATED BY SHORT-TERM PARENTERAL AMIODARONE THERAPY. Acta Clin Croat 2019; 58:751-756. [PMID: 32665746 PMCID: PMC7356489 DOI: 10.20471/acc.2019.58.04.23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 09/11/2017] [Indexed: 11/24/2022] Open
Abstract
One of the drugs that are widely used in the treatment of atrial fibrillation is amiodarone. Despite considerable prolongation of the corrected QT interval and a substantial degree of bradycardia, amiodarone exhibits a remarkably low frequency of pro-arrhythmic events and <1.0% incidence of torsades de pointes, mostly after long-term usage. We present a case of an 80-year-old female with paroxysmal atrial fibrillation accompanied by acute heart failure treated by short-term parenteral amiodarone therapy and development of torsades de pointes.
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