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Young WJ, van der Most PJ, Bartz TM, Bos MM, Biino G, Duong T, Foco L, Lominchar JT, Müller‐Nurasyid M, Nardone GG, Pecori A, Ramirez J, Repetto L, Schramm K, Shen X, van Duijvenboden S, van Heemst D, Weiss S, Yao J, Benjamins J, Alonso A, Spedicati B, Biggs ML, Brody JA, Dörr M, Fuchsberger C, Gögele M, Guo X, Ikram MA, Jukema JW, Kääb S, Kanters JK, Lifelines Cohort Study, Lin HJ, Linneberg A, Nauck M, Nolte IM, Pianigiani G, Santin A, Soliman EZ, Tesolin P, Vaccargiu S, Waldenberger M, van der Harst P, Verweij N, Arking DE, Concas MP, De Grandi A, Girotto G, Grarup N, Kavousi M, Mook‐Kanamori DO, Navarro P, Orini M, Padmanabhan S, Pattaro C, Peters A, Pirastu M, Pramstaller PP, Heckbert SR, Sinner M, Snieder H, Völker U, Wilson JF, Gauderman WJ, Lambiase PD, Sotoodehnia N, Tinker A, Warren HR, Noordam R, Munroe PB. Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants. J Am Heart Assoc 2024; 13:e034760. [PMID: 39206732 PMCID: PMC11646519 DOI: 10.1161/jaha.123.034760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. METHODS AND RESULTS We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10-8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6). CONCLUSIONS We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.
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Affiliation(s)
- William J. Young
- Clinical Pharmacology and Precision MedicineWilliam Harvey Research Institute, Queen Mary University of LondonUnited Kingdom
- Barts Heart CentreSt Bartholomew’s Hospital, Barts Health NHS TrustLondonUnited Kingdom
| | - Peter J. van der Most
- Department of EpidemiologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Traci M. Bartz
- Cardiovascular Health Research Unit, Department of Biostatistics and MedicineUniversity of WashingtonSeattleWAUSA
| | - Maxime M. Bos
- Department of EpidemiologyErasmus MC University Medical CenterRotterdamNetherlands
| | - Ginevra Biino
- Institute of Molecular Genetics, National Research Council of ItalyPaviaItaly
| | - ThuyVy Duong
- Department of Genetic MedicineMcKusick‐Nathans Institute, Johns Hopkins University School of MedicineBaltimoreMDUSA
| | - Luisa Foco
- Eurac ResearchInstitute for Biomedicine (Affiliated with the University of Lübeck)BolzanoItaly
| | - Jesus T. Lominchar
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenDenmark
| | - Martina Müller‐Nurasyid
- German Research Center for Environmental HealthInstitute of Genetic Epidemiology, Helmholtz Zentrum MünchenNeuherbergGermany
- IBE, Faculty of Medicine, LMU MunichMunichGermany
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg UniversityMainzGermany
| | | | - Alessandro Pecori
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”TriesteItaly
| | - Julia Ramirez
- Clinical Pharmacology and Precision MedicineWilliam Harvey Research Institute, Queen Mary University of LondonUnited Kingdom
- Aragon Institute of Engineering Research, University of ZaragozaSpain
- Centro de Investigación Biomédica en Red—Bioingeniería, Biomateriales y NanomedicinaZaragozaSpain
| | - Linda Repetto
- Centre for Global Health ResearchUsher Institute, University of EdinburghScotland
| | - Katharina Schramm
- German Research Center for Environmental HealthInstitute of Genetic Epidemiology, Helmholtz Zentrum MünchenNeuherbergGermany
- IBE, Faculty of Medicine, LMU MunichMunichGermany
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg UniversityMainzGermany
| | - Xia Shen
- Centre for Global Health ResearchUsher Institute, University of EdinburghScotland
- Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
- Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan UniversityGuangzhouChina
| | - Stefan van Duijvenboden
- Clinical Pharmacology and Precision MedicineWilliam Harvey Research Institute, Queen Mary University of LondonUnited Kingdom
- Institute of Cardiovascular Sciences, University of College LondonLondonUnited Kingdom
- Nuffield Department of Population HealthUniversity of OxfordUnited Kingdom
| | - Diana van Heemst
- Department of Internal Medicine, Section of Gerontology and GeriatricsLeiden University Medical CenterLeidenThe Netherlands
| | - Stefan Weiss
- DZHK (German Centre for Cardiovascular Research), partner site GreifswaldGreifswaldGermany
- Interfaculty Institute for Genetics and Functional Genomics; Department of Functional GenomicsUniversity Medicine GreifswaldGreifswaldGermany
| | - Jie Yao
- Department of PediatricsThe Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor‐UCLA Medical CenterTorranceCAUSA
| | - Jan‐Walter Benjamins
- Department of CardiologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Alvaro Alonso
- Department of EpidemiologyRollins School of Public Health, Emory UniversityAtlantaGAUSA
| | - Beatrice Spedicati
- Department of Medicine, Surgery and Health SciencesUniversity of TriesteItaly
| | - Mary L. Biggs
- Cardiovascular Health Research Unit, Department of MedicineUniversity of WashingtonSeattleWAUSA
- Department of BiostatisticsUniversity of WashingtonSeattleWAUSA
| | - Jennifer A. Brody
- Cardiovascular Health Research Unit, Department of MedicineUniversity of WashingtonSeattleWAUSA
| | - Marcus Dörr
- DZHK (German Centre for Cardiovascular Research), partner site GreifswaldGreifswaldGermany
- Department of Internal Medicine B—Cardiology, Pneumology, Infectious Diseases, Intensive Care MedicineUniversity Medicine GreifswaldGreifswaldGermany
| | - Christian Fuchsberger
- Eurac ResearchInstitute for Biomedicine (Affiliated with the University of Lübeck)BolzanoItaly
- Department of BiostatisticsUniversity of Michigan School of Public HealthAnn ArborMIUSA
- Center for Statistical GeneticsUniversity of Michigan School of Public HealthAnn ArborMIUSA
| | - Martin Gögele
- Eurac ResearchInstitute for Biomedicine (Affiliated with the University of Lübeck)BolzanoItaly
| | - Xiuqing Guo
- Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor‐UCLA Medical CenterTorranceCAUSA
- Department of PediatricsDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - M. Arfan Ikram
- Department of EpidemiologyErasmus MC University Medical CenterRotterdamNetherlands
| | - J. Wouter Jukema
- Department of CardiologyLeiden University Medical CenterLeidenThe Netherlands
- Netherlands Heart InstituteUtrechtThe Netherlands
| | - Stefan Kääb
- Department of CardiologyUniversity Hospital, LMU MunichMunichGermany
- DZHK (German Centre for Cardiovascular Research), partner site: Munich Heart AllianceMunichGermany
| | - Jørgen K. Kanters
- Laboratory of Experimental Cardiology, Department of Biomedical SciencesUniversity of CopenhagenDenmark
| | | | - Henry J. Lin
- Department of PediatricsThe Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor‐UCLA Medical CenterTorranceCAUSA
- Department of PediatricsDavid Geffen School of Medicine at UCLALos AngelesCAUSA
- Department of Pediatrics/Harbor‐UCLA Medical CenterTorranceCAUSA
| | - Allan Linneberg
- Center for Clinical Research and PreventionBispebjerg and Frederiksberg Hospital, The Capital RegionCopenhagenDenmark
- Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenDenmark
| | - Matthias Nauck
- DZHK (German Centre for Cardiovascular Research), partner site GreifswaldGreifswaldGermany
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine GreifswaldGreifswaldGermany
| | - Ilja M. Nolte
- Department of EpidemiologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Giulia Pianigiani
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”TriesteItaly
| | - Aurora Santin
- Department of Medicine, Surgery and Health SciencesUniversity of TriesteItaly
| | - Elsayed Z. Soliman
- Epidemiological Cardiology Research Center (EPICARE)Wake Forest School of MedicineWinston SalemUSA
| | - Paola Tesolin
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”TriesteItaly
| | - Simona Vaccargiu
- Institute for Genetic and Biomedical Research, National Research Council of ItalyCagliariItaly
| | - Melanie Waldenberger
- DZHK (German Centre for Cardiovascular Research), partner site: Munich Heart AllianceMunichGermany
- Research Unit Molecular EpidemiologyInstitute of Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental HealthNeuherbergGermany
| | - Pim van der Harst
- Department of CardiologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
- Department of Cardiology, Heart and Lung DivisionUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Niek Verweij
- Department of CardiologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Dan E. Arking
- Department of Genetic MedicineMcKusick‐Nathans Institute, Johns Hopkins University School of MedicineBaltimoreMDUSA
| | - Maria Pina Concas
- Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”TriesteItaly
| | - Alessandro De Grandi
- Eurac ResearchInstitute for Biomedicine (Affiliated with the University of Lübeck)BolzanoItaly
| | - Giorgia Girotto
- Department of Medicine, Surgery and Health SciencesUniversity of TriesteItaly
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenDenmark
| | - Maryam Kavousi
- Department of EpidemiologyErasmus MC University Medical CenterRotterdamNetherlands
| | - Dennis O. Mook‐Kanamori
- Department of Clinical EpidemiologyLeiden University Medical CenterLeidenThe Netherlands
- Department of Public Health and Primary CareLeiden University Medical CenterLeidenThe Netherlands
| | - Pau Navarro
- MRC Human Genetics UnitInstitute of Genetics and Cancer, University of EdinburghScotland
| | - Michele Orini
- Barts Heart CentreSt Bartholomew’s Hospital, Barts Health NHS TrustLondonUnited Kingdom
- Institute of Cardiovascular Sciences, University of College LondonLondonUnited Kingdom
| | | | - Cristian Pattaro
- Eurac ResearchInstitute for Biomedicine (Affiliated with the University of Lübeck)BolzanoItaly
| | - Annette Peters
- German Research Center for Environmental HealthInstitute of Genetic Epidemiology, Helmholtz Zentrum MünchenNeuherbergGermany
- IBE, Faculty of Medicine, LMU MunichMunichGermany
- DZHK (German Centre for Cardiovascular Research), partner site: Munich Heart AllianceMunichGermany
| | - Mario Pirastu
- Institute for Genetic and Biomedical Research, Sassari Unit, National Research Council of ItalySassariItaly
| | - Peter P. Pramstaller
- Eurac ResearchInstitute for Biomedicine (Affiliated with the University of Lübeck)BolzanoItaly
- Department of NeurologyUniversity of LübeckGermany
| | - Susan R. Heckbert
- Cardiovascular Health Research Unit, Department of MedicineUniversity of WashingtonSeattleWAUSA
- Department of EpidemiologyUniversity of WashingtonSeattleWAUSA
| | - Mortiz Sinner
- Department of CardiologyUniversity Hospital, LMU MunichMunichGermany
- DZHK (German Centre for Cardiovascular Research), partner site: Munich Heart AllianceMunichGermany
| | - Harold Snieder
- Department of EpidemiologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Uwe Völker
- DZHK (German Centre for Cardiovascular Research), partner site GreifswaldGreifswaldGermany
- Interfaculty Institute for Genetics and Functional Genomics; Department of Functional GenomicsUniversity Medicine GreifswaldGreifswaldGermany
| | - James F. Wilson
- Centre for Global Health ResearchUsher Institute, University of EdinburghScotland
- MRC Human Genetics UnitInstitute of Genetics and Cancer, University of EdinburghScotland
| | - W. James Gauderman
- Department of population and public health sciencesUniversity of Southern CaliforniaLos AngelesCAUSA
| | - Pier D. Lambiase
- Barts Heart CentreSt Bartholomew’s Hospital, Barts Health NHS TrustLondonUnited Kingdom
- Institute of Cardiovascular Sciences, University of College LondonLondonUnited Kingdom
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, Department of MedicineUniversity of WashingtonSeattleWAUSA
| | - Andrew Tinker
- Clinical Pharmacology and Precision MedicineWilliam Harvey Research Institute, Queen Mary University of LondonUnited Kingdom
- NIHR Barts Biomedical Research CentreBarts and The London Faculty of Medicine and Dentistry, Queen Mary University of LondonUnited Kingdom
| | - Helen R. Warren
- Clinical Pharmacology and Precision MedicineWilliam Harvey Research Institute, Queen Mary University of LondonUnited Kingdom
- NIHR Barts Biomedical Research CentreBarts and The London Faculty of Medicine and Dentistry, Queen Mary University of LondonUnited Kingdom
| | - Raymond Noordam
- Department of Internal Medicine, Section of Gerontology and GeriatricsLeiden University Medical CenterLeidenThe Netherlands
| | - Patricia B. Munroe
- Clinical Pharmacology and Precision MedicineWilliam Harvey Research Institute, Queen Mary University of LondonUnited Kingdom
- NIHR Barts Biomedical Research CentreBarts and The London Faculty of Medicine and Dentistry, Queen Mary University of LondonUnited Kingdom
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Trayanova NA, Lyon A, Shade J, Heijman J. Computational modeling of cardiac electrophysiology and arrhythmogenesis: toward clinical translation. Physiol Rev 2024; 104:1265-1333. [PMID: 38153307 PMCID: PMC11381036 DOI: 10.1152/physrev.00017.2023] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 12/19/2023] [Accepted: 12/21/2023] [Indexed: 12/29/2023] Open
Abstract
The complexity of cardiac electrophysiology, involving dynamic changes in numerous components across multiple spatial (from ion channel to organ) and temporal (from milliseconds to days) scales, makes an intuitive or empirical analysis of cardiac arrhythmogenesis challenging. Multiscale mechanistic computational models of cardiac electrophysiology provide precise control over individual parameters, and their reproducibility enables a thorough assessment of arrhythmia mechanisms. This review provides a comprehensive analysis of models of cardiac electrophysiology and arrhythmias, from the single cell to the organ level, and how they can be leveraged to better understand rhythm disorders in cardiac disease and to improve heart patient care. Key issues related to model development based on experimental data are discussed, and major families of human cardiomyocyte models and their applications are highlighted. An overview of organ-level computational modeling of cardiac electrophysiology and its clinical applications in personalized arrhythmia risk assessment and patient-specific therapy of atrial and ventricular arrhythmias is provided. The advancements presented here highlight how patient-specific computational models of the heart reconstructed from patient data have achieved success in predicting risk of sudden cardiac death and guiding optimal treatments of heart rhythm disorders. Finally, an outlook toward potential future advances, including the combination of mechanistic modeling and machine learning/artificial intelligence, is provided. As the field of cardiology is embarking on a journey toward precision medicine, personalized modeling of the heart is expected to become a key technology to guide pharmaceutical therapy, deployment of devices, and surgical interventions.
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Affiliation(s)
- Natalia A Trayanova
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States
- Alliance for Cardiovascular Diagnostic and Treatment Innovation, Johns Hopkins University, Baltimore, Maryland, United States
| | - Aurore Lyon
- Department of Biomedical Engineering, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
- Division of Heart and Lungs, Department of Medical Physiology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Julie Shade
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States
- Alliance for Cardiovascular Diagnostic and Treatment Innovation, Johns Hopkins University, Baltimore, Maryland, United States
| | - Jordi Heijman
- Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
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Himeno Y, Zhang Y, Enomoto S, Nomura H, Yamamoto N, Kiyokawa S, Ujihara M, Muangkram Y, Noma A, Amano A. Ionic Mechanisms of Propagated Repolarization in a One-Dimensional Strand of Human Ventricular Myocyte Model. Int J Mol Sci 2023; 24:15378. [PMID: 37895058 PMCID: PMC10607672 DOI: 10.3390/ijms242015378] [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: 09/30/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Although repolarization has been suggested to propagate in cardiac tissue both theoretically and experimentally, it has been challenging to estimate how and to what extent the propagation of repolarization contributes to relaxation because repolarization only occurs in the course of membrane excitation in normal hearts. We established a mathematical model of a 1D strand of 600 myocytes stabilized at an equilibrium potential near the plateau potential level by introducing a sustained component of the late sodium current (INaL). By applying a hyperpolarizing stimulus to a small part of the strand, we succeeded in inducing repolarization which propagated along the strand at a velocity of 1~2 cm/s. The ionic mechanisms responsible for repolarization at the myocyte level, i.e., the deactivation of both the INaL and the L-type calcium current (ICaL), and the activation of the rapid component of delayed rectifier potassium current (IKr) and the inward rectifier potassium channel (IK1), were found to be important for the propagation of repolarization in the myocyte strand. Using an analogy with progressive activation of the sodium current (INa) in the propagation of excitation, regenerative activation of the predominant magnitude of IK1 makes the myocytes at the wave front start repolarization in succession through the electrical coupling via gap junction channels.
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Affiliation(s)
- Yukiko Himeno
- Department of Bioinformatics, College of Life Sciences, Ritsumeikan University, Shiga 525-8577, Japan; (Y.Z.); (A.N.); (A.A.)
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Electro-anatomical computational cardiology in humans and experimental animal models. TRANSLATIONAL RESEARCH IN ANATOMY 2022. [DOI: 10.1016/j.tria.2022.100162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Tang JKK, Rabkin SW. Hypocalcemia-Induced QT Interval Prolongation. Cardiology 2022; 147:191-195. [PMID: 35078204 DOI: 10.1159/000515985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 03/10/2021] [Indexed: 11/19/2022]
Abstract
An 87-year-old man with a history of transcatheter aortic valve replacement, pulmonary hypertension, diastolic dysfunction with preserved systolic function, and myelofibrosis had a 12-lead ECG showed a prolonged QT interval of 508 ms with heart-rate correction placing it in the 99th percentile of the population. Reduction in the dose of furosemide and calcium supplementation increased serum calcium and shortened the QT interval. This case provides an opportunity to examine newer concepts for the understanding of the mechanisms by which hypocalcemia might induce QT prolongation. Hypocalcemia likely produces corrected QT interval prolongation primarily through a calcium-dependent inactivation (CDI) mechanism on the L-type calcium channel (LTCC). Lower extracellular calcium leads to a decreased ICaL, subsequently causing intracellular calcium to take longer to reach the critical threshold to induce CDI of the LTCC. The resulting prolonged repolarization of the ventricular myocyte can lead to early after-depolarizations and ensuing life-threatening ventricular arrhythmias. Genetic polymorphisms in Ca2+-binding protein calmodulin which can prolong QT, underscore the role for disturbances of intracellular myocardial calcium handling in arrhythmogenesis. Hypocalcemia is an under-recognized cause of QT prolongation and should be taken into careful consideration in patients presenting with incidental findings of a prolonged QT interval.
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Affiliation(s)
- Jacky K K Tang
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Simon W Rabkin
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
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Wang J, Xu Z, Lv K, Ye Y, Luo D, Wan L, Zhou F, Yu A, Wang S, Liu J, Gao L. The Predictive Value of Serum Calcium on Heart Rate Variability and Cardiac Function in Type 2 Diabetes Patients. Front Endocrinol (Lausanne) 2022; 13:864008. [PMID: 35498438 PMCID: PMC9047897 DOI: 10.3389/fendo.2022.864008] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 01/27/2022] [Accepted: 03/03/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Cardiovascular autonomic neuropathy (CAN) is common in patients with type 2 diabetes mellitus (T2DM), mainly presented as decreased heart rate variability (HRV) which often leads to cardiac death. However, HRV measurement is not convenient in most clinics. Therefore, identifying high-risk patients for CAN in diabetes with easier measurements is crucial for the early intervention and prevention of catastrophic consequences. METHODS In this cross-sectional study, 675 T2DM patients with normocalcemia were selected. Of these, they were divided into two groups: normal HRV group (n = 425, 100 ms≤ SDNN ≤180 ms) vs. declined HRV group (n = 250, SDNN <100 ms). All patients' clinical data were collected and the correlation of clinical variables with HRV were analyzed by correlation and logistic regression analysis. The area below the ROC curve was used to evaluate the predictive performance of serum calcium on HRV. RESULTS In this study, declines in HRV were present in 37.0% of T2DM patients. Significant differences in albumin-adjusted serum calcium levels (CaA) (8.86 ± 0.27 vs. 9.13 ± 0.39 mg/dl, p <0.001) and E/A (0.78 ± 0.22 vs. 0.83 ± 0.26, p = 0.029) were observed between declined HRV and normal HRV groups. Bivariate linear correlation analysis showed that CaA and E/A were positively correlated with HRV parameters including SDNN (p < 0.001), SDNN index (p < 0.001), and Triangle index (p < 0.05). The AUC in the ROC curve for the prediction of CaA on HRV was 0.730 (95% CI (0.750-0.815), p < 0.001). The cutoff value of CaA was 8.87 mg/dl (sensitivity 0.644, specificity 0.814). The T2DM patients with CaA <8.87 mg/dl had significantly lower HRV parameters (SDNN, SDNN index, rMSSD, and triangle index) than those with CaA ≥8.87 mg/dl (p < 0.01, respectively). Multivariate logistic regression analysis showed a significantly increased risk of declined HRV in subjects with CaA level <8.87 mg/dl [OR (95% CI), 0.049 (0.024-0.099), p < 0.001]. CONCLUSIONS Declined HRV is associated with a lower CaA level and worse cardiac function. The serum calcium level can be used for risk evaluation of declined HRV in T2DM patients even within the normocalcemic range.
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Affiliation(s)
- Junyi Wang
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zihui Xu
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
| | - Kang Lv
- Shenzhen University, College of Big Data and Internet, Shenzhen, China
| | - Yingchun Ye
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
| | - Deng Luo
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
| | - Li Wan
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fen Zhou
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ailin Yu
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shuo Wang
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jingcheng Liu
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ling Gao
- Department of Endocrinology & Metabolism, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Ling Gao,
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Nashawi M, Ahmed MS, Amin T, Abualfoul M, Chilton R. Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy. World J Cardiol 2021; 13:676-694. [PMID: 35070111 PMCID: PMC8716977 DOI: 10.4330/wjc.v13.i12.676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/02/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.
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Affiliation(s)
- Mouhamed Nashawi
- Department of Internal Medicine, Baylor Scott and White All Saints Medical Center, Fort Worth, TX 76132, United States.
| | - Mahmoud S Ahmed
- Division of Medicine-Cardiology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Toka Amin
- Division of Medicine-Cardiology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Mujahed Abualfoul
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Dallas, TX 75203, United States
| | - Robert Chilton
- Department of Internal Medicine, Methodist Dallas Medical Center, Dallas, TX 75203, United States
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Young WJ, Warren HR, Mook-Kanamori DO, Ramírez J, van Duijvenboden S, Orini M, Tinker A, van Heemst D, Lambiase PD, Jukema JW, Munroe PB, Noordam R. Genetically Determined Serum Calcium Levels and Markers of Ventricular Repolarization: A Mendelian Randomization Study in the UK Biobank. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2021; 14:e003231. [PMID: 33887147 PMCID: PMC8208093 DOI: 10.1161/circgen.120.003231] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 04/02/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND ECG markers of ventricular depolarization and repolarization are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian randomization (MR). METHODS Independent lead variants from a newly performed genome-wide association study for serum calcium in >300 000 European-ancestry participants from UK Biobank were used as instrumental variables. Two-sample MR analyses were performed to approximate the causal effect of serum calcium on QT, JT, and QRS intervals using an inverse-weighted method in 76 226 participants not contributing to the serum calcium genome-wide association study. Sensitivity analyses including MR-Egger, weighted-median estimator, and MR pleiotropy residual sum and outlier were performed to test for the presence of horizontal pleiotropy. RESULTS Two hundred five independent lead calcium-associated variants were used as instrumental variables for MR. A decrease of 0.1 mmol/L serum calcium was associated with longer QT (3.01 ms [95% CI, 2.03 to 3.99]) and JT (2.89 ms [1.91 to 3.87]) intervals. A weak association was observed for QRS duration (secondary analyses only). Results were concordant in all sensitivity analyses. CONCLUSIONS These analyses support a causal effect of serum calcium levels on ventricular repolarization, in a middle-aged population of European-ancestry where serum calcium concentrations are likely stable and chronic. Modulation of calcium concentration may, therefore, directly influence cardiovascular disease risk.
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Affiliation(s)
- William J. Young
- Clinical Pharmacology Department, William Harvey Research Institute (W.J.Y., H.R.W., J.R., S.v.D., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London
- Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS trust (W.J.Y., M.O., P.D.L.)
| | - Helen R. Warren
- Clinical Pharmacology Department, William Harvey Research Institute (W.J.Y., H.R.W., J.R., S.v.D., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London
- NIHR Barts Cardiovascular Biomedical Research Unit (H.R.W., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London
| | - Dennis O. Mook-Kanamori
- Department of Clinical Epidemiology (D.O.M.-K.), Leiden University Medical Center, the Netherlands
- Department of Public Health and Primary Care (D.O.M.-K.), Leiden University Medical Center, the Netherlands
| | - Julia Ramírez
- Clinical Pharmacology Department, William Harvey Research Institute (W.J.Y., H.R.W., J.R., S.v.D., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London
- Institute of Cardiovascular Sciences, University of College London, United Kingdom (J.R., S.v.D., M.O., P.D.L.)
| | - Stefan van Duijvenboden
- Clinical Pharmacology Department, William Harvey Research Institute (W.J.Y., H.R.W., J.R., S.v.D., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London
- Institute of Cardiovascular Sciences, University of College London, United Kingdom (J.R., S.v.D., M.O., P.D.L.)
| | - Michele Orini
- Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS trust (W.J.Y., M.O., P.D.L.)
- Institute of Cardiovascular Sciences, University of College London, United Kingdom (J.R., S.v.D., M.O., P.D.L.)
| | - Andrew Tinker
- Clinical Pharmacology Department, William Harvey Research Institute (W.J.Y., H.R.W., J.R., S.v.D., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London
- NIHR Barts Cardiovascular Biomedical Research Unit (H.R.W., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London
| | - Diana van Heemst
- Department of Internal Medicine (D.v.H., R.N.), Leiden University Medical Center, the Netherlands
| | - Pier D. Lambiase
- Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS trust (W.J.Y., M.O., P.D.L.)
- Institute of Cardiovascular Sciences, University of College London, United Kingdom (J.R., S.v.D., M.O., P.D.L.)
| | - J. Wouter Jukema
- Department of Cardiology (J.W.J.), Leiden University Medical Center, the Netherlands
- Netherlands Heart Institute, Utrecht, the Netherlands (J.W.J.)
| | - Patricia B. Munroe
- Clinical Pharmacology Department, William Harvey Research Institute (W.J.Y., H.R.W., J.R., S.v.D., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London
- NIHR Barts Cardiovascular Biomedical Research Unit (H.R.W., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London
| | - Raymond Noordam
- Department of Internal Medicine (D.v.H., R.N.), Leiden University Medical Center, the Netherlands
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Wang M, Yan S, Peng Y, Shi Y, Tsauo JY, Chen M. Serum calcium levels correlates with coronary artery disease outcomes. Open Med (Wars) 2020; 15:1128-1136. [PMID: 33336068 PMCID: PMC7718611 DOI: 10.1515/med-2020-0154] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 08/29/2020] [Accepted: 09/02/2020] [Indexed: 02/05/2023] Open
Abstract
Background Effect of serum calcium levels on prognosis of patients with coronary artery disease (CAD) is not well evaluated. We aimed to assess the associations of baseline serum calcium levels with both short-term and long-term outcomes in CAD patients. Methods This study included 3,109 consecutive patients with angiographically confirmed CAD. Patients were categorized into quartiles according to admission serum calcium. Multivariable regression analysis was used to determine the association of serum calcium with mortality. Results Compared to patients in the lowest quartile of serum calcium, patients in upper quartiles were presented with lower all-cause mortality (Hazard ratios [HRs] were -0.636 [95% CI: -0.424 to -0.954], -0.545 [95% CI: -0.351 to -0.846] and -0.641 [95% CI: -0.450 to -0.913] for three upper quartiles versus lowest quartile respectively), cardiovascular mortality (HRs 0.594 [0.368-0.961], 0.261 [0.124-0.551] and 0.407 [0.229-0.725]), and in-hospital mortality (Odd ratios [ORs] 0.391 [0.188-0.812], 0.231 [0.072-0.501] and 0.223 [0.093-0.534]). Consistent associations between serum calcium and long-term mortality were also obtained in subgroup analysis of ACS patients, stable CAD patients and discharged patients. Conclusions Serum calcium is inversely associated with CAD and can independently predict both in-hospital and long-term mortality among CAD patients.
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Affiliation(s)
- Mian Wang
- Department of Cardiology, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, 518057, China
- Shenzhen University School of Medicine, Shenzhen, 518060, China
| | - Shaodi Yan
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu, 610041, China
| | - Yong Peng
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu, 610041, China
| | - Yu Shi
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, 518057, Guangdong Province, China
- Department of Clinical Research and Epidemiology, Shenzhen Institute for Cardiovascular Disease, Shenzhen, 518057, Guangdong Province, China
| | - Jiay-Yu Tsauo
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu, 610041, China
| | - Mao Chen
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guoxue Street, Chengdu, 610041, China
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10
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Pilia N, Severi S, Raimann JG, Genovesi S, Dössel O, Kotanko P, Corsi C, Loewe A. Quantification and classification of potassium and calcium disorders with the electrocardiogram: What do clinical studies, modeling, and reconstruction tell us? APL Bioeng 2020; 4:041501. [PMID: 33062908 PMCID: PMC7532940 DOI: 10.1063/5.0018504] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/13/2020] [Indexed: 11/14/2022] Open
Abstract
Diseases caused by alterations of ionic concentrations are frequently observed challenges and play an important role in clinical practice. The clinically established method for the diagnosis of electrolyte concentration imbalance is blood tests. A rapid and non-invasive point-of-care method is yet needed. The electrocardiogram (ECG) could meet this need and becomes an established diagnostic tool allowing home monitoring of the electrolyte concentration also by wearable devices. In this review, we present the current state of potassium and calcium concentration monitoring using the ECG and summarize results from previous work. Selected clinical studies are presented, supporting or questioning the use of the ECG for the monitoring of electrolyte concentration imbalances. Differences in the findings from automatic monitoring studies are discussed, and current studies utilizing machine learning are presented demonstrating the potential of the deep learning approach. Furthermore, we demonstrate the potential of computational modeling approaches to gain insight into the mechanisms of relevant clinical findings and as a tool to obtain synthetic data for methodical improvements in monitoring approaches.
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Affiliation(s)
- N Pilia
- Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany
| | - S Severi
- Department of Electrical, Electronic, and Information Engineering "Guglielmo Marconi," University of Bologna, 47522 Cesena, Italy
| | - J G Raimann
- Renal Research Institute, New York, New York 10065, USA
| | - S Genovesi
- Department of Medicine and Surgery, University of Milan-Bicocca, 20100 Milan, Italy
| | - O Dössel
- Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany
| | | | - C Corsi
- Department of Electrical, Electronic, and Information Engineering "Guglielmo Marconi," University of Bologna, 47522 Cesena, Italy
| | - A Loewe
- Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany
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11
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Salvadori FA, Moreira EM, Dias MB, Duarte-Neto AN, Paiva EFD. Cardiac Arrest Due to Hypocalcemia. INTERNATIONAL JOURNAL OF CARDIOVASCULAR SCIENCES 2020. [DOI: 10.36660/ijcs.20200034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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12
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Joseph JJ, McIntyre CW, Kharche SR. Proarrhythmic Effects of Electrolyte Imbalance in Virtual Human Atrial and Ventricular Cardiomyocytes. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2020; 2020:2315-2318. [PMID: 33018471 DOI: 10.1109/embc44109.2020.9176060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Dialysis is prescribed to renal failure patients as a long-term chronic treatment. Whereas dialysis therapeutically normalizes serum electrolytes and removes small toxin molecules, it fails to alleviate fibroblast induced structural fibrosis, and unresponsive uremia. The simultaneous presence of altered electrolytes and fibrosis or uremia is thought to be pro-arrhythmogenic. This study explored potential arrhythmogenesis under pre-dialysis (high electrolyte levels) and post-dialysis (low physiological electrolyte levels) in the presence of fibrosis and uremia in human atrial and ventricular model cardiomyocytes.Two validated human cardiomyocyte models were used in this study that permitted simulation of cardiac atrial and ventricular detailed electrophysiology. Pathological conditions simulating active fibrosis and uremia were implemented in both models. Pre- and post-dialysis conditions were simulated using high and low electrolyte levels respectively. Arrythmogenesis was quantified by computing restitution curves that permitted identification of action potential duration and calcium transient alternans instabilities.In comparison to control conditions, fibrosis abbreviated action potential durations while uremia prolonged the same. Under pre-dialysis conditions, an elevation of serum electrolyte levels caused action potential durations to be abbreviated under both fibrosis and uremia. Alternans instability was observed in the ventricular cardiomyocyte model. Under post-dialysis conditions, lower levels of serum electrolytes promoted an abbreviated action potential duration under fibrosis but caused a large increase of the control and uremic action potential durations. Alternans instabilities were observed in the atrial cardiomyocyte model under post-dialysis conditions at physiological heart rates. The calcium transient restitution showed similar alternans instabilities.Co-existing conditions such as fibrosis and uremia in the presence of unphysiological electrolyte levels promote arrhythmogenesis and may require additional treatment to improve dialysis outcomes.Clinical Relevance. Knowledge of model response to clinically relevant conditions permits use of in silico modeling to better understand and dissect underlying arrhythmia mechanisms.
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Bartolucci C, Passini E, Hyttinen J, Paci M, Severi S. Simulation of the Effects of Extracellular Calcium Changes Leads to a Novel Computational Model of Human Ventricular Action Potential With a Revised Calcium Handling. Front Physiol 2020; 11:314. [PMID: 32351400 PMCID: PMC7174690 DOI: 10.3389/fphys.2020.00314] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 03/19/2020] [Indexed: 01/13/2023] Open
Abstract
The importance of electrolyte concentrations for cardiac function is well established. Electrolyte variations can lead to arrhythmias onset, due to their important role in the action potential (AP) genesis and in maintaining cell homeostasis. However, most of the human AP computer models available in literature were developed with constant electrolyte concentrations, and fail to simulate physiological changes induced by electrolyte variations. This is especially true for Ca2+, even in the O'Hara-Rudy model (ORd), one of the most widely used models in cardiac electrophysiology. Therefore, the present work develops a new human ventricular model (BPS2020), based on ORd, able to simulate the inverse dependence of AP duration (APD) on extracellular Ca2+ concentration ([Ca2+]o), and APD rate dependence at 4 mM extracellular K+. The main changes needed with respect to ORd are: (i) an increased sensitivity of L-type Ca2+ current inactivation to [Ca2+]o; (ii) a single compartment description of the sarcoplasmic reticulum; iii) the replacement of Ca2+ release. BPS2020 is able to simulate the physiological APD-[Ca2+]o relationship, while also retaining the well-reproduced properties of ORd (APD rate dependence, restitution, accommodation and current block effects). We also used BPS2020 to generate an experimentally-calibrated population of models to investigate: (i) the occurrence of repolarization abnormalities in response to hERG current block; (ii) the rate adaptation variability; (iii) the occurrence of alternans and delayed after-depolarizations at fast pacing. Our results indicate that we successfully developed an improved version of ORd, which can be used to investigate electrophysiological changes and pro-arrhythmic abnormalities induced by electrolyte variations and current block at multiple rates and at the population level.
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Affiliation(s)
- Chiara Bartolucci
- Computational Physiopathology Unit, Department of Electrical, Electronic and Information Engineering “Guglielmo Marconi”, University of Bologna, Cesena, Italy
| | - Elisa Passini
- Computational Physiopathology Unit, Department of Electrical, Electronic and Information Engineering “Guglielmo Marconi”, University of Bologna, Cesena, Italy
- Department of Computer Science, University of Oxford, Oxford, United Kingdom
| | - Jari Hyttinen
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Michelangelo Paci
- BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Stefano Severi
- Computational Physiopathology Unit, Department of Electrical, Electronic and Information Engineering “Guglielmo Marconi”, University of Bologna, Cesena, Italy
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14
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Noordam R, Young WJ, Salman R, Kanters JK, van den Berg ME, van Heemst D, Lin HJ, Barreto SM, Biggs ML, Biino G, Catamo E, Concas MP, Ding J, Evans DS, Foco L, Grarup N, Lyytikäinen LP, Mangino M, Mei H, van der Most PJ, Müller-Nurasyid M, Nelson CP, Qian Y, Repetto L, Said MA, Shah N, Schramm K, Vidigal PG, Weiss S, Yao J, Zilhao NR, Brody JA, Braund PS, Brumat M, Campana E, Christofidou P, Caulfield MJ, De Grandi A, Dominiczak AF, Doney ASF, Eiriksdottir G, Ellervik C, Giatti L, Gögele M, Graff C, Guo X, van der Harst P, Joshi PK, Kähönen M, Kestenbaum B, Lima-Costa MF, Linneberg A, Maan AC, Meitinger T, Padmanabhan S, Pattaro C, Peters A, Petersmann A, Sever P, Sinner MF, Shen X, Stanton A, Strauch K, Soliman EZ, Tarasov KV, Taylor KD, Thio CHL, Uitterlinden AG, Vaccargiu S, Waldenberger M, Robino A, Correa A, Cucca F, Cummings SR, Dörr M, Girotto G, Gudnason V, Hansen T, Heckbert SR, Juhl CR, Kääb S, Lehtimäki T, Liu Y, Lotufo PA, Palmer CNA, Pirastu M, Pramstaller PP, Ribeiro ALP, Rotter JI, Samani NJ, Snieder H, Spector TD, Stricker BH, Verweij N, Wilson JF, Wilson JG, Jukema JW, Tinker A, Newton-Cheh CH, Sotoodehnia N, et alNoordam R, Young WJ, Salman R, Kanters JK, van den Berg ME, van Heemst D, Lin HJ, Barreto SM, Biggs ML, Biino G, Catamo E, Concas MP, Ding J, Evans DS, Foco L, Grarup N, Lyytikäinen LP, Mangino M, Mei H, van der Most PJ, Müller-Nurasyid M, Nelson CP, Qian Y, Repetto L, Said MA, Shah N, Schramm K, Vidigal PG, Weiss S, Yao J, Zilhao NR, Brody JA, Braund PS, Brumat M, Campana E, Christofidou P, Caulfield MJ, De Grandi A, Dominiczak AF, Doney ASF, Eiriksdottir G, Ellervik C, Giatti L, Gögele M, Graff C, Guo X, van der Harst P, Joshi PK, Kähönen M, Kestenbaum B, Lima-Costa MF, Linneberg A, Maan AC, Meitinger T, Padmanabhan S, Pattaro C, Peters A, Petersmann A, Sever P, Sinner MF, Shen X, Stanton A, Strauch K, Soliman EZ, Tarasov KV, Taylor KD, Thio CHL, Uitterlinden AG, Vaccargiu S, Waldenberger M, Robino A, Correa A, Cucca F, Cummings SR, Dörr M, Girotto G, Gudnason V, Hansen T, Heckbert SR, Juhl CR, Kääb S, Lehtimäki T, Liu Y, Lotufo PA, Palmer CNA, Pirastu M, Pramstaller PP, Ribeiro ALP, Rotter JI, Samani NJ, Snieder H, Spector TD, Stricker BH, Verweij N, Wilson JF, Wilson JG, Jukema JW, Tinker A, Newton-Cheh CH, Sotoodehnia N, Mook-Kanamori DO, Munroe PB, Warren HR. Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals. J Am Coll Cardiol 2019; 73:3118-3131. [PMID: 31221261 DOI: 10.1016/j.jacc.2019.03.519] [Show More Authors] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 03/22/2019] [Accepted: 03/27/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.
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Affiliation(s)
- Raymond Noordam
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
| | - William J Young
- Barts Heart Centre, St. Bartholomew's Hospital, London, United Kingdom; Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Reem Salman
- Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Jørgen K Kanters
- Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marten E van den Berg
- Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Diana van Heemst
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
| | - Henry J Lin
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Sandhi Maria Barreto
- Faculty of Medicine and Clinical Hospital, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mary L Biggs
- Cardiovascular Health Research Unit, Department of Medicine, and Department of Biostatistics, University of Washington, Seattle, Washington
| | - Ginevra Biino
- Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy
| | - Eulalia Catamo
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Maria Pina Concas
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Jun Ding
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - Daniel S Evans
- California Pacific Medical Center Research Institute, San Francisco, California
| | - Luisa Foco
- Eurac Research, Institute for Biomedicine, affiliated to the University of Lübeck, Bolzano, Italy
| | - Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Massimo Mangino
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, United Kingdom
| | - Hao Mei
- Department of Data Science, University of Mississippi Medical Center, Jackson, Mississippi
| | - Peter J van der Most
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Martina Müller-Nurasyid
- Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Christopher P Nelson
- Cardiovascular Research Centre, Glenfield Hospital, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Yong Qian
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - Linda Repetto
- Centre for Global Health Reasearch, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
| | - M Abdullah Said
- Department of Cardiology and Thorax Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Nabi Shah
- Division of Molecular and Clinical Medicine, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom; Department of Pharmacy, COMSATS University Islamabad, Abbottabad, Pakistan
| | - Katharina Schramm
- Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany
| | - Pedro G Vidigal
- School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil
| | - Stefan Weiss
- Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany; German Centre for Cardiovascular Research, partner site Greifswald, Greifswald, Germany
| | - Jie Yao
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California
| | | | - Jennifer A Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
| | - Peter S Braund
- Cardiovascular Research Centre, Glenfield Hospital, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Marco Brumat
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Eric Campana
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Paraskevi Christofidou
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Mark J Caulfield
- Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, United Kingdom
| | - Alessandro De Grandi
- Eurac Research, Institute for Biomedicine, affiliated to the University of Lübeck, Bolzano, Italy
| | - Anna F Dominiczak
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Alex S F Doney
- Division of Molecular and Clinical Medicine, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
| | | | - Christina Ellervik
- Department of Production, Research and Innovation, Region Zealand, SorØ, Denmark; Harvard Medical School, Boston, Massachusetts; Department of Laboratory Medicine, Boston Children's Hospital, Boston, Massachusetts; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Luana Giatti
- Faculty of Medicine and Clinical Hospital, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Martin Gögele
- Eurac Research, Institute for Biomedicine, affiliated to the University of Lübeck, Bolzano, Italy
| | - Claus Graff
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Xiuqing Guo
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California
| | - Pim van der Harst
- Department of Cardiology and Thorax Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Peter K Joshi
- Centre for Global Health Reasearch, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Bryan Kestenbaum
- Kidney Research Institute, University of Washington, Seattle, Washington
| | - Maria F Lima-Costa
- Rene Rachou Reserch Institute, Oswaldo Cruz Foundation, Belo Horizonte, Brazil
| | - Allan Linneberg
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Arie C Maan
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Thomas Meitinger
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany
| | - Sandosh Padmanabhan
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Cristian Pattaro
- Eurac Research, Institute for Biomedicine, affiliated to the University of Lübeck, Bolzano, Italy
| | - Annette Peters
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Astrid Petersmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Peter Sever
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Mortiz F Sinner
- Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Xia Shen
- Centre for Global Health Reasearch, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Biostatistics Group, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Alice Stanton
- Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Konstantin Strauch
- Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute for Medical Information Processing, Biometry, and Epidemiology, Faculty of Medicine, Ludwig Maximilian University of Munich, Munich, Germany
| | - Elsayed Z Soliman
- Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina; Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina; Department of Internal Medicine, Cardiology Section, Wake Forest School of Medicine, Winston Salem, North Carolina
| | - Kirill V Tarasov
- Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California
| | - Chris H L Thio
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - André G Uitterlinden
- Human Genotyping Facility, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Simona Vaccargiu
- Institute of Genetic and Biomedical Research, National Research Council of Italy, UOS of Sassari, Sassari, Italy
| | - Melanie Waldenberger
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
| | - Antonietta Robino
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Adolfo Correa
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - Francesco Cucca
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Steven R Cummings
- California Pacific Medical Center Research Institute, San Francisco, California
| | - Marcus Dörr
- German Centre for Cardiovascular Research, partner site Greifswald, Greifswald, Germany; Department of Internal Medicine B - Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany
| | - Giorgia Girotto
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy; Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Vilmundur Gudnason
- Icelandic Heart Association, Kópavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Susan R Heckbert
- Cardiovascular Health Research Unit and the Department of Epidemiology, University of Washington, Seattle, Washington
| | - Christian R Juhl
- Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefan Kääb
- Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Yongmei Liu
- Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina
| | - Paulo A Lotufo
- Medical School and Center for Clinical and Epidemiologic Research, University of São Paulo, São Paulo, Brazil
| | - Colin N A Palmer
- Division of Molecular and Clinical Medicine, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom
| | - Mario Pirastu
- Institute of Genetic and Biomedical Research, National Research Council of Italy, UOS of Sassari, Sassari, Italy
| | - Peter P Pramstaller
- Eurac Research, Institute for Biomedicine, affiliated to the University of Lübeck, Bolzano, Italy; Department of Neurology, General Central Hospital, Bolzano, Italy; Department of Neurology, University of Lübeck, Lübeck, Germany
| | - Antonio Luiz P Ribeiro
- Hospital das Clínicas and School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Division of Genomic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California
| | - Nilesh J Samani
- Cardiovascular Research Centre, Glenfield Hospital, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
| | - Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Tim D Spector
- Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
| | - Bruno H Stricker
- Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Niek Verweij
- Department of Cardiology and Thorax Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - James F Wilson
- Centre for Global Health Reasearch, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - James G Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi
| | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Andrew Tinker
- Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, United Kingdom
| | - Christopher H Newton-Cheh
- Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nona Sotoodehnia
- Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington
| | - Dennis O Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
| | - Patricia B Munroe
- Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, United Kingdom.
| | - Helen R Warren
- Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, United Kingdom
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Mosebach CM, Kluger J. Probable Hypocalcemia Induced Ventricular Fibrillation and Torsades de Pointes following Blood Product Administration. Cureus 2018; 10:e3765. [PMID: 30820384 PMCID: PMC6389027 DOI: 10.7759/cureus.3765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
A 35-year-old male underwent open-heart surgery and required multiple blood product transfusions. Citrate, a preservative in blood products, caused serum ionized calcium chelation leading to hypocalcemia, a prolonged corrected QT (QTc) interval, and separate episodes of ventricular fibrillation and torsades de pointes (TdP). This case highlights an uncommon complication of blood product transfusion-induced hypocalcemia with precipitant arrhythmia.
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16
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Risk Evaluation of Azithromycin-Induced QT Prolongation in Real-World Practice. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1574806. [PMID: 30406128 PMCID: PMC6204160 DOI: 10.1155/2018/1574806] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 09/21/2018] [Accepted: 10/01/2018] [Indexed: 12/21/2022]
Abstract
Background Azithromycin exposure has been reported to increase the risk of QT prolongation and cardiovascular death. However, findings on the association between azithromycin and cardiovascular death are controversial, and azithromycin is still used in actual practice. Additionally, quantitative assessments of risk have not been performed, including the risk of QT prolongation when patients are exposed to azithromycin in a real-world clinical setting. Therefore, in this study, we aimed to evaluate the risk of exposure to azithromycin on QT prolongation in a real-world clinical setting using a 21-year medical history database of a tertiary medical institution. Methods We analyzed the electrocardiogram results and relevant electronic health records of 402,607 subjects in a tertiary teaching hospital in Korea from 1996 to 2015. To evaluate the risk of QT prolongation of azithromycin, we conducted a case-control analysis using amoxicillin for comparison. Multiple logistic regression analysis was performed to correct for age, sex, accompanying drugs, and disease. Results The odds ratio (OR) for QT prolongation (QTc>450 ms in male and >460 ms in female) on azithromycin exposure was 1.40 (95% confidence interval [CI], 1.23-1.59), and the OR for severe QT prolongation (QTc>500 ms) was 1.43 (95% CI, 1.13-1.82). On the other hand, the ORs on exposure to amoxicillin were 1.06 (95% CI, 0.97-1.15) and 0.88 (95% CI, 0.70-1.09). In a subgroup analysis, the risk of QT prolongation in patients aged between 60 and 80 years was significantly higher when they are exposed to azithromycin. Conclusions The risk of QT prolongation was increased when patients, particularly the elderly aged 60-79 years, were exposed to azithromycin. Therefore, clinicians should pay exercise caution using azithromycin or consider using other antibiotics, such as amoxicillin, instead of azithromycin.
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17
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Kharche SR, Vigmond E, Efimov IR, Dobrzynski H. Computational assessment of the functional role of sinoatrial node exit pathways in the human heart. PLoS One 2017; 12:e0183727. [PMID: 28873427 PMCID: PMC5584965 DOI: 10.1371/journal.pone.0183727] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 08/09/2017] [Indexed: 11/19/2022] Open
Abstract
AIM The human right atrium and sinoatrial node (SAN) anatomy is complex. Optical mapping experiments suggest that the SAN is functionally insulated from atrial tissue except at discrete SAN-atrial electrical junctions called SAN exit pathways, SEPs. Additionally, histological imaging suggests the presence of a secondary pacemaker close to the SAN. We hypothesise that a) an insulating border-SEP anatomical configuration is related to SAN arrhythmia; and b) a secondary pacemaker, the paranodal area, is an alternate pacemaker but accentuates tachycardia. A 3D electro-anatomical computational model was used to test these hypotheses. METHODS A detailed 3D human SAN electro-anatomical mathematical model was developed based on our previous anatomical reconstruction. Electrical activity was simulated using tissue specific variants of the Fenton-Karma action potential equations. Simulation experiments were designed to deploy this complex electro-anatomical system to assess the roles of border-SEPs and paranodal area by mimicking experimentally observed SAN arrhythmia. Robust and accurate numerical algorithms were implemented for solving the mono domain reaction-diffusion equation implicitly, calculating 3D filament traces, and computing dominant frequency among other quantitative measurements. RESULTS A centre to periphery gradient of increasing diffusion was sufficient to permit initiation of pacemaking at the centre of the 3D SAN. Re-entry within the SAN, micro re-entry, was possible by imposing significant SAN fibrosis in the presence of the insulating border. SEPs promoted the micro re-entry to generate more complex SAN-atrial tachycardia. Simulation of macro re-entry, i.e. re-entry around the SAN, was possible by inclusion of atrial fibrosis in the presence of the insulating border. The border shielded the SAN from atrial tachycardia. However, SAN micro-structure intercellular gap junctional coupling and the paranodal area contributed to prolonged atrial fibrillation. Finally, the micro-structure was found to be sufficient to explain shifts of leading pacemaker site location. CONCLUSIONS The simulations establish a relationship between anatomy and SAN electrical function. Microstructure, in the form of intercellular gap junction coupling, was found to regulate SAN function and arrhythmia.
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Affiliation(s)
- Sanjay R. Kharche
- Institute of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Edward Vigmond
- University of Bordeaux, IMB, UMR 5251, Talence, France
- IHU Liryc, Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université, Pessac- Bordeaux, France
| | - Igor R. Efimov
- Department of Biomedical Engineering, The George Washington University, Washington, DC, United States of America
| | - Halina Dobrzynski
- Institute of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
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18
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Kazama I. High-calcium exposure to frog heart: a simple model representing hypercalcemia-induced ECG abnormalities. J Vet Med Sci 2016; 79:71-75. [PMID: 27773880 PMCID: PMC5289240 DOI: 10.1292/jvms.16-0413] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
By simply adding a high concentration of calcium solution to the surface of the bullfrog heart, we reproduced electrocardiogram (ECG) abnormalities representing those observed in hypercalcemia, such as Osborn waves and shortening of the QT interval. The rise in extracellular calcium concentration may have activated the outward potassium currents during phase 3 of the action potential, and thus decreased its duration. In addition to the known decrease in the duration of phase 2, such changes in phase 3 were also likely to contribute to the shortening of the QT interval. The dual recordings of the action potential in cardiomyocytes and the ECG waves enabled us to demonstrate the mechanisms of ECG abnormalities induced by hypercalcemia.
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Affiliation(s)
- Itsuro Kazama
- Department of Physiology, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi 980-8575, Japan
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19
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Pueyo E, Orini M, Rodríguez JF, Taggart P. Interactive effect of beta-adrenergic stimulation and mechanical stretch on low-frequency oscillations of ventricular action potential duration in humans. J Mol Cell Cardiol 2016; 97:93-105. [DOI: 10.1016/j.yjmcc.2016.05.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 03/21/2016] [Accepted: 05/03/2016] [Indexed: 01/27/2023]
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20
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Himeno Y, Asakura K, Cha CY, Memida H, Powell T, Amano A, Noma A. A human ventricular myocyte model with a refined representation of excitation-contraction coupling. Biophys J 2016. [PMID: 26200878 DOI: 10.1016/j.bpj.2015.06.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Cardiac Ca(2+)-induced Ca(2+) release (CICR) occurs by a regenerative activation of ryanodine receptors (RyRs) within each Ca(2+)-releasing unit, triggered by the activation of L-type Ca(2+) channels (LCCs). CICR is then terminated, most probably by depletion of Ca(2+) in the junctional sarcoplasmic reticulum (SR). Hinch et al. previously developed a tightly coupled LCC-RyR mathematical model, known as the Hinch model, that enables simulations to deal with a variety of functional states of whole-cell populations of a Ca(2+)-releasing unit using a personal computer. In this study, we developed a membrane excitation-contraction model of the human ventricular myocyte, which we call the human ventricular cell (HuVEC) model. This model is a hybrid of the most recent HuVEC models and the Hinch model. We modified the Hinch model to reproduce the regenerative activation and termination of CICR. In particular, we removed the inactivated RyR state and separated the single step of RyR activation by LCCs into triggering and regenerative steps. More importantly, we included the experimental measurement of a transient rise in Ca(2+) concentrations ([Ca(2+)], 10-15 μM) during CICR in the vicinity of Ca(2+)-releasing sites, and thereby calculated the effects of the local Ca(2+) gradient on CICR as well as membrane excitation. This HuVEC model successfully reconstructed both membrane excitation and key properties of CICR. The time course of CICR evoked by an action potential was accounted for by autonomous changes in an instantaneous equilibrium open probability of couplons. This autonomous time course was driven by a core feedback loop including the pivotal local [Ca(2+)], influenced by a time-dependent decay in the SR Ca(2+) content during CICR.
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Affiliation(s)
- Yukiko Himeno
- Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan
| | - Keiichi Asakura
- Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan; Nippon Shinyaku Co., Ltd., Kyoto, Japan
| | - Chae Young Cha
- Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Hiraku Memida
- Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan
| | - Trevor Powell
- Department of Pharmacology, University of Oxford, Oxford, UK
| | - Akira Amano
- Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan
| | - Akinori Noma
- Biosimulation Research Center, College of Life Sciences, Ritsumeikan University, Shiga, Japan.
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Nagy N, Kormos A, Kohajda Z, Szebeni Á, Szepesi J, Pollesello P, Levijoki J, Acsai K, Virág L, Nánási PP, Papp JG, Varró A, Tóth A. Selective Na(+) /Ca(2+) exchanger inhibition prevents Ca(2+) overload-induced triggered arrhythmias. Br J Pharmacol 2015; 171:5665-81. [PMID: 25073832 DOI: 10.1111/bph.12867] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 07/03/2014] [Accepted: 07/25/2014] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND AND PURPOSE Augmented Na(+) /Ca(2+) exchanger (NCX) activity may play a crucial role in cardiac arrhythmogenesis; however, data regarding the anti-arrhythmic efficacy of NCX inhibition are debatable. Feasible explanations could be the unsatisfactory selectivity of NCX inhibitors and/or the dependence of the experimental model on the degree of Ca(2+) i overload. Hence, we used NCX inhibitors SEA0400 and the more selective ORM10103 to evaluate the efficacy of NCX inhibition against arrhythmogenic Ca(2+) i rise in conditions when [Ca(2+) ]i was augmented via activation of the late sodium current (INaL ) or inhibition of the Na(+) /K(+) pump. EXPERIMENTAL APPROACH Action potentials (APs) were recorded from canine papillary muscles and Purkinje fibres by microelectrodes. NCX current (INCX ) was determined in ventricular cardiomyocytes utilizing the whole-cell patch clamp technique. Ca(2+) i transients (CaTs) were monitored with a Ca(2+) -sensitive fluorescent dye, Fluo-4. KEY RESULTS Enhanced INaL increased the Ca(2+) load and AP duration (APD). SEA0400 and ORM10103 suppressed INCX and prevented/reversed the anemone toxin II (ATX-II)-induced [Ca(2+) ]i rise without influencing APD, CaT or cell shortening, or affecting the ATX-II-induced increased APD. ORM10103 significantly decreased the number of strophanthidin-induced spontaneous diastolic Ca(2+) release events; however, SEA0400 failed to restrict the veratridine-induced augmentation in Purkinje-ventricle APD dispersion. CONCLUSIONS AND IMPLICATIONS Selective NCX inhibition - presumably by blocking rev INCX (reverse mode NCX current) - is effective against arrhythmogenesis caused by [Na(+) ]i -induced [Ca(2+) ]i elevation, without influencing the AP waveform. Therefore, selective INCX inhibition, by significantly reducing the arrhythmogenic trigger activity caused by the perturbed Ca(2+) i handling, should be considered as a promising anti-arrhythmic therapeutic strategy.
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Affiliation(s)
- Norbert Nagy
- MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary
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Alpha-adrenoceptor antagonism by Crassostrea gigas oyster extract inhibits noradrenaline-induced vascular contraction in Wistar rats. JOURNAL OF INTEGRATIVE MEDICINE-JIM 2015; 13:194-200. [PMID: 26006032 DOI: 10.1016/s2095-4964(15)60167-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
OBJECTIVE Crassostrea gigas oyster extract has been reported to have antioxidant, antihypertensive and lipid-lowering properties that may be useful for treating cardiovascular diseases. This study aimed to evaluate the effect of C. gigas oyster extract on cardiovascular function in tissues from healthy rats. METHODS Single-cell microelectrode and isolated thoracic aortic organ bath studies were performed on tissues from 8-week-old healthy Wistar rats, using varying concentrations of C. gigas oyster extract. To elucidate a mechanism of action for the oyster's vasoactive properties, concentration response curves were carried out in the presence of a calcium channel inhibitior (verapamil), a nitric oxide synthase inhibitor (N(G)-nitro-L-arginine methyl ester), a potassium channel inhibitor (4-aminopyridine), in addition to the α-adrenoceptor inhibitor prazosin. RESULTS Oyster solution at 7 500 mg/mL inhibited noradrenaline-induced contraction in isolated aortic rings. Cardiac electrophysiology results showed that neither concentration of oyster solution was able to significantly reduce action potential duration at all phases of repolarisation in left ventricular papillary muscles from healthy animals. CONCLUSION When administered to healthy vascular tissue, C. gigas oyster extract inhibits contraction induced by noradrenaline. This effect is likely to be mediated through α-adrenoceptor inhibition, and to a lesser extent, calcium modulating activity.
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Human atrial cell models to analyse haemodialysis-related effects on cardiac electrophysiology: work in progress. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2014; 2014:291598. [PMID: 25587348 PMCID: PMC4284940 DOI: 10.1155/2014/291598] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 11/05/2014] [Accepted: 11/12/2014] [Indexed: 11/25/2022]
Abstract
During haemodialysis (HD) sessions, patients undergo alterations in the extracellular environment, mostly concerning plasma electrolyte concentrations, pH, and volume, together with a modification of sympathovagal balance. All these changes affect cardiac electrophysiology, possibly leading to an increased arrhythmic risk. Computational modeling may help to investigate the impact of HD-related changes on atrial electrophysiology. However, many different human atrial action potential (AP) models are currently available, all validated only with the standard electrolyte concentrations used in experiments. Therefore, they may respond in different ways to the same environmental changes. After an overview on how the computational approach has been used in the past to investigate the effect of HD therapy on cardiac electrophysiology, the aim of this work has been to assess the current state of the art in human atrial AP models, with respect to the HD context. All the published human atrial AP models have been considered and tested for electrolytes, volume changes, and different acetylcholine concentrations. Most of them proved to be reliable for single modifications, but all of them showed some drawbacks. Therefore, there is room for a new human atrial AP model, hopefully able to physiologically reproduce all the HD-related effects. At the moment, work is still in progress in this specific field.
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Differentiating Drug-Induced Multichannel Block on the Electrocardiogram: Randomized Study of Dofetilide, Quinidine, Ranolazine, and Verapamil. Clin Pharmacol Ther 2014; 96:549-58. [DOI: 10.1038/clpt.2014.155] [Citation(s) in RCA: 180] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 07/09/2014] [Indexed: 01/08/2023]
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25
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Beta-adrenergic stimulation reverses the I Kr-I Ks dominant pattern during cardiac action potential. Pflugers Arch 2014; 466:2067-76. [PMID: 24535581 DOI: 10.1007/s00424-014-1465-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 01/06/2014] [Accepted: 01/28/2014] [Indexed: 12/21/2022]
Abstract
β-Adrenergic stimulation differentially modulates different K(+) channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of I Ks, I Kr, and I K1 currents in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K(+) current to the total repolarization reserve. In this study, we used an innovative AP-clamp sequential dissection technique to directly record the dynamic I Ks, I Kr, and I K1 currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of I Ks, I Kr, and I K1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca(2+) homeostasis. We found that isoproterenol treatment significantly enhanced I Ks, moderately increased I K1, but slightly decreased I Kr in a dose-dependent manner. The dominance pattern of the K(+) currents was I Kr > I K1 > I Ks at the control condition, but reversed to I Kr < I K1 < I Ks following β-adrenergic stimulation. We systematically determined the changes in the relative contribution of I Ks, I Kr, and I K1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K(+) currents in a dose-dependent manner. This knowledge is important for designing antiarrhythmic drug strategies to treat hearts exposed to various sympathetic tones.
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Li X, Wang T, Han K, Zhuo X, Lu Q, Ma A. Bisoprolol reverses down-regulation of potassium channel proteins in ventricular tissues of rabbits with heart failure. J Biomed Res 2013; 25:274-9. [PMID: 23554701 PMCID: PMC3597065 DOI: 10.1016/s1674-8301(11)60037-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Revised: 04/28/2011] [Accepted: 05/14/2011] [Indexed: 11/24/2022] Open
Abstract
Remodeling of ion channels is an important mechanism of arrhythmia induced by heart failure (HF). We investigated the expression of potassium channel encoding genes in the ventricles of rabbit established by volume-overload operation followed with pressure-overload. The reversible effect of these changes with bisoprolol was also evaluated. The HF group exhibited left ventricular enlargement, systolic dysfunction, prolongation of corrected QT interval (QTc), and increased plasma brain natriuretic peptide levels in the HF rabbits. Several potassium channel subunit encoding genes were consistently down-regulated in the HF rabbits. After bisoprolol treatment, heart function was improved significantly and QTc was shortened. Additionally, the mRNA expression of potassium channel subunit genes could be partially reversed. The down-regulated expression of potassium channel subunits Kv4.3, Kv1.4, KvLQT1, minK and Kir 2.1 may contribute to the prolongation of action potential duration in the heart of rabbits induced by volume combined with pressure overload HF. Bisoprolol could partially reverse these down-regulations and improve heart function.
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Affiliation(s)
- Xi Li
- Department of Cardiovascular Medicine, the First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
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Nagy N, Acsai K, Kormos A, Sebők Z, Farkas AS, Jost N, Nánási PP, Papp JG, Varró A, Tóth A. [Ca2+]i-induced augmentation of the inward rectifier potassium current (IK1) in canine and human ventricular myocardium. Pflugers Arch 2013; 465:1621-35. [DOI: 10.1007/s00424-013-1309-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 06/07/2013] [Accepted: 06/07/2013] [Indexed: 11/30/2022]
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Paci M, Hyttinen J, Aalto-Setälä K, Severi S. Computational models of ventricular- and atrial-like human induced pluripotent stem cell derived cardiomyocytes. Ann Biomed Eng 2013; 41:2334-48. [PMID: 23722932 DOI: 10.1007/s10439-013-0833-3] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Accepted: 05/21/2013] [Indexed: 02/06/2023]
Abstract
The clear importance of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as an in-vitro model highlights the relevance of studying these cells and their function also in-silico. Moreover, the phenotypical differences between the hiPSC-CM and adult myocyte action potentials (APs) call for understanding of how hiPSC-CMs are maturing towards adult myocytes. Using recently published experimental data, we developed two computational models of the hiPSC-CM AP, distinguishing between the ventricular-like and atrial-like phenotypes, emerging during the differentiation process of hiPSC-CMs. Also, we used the computational approach to quantitatively assess the role of ionic mechanisms which are likely responsible for the not completely mature phenotype of hiPSC-CMs. Our models reproduce the typical hiPSC-CM ventricular-like and atrial-like spontaneous APs and the response to prototypical current blockers, namely tetrodotoxine, nifedipine, E4041 and 3R4S-Chromanol 293B. Moreover, simulations using our ventricular-like model suggest that the interplay of immature I Na, I f and I K1 currents has a fundamental role in the hiPSC-CM spontaneous beating whereas a negative shift in I CaL activation causes the observed long lasting AP. In conclusion, this work provides two novel tools useful in investigating the electrophysiological features of hiPSC-CMs, whose importance is growing fast as in-vitro models for pharmacological studies.
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Affiliation(s)
- Michelangelo Paci
- Biomedical Engineering Laboratory-DEI, University of Bologna, Via Venezia 52, 47521, Cesena, FC, Italy
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Paci M, Sartiani L, Del Lungo M, Jaconi M, Mugelli A, Cerbai E, Severi S. Mathematical modelling of the action potential of human embryonic stem cell derived cardiomyocytes. Biomed Eng Online 2012; 11:61. [PMID: 22929020 PMCID: PMC3477113 DOI: 10.1186/1475-925x-11-61] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Accepted: 06/27/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Human embryonic stem cell derived cardiomyocytes (hESC-CMs) hold high potential for basic and applied cardiovascular research. The development of a reliable simulation platform able to mimic the functional properties of hESC-CMs would be of considerable value to perform preliminary test complementing in vitro experimentations. METHODS We developed the first computational model of hESC-CM action potential by integrating our original electrophysiological recordings of transient-outward, funny, and sodium-calcium exchanger currents and data derived from literature on sodium, calcium and potassium currents in hESC-CMs. RESULTS The model is able to reproduce basal electrophysiological properties of hESC-CMs at 15 40 days of differentiation (Early stage). Moreover, the model reproduces the modifications occurring through the transition from Early to Late developmental stage (50-110, days of differentiation). After simulated blockade of ionic channels and pumps of the sarcoplasmic reticulum, Ca2+ transient amplitude was decreased by 12% and 33% in Early and Late stage, respectively, suggesting a growing contribution of a functional reticulum during maturation. Finally, as a proof of concept, we tested the effects induced by prototypical channel blockers, namely E4031 and nickel, and their qualitative reproduction by the model. CONCLUSIONS This study provides a novel modelling tool that may serve useful to investigate physiological properties of hESC-CMs.
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Affiliation(s)
- Michelangelo Paci
- Biomedical Engineering Laboratory - D.E.I.S. University of Bologna, Via Venezia 52, Cesena, 47521, Italy
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Noble D, Garny A, Noble PJ. How the Hodgkin-Huxley equations inspired the Cardiac Physiome Project. J Physiol 2012; 590:2613-28. [PMID: 22473779 DOI: 10.1113/jphysiol.2011.224238] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Early modelling of cardiac cells (1960-1980) was based on extensions of the Hodgkin-Huxley nerve axon equations with additional channels incorporated, but after 1980 it became clear that processes other than ion channel gating were also critical in generating electrical activity. This article reviews the development of models representing almost all cell types in the heart, many different species, and the software tools that have been created to facilitate the cardiac Physiome Project.
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Affiliation(s)
- Denis Noble
- Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford OX1 3PT, UK.
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Marangoni S, Di Resta C, Rocchetti M, Barile L, Rizzetto R, Summa A, Severi S, Sommariva E, Pappone C, Ferrari M, Benedetti S, Zaza A. A Brugada syndrome mutation (p.S216L) and its modulation by p.H558R polymorphism: standard and dynamic characterization. Cardiovasc Res 2011; 91:606-16. [PMID: 21705349 DOI: 10.1093/cvr/cvr142] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
AIMS The Na(+) channel mutation (p.S216L), previously associated with type 3 long-QT syndrome (LQT3) phenotype, and a common polymorphism (p.H558R) were detected in a patient with an intermittent Brugada syndrome (BS) ECG pattern. The study was aimed to assess the p.S216L electrical phenotype, its modulation by p.H558R, and to identify abnormalities compatible with a mixed BS-LQT3 phenotype. METHODS AND RESULTS The mutation was expressed alone (S216L channels), or in combination with the polymorphism (S216L-H558R channels), in a mammalian cell line (TSA201). Functional analysis included standard voltage clamp and dynamic clamp with endo- and epicardial action potential waveforms. Expression of S216L channels was associated with a 60% reduction in maximum Na(+) current (I(Na)) density, attributable to protein misfolding (rescued by mexiletine pretreatment) and moderate slowing of inactivation. I(Na) density partially recovered in S216L-H558R channels, but I(Na) inactivation and its recovery were further delayed. The persistent component of I(Na) (I(NaL)) was unchanged. Under dynamic clamp conditions, I(Na) decreased in S216L channels and displayed a 'resurgent' component during late repolarization. In S216L-H558R channels, I(Na) density partially recovered and did not display a resurgent component. I(Na) changes during dynamic clamp were interpreted by numerical modelling. CONCLUSION The BS pattern of p.S216L might result from a decrease in I(Na) density, which masked gating abnormalities that might otherwise result in a LQT phenotype. The p.H558R polymorphism decreased p.S216L expressivity, partly by lessening p.S216L effects and partly through the induction of further gating abnormalities suitable to blunt p.S216L effects during repolarization.
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Affiliation(s)
- Stefano Marangoni
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy
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Cooper J, Mirams GR, Niederer SA. High-throughput functional curation of cellular electrophysiology models. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2011; 107:11-20. [PMID: 21704062 DOI: 10.1016/j.pbiomolbio.2011.06.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Accepted: 06/06/2011] [Indexed: 10/18/2022]
Abstract
Effective reuse of a quantitative mathematical model requires not just access to curated versions of the model equations, but also an understanding of the functional capabilities of the model, and the advisable scope of its application. To enable this "functional curation" we have developed a simulation environment that provides high-throughput evaluation of a mathematical model's functional response to an arbitrary user-defined protocol, and optionally compares the results against experimental data. In this study we demonstrate the efficacy of this simulation environment on 31 cardiac electrophysiology cell models using two test cases. The S1-S2 response is evaluated to characterise the models' restitution curves, and their L-type calcium channel current-voltage curves are evaluated. The significant variation in the response of these models, even when the models represent the same species and temperature, demonstrates the importance of knowing the functional characteristics of a model prior to its reuse. We also discuss the wider implications for this approach, in improving the selection of models for reuse, enabling the identification of models that exhibit particular experimentally observed phenomena, and making the incremental development of models more robust.
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Affiliation(s)
- Jonathan Cooper
- Oxford University Computing Laboratory, University of Oxford, Wolfson Building, Parks Road, Oxford OX13QD, UK.
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Farkas AS, Nattel S. Minimizing Repolarization-Related Proarrhythmic Risk in Drug Development and Clinical Practice. Drugs 2010; 70:573-603. [DOI: 10.2165/11535230-000000000-00000] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Interplay of voltage and Ca-dependent inactivation of L-type Ca current. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2010; 103:44-50. [PMID: 20184915 DOI: 10.1016/j.pbiomolbio.2010.02.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2010] [Accepted: 02/16/2010] [Indexed: 11/22/2022]
Abstract
Inactivation of L-type Ca channels (LTCC) is regulated by both Ca and voltage-dependent processes (CDI and VDI). To differentiate VDI and CDI, several experimental and theoretical studies have considered the inactivation of Ba current through LTCC (I(Ba)) as a measure of VDI. However, there is evidence that Ba can weakly mimic Ca, such that I(Ba) inactivation is still a mixture of CDI and VDI. To avoid this complication, some have used the monovalent cation current through LTCC (I(NS)), which can be measured when divalent cation concentrations are very low. Notably, I(NS) inactivation rate does not depend on current amplitude, and hence may reflect purely VDI. However, based on analysis of existent and new data, and modeling, we find that I(NS) can inactivate more rapidly and completely than I(Ba), especially at physiological temperature. Thus VDI that occurs during I(Ba) (or I(Ca)) must differ intrinsically from VDI during I(NS). To account for this, we have extended a previously published LTCC mathematical model of VDI and CDI into an excitation-contraction coupling model, and assessed whether and how experimental I(Ba) inactivation results (traditionally used in VDI experiments and models) could be recapitulated by modifying CDI to account for Ba-dependent inactivation. Thus, the view of a slow and incomplete I(NS) inactivation should be revised, and I(NS) inactivation is a poor measure of VDI during I(Ca) or I(Ba). This complicates VDI analysis experimentally, but raises intriguing new questions about how the molecular mechanisms of VDI differ for divalent and monovalent currents through LTCCs.
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Severi S, Corsi C, Cerbai E. From in vivo plasma composition to in vitro cardiac electrophysiology and in silico virtual heart: the extracellular calcium enigma. PHILOSOPHICAL TRANSACTIONS. SERIES A, MATHEMATICAL, PHYSICAL, AND ENGINEERING SCIENCES 2009; 367:2203-2223. [PMID: 19414453 DOI: 10.1098/rsta.2009.0032] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
In spite of its potential impact on simulation results, the problem of setting the appropriate Ca(2+) concentration ([Ca(2+)](o)) in computational cardiac models has not yet been properly considered. Usually [Ca(2+)](o) values are derived from in vitro electrophysiology. Unfortunately, [Ca(2+)](o) in the experiments is set significantly far (1.8 or 2 mM) from the physiological [Ca(2+)] in blood (1.0-1.3 mM). We analysed the inconsistency of [Ca(2+)](o) among in vivo, in vitro and in silico studies and the dependence of cardiac action potential (AP) duration (APD) on [Ca(2+)](o). Laboratory measurements confirmed the difference between standard extracellular solutions and normal blood [Ca(2+)]. Experimental data on human atrial cardiomyocytes confirmed literature data, demonstrating an inverse relationship between APD and [Ca(2+)](o). Sensitivity analysis of APD on [Ca(2+)](o) for five of the most used cardiac cell models was performed. Most of the models responded with AP prolongation to increases in [Ca(2+)](o), i.e. opposite to the AP shortening observed in vitro and in vivo. Modifications to the Ten Tusscher-Panfilov model were implemented to demonstrate that qualitative consistency among in vivo, in vitro and in silico studies can be achieved. The Courtemanche atrial model was used to test the effect of changing [Ca(2+)](o) on quantitative predictions about the effect of K(+) current blockade. The present analysis suggests that (i) [Ca(2+)](o) in cardiac AP models should be changed from 1.8 to 2 mM to approximately 1.15 mM in order to reproduce in vivo conditions, (ii) the sensitivity to [Ca(2+)](o) of ventricular AP models should be improved in order to simulate real conditions, (iii) modifications to the formulation of Ca(2+)-dependent I(CaL) inactivation can make models more suitable to analyse AP when [Ca(2+)](o) is set to lower physiological values, and (iv) it could be misleading to use non-physiological high [Ca(2+)](o) when the quantitative analysis of in vivo pathophysiological mechanisms is the ultimate aim of simulation.
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Affiliation(s)
- Stefano Severi
- Biomedical Engineering Laboratory, DEIS, University of Bologna, Cesena 47023, Italy.
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