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Wiedenmann LC, Ehrlich JR, Goldenberg I. Postpartum QT Prolongation in a Long QT Syndrome Type 1 Patient. Ann Noninvasive Electrocardiol 2025; 30:e70079. [PMID: 40492454 DOI: 10.1111/anec.70079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 03/23/2025] [Accepted: 03/30/2025] [Indexed: 06/12/2025] Open
Abstract
BACKGROUND Female LQTS patients are at high risk for arrhythmogenic events during the postpartum period due to hormonal influence on cardiac repolarization. METHODS We observed an LQT1 patient with previous cardiac events during pregnancy and 3 weeks postpartum. We obtained ECG recordings and quantified sex hormone levels. RESULTS Peak pregnancy: QTc: 420 ± 7 ms, Estradiol: 24.18 ng/mL, Progesterone: 218 ng/mL. Seven days postpartum: QTc prolongation to 455 ± 5 ms. 22 days postpartum: QTc: 452 ± 5, Estradiol: 0.013 ng/mL, Progesterone: 0.25 ng/mL. CONCLUSIONS Estradiol and Progesterone decline rapidly after birth, correlating to QTc prolongation and elevated risk for arrhythmogenic events. Therefore, modification of pharmacological or device therapy may be considered.
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Affiliation(s)
| | | | - Ilan Goldenberg
- University of Rochester Medical Center, Rochester, New York, USA
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2
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Singh V, Wagner KT, Williams LG, Ryan JM, Keller KR, Mohnkern JD, Gardner RS, Dang LT, Ziobro JM, Wojcikiewicz RJH, Tucker NR, Auerbach DS. Knock-in Kcnh2 rabbit model of long QT syndrome type-2, epilepsy, and sudden death. J Transl Med 2025; 23:446. [PMID: 40234944 PMCID: PMC12001650 DOI: 10.1186/s12967-025-06382-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/13/2025] [Indexed: 04/17/2025] Open
Abstract
BACKGROUND Long QT Syndrome Type-2 (LQT2) is due to loss-of-function KCNH2 variants. KCNH2 encodes Kv11.1 that forms a delayed-rectifier potassium channel in the brain and heart. LQT2 is associated with arrhythmias, seizures, sudden cardiac death, and sudden unexpected death in epilepsy (SUDEP). The goal of the study is to develop a translational model that reproduces the neuro-cardiac electrical abnormalities and sudden death seen in people with LQT2. METHODS We generated the first knock-in rabbit model of LQT2 (Kcnh2(+/7bp-del)), due to a 7 base-pair (7bp) deletion in the pore domain of the endogenous rabbit Kcnh2 gene. RESULTS Mutant Kcnh2 is expressed in the heart and brain and constitutes 11% of total Kcnh2 in Kcnh2(+/7bp-del) rabbits. Total Kcnh2, WT Kcnh2, and WT Kv11.1 expression is lower in Kcnh2(+/7bp-del) vs. WT rabbits. Kcnh2(+/7bp-del) rabbits exhibit prolonged cardiac ventricular repolarization (QTc, JTec, JTpc). There is an increased prevalence of spontaneous epileptiform activity and clinical seizures in Kcnh2(+/7bp-del) (7 of 37 rabbits) vs. WT rabbits (1:68 rabbits, p < 0.003). 18.9% of Kcnh2(+/7bp-del) vs. 1.5% of WT rabbits died suddenly and spontaneously (p < 0.003). We recorded 2 spontaneous lethal events in Kcnh2(+/7bp-del) rabbits: (1) sudden cardiac death and (2) seizure-mediated sudden death due to generalized tonic-clonic seizures, post-ictal generalized EEG suppression, bradycardia, ECG-T-wave inversion, focal cardiac activity, and asystole/death. CONCLUSIONS We developed the first genetic rabbit model of LQT2 that reproduces the cardiac and epileptic phenotypes seen in people with LQT2. Kcnh2(+/7bp-del) rabbits provide a valuable tool for future mechanistic studies, development of neurotherapeutics, and cardiac-safety testing.
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Affiliation(s)
- Veronica Singh
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Kyle T Wagner
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Laura G Williams
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Justin M Ryan
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Katherine R Keller
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Jonathan D Mohnkern
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Robert S Gardner
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Louis T Dang
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Julie M Ziobro
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | | | - Nathan R Tucker
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - David S Auerbach
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
- Department of Medicine-Cardiology, SUNY Upstate Medical University, Syracuse, NY, USA.
- Department of Pharmacology, Department of Medicine - Cardiology, SUNY Upstate Medical University, 750 East Adams St, Syracuse, NY, 13210, USA.
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3
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Chan M, Pourrier M, Eldstrom J, Sahakyan H, Vardanyan V, Fedida D. Dual effects of mefenamic acid on the I Ks molecular complex. Br J Pharmacol 2025; 182:1075-1089. [PMID: 39520043 DOI: 10.1111/bph.17389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 09/26/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND AND PURPOSE Mutations in both KCNQ1 and KCNE1, which together form the cardiac IKs current, are associated with inherited conditions such as long and short QT syndromes. Mefenamic acid, a non-steroidal anti-inflammatory drug, is an IKs potentiator and may be utilised as an archetype to design therapeutically useful IKs agonists. However, here we show that mefenamic acid can also act as an IKs inhibitor, and our data reveal its dual effects on KCNQ1/KCNE1 channels. EXPERIMENTAL APPROACH Effects of mefenamic acid on wild type (WT) and mutant KCNQ1/KCNE1 channels expressed in tsA201 cells were studied using whole cell patch clamp. Molecular dynamics simulations were used to determine trajectory clustering. KEY RESULTS Mefenamic acid inhibits WT IKs at high concentrations while preserving some attributes of current potentiation. Inhibitory actions of mefenamic acid are unmasked at lower drug concentrations by KCNE1 and KCNQ1 mutations in the mefenamic acid binding pocket, at the extracellular end of KCNE1 and in the KCNQ1 S6 helix. Mefenamic acid does not inhibit KCNQ1 in the absence of KCNE1 but inhibits IKs current in a concentration-dependent manner in the mutant channels. Inhibition involves modulation of pore kinetics and/or voltage sensor domain-pore coupling in WT and in the KCNE1 E43C mutant. CONCLUSION AND IMPLICATIONS This work highlights the importance of structural motifs at the extracellular inter-subunit interface of KCNQ1 and KCNE1 channels, and their interactions, in determining the nature of drug effects on the IKs channel complex and has important implications for treating patients with specific long QT mutations.
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Affiliation(s)
- Magnus Chan
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Marc Pourrier
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jodene Eldstrom
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Harutyun Sahakyan
- Laboratory of Computational Modeling of Biological Processes, Institute of Molecular Biology, Yerevan, Armenia
- Currently at National Center for Biotechnology Information, National Library of Medicine, National Institutes for Health, Bethesda, Maryland, USA
| | - Vitya Vardanyan
- Molecular Neuroscience Group, Institute of Molecular Biology, Yerevan, Armenia
| | - David Fedida
- Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
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4
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Kanchan K, Mohamed A, Kumar P. Exceptional Seizure-Like Presentation of Torsades De Pointes. Cureus 2025; 17:e77403. [PMID: 39958001 PMCID: PMC11825220 DOI: 10.7759/cureus.77403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2025] [Indexed: 02/18/2025] Open
Abstract
We present a rare case of a 40-year-old male who experienced a seizure-like episode, later diagnosed as torsades de pointes (TDP), following an R-on-T phenomenon feature on ECG. This case underscores the importance of considering cardiac arrhythmias in the differential diagnosis of atypical seizure presentations. The patient underwent successful treatment with antiarrhythmics and coronary stenting for underlying coronary artery stenosis, emphasizing a comprehensive approach to managing such complex cases.
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Affiliation(s)
- Kanchan Kanchan
- Cardiology, University Hospitals Birmingham, Birmingham, GBR
| | - Ahmed Mohamed
- Cardiology, University Hospitals Birmingham, Birmingham, GBR
| | - Pawan Kumar
- General Internal Medicine, University Hospitals Birmingham, Birmingham, GBR
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5
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Singh V, Wagner KT, Williams LG, Ryan JM, Keller KR, Mohnkern JD, Gardner RS, Dang LT, Ziobro JM, Wojcikiewicz RJH, Tucker NR, Auerbach DS. Knock-in Kcnh2 Rabbit Model of Long QT Syndrome Type-2, Epilepsy, and Sudden Death. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.11.627988. [PMID: 39763998 PMCID: PMC11702556 DOI: 10.1101/2024.12.11.627988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2025]
Abstract
Background Long QT Syndrome Type-2 (LQT2) is due to loss-of-function KCNH2 variants. KCNH2 encodes K v 11.1 that forms a delayed-rectifier potassium channel in the brain and heart. LQT2 is associated with arrhythmias, seizures, sudden cardiac death, and sudden unexpected death in epilepsy (SUDEP). The goal of the study is to develop a translational model that reproduces the neuro-cardiac electrical abnormalities and sudden death seen in people with LQT2. Methods We generated the first knock-in rabbit model of LQT2 ( Kcnh2 (+/7bp-del) ), due to a 7 base-pair (7bp) deletion in the pore domain of the endogenous rabbit Kcnh2 gene. Results Mutant Kcnh2 is expressed in the heart and brain and constitutes 11% of total Kcnh2 in Kcnh2 (+/7bp-del) rabbits. Total Kcnh2 , WT Kcnh2 , and WT K v 11.1 expression is lower in Kcnh2 (+/7bp-del) vs. WT rabbits. Kcnh2 (+/7bp-del) rabbits exhibit prolonged cardiac ventricular repolarization (QT c , JT ec , JT pc ). There is an increased prevalence of spontaneous epileptiform activity and clinical seizures in Kcnh2 (+/7bp-del) (7 of 37 rabbits) vs. WT rabbits (1:68 rabbits, p <0.003). 18.9% of Kcnh2 (+/7bp-del) vs. 1.5% of WT rabbits died suddenly and spontaneously ( p <0.003). We recorded 2 spontaneous lethal events in Kcnh2 (+/7bp-del) rabbits: (1) sudden cardiac death and (2) seizure-mediated sudden death due to generalized tonic-clonic seizures, post-ictal generalized EEG suppression, bradycardia, ECG-T-wave inversion, focal cardiac activity, and asystole/death. Conclusions We developed the first genetic rabbit model of LQT2 that reproduces the cardiac and epileptic phenotypes seen in people with LQT2. Kcnh2 (+/7bp-del) rabbits provide a valuable tool for future mechanistic studies, development of neurotherapeutics, and cardiac-safety testing.
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Mun D, Kang JY, Park M, Yoo G, Kim H, Yun N, Mi Hwang Y, Joung B. Establishment of a human-induced pluripotent stem cell line from a long QT syndrome type 2 patient harboring a KCNH2 mutation. Stem Cell Res 2024; 81:103592. [PMID: 39454535 DOI: 10.1016/j.scr.2024.103592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 08/13/2024] [Accepted: 10/18/2024] [Indexed: 10/28/2024] Open
Abstract
Long QT syndrome type 2 (LQT2) is a heart disorder resulting from a loss-of-function mutation in theKCNH2gene that causes loss of Kv11.1 channel function, potentially resulting in syncope, arrhythmias, and sudden death. We derived induced pluripotent stem cell line from PBMC of LQT2 patient carrying a variant of pathogenic variant (c.157G > A; p.Gly53Ser). The generation of iPSC lines was achieved using the non-integrative Sendai virus-mediated iPSC reprogramming method. The iPSC cell line exhibit pluripotency, normal karyotype, stem cell morphology, and differentiation capability, resulting a reliable cell source to study the effects of KCNH2 mutation in disease-specific cell types.
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Affiliation(s)
- Dasom Mun
- Division of Cardiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Ji-Young Kang
- Division of Cardiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Malgeum Park
- Division of Cardiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Gyeongseo Yoo
- Division of Cardiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Hyoeun Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Nuri Yun
- GNTPharma Science and Technology Center for Health, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
| | - You Mi Hwang
- Department of Cardiology, St. Vincent's Hospital, The Catholic University of Korea, 93 Jungbu-daero, Paldal-gu, Suwon 16247, Republic of Korea; Catholic Research Institute for Intractable Cardiovascular Disease (CRID), College of Medicine, The Catholic University of Korea, 93 Jungbu-daero, Paldal-gu, Suwon 16247, Republic of Korea
| | - Boyoung Joung
- Division of Cardiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
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7
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Zhu W, Bian X, Lv J. From genes to clinical management: A comprehensive review of long QT syndrome pathogenesis and treatment. Heart Rhythm O2 2024; 5:573-586. [PMID: 39263612 PMCID: PMC11385408 DOI: 10.1016/j.hroo.2024.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2024] Open
Abstract
Background Long QT syndrome (LQTS) is a rare cardiac disorder characterized by prolonged ventricular repolarization and increased risk of ventricular arrhythmias. This review summarizes current knowledge of LQTS pathogenesis and treatment strategies. Objectives The purpose of this study was to provide an in-depth understanding of LQTS genetic and molecular mechanisms, discuss clinical presentation and diagnosis, evaluate treatment options, and highlight future research directions. Methods A systematic search of PubMed, Embase, and Cochrane Library databases was conducted to identify relevant studies published up to April 2024. Results LQTS involves mutations in ion channel-related genes encoding cardiac ion channels, regulatory proteins, and other associated factors, leading to altered cellular electrophysiology. Acquired causes can also contribute. Diagnosis relies on clinical history, electrocardiographic findings, and genetic testing. Treatment strategies include lifestyle modifications, β-blockers, potassium channel openers, device therapy, and surgical interventions. Conclusion Advances in understanding LQTS have improved diagnosis and personalized treatment approaches. Challenges remain in risk stratification and management of certain patient subgroups. Future research should focus on developing novel pharmacological agents, refining device technologies, and conducting large-scale clinical trials. Increased awareness and education are crucial for early detection and appropriate management of LQTS.
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Affiliation(s)
- Wenjing Zhu
- Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xueyan Bian
- Department of Pediatrics, Lixia District People's Hospital, Jinan, Shandong, China
| | - Jianli Lv
- Department of Pediatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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8
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Macias-Contreras M, Granados JP, Hernandez DS. ION Thallos-HTL: a fluorescent thallium indicator that enables cell-selective and localizable thallium flux assays. Org Biomol Chem 2024; 22:4748-4756. [PMID: 38804097 DOI: 10.1039/d4ob00535j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Ion channels are essential proteins for all organisms. Electrophysiology is a useful and commonly employed method to study ion channels, however there is a need for operationally simpler, cost-effective and higher throughput techniques to study ion channel functions in their native environments. Fluorescent ion indicators, such as Fluo-4 and Thallos, have been used for decades to study ion channel activity by measuring the flux of ions through channels of interest. In this work, we present ION Thallos-HTL, a thallium indicator that can be localized using HaloTag technology. This novel indicator enables specific labeling of cells and intracellular compartments in live cells and responds to changes in thallium concentration within these environments. We demonstrate the utility of ION Thallos-HTL by conducting a thallium flux assay using high-throughput instrumentation in a mixed cell population where some cells are expressing HaloTag and some are not.
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Orji R, Morgans A, Jahangir E, Markson F, Ilelaboye A, Tan A, Okwuosa TM. Androgen Deprivation Therapy/Androgen Receptor Signaling Inhibitor Treatments for Prostate Cancer: Pathophysiology and Review of Effects on Cardiovascular Disease. South Med J 2024; 117:245-253. [PMID: 38701845 DOI: 10.14423/smj.0000000000001687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Androgen deprivation therapy is the cornerstone of systemic management for prostate cancer but is associated with multiple adverse effects that must be considered during treatment. These effects occur because of the profound hypogonadism that is induced from lack of testosterone or due to the medications used in the treatment or in combination with androgen receptor signaling inhibitors. This article critically reviews the associations between androgen deprivation therapy, androgen receptor signaling inhibitors, and cardiovascular complications such as prolonged QT interval, atrial fibrillation, heart failure, atherosclerosis, coronary heart disease, venous thromboembolism, and peripheral arterial occlusive disease. These unfavorable outcomes reinforce the need for regular cardiovascular screening of patients undergoing androgen deprivation for the management of prostate cancer.
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Affiliation(s)
| | - Alicia Morgans
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Eiman Jahangir
- Division of Cardiovascular Medicine, Section of Cardio-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Favor Markson
- Department of Internal Medicine, Lincoln Medical Center, Bronx, New York
| | - Ayodeji Ilelaboye
- Department of Internal Medicine, Lagos University Teaching Hospital, Lagos, Nigeria
| | - Alan Tan
- Division of Hematology-Oncology, Rush University Medical Center, Chicago, Illinois
| | - Tochukwu M Okwuosa
- Division of Cardiovascular Medicine, Section of Cardio-Oncology, Rush University Medical Center, Chicago, Illinois
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10
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Ramírez-Piscina L, Sancho JM. Subconductance states in a semimicroscopic model for a tetrameric pore. Phys Rev E 2024; 109:044402. [PMID: 38755917 DOI: 10.1103/physreve.109.044402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/22/2024] [Indexed: 05/18/2024]
Abstract
A physical model for a structured tetrameric pore is studied. The pore is modeled as a device composed of four subunits, each one exhibiting two possible states (open and closed). The pore is located within a membrane that separates two reservoirs with ionic solutions. All variables of the model follow physical dynamical equations accounting for the internal structure of the pore, derived from a single energy functional and supplemented with thermal noises. An extensive study of the resulting ionic intensity is performed for different values of the control parameters, mainly membrane potential and reservoir ion concentrations. Two possible physical devices are studied: voltage-gated (including a voltage sensor in each subunit) and non-voltage-gated pores. The ionic flux through the pore exhibits several distinct dynamical configurations, in particular subconductance states, which indicate very different dynamical internal states of the subunits. Such subconductance states become much easier to observe in sensorless pores. These results are compared with available experimental data on tetrameric K channels and analytical predictions.
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Affiliation(s)
- L Ramírez-Piscina
- Departament de Física Aplicada, EPSEB, Universitat Politécnica de Catalunya, Avinguda Doctor Marañón, 44, E-08028 Barcelona, Spain
| | - J M Sancho
- Universitat de Barcelona, Departament de Física de la Matèria Condensada, Martí i Franqués, 1, E-08028 Barcelona, Spain
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Bjelic M, Goldenberg I, Younis A, Chen AY, Huang DT, Yoruk A, Aktas MK, Rosero S, Cutter K, McNitt S, Sotoodehnia N, Kudenchuk PJ, Rea TD, Arking DE, Zareba W, Ackerman MJ, Goldenberg I. Risk Prediction in Male Adolescents With Congenital Long QT Syndrome: Implications for Sex-Specific Risk Stratification in Potassium Channel-Mediated Long QT Syndrome. J Am Heart Assoc 2024; 13:e028902. [PMID: 38240206 PMCID: PMC11056131 DOI: 10.1161/jaha.122.028902] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 07/06/2023] [Indexed: 02/07/2024]
Abstract
BACKGROUND Sex-specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life-threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel-mediated LQTS. METHODS AND RESULTS The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and β-blocker therapy. Anderson-Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow-up. The genotype-phenotype risk prediction model identified low-, intermediate-, and high-risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low-risk group, high-risk male subjects experienced a pronounced 5.2-fold increased risk of recurrent CEs (P<0.001), whereas intermediate-risk patients had a 2.1-fold (P=0.004) increased risk . At age 20 years, the low-, intermediate-, and high-risk adolescent male patients had on average 0.3, 0.6, and 1.4 CEs per person, respectively. Corresponding 10-year adjusted probabilities for a first LTE were 2%, 6%, and 8%. CONCLUSIONS Personalized genotype-phenotype risk estimates can be used to guide sex-specific management in male adolescents with potassium channel-mediated LQTS.
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Affiliation(s)
- Milica Bjelic
- Clinical Cardiovascular Research Center, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
- Department of AnesthesiologySt. Elizabeth’s Medical Center Boston University School of MedicineBostonMAUSA
| | - Ido Goldenberg
- Clinical Cardiovascular Research Center, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
- Department of Medicine, Rochester Regional HealthRochesterNYUSA
| | - Arwa Younis
- Clinical Cardiovascular Research Center, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
- Department of Cardiovascular MedicineCleveland ClinicClevelandOHUSA
| | - Anita Y. Chen
- Department of Biostatistics and Computational BiologyUniversity of Rochester Medical CenterRochesterNYUSA
| | - David T. Huang
- Department of Medicine, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
| | - Ayhan Yoruk
- Division of CardiologyThe University of California, San Francisco Medical CenterSan FranciscoCAUSA
| | - Mehmet K. Aktas
- Department of Medicine, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
| | - Spencer Rosero
- Department of Medicine, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
| | - Kristina Cutter
- Clinical Cardiovascular Research Center, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
| | - Scott McNitt
- Clinical Cardiovascular Research Center, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
| | - Nona Sotoodehnia
- Department of Medicine, Division of CardiologyUniversity of WashingtonSeattleWAUSA
| | | | - Thomas D. Rea
- Department of MedicineUniversity of WashingtonSeattleWAUSA
| | - Dan E. Arking
- The McKusick‐Nathans Institute, Department of Genetic MedicineJohn Hopkins University School of MedicineBaltimoreMDUSA
| | - Wojciech Zareba
- Clinical Cardiovascular Research Center, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
| | - Michael J. Ackerman
- Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and Windland Smith Rice Sudden Death Genomics LaboratoryMayo ClinicRochesterMNUSA
| | - Ilan Goldenberg
- Clinical Cardiovascular Research Center, Division of CardiologyUniversity of Rochester Medical CenterRochesterNYUSA
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Casis O, Echeazarra L, Sáenz-Díez B, Gallego M. Deciphering the roles of triiodothyronine (T3) and thyroid-stimulating hormone (TSH) on cardiac electrical remodeling in clinical and experimental hypothyroidism. J Physiol Biochem 2024; 80:1-9. [PMID: 38019451 PMCID: PMC10808292 DOI: 10.1007/s13105-023-01000-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 11/20/2023] [Indexed: 11/30/2023]
Abstract
Hypothyroidism is the most frequent endocrine pathology. Although clinical or overt hypothyroidism has been traditionally associated to low T3 / T4 and high thyrotropin (TSH) circulating levels, other forms exist such as subclinical hypothyroidism, characterized by normal blood T3 / T4 and high TSH. In its different forms is estimated to affect approximately 10% of the population, especially women, in a 5:1 ratio with respect to men. Among its consequences are alterations in cardiac electrical activity, especially in the repolarization phase, which is accompanied by an increased susceptibility to cardiac arrhythmias. Although these alterations have traditionally been attributed to thyroid hormone deficiency, recent studies, both clinical trials and experimental models, demonstrate a fundamental role of TSH in cardiac electrical remodeling. Thus, both metabolic thyroid hormones and TSH regulate cardiac ion channel expression in many and varied ways. This means that the different combinations of hormones that predominate in different types of hypothyroidism (overt, subclinic, primary, central) can generate different forms of cardiac electrical remodeling. These new findings are raising the relevant question of whether serum TSH reference ranges should be redefined.
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Affiliation(s)
- Oscar Casis
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006, Vitoria-Gasteiz, Spain.
| | - Leire Echeazarra
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006, Vitoria-Gasteiz, Spain
| | - Beatriz Sáenz-Díez
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006, Vitoria-Gasteiz, Spain
| | - Mónica Gallego
- Department of Physiology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Paseo de la Universidad 7, 01006, Vitoria-Gasteiz, Spain
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Zhang M, Hillegass WB, Yu X, Majumdar S, Daryl Pollard J, Jackson E, Knudson J, Wolfe D, Kato GJ, Maher JF, Mei H. Genetic variants and effect modifiers of QT interval prolongation in patients with sickle cell disease. Gene 2024; 890:147824. [PMID: 37741592 DOI: 10.1016/j.gene.2023.147824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/17/2023] [Accepted: 09/20/2023] [Indexed: 09/25/2023]
Abstract
BACKGROUND Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. METHODS In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. RESULTS Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). CONCLUSION Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms.
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Affiliation(s)
- Mengna Zhang
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - William B Hillegass
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Xue Yu
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Suvankar Majumdar
- Division of Hematology, Children's National Hospital, Washington, DC, USA
| | - J Daryl Pollard
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Erin Jackson
- Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Jarrod Knudson
- Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Douglas Wolfe
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Gregory J Kato
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Joseph F Maher
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Internal Medicine/Cancer Genetics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.
| | - Hao Mei
- Department of Data Science, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
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Pan Z, Fu Q, Jiang H, Wei Z, Zhang S. Computational analysis of long QT syndrome type 2 and the therapeutic effects of KCNQ1 antibodies. Digit Health 2024; 10:20552076241277032. [PMID: 39484649 PMCID: PMC11526401 DOI: 10.1177/20552076241277032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 08/05/2024] [Indexed: 11/03/2024] Open
Abstract
Objective Long QT interval syndrome (LQTS) is a highly dangerous cardiac disease that can lead to sudden cardiac death; however, its underlying mechanism remains largely unknown. This study is conceived to investigate the impact of two general genotypes of LQTS type 2, and also the therapeutic effects of an emerging immunology-based treatment named KCNQ1 antibody. Methods A multiscale virtual heart is developed, which contains multiple biological levels ranging from ion channels to a three-dimensional cardiac structure with realistic geometry. Critical biomarkers at different biological levels are monitored to investigate the remodeling of cardiac electrophysiology induced by mutations. Results Simulations revealed multiple important mechanisms that are hard to capture via conventional clinical techniques, including the augmented dispersion of repolarization, the increased vulnerability to arrhythmias, the impaired adaptability in tissue to high heart rates, and so on. An emerging KCNQ1 antibody-based therapy could rescue the prolonged QT interval but did not reduce the vulnerable window. Conclusions Tiny molecular alterations can lead to cardiac electrophysiological remodeling at multiple biological levels, which in turn contributes to higher susceptibility to lethal arrhythmias in long QT syndrome type 2 patients. The KCNQ1 antibody-based therapy has proarrhythmic risks notwithstanding its QT-rescuing effects.
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Affiliation(s)
- Zhujun Pan
- College of Computer Science and Technology, Ocean University of China, Qingdao, China
| | - Qi Fu
- College of Computer Science and Technology, Ocean University of China, Qingdao, China
| | - Huasen Jiang
- College of Computer Science and Technology, Ocean University of China, Qingdao, China
| | - Zhiqiang Wei
- College of Computer Science and Technology, Ocean University of China, Qingdao, China
| | - Shugang Zhang
- College of Computer Science and Technology, Ocean University of China, Qingdao, China
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Passantino S, Chiellino S, Girolami F, Zampieri M, Calabri GB, Spaziani G, Bennati E, Porcedda G, Procopio E, Olivotto I, Favilli S. Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort. Diagnostics (Basel) 2023; 13:3674. [PMID: 38132258 PMCID: PMC10742676 DOI: 10.3390/diagnostics13243674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 12/01/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Cardiac involvement is reported in a significant proportion of patients with classical organic acidurias (OAs), contributing to disability and premature death. Different cardiac phenotypes have been described, among which dilated cardiomyopathy (DCM) is predominant. Despite recent progress in diagnosis and treatment, the natural history of patients with OAs remains unresolved, specifically with regard to the impact of cardiac complications. We therefore performed a retrospective study to address this issue at our Referral Center for Pediatric Inherited Errors of Metabolism. METHODS Sixty patients with OAs (propionic (PA), methylmalonic (MMA) and isovaleric acidemias and maple syrup urine disease) diagnosed from 2000 to 2022 were systematically assessed at baseline and at follow-up. RESULTS Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients). The presence of DCM was associated with the worst prognosis. The rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA with cardiomyopathy; 35% in MMA with cardiomyopathy; and 23% in MMA without cardiomyopathy. Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function. CONCLUSIONS Cardiac involvement was documented in about one third of children diagnosed with classical OAs, confined to PA and MMA, and was often associated with poor outcome in over 50%. Etiological diagnosis of OAs is essential in guiding management and risk stratification.
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Affiliation(s)
- Silvia Passantino
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
| | - Serena Chiellino
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
| | - Francesca Girolami
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
| | - Mattia Zampieri
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
| | - Giovanni Battista Calabri
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
| | - Gaia Spaziani
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
| | - Elena Bennati
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
| | - Giulio Porcedda
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
| | - Elena Procopio
- Inborn Metabolic and Muscular Disorders Unit, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy;
| | - Iacopo Olivotto
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
| | - Silvia Favilli
- Department of Paediatric Cardiology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (S.C.); (F.G.); (G.B.C.); (G.S.); (E.B.); (G.P.); (I.O.); (S.F.)
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Dahlberg P, Axelsson KJ, Rydberg A, Lundahl G, Gransberg L, Bergfeldt L. Spatiotemporal repolarization dispersion before and after exercise in patients with long QT syndrome type 1 versus controls: probing into the arrhythmia substrate. Am J Physiol Heart Circ Physiol 2023; 325:H1279-H1289. [PMID: 37773058 DOI: 10.1152/ajpheart.00335.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 09/30/2023]
Abstract
Congenital long QT syndrome (LQTS) carries an increased risk for syncope and sudden death. QT prolongation promotes ventricular extrasystoles, which, in the presence of an arrhythmia substrate, might trigger ventricular tachycardia degenerating into fibrillation. Increased electrical heterogeneity (dispersion) is the suggested arrhythmia substrate in LQTS. In the most common subtype LQT1, physical exercise predisposes for arrhythmia and spatiotemporal dispersion was therefore studied in this context. Thirty-seven patients (57% on β-blockers) and 37 healthy controls (mean age, 31 vs. 35; range, 6-68 vs. 6-72 yr) performed an exercise test. Frank vectorcardiography was used to assess spatiotemporal dispersion as Tampl, Tarea, the ventricular gradient (VG), and the Tpeak-end interval from 10-s signal averages before and 7 ± 2 min after exercise; during exercise too much signal disturbance excluded analysis. Baseline and maximum heart rates as well as estimated exercise intensity were similar, but heart rate recovery was slower in patients. At baseline, QT and heart rate-corrected QT (QTcB) were significantly longer in patients (as expected), whereas dispersion parameters were numerically larger in controls. After exercise, QTpeakcB and Tpeak-endcB increased significantly more in patients (18 ± 23 vs. 7 ± 10 ms and 12 ± 17 vs. 2 ± 6 ms; P < 0.001 and P < 0.01). There was, however, no difference in the change in Tampl, Tarea, and VG between groups. In conclusion, although temporal dispersion of repolarization increased significantly more after exercise in patients with LQT1, there were no signs of exercise-induced increase in global dispersion of action potential duration and morphology. The arrhythmia substrate/mechanism in LQT1 warrants further study.NEW & NOTEWORTHY Physical activity increases the risk for life-threatening arrhythmias in LQTS type 1 (LQT1). The arrhythmia substrate is presumably altered electrical heterogeneity (a.k.a. dispersion). Spatiotemporal dispersion parameters were therefore compared before and after exercise in patients versus healthy controls using Frank vectorcardiography, a novelty. Physical exercise prolonged the time between the earliest and latest complete repolarization in patients versus controls, but did not increase parameters reflecting global dispersion of action potential duration and morphology, another novelty.
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Affiliation(s)
- Pia Dahlberg
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Vaestra Goetaland, Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Karl-Jonas Axelsson
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Vaestra Goetaland, Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Annika Rydberg
- Division of Pediatrics, Department of Clinical Sciences, Umeå University, Umeå, Sweden
| | - Gunilla Lundahl
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lennart Gransberg
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lennart Bergfeldt
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Vaestra Goetaland, Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
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Corrall S, Laws S, Rice A. Low-voltage electrical injuries and the electrocardiogram: is a 'normal' electrocardiogram sufficient for safe discharge from care? A systematic review. Br Paramed J 2023; 8:27-36. [PMID: 38046790 PMCID: PMC10690487 DOI: 10.29045/14784726.2023.12.8.3.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2023] Open
Abstract
Introduction The current Joint Royal Colleges Ambulance Liaison Committee guidelines in the United Kingdom provide clear national guidance for low-voltage electrical injury patients. While patients can be considered safe to discharge with an apparently 'normal' initial electrocardiogram (ECG), some evidence questions the safety profile of these patients with a risk of a 'delayed arrhythmia'. This review aims to examine this as well as identifying the frequency and common arrhythmias that require patients to be conveyed to hospital for further monitoring post electrical injury. It will also aim to improve the understanding of potentially clinically significant arrhythmias that may require clinical intervention or even admission within an in-hospital environment. Methods A systematic review using three electronic databases (CINAHL, MEDLINE, AMED) was conducted in January 2022. A preferred reporting items for systematic reviews and meta-analyses (PRISMA) approach was used to identify relevant studies with a suitable quality to support a critical review of the topic. A modified Critical Appraisal Skills Programme quality assessment checklist was used across suitable studies and a descriptive statistics approach was adopted to present the findings. Results Seven studies, largely retrospective reviews, met the inclusion criteria. The findings showed 26% of patients had an arrhythmia on initial presentation (n = 364/1234) with incidences of sinus tachycardia, sinus bradycardia and premature ventricular contractions. However, making definitive statements is challenging due to the lack of access to individual patients' past ECGs. Within these arrhythmias' ST segment changes, atrial fibrillation and long QT syndrome could be considered potentially significant, however associated prognosis with these and electrical injuries is unknown. Only six (0.5%) patients required treatment by drug therapy, and a further three died from associated complications. Most patients with a normal ECG were discharged immediately with only a limited follow-up. No presentation of a 'delayed arrhythmia' was identified throughout the studies. Conclusion The data for low-voltage electrical injuries are limited, but the potential arrhythmias for this patient group seldom require intervention. The entity of the 'delayed arrhythmia' may not be a reason to admit or monitor patients for prolonged periods. Further studies should consider the safety profile of discharging a patient with a normal ECG.
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18
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Lima B, Razmjouei S, Bajwa MT, Shahzad Z, Shoewu OA, Ijaz O, Mange P, Khanal S, Gebregiorgis T. Polypharmacy, Gender Disparities, and Ethnic and Racial Predispositions in Long QT Syndrome: An In-Depth Review. Cureus 2023; 15:e46009. [PMID: 37900391 PMCID: PMC10600617 DOI: 10.7759/cureus.46009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2023] [Indexed: 10/31/2023] Open
Abstract
Long QT syndrome (LQTS) is a complex disorder of cardiac electrophysiology. It is characterized by delayed myocardial polarization leading to QT prolongation and alterations on the ST segment and T wave visible on electrocardiogram (ECG). Syncope is a common manifestation, and torsade de pointes (TdP) can lead to sudden cardiac death. Three major LQTS genes (KCI31, KCNH2, and SCN5) lead to most of the cases of LQTS. Lifestyle modifications, beta blockers, and implantable cardioverter defibrillator (ICD) placement are the main treatments for LQTS. Polypharmacy, including QT-prolonging drugs, has been shown to worsen LQTS. The impact on potassium channels and the human ether-a-go-go-related gene (hERG) is the mechanism behind the QT interval prolongation caused by these medications. There is an increased incidence of LQTS among African-American men and women as compared to Caucasians. Women with LQTS tend to have a higher mortality rate from the condition, especially during menstruation and shortly after giving birth. Genetic testing is reserved to those patientswho exhibit either a strong clinical index of suspicion or experience persistent QT prolongation despite their lack of symptoms. Knowing the genetics, racial, and gender discrepancies can help improve patient management and a better comprehension on each case. Proper understanding of how ion channels function and their interaction with medications will lead to a better comprehension and to develop effective forms to treat those patients.
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Affiliation(s)
- Bruno Lima
- Medicine, University of Grande Rio, Rio Grande, USA
| | - Soha Razmjouei
- Anesthesiology, Case Western Reserve University School of Medicine, Cleveland, USA
| | | | - Zoha Shahzad
- Internal Medicine, Fatima Jinnah Medical University, Lahore, PAK
| | | | - Osama Ijaz
- Internal Medicine, Services Hospital Lahore, Lahore, PAK
| | - Pooja Mange
- Internal Medicine, K.J. Somaiya Hospital and Research Center, Mumbai, IND
| | | | - Tsion Gebregiorgis
- General Practice, Addis Ababa University Medical Faculty, Addis Ababa, ETH
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Fazelifar AF, Pourirahim M, Masoumi T, Biglari A, Maleki M, Kalayinia S. Identification of a novel pathogenic variant in KCNH2 in an Iranian family with long QT syndrome 2 by whole-exome sequencing. J Arrhythm 2023; 39:430-453. [PMID: 37324772 PMCID: PMC10264754 DOI: 10.1002/joa3.12857] [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] [Received: 12/28/2022] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 06/17/2023] Open
Abstract
Background Long QT syndrome (LQTS) is a lethal cardiac condition. However, the clinical implementation of genetic testing has now made LQTS eminently treatable. Next-generation sequencing has remarkable potential for both clinical diagnostics and research of LQTS. Here, we investigated the genetic etiology in an LQTS-suspected Iranian pedigree by whole-exome sequencing and collected all KCNH2 variants with consensus based on publications. Methods WES was performed on the proband of this pedigree to reveal the underlying cause of sudden cardiac death (SCD). The variant found was validated and segregated by polymerase chain reaction and Sanger sequencing. Based on the literature review, KCNH2 variants were retrospectively analyzed to identify pathogenic variants, likely pathogenic variants, and variants of uncertain significance by using different prediction tools. Results WES identified an autosomal dominant nonsense variant, c.1425C>A: p.Tyr475Ter, in the KCNH2 gene, which appeared to be the most likely cause of LQTS in this pedigree. Moreover, our comprehensive literature review yielded 511 KCNH2 variants in association with the LQTS phenotype, with c.3002G>A (CADD Phred=49) being the most pathogenic variant. Conclusions Variants in the KCNH2 gene are considered a major cause of LQTS worldwide. The detected c.1425C>A is a novel variant to be reported from Iran for the first time. This result indicates the importance of KCNH2 screening in a pedigree with SCD cases.
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Affiliation(s)
- Amir Farjam Fazelifar
- Rajaie Cardiovascular Medical and Research CenterIran University of Medical SciencesTehranIran
| | - Maryam Pourirahim
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research CenterIran University of Medical SciencesTehranIran
| | - Tannaz Masoumi
- Rajaie Cardiovascular Medical and Research CenterIran University of Medical SciencesTehranIran
| | - Alireza Biglari
- Department of Genetics & Molecular Medicine, School of MedicineZanjan University of Medical SciencesZanjanIran
| | - Majid Maleki
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research CenterIran University of Medical SciencesTehranIran
| | - Samira Kalayinia
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research CenterIran University of Medical SciencesTehranIran
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Zhou W, Ye D, Tester DJ, Bains S, Giudicessi JR, Haglund-Turnquist CM, Orland KM, January CT, Eckhardt LL, Maginot KR, Ackerman MJ. Elucidation of ALG10B as a Novel Long-QT Syndrome-Susceptibility Gene. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2023; 16:e003726. [PMID: 37071726 PMCID: PMC10844923 DOI: 10.1161/circgen.122.003726] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 11/04/2022] [Indexed: 02/24/2023]
Abstract
BACKGROUND Long-QT syndrome (LQTS) is characterized by QT prolongation and increased risk for syncope, seizures, and sudden cardiac death. The majority of LQTS stems from pathogenic mutations in KCNQ1, KCNH2, or SCN5A. However, ≈10% of patients with LQTS remain genetically elusive. We utilized genome sequencing to identify a novel LQTS genetic substrate in a multigenerational genotype-negative LQTS pedigree. METHODS Genome sequencing was performed on 5 affected family members. Only rare nonsynonymous variants present in all affected family members were considered. The candidate variant was characterized functionally in patient-derived induced pluripotent stem cell and gene-edited, variant corrected, isogenic control induced pluripotent stem cell-derived cardiomyocytes. RESULTS A missense variant (p.G6S) was identified in ALG10B-encoded α-1,2-glucosyltransferase B protein. ALG10B (alpha-1,2-glucosyltransferase B protein) is a known interacting protein of KCNH2-encoded Kv11.1 (HERG [human Ether-à-go-go-related gene]). Compared with isogenic control, ALG10B-p.G6S induced pluripotent stem cell-derived cardiomyocytes showed (1) decreased protein expression of ALG10B (p.G6S, 0.7±0.18, n=8 versus control, 1.25±0.16, n=9; P<0.05), (2) significant retention of HERG in the endoplasmic reticulum (P<0.0005), and (3) a significantly prolonged action potential duration confirmed by both patch clamp (p.G6S, 531.1±38.3 ms, n=15 versus control, 324.1±21.8 ms, n=13; P<0.001) and multielectrode assay (P<0.0001). Lumacaftor-a compound known to rescue HERG trafficking-shortened the pathologically prolonged action potential duration of ALG10B-p.G6S induced pluripotent stem cell-derived cardiomyocytes by 10.6% (n=31 electrodes; P<0.001). CONCLUSIONS Here, we demonstrate that ALG10B-p.G6S downregulates ALG10B, resulting in defective HERG trafficking and action potential duration prolongation. Therefore, ALG10B is a novel LQTS-susceptibility gene underlying the LQTS phenotype observed in a multigenerational pedigree. ALG10B mutation analysis may be warranted, especially in genotype-negative patients with an LQT2-like phenotype.
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Affiliation(s)
- Wei Zhou
- Departments of Cardiovascular Medicine (Division of Heart
Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric
Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland
Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
| | - Dan Ye
- Departments of Cardiovascular Medicine (Division of Heart
Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric
Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland
Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
| | - David J. Tester
- Departments of Cardiovascular Medicine (Division of Heart
Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric
Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland
Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
| | - Sahej Bains
- Departments of Cardiovascular Medicine (Division of Heart
Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric
Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland
Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
| | - John R. Giudicessi
- Departments of Cardiovascular Medicine (Division of Heart
Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric
Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland
Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
- Departments of Cardiovascular Medicine
(Clinician-Investigator Training Program), Mayo Clinic, Rochester, MN
| | - Carla M. Haglund-Turnquist
- Departments of Cardiovascular Medicine (Division of Heart
Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric
Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland
Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
| | - Kate M. Orland
- Department of Medicine, Division of Cardiovascular
Medicine, Cellular and Molecular Arrhythmia Research Program and Inherited
Arrhythmia Clinic, University of Wisconsin-Madison, Madison, WI
| | - Craig T. January
- Department of Medicine, Division of Cardiovascular
Medicine, Cellular and Molecular Arrhythmia Research Program and Inherited
Arrhythmia Clinic, University of Wisconsin-Madison, Madison, WI
| | - Lee L. Eckhardt
- Department of Medicine, Division of Cardiovascular
Medicine, Cellular and Molecular Arrhythmia Research Program and Inherited
Arrhythmia Clinic, University of Wisconsin-Madison, Madison, WI
| | - Kathleen R. Maginot
- Department of Pediatrics, University of Wisconsin School of
Medicine and Public Health, Madison, WI
| | - Michael J. Ackerman
- Departments of Cardiovascular Medicine (Division of Heart
Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric
Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland
Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN
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Achmad C, Kamarullah W, Putra ICS, Firmansyah DK, Iqbal M, Karwiky G, Pramudyo M, Martha JW, Akbar MR. Investigation of High-Risk Electrocardiographic Markers as Predictors of Major Arrhythmic Events in Brugada Syndrome: A Systematic Review and Meta-analysis. Curr Probl Cardiol 2023; 48:101727. [PMID: 36997139 DOI: 10.1016/j.cpcardiol.2023.101727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/22/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023]
Abstract
INTRODUCTION Numerous studies have demonstrated that a type I Brugada electrocardiographic (ECG) pattern, history of syncope, prior sudden cardiac arrest, and previously documented ventricular tachyarrhythmias are still insufficient to stratify the risk of sudden cardiac death in Brugada syndrome (BrS). Several auxiliary risk stratification parameters are pursued to yield a better prognostic model. Our aim was to assess the association between several ECG markers (wide QRS, fragmented QRS, S-wave in lead I, aVR sign, early repolarization pattern in inferolateral leads, and repolarization dispersion pattern) with the risk of developing poor outcomes in BrS. METHODS A systematic literature search from several databases was conducted from database inception until August 17th, 2022. Studies were eligible if it investigated the relationship between the ECG markers with the likelihood of acquiring major arrhythmic events (MAE). RESULTS This meta-analysis comprised 27 studies with a total of 6552 participants. Our study revealed that wide QRS, fragmented QRS, S-wave in lead I, aVR sign, early repolarization pattern in inferolateral leads, and repolarization dispersion ECG pattern were associated with the incremental risk of syncope, ventricular tachyarrhythmias, implantable cardioverter-defibrillator shock, and sudden cardiac death in the future, with the risk ratios ranging from 1.41 to 2.00. Moreover, diagnostic test accuracy meta-analysis indicated that the repolarization dispersion ECG pattern had the highest overall area under curve (AUC) value amid other ECG markers regarding our outcomes of interest. CONCLUSION A multivariable risk assessment approach based on the prior mentioned ECG markers potentially improves the current risk stratification models in BrS patients.
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Affiliation(s)
- Chaerul Achmad
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, Indonesia.
| | - William Kamarullah
- R. Syamsudin SH Regional Public Hospital, Sukabumi, West Java, Indonesia
| | - Iwan Cahyo Santosa Putra
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, Indonesia
| | - Dena Karina Firmansyah
- Department of Cardiology and Vascular Medicine, R. Syamsudin SH Regional Public Hospital, Sukabumi, West Java, Indonesia
| | - Mohammad Iqbal
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, University of Padjadjaran, Bandung, Indonesia
| | - Giky Karwiky
- Department of Cardiology and Vascular Medicine, Faculty of Medicine University of Padjadjaran, Bandung, Indonesia
| | - Miftah Pramudyo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine University of Padjadjaran, Bandung, Indonesia
| | - Januar Wibawa Martha
- Department of Cardiology and Vascular Medicine, Faculty of Medicine University of Padjadjaran, Bandung, Indonesia
| | - Mohammad Rizki Akbar
- Department of Cardiology and Vascular Medicine, Faculty of Medicine University of Padjadjaran, Bandung, Indonesia
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22
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Yu C, Deng XJ, Xu D. Gene mutations in comorbidity of epilepsy and arrhythmia. J Neurol 2023; 270:1229-1248. [PMID: 36376730 DOI: 10.1007/s00415-022-11430-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 10/14/2022] [Accepted: 10/15/2022] [Indexed: 11/16/2022]
Abstract
Epilepsy is one of the most common neurological disorders, and sudden unexpected death in epilepsy (SUDEP) is the most severe outcome of refractory epilepsy. Arrhythmia is one of the heterogeneous factors in the pathophysiological mechanism of SUDEP with a high incidence in patients with refractory epilepsy, increasing the risk of premature death. The gene co-expressed in the brain and heart is supposed to be the genetic basis between epilepsy and arrhythmia, among which the gene encoding ion channel contributes to the prevalence of "cardiocerebral channelopathy" theory. Nevertheless, this theory could only explain the molecular mechanism of comorbid arrhythmia in part of patients with epilepsy (PWE). Therefore, we summarized the mutant genes that can induce comorbidity of epilepsy and arrhythmia and the possible corresponding treatments. These variants involved the genes encoding sodium, potassium, calcium and HCN channels, as well as some non-ion channel coding genes such as CHD4, PKP2, FHF1, GNB5, and mitochondrial genes. The relationship between genotype and clinical phenotype was not simple linear. Indeed, genes co-expressed in the brain and heart could independently induce epilepsy and/or arrhythmia. Mutant genes in brain could affect cardiac rhythm through central or peripheral regulation, while in the heart it could also affect cerebral electrical activity by changing the hemodynamics or internal environment. Analysis of mutations in comorbidity of epilepsy and arrhythmia could refine and expand the theory of "cardiocerebral channelopathy" and provide new insights for risk stratification of premature death and corresponding precision therapy in PWE.
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Affiliation(s)
- Cheng Yu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China
| | - Xue-Jun Deng
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China
| | - Da Xu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei Province, China.
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23
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Min S, Cho SW. Engineered human cardiac tissues for modeling heart diseases. BMB Rep 2023; 56:32-42. [PMID: 36443005 PMCID: PMC9887099 DOI: 10.5483/bmbrep.2022-0185] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/28/2022] [Accepted: 11/28/2022] [Indexed: 07/30/2023] Open
Abstract
Heart disease is one of the major life-threatening diseases with high mortality and incidence worldwide. Several model systems, such as primary cells and animals, have been used to understand heart diseases and establish appropriate treatments. However, they have limitations in accuracy and reproducibility in recapitulating disease pathophysiology and evaluating drug responses. In recent years, three-dimensional (3D) cardiac tissue models produced using tissue engineering technology and human cells have outperformed conventional models. In particular, the integration of cell reprogramming techniques with bioengineering platforms (e.g., microfluidics, scaffolds, bioprinting, and biophysical stimuli) has facilitated the development of heart-ona- chip, cardiac spheroid/organoid, and engineered heart tissue (EHT) to recapitulate the structural and functional features of the native human heart. These cardiac models have improved heart disease modeling and toxicological evaluation. In this review, we summarize the cell types for the fabrication of cardiac tissue models, introduce diverse 3D human cardiac tissue models, and discuss the strategies to enhance their complexity and maturity. Finally, recent studies in the modeling of various heart diseases are reviewed. [BMB Reports 2023; 56(1): 32-42].
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Affiliation(s)
- Sungjin Min
- Department of Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Seung-Woo Cho
- Department of Biotechnology, Yonsei University, Seoul 03722, Korea
- Center for Nanomedicine, Institute for Basic Science (IBS), Seoul 03722, Korea
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24
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Min S, Cho SW. Engineered human cardiac tissues for modeling heart diseases. BMB Rep 2023; 56:32-42. [PMID: 36443005 PMCID: PMC9887099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/28/2022] [Accepted: 11/28/2022] [Indexed: 01/28/2023] Open
Abstract
Heart disease is one of the major life-threatening diseases with high mortality and incidence worldwide. Several model systems, such as primary cells and animals, have been used to understand heart diseases and establish appropriate treatments. However, they have limitations in accuracy and reproducibility in recapitulating disease pathophysiology and evaluating drug responses. In recent years, three-dimensional (3D) cardiac tissue models produced using tissue engineering technology and human cells have outperformed conventional models. In particular, the integration of cell reprogramming techniques with bioengineering platforms (e.g., microfluidics, scaffolds, bioprinting, and biophysical stimuli) has facilitated the development of heart-ona- chip, cardiac spheroid/organoid, and engineered heart tissue (EHT) to recapitulate the structural and functional features of the native human heart. These cardiac models have improved heart disease modeling and toxicological evaluation. In this review, we summarize the cell types for the fabrication of cardiac tissue models, introduce diverse 3D human cardiac tissue models, and discuss the strategies to enhance their complexity and maturity. Finally, recent studies in the modeling of various heart diseases are reviewed. [BMB Reports 2023; 56(1): 32-42].
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Affiliation(s)
- Sungjin Min
- Department of Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Seung-Woo Cho
- Department of Biotechnology, Yonsei University, Seoul 03722, Korea
- Center for Nanomedicine, Institute for Basic Science (IBS), Seoul 03722, Korea
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25
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Inbaraj G, Udupa K, Vasuki PP, Nalini A, Sathyaprabha TN. Resting heart rate variability as a diagnostic marker of cardiovascular dysautonomia in postural tachycardia syndrome. J Basic Clin Physiol Pharmacol 2023; 34:103-109. [PMID: 36367272 DOI: 10.1515/jbcpp-2022-0069] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 10/17/2022] [Indexed: 11/13/2022]
Abstract
OBJECTIVES Postural orthostatic tachycardia syndrome (POTS) is a disorder of the autonomic nervous system characterised by orthostatic intolerance and orthostatic tachycardia without hypotension. Heart rate variability (HRV) is the most reliable and objective tool for assessing autonomic dysfunction severity. In the present study, we aimed to investigate HRV changes in resting supine position, predicting severity and cardiovascular risk in patients with POTS. METHODS We compared 100 POTS patients with 160 healthy controls matched for age and gender in a case-control design. Along with clinical characterization, heart rate variability was evaluated using ambulatory 5 min ECG in lead II and expressed in frequency and time-domain measures. RESULTS The resting heart rate of patients with POTS was significantly higher than that of healthy controls. In HRV measures, root mean square successive difference of RR intervals (RMSSD), total and high frequency (HF) powers were statistically lower with an increased low frequency (LF) to high-frequency ratio in patients with POTS compared to healthy controls. Further, stepwise logistic regression analysis showed increased basal HR and LF/HF as significant predictors of POTS and its severity. CONCLUSIONS This is the first study on a large cohort of patients with POTS from India wherein HRV was assessed. The study showed reduced parasympathetic activity and increased sympathetic activity in patients with POTS compared to healthy controls. These findings of increased resting heart rate and LF/HF were found to be potential predictors of POTS and future cardiovascular risks, which need to be replicated in a larger and more homogenized cohort.
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Affiliation(s)
- Ganagarajan Inbaraj
- Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Kaviraja Udupa
- Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | | | - Atchayaram Nalini
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Talakad N Sathyaprabha
- Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
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26
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Bains S, Zhou W, Dotzler SM, Martinez K, Kim CJ, Tester DJ, Ye D, Ackerman MJ. Suppression and Replacement Gene Therapy for KCNH2-Mediated Arrhythmias. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2022; 15:e003719. [PMID: 36252106 DOI: 10.1161/circgen.122.003719] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND KCNH2-mediated arrhythmia syndromes are caused by loss-of-function (type 2 long QT syndrome [LQT2]) or gain-of-function (type 1 short QT syndrome [SQT1]) pathogenic variants in the KCNH2-encoded Kv11.1 potassium channel, which is essential for the cardiac action potential. METHODS A dual-component "suppression-and-replacement" (SupRep) KCNH2 gene therapy was created by cloning into a single construct a custom-designed KCNH2 short hairpin RNA with ~80% knockdown (suppression) and a "short hairpin RNA-immune" KCNH2 cDNA (replacement). Induced pluripotent stem cell-derived cardiomyocytes and their CRISPR-Cas9 variant-corrected isogenic control (IC) induced pluripotent stem cell-derived cardiomyocytes were made for 2 LQT2- (G604S, N633S) and 1 SQT1- (N588K) causative variants. All variant lines were treated with KCNH2-SupRep or non-targeting control short hairpin RNA (shCT). The action potential duration (APD) at 90% repolarization (APD90) was measured using FluoVolt voltage dye. RESULTS KCNH2-SupRep achieved variant-independent rescue of both pathologic phenotypes. For LQT2-causative variants, treatment with KCNH2-SupRep resulted in shortening of the pathologically prolonged APD90 to near curative (IC-like) APD90 levels (G604S IC, 471±25 ms; N633S IC, 405±55 ms) compared with treatment with shCT (G604S: SupRep-treated, 452±76 ms versus shCT-treated, 550±41 ms; P<0.0001; N633S: SupRep-treated, 399±105 ms versus shCT-treated, 577±39 ms, P<0.0001). Conversely, for the SQT1-causative variant, N588K, treatment with KCNH2-SupRep resulted in therapeutic prolongation of the pathologically shortened APD90 (IC: 429±16 ms; SupRep-treated: 396±61 ms; shCT-treated: 274±12 ms). CONCLUSIONS We provide the first proof-of-principle gene therapy for correction of both LQT2 and SQT1. KCNH2-SupRep gene therapy successfully normalized the pathologic APD90, thereby eliminating the pathognomonic feature of both LQT2 and SQT1.
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Affiliation(s)
- Sahej Bains
- Medical Scientist Training Program (S.B., S.M.D.), Mayo Clinic, Rochester, MN.,Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN
| | - Wei Zhou
- Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN
| | - Steven M Dotzler
- Medical Scientist Training Program (S.B., S.M.D.), Mayo Clinic, Rochester, MN.,Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN
| | - Katherine Martinez
- Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN
| | - Cs John Kim
- Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN
| | - David J Tester
- Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN.,Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (D.J.T., M.J.A.), Mayo Clinic, Rochester, MN
| | - Dan Ye
- Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN.,Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic (D.J.T., M.J.A.), Mayo Clinic, Rochester, MN
| | - Michael J Ackerman
- Department of Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (S.B., W.Z., S.M.D., K.M., C.S.J.K., D.J.T., D.Y., M.J.A.), Mayo Clinic, Rochester, MN.,Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (D.J.T., M.J.A.), Mayo Clinic, Rochester, MN.,Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Windland Smith Rice Genetic Heart Rhythm Clinic (D.J.T., M.J.A.), Mayo Clinic, Rochester, MN
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27
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Comollo TW, Zou X, Zhang C, Kesters D, Hof T, Sampson KJ, Kass RS. Exploring mutation specific beta blocker pharmacology of the pathogenic late sodium channel current from patient-specific pluripotent stem cell myocytes derived from long QT syndrome mutation carriers. Channels (Austin) 2022; 16:173-184. [PMID: 35949058 PMCID: PMC9373745 DOI: 10.1080/19336950.2022.2106025] [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: 01/31/2023] Open
Abstract
The congenital long QT syndrome (LQTS), one of the most common cardiac channelopathies, is characterized by delayed ventricular repolarization underlying prolongation of the QT interval of the surface electrocardiogram. LQTS is caused by mutations in genes coding for cardiac ion channels or ion channel-associated proteins. The major therapeutic approach to LQTS management is beta blocker therapy which has been shown to be effective in treatment of LQTS variants caused by mutations in K+ channels. However, this approach has been questioned in the treatment of patients identified as LQTS variant 3(LQT3) patients who carry mutations in SCN5A, the gene coding for the principal cardiac Na+ channel. LQT3 mutations are gain of function mutations that disrupt spontaneous Na+ channel inactivation and promote persistent or late Na+ channel current (INaL) that delays repolarization and underlies QT prolongation. Clinical investigation of patients with the two most common LQT3 mutations, the ΔKPQ and the E1784K mutations, found beta blocker treatment a useful therapeutic approach for managing arrhythmias in this patient population. However, there is little experimental data that reveals the mechanisms underlying these antiarrhythmic actions. Here, we have investigated the effects of the beta blocker propranolol on INaL expressed by ΔKPQ and E1784K channels in induced pluripotent stem cells derived from patients carrying these mutations. Our results indicate that propranolol preferentially inhibits INaL expressed by these channels suggesting that the protective effects of propranolol in treating LQT3 patients is due in part to modulation of INaL.
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Affiliation(s)
- Thomas W. Comollo
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia, NY, USA
| | - Xinle Zou
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia, NY, USA
| | - Chuangeng Zhang
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia, NY, USA
| | - Divya Kesters
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia, NY, USA
| | - Thomas Hof
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia, NY, USA
| | - Kevin J. Sampson
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia, NY, USA
| | - Robert S. Kass
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia, NY, USA,CONTACT Robert S. Kass
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28
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Experimental hypothyroidism induces cardiac arrhythmias and ranolazine reverts and prevents the phenotype. Life Sci 2022; 308:120945. [PMID: 36096245 DOI: 10.1016/j.lfs.2022.120945] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/30/2022] [Accepted: 09/07/2022] [Indexed: 11/24/2022]
Abstract
AIMS Hypothyroidism is associated with an increased risk of cardiovascular disease and enhanced susceptibility to arrhythmias. In our investigation, we evaluated the potential involvement of late sodium current (INa,late) in cardiac arrhythmias in an experimental murine model of hypothyroidism. MAIN METHODS Male Swiss mice were treated with methimazole (0.1 % w/vol, during 21 days) to induce experimental hypothyroidism before ECG, action potential (AP) and intracellular Ca2+ dynamics were evaluated. Susceptibility to arrhythmia was measured in vitro and in vivo. KEY FINDINGS The results revealed that hypothyroid animals presented ECG alterations (e.g. increased QTc) with the presence of spontaneous sustained ventricular tachycardia. These changes were associated with depolarized resting membrane potential in isolated cardiomyocytes and increased AP duration and dispersion at 90 % of the repolarization. Aberrant AP waveforms were related to increased Ca2+ sparks and out-of-pace Ca2+ waves. These changes were observed in a scenario of enhanced INa,late. Interestingly, ranolazine, a clinically used blocker of INa,late, restored the ECG alterations, reduced Ca2+ sparks and aberrant waves, decreased the in vitro events and the severity of arrhythmias observed in isolated cardiomyocytes from hypothyroid animals. Using the in vivo dobutamine + caffeine protocol, animals with hypothyroidism developed catecholaminergic bidirectional ventricular tachycardia, but pre-treatment with ranolazine prevented this. SIGNIFICANCE We concluded that animals with hypothyroidism have increased susceptibility to developing arrhythmias and ranolazine, a clinically used blocker of INa,late, is able to correct the arrhythmic phenotype.
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29
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Jiang C, Richardson E, Farr J, Hill AP, Ullah R, Kroncke BM, Harrison SM, Thomson KL, Ingles J, Vandenberg JI, Ng CA. A calibrated functional patch-clamp assay to enhance clinical variant interpretation in KCNH2-related long QT syndrome. Am J Hum Genet 2022; 109:1199-1207. [PMID: 35688147 PMCID: PMC9300752 DOI: 10.1016/j.ajhg.2022.05.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/03/2022] [Indexed: 01/09/2023] Open
Abstract
Modern sequencing technologies have revolutionized our detection of gene variants. However, in most genes, including KCNH2, the majority of missense variants are currently classified as variants of uncertain significance (VUSs). The aim of this study was to investigate the utility of an automated patch-clamp assay for aiding clinical variant classification in KCNH2. The assay was designed according to recommendations proposed by the Clinical Genome Sequence Variant Interpretation Working Group. Thirty-one variants (17 pathogenic/likely pathogenic, 14 benign/likely benign) were classified internally as variant controls. They were heterozygously expressed in Flp-In HEK293 cells for assessing the effects of variants on current density and channel gating in order to determine the sensitivity and specificity of the assay. All 17 pathogenic variant controls had reduced current density, and 13 of 14 benign variant controls had normal current density, which enabled determination of normal and abnormal ranges for applying evidence of moderate or supporting strength for VUS reclassification. Inclusion of functional assay evidence enabled us to reclassify 6 out of 44 KCNH2 VUSs as likely pathogenic. The high-throughput patch-clamp assay can provide moderate-strength evidence for clinical interpretation of clinical KCNH2 variants and demonstrates the value of developing automated patch-clamp assays for functional characterization of ion channel gene variants.
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Affiliation(s)
- Connie Jiang
- Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW, Australia
| | - Ebony Richardson
- Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia
| | - Jessica Farr
- Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; School of Computer Science and Engineering, UNSW Sydney, Kensington, NSW, Australia
| | - Adam P Hill
- Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Darlinghurst, NSW, Australia
| | - Rizwan Ullah
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Brett M Kroncke
- Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Kate L Thomson
- Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford, UK
| | - Jodie Ingles
- Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Australia
| | - Jamie I Vandenberg
- Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Darlinghurst, NSW, Australia.
| | - Chai-Ann Ng
- Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, UNSW Sydney, Darlinghurst, NSW, Australia.
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30
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Coyote-Maestas W, Nedrud D, He Y, Schmidt D. Determinants of trafficking, conduction, and disease within a K + channel revealed through multiparametric deep mutational scanning. eLife 2022; 11:e76903. [PMID: 35639599 PMCID: PMC9273215 DOI: 10.7554/elife.76903] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 05/27/2022] [Indexed: 01/04/2023] Open
Abstract
A long-standing goal in protein science and clinical genetics is to develop quantitative models of sequence, structure, and function relationships to understand how mutations cause disease. Deep mutational scanning (DMS) is a promising strategy to map how amino acids contribute to protein structure and function and to advance clinical variant interpretation. Here, we introduce 7429 single-residue missense mutations into the inward rectifier K+ channel Kir2.1 and determine how this affects folding, assembly, and trafficking, as well as regulation by allosteric ligands and ion conduction. Our data provide high-resolution information on a cotranslationally folded biogenic unit, trafficking and quality control signals, and segregated roles of different structural elements in fold stability and function. We show that Kir2.1 surface trafficking mutants are underrepresented in variant effect databases, which has implications for clinical practice. By comparing fitness scores with expert-reviewed variant effects, we can predict the pathogenicity of 'variants of unknown significance' and disease mechanisms of known pathogenic mutations. Our study in Kir2.1 provides a blueprint for how multiparametric DMS can help us understand the mechanistic basis of genetic disorders and the structure-function relationships of proteins.
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Affiliation(s)
- Willow Coyote-Maestas
- Department of Biochemistry, Molecular Biology and Biophysics, University of MinnesotaMinneapolisUnited States
| | - David Nedrud
- Department of Biochemistry, Molecular Biology and Biophysics, University of MinnesotaMinneapolisUnited States
| | - Yungui He
- Department of Genetics, Cell Biology and Development, University of MinnesotaMinneapolisUnited States
| | - Daniel Schmidt
- Department of Genetics, Cell Biology and Development, University of MinnesotaMinneapolisUnited States
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31
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Ross RL, Mavria G, Del Galdo F, Elies J. Downregulation of Vascular Hemeoxygenase-1 Leads to Vasculopathy in Systemic Sclerosis. Front Physiol 2022; 13:900631. [PMID: 35600300 PMCID: PMC9117635 DOI: 10.3389/fphys.2022.900631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 04/12/2022] [Indexed: 11/13/2022] Open
Abstract
Systemic sclerosis (SSc) is a terminal disease characterized by vasculopathy, tissue fibrosis, and autoimmunity. Although the exact etiology of SSc remains unknown, endothelial dysfunction, oxidative stress, and calcium handling dysregulation have been associated with a large number of SSc-related complications such as neointima formation, vasculogenesis, pulmonary arterial hypertension, impaired angiogenesis, and cardiac arrhythmias. Hemeoxygenase-1 (HO-1) is an antioxidant enzyme involved in multiple biological actions in the cardiovascular system including vascular tone, angiogenesis, cellular proliferation, apoptosis, and oxidative stress. The aim of this work was to investigate the physiological role of HO-1 and its relevance in the cardiovascular complications occurring in SSc. We found that, in early phases of SSc, the expression of HO-1 in dermal fibroblast is lower compared to those isolated from healthy control individuals. This is particularly relevant as reduction of the HO-1/CO signaling pathway is associated with endothelial dysfunction and vasculopathy. We show evidence of the role of HO-1/carbon monoxide (CO) signaling pathway in calcium handling. Using an in vitro model of pulmonary arterial hypertension (PAH) we investigated the role of HO-1 in Ca2+ mobilization from intracellular stores. Our results indicate that HO-1 regulates calcium release from intracellular stores of human pulmonary arterial endothelial cells. We interrogated the activity of HO-1 in angiogenesis using an organotypic co-culture of fibroblast-endothelial cell. Inhibition of HO-1 significantly reduced the ability of endothelial cells to form tubules. We further investigated if this could be associated with cell motility or migration of endothelial cells into the extracellular matrix synthesized by fibroblasts. By mean of holographic imaging, we studied the morphological and functional features of endothelial cells in the presence of an HO-1 activator and selective inhibitors. Our results demonstrate that inhibition of HO-1 significantly reduces cell proliferation and cell motility (migration) of cultured endothelial cells, whilst activation of HO-1 does not modify either morphology, proliferation or motility. In addition, we investigated the actions of CO on the Kv7.1 (KCQN1) channel current, an important component of the cardiac action potential repolarization. Using electrophysiology (whole-cell patch-clamp in a recombinant system overexpressing the KCQN1 channel), we assessed the regulation of KCQN1 by CO. CORM-2, a CO donor, significantly reduced the Kv7.1 current, suggesting that HO-1/CO signaling may play a role in the modulation of the cardiac action potential via regulation of this ion channel. In summary, our results indicate a clear link between: 1) downregulation of HO-1/CO signaling; and 2) pathophysiological processes occurring in early phases of SSc, such as calcium homeostasis dysregulation, impaired angiogenesis and cardiac arrhythmias. A better understanding of the canonical actions (mainly due to the biological actions of CO), and non-canonical actions of HO-1, as well as the interaction of HO-1/CO signaling with other gasotransmitters in SSc will contribute to the development of novel therapeutic approaches.
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Affiliation(s)
- Rebecca L Ross
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
- Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, United Kingdom
| | - Georgia Mavria
- Signal Transduction and Tumour Microenvironment Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
| | - Francesco Del Galdo
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
- Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds, United Kingdom
| | - Jacobo Elies
- Cardiovascular Research Group, Faculty of Life Sciences, University of Bradford, Bradford, United Kingdom
- *Correspondence: Jacobo Elies,
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32
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Genetic Diagnostics Contribute to the Risk Stratification for Major Arrhythmic Events in Pediatric Patients with Long QT Syndrome Type 1–3. CARDIOGENETICS 2022. [DOI: 10.3390/cardiogenetics12010009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Long QT syndrome (LQTS) is an inherited arrhythmic disorder associated with sudden cardiac death (SCD). This study aimed to identify the clinical and molecular genetic risk factors that contribute to major arrhythmic events (MAEs) in patients with genetically confirmed childhood onset LQTS 1–3. This study was a retrospective double-center study. An MAE was defined as the occurrence of SCD, aborted SCD, appropriate implantable cardioverter defibrillator discharge, or sustained ventricular tachycardia. During a median follow-up of 4.6 years (range 0.1–24.3 years), MAEs occurred in 18 (17.8%) of 101 patients diagnosed with LQTS at a median of 7.7 years (range 0.0–18.0 years) despite the use of beta-blockers in 91.6% of patients at the last follow-up. A multivariate analysis identified a genetic diagnosis of LQTS2 and LQTS3 and variants within the KCNH2 S5-loop-S6 pore region as independent risk factors for MAEs, independent of the QTc value or a history of syncope detected from a univariate analysis. MAEs occur frequently in childhood onset LQTS despite beta-blocker treatment. A detailed molecular genetic diagnosis can contribute to the arrhythmia risk stratification and optimize the use of preventive measures in this vulnerable patient population.
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33
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Gou X, Hu T, Gou Y, Li C, Yi M, Jia M. Specific protein kinase C isoform exerts chronic inhibition on the slowly activating delayed-rectifier potassium current by affecting channel trafficking. Channels (Austin) 2021; 15:262-272. [PMID: 33535882 PMCID: PMC7872027 DOI: 10.1080/19336950.2021.1882112] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/22/2021] [Accepted: 01/22/2021] [Indexed: 11/04/2022] Open
Abstract
The slowly activating delayed rectifier K+ current (IKs) plays a key role in the repolarization of ventricular action potential in the human heart and is formed by the pore-forming α-subunit encoded by KCNQ1 (Kv7.1) and β-subunit encoded by KCNE1. Evidence suggested that IKs was regulated through protein kinase C (PKC) pathway, but the mechanism is controversial. This study was designed to identify the specific PKC isoform involved in the long-term regulation of IKs current. The IKs current was recorded using whole-cell patch-clamp technique in human embryonic kidney (HEK) 293B cell co-transfected with human KCNQ1/KCNE1 genes. The results revealed that both chronic activation of Ang II and PMA reduced the IKs current in a long-term regulation (about 24 hours). Further evidence showed that PKCε knockdown by siRNA antagonized the AngII-induced chronic inhibition on the IKs current, whereas knockdown of cPKC (PKCα and PKCβ) attenuated the inhibition effect of PMA on the current. Moreover, the forward transport inhibition of the channel with brefeldin A alleviated the Ang II-induced chronic inhibition on IKs current, while the channel endocytosis inhibition with dynasore alleviated both Ang II and PMA-induced chronic inhibition on IKs current. The above results showed that PKCε activation promoted the channel endocytosis and inhibited the channel forward transport to the plasma membrane, while cPKC activation only promoted the channel endocytosis, which both down regulated the channel current.
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Affiliation(s)
- Xiangbo Gou
- Tianjin Key Labortory of Drug Targeting and Bioimaging, Tianjin University of Technology, Tianjin, China
- School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin, China
| | - Tingting Hu
- Department of Orthopaedic Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
- Department of Neurobiology, School of Basic Medical Science, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Yu Gou
- Department of Orthopaedic Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Chaoqi Li
- School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin, China
| | - Ming Yi
- School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin, China
| | - Mengran Jia
- School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin, China
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34
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Approach to inherited arrhythmias in pregnancy. INTERNATIONAL JOURNAL OF CARDIOLOGY CONGENITAL HEART DISEASE 2021. [DOI: 10.1016/j.ijcchd.2021.100264] [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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35
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Gomez‐Galeno J, Okolotowicz K, Johnson M, McKeithan WL, Mercola M, Cashman JR. Human-induced pluripotent stem cell-derived cardiomyocytes: Cardiovascular properties and metabolism and pharmacokinetics of deuterated mexiletine analogs. Pharmacol Res Perspect 2021; 9:e00828. [PMID: 34327875 PMCID: PMC8322572 DOI: 10.1002/prp2.828] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 04/19/2021] [Indexed: 01/08/2023] Open
Abstract
Prolongation of the cardiac action potential (AP) and early after depolarizations (EADs) are electrical anomalies of cardiomyocytes that can lead to lethal arrhythmias and are potential liabilities for existing drugs and drug candidates in development. For example, long QT syndrome-3 (LQTS3) is caused by mutations in the Nav 1.5 sodium channel that debilitate channel inactivation and cause arrhythmias. We tested the hypothesis that a useful drug (i.e., mexiletine) with potential liabilities (i.e., potassium channel inhibition and adverse reactions) could be re-engineered by dynamic medicinal chemistry to afford a new drug candidate with greater efficacy and less toxicity. Human cardiomyocytes were generated from LQTS3 patient-derived induced pluripotent stem cells (hIPSCs) and normal hIPSCs to determine beneficial (on-target) and detrimental effects (off-target) of mexiletine and synthetic analogs, respectively. The approach combined "drug discovery" and "hit to lead" refinement and showed that iterations of medicinal chemistry and physiological testing afforded optimized compound 22. Compared to mexiletine, compound 22 showed a 1.85-fold greater AUC and no detectable CNS toxicity at 100 mg/kg. In vitro hepatic metabolism studies showed that 22 was metabolized via cytochrome P-450, as previously shown, and by the flavin-containing monooxygenase (FMO). Deuterated-22 showed decreased metabolism and showed acceptable cardiovascular and physicochemical properties.
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Affiliation(s)
| | - Karl Okolotowicz
- Department of MedicineCardiovascular InstituteStanford UniversityStanfordCAUSA
| | - Mark Johnson
- Human BioMolecular Research InstituteSan DiegoCAUSA
| | - Wesley L. McKeithan
- Department of MedicineCardiovascular InstituteStanford UniversityStanfordCAUSA
| | - Mark Mercola
- Department of MedicineCardiovascular InstituteStanford UniversityStanfordCAUSA
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Goldenberg I, Bos JM, Yoruk A, Chen AY, Lopes C, Huang DT, Kutyifa V, Younis A, Aktas MK, Z Rosero S, McNitt S, Sotoodehnia N, Kudenchuk PJ, Rea TD, Arking DE, Scott CG, Briske KA, Sorensen K, J Ackerman M, Zareba W. Risk Prediction in Women With Congenital Long QT Syndrome. J Am Heart Assoc 2021; 10:e021088. [PMID: 34238014 PMCID: PMC8483453 DOI: 10.1161/jaha.121.021088] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life‐threatening events in women with either type 1 or type 2 long QT. Methods and Results The prognostic model was derived from the Rochester Long QT Syndrome Registry, comprising 767 women with type 1 long QT (n=404) and type 2 long QT (n=363) from age 15 through 60 years. The risk prediction model included the following variables: genotype/mutation location, QTc‐specific thresholds, history of syncope, and β‐blocker therapy. A model was developed with the end point of CEs (syncope, aborted cardiac arrest, or long QT syndrome–related sudden cardiac death), and was applied with the end point of life‐threatening events (aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shocks). External validation was performed with data from the Mayo Clinic Genetic Heart Rhythm Clinic (N=467; type 1 long QT [n=286] and type 2 long QT [n=181]). The cumulative follow‐up duration among the 767 enrolled women was 22 243 patient‐years, during which 323 patients (42%) experienced ≥1 CE. Based on genotype‐phenotype data, we identified 3 risk groups with 10‐year projected rates of CEs ranging from 15%, 29%, to 51%. The corresponding 10‐year projected rates of life‐threatening events were 2%, 5%, and 14%. C statistics for the prediction model for the 2 respective end points were 0.68 (95% CI 0.65–0.71) and 0.71 (95% CI 0.66–0.76). Corresponding C statistics for the model in the external validation Mayo Clinic cohort were 0.65 (95% CI 0.60–0.70) and 0.77 (95% CI 0.70–0.84). Conclusions This is the first risk prediction model that provides absolute risk estimates for CEs and life‐threatening events in women with type 1 or type 2 long QT based on personalized genotype‐phenotype data. The projected risk estimates can be used to guide female‐specific management in long QT syndrome.
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Affiliation(s)
- Ilan Goldenberg
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY
| | - J Martijn Bos
- Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology and the Windland Smith Rice Genetic Heart Rhythm Clinic), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) Mayo Clinic Rochester MN
| | - Ayhan Yoruk
- Division of Cardiology The University of California, San Francisco Medical Center San Francisco CA
| | - Anita Y Chen
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY.,Department of Biostatistics and Computational Biology University of Rochester Medical Center Rochester NY
| | - Coeli Lopes
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY
| | - David T Huang
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY
| | - Valentina Kutyifa
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY
| | - Arwa Younis
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY
| | - Mehmet K Aktas
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY
| | - Spencer Z Rosero
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY
| | - Scott McNitt
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY
| | - Nona Sotoodehnia
- Division of Cardiology Department of Medicine University of Washington Seattle WA
| | - Peter J Kudenchuk
- Division of Cardiology Department of Medicine University of Washington Seattle WA
| | - Thomas D Rea
- Center for Progress in Resuscitation University of Washington Seattle WA
| | - Dan E Arking
- Department of Genetic Medicine The McKusick-Nathans InstituteJohn Hopkins University School of Medicine Baltimore MD
| | - Christopher G Scott
- Division of Biostatistics and Informatics Department of Health Sciences Research Mayo Clinic Rochester MN
| | - Kaylie A Briske
- Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology and the Windland Smith Rice Genetic Heart Rhythm Clinic), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) Mayo Clinic Rochester MN
| | - Katrina Sorensen
- Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology and the Windland Smith Rice Genetic Heart Rhythm Clinic), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) Mayo Clinic Rochester MN
| | - Michael J Ackerman
- Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology and the Windland Smith Rice Genetic Heart Rhythm Clinic), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) Mayo Clinic Rochester MN
| | - Wojciech Zareba
- Division of Cardiology Clinical Cardiovascular Research Center University of Rochester Medical Center Rochester NY
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37
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Cashman JR, Ryan D, McKeithan WL, Okolotowicz K, Gomez-Galeno J, Johnson M, Sampson KJ, Kass RS, Pezhouman A, Karagueuzian HS, Mercola M. Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes. J Med Chem 2021; 64:5384-5403. [PMID: 33942619 DOI: 10.1021/acs.jmedchem.0c01545] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Ventricular cardiac arrhythmia (VA) arises in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a congenital form of VA caused by cardiac sodium channel (INaL) SCN5A mutations that prolongs cardiac action potential (AP) and enhances INaL current. Mexiletine inhibits INaL and shortens the QT interval in LQT3 patients. Above therapeutic doses, mexiletine prolongs the cardiac AP. We explored structure-activity relationships (SAR) for AP shortening and prolongation using dynamic medicinal chemistry and AP kinetics in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using patient-derived LQT3 and healthy hiPSC-CMs, we resolved distinct SAR for AP shortening and prolongation effects in mexiletine analogues and synthesized new analogues with enhanced potency and selectivity for INaL. This resulted in compounds with decreased AP prolongation effects, increased metabolic stability, increased INaL selectivity, and decreased avidity for the potassium channel. This study highlights using hiPSC-CMs to guide medicinal chemistry and "drug development in a dish".
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Affiliation(s)
- John R Cashman
- Human BioMolecular Research Institute, San Diego, California 92121, United States
| | - Daniel Ryan
- Human BioMolecular Research Institute, San Diego, California 92121, United States
| | - Wesley L McKeithan
- Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California 94305, United States.,Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, San Diego, California 92037, United States
| | - Karl Okolotowicz
- Human BioMolecular Research Institute, San Diego, California 92121, United States
| | - Jorge Gomez-Galeno
- Human BioMolecular Research Institute, San Diego, California 92121, United States
| | - Mark Johnson
- Human BioMolecular Research Institute, San Diego, California 92121, United States
| | - Kevin J Sampson
- Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, United States
| | - Robert S Kass
- Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, United States
| | - Arash Pezhouman
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States
| | - Hrayr S Karagueuzian
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States
| | - Mark Mercola
- Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California 94305, United States.,Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, San Diego, California 92037, United States
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38
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Alahmadi A, Davies A, Royle J, Goodwin L, Cresswell K, Arain Z, Vigo M, Jay C. An explainable algorithm for detecting drug-induced QT-prolongation at risk of torsades de pointes (TdP) regardless of heart rate and T-wave morphology. Comput Biol Med 2021; 131:104281. [PMID: 33636421 DOI: 10.1016/j.compbiomed.2021.104281] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 12/23/2022]
Abstract
Torsade de points (TdP), a life-threatening arrhythmia that can increase the risk of sudden cardiac death, is associated with drug-induced QT-interval prolongation on the electrocardiogram (ECG). While many modern ECG machines provide automated measurements of the QT-interval, these automated QT values are usually correct only for a noise-free normal sinus rhythm, in which the T-wave morphology is well defined. As QT-prolonging drugs often affect the morphology of the T-wave, automated QT measurements taken under these circumstances are easily invalidated. An additional challenge is that the QT-value at risk of TdP varies with heart rate, with the slower the heart rate, the greater the risk of TdP. This paper presents an explainable algorithm that uses an understanding of human visual perception and expert ECG interpretation to automate the detection of QT-prolongation at risk of TdP regardless of heart rate and T-wave morphology. It was tested on a large number of ECGs (n=5050) with variable QT-intervals at varying heart rates, acquired from a clinical trial that assessed the effect of four known QT-prolonging drugs versus placebo on healthy subjects. The algorithm yielded a balanced accuracy of 0.97, sensitivity of 0.94, specificity of 0.99, F1-score of 0.88, ROC (AUC) of 0.98, precision-recall (AUC) of 0.88, and Matthews correlation coefficient (MCC) of 0.88. The results indicate that a prolonged ventricular repolarisation area can be a significant risk predictor of TdP, and detection of this is potentially easier and more reliable to automate than measuring the QT-interval distance directly. The proposed algorithm can be visualised using pseudo-colour on the ECG trace, thus intuitively 'explaining' how its decision was made, which results of a focus group show may help people to self-monitor QT-prolongation, as well as ensuring clinicians can validate its results.
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Affiliation(s)
- Alaa Alahmadi
- Department of Computer Science, The University of Manchester, Manchester, UK.
| | - Alan Davies
- Division of Informatics, Imaging and Data Sciences, School of Health Sciences, The University of Manchester, Manchester, UK.
| | - Jennifer Royle
- Digital Experimental Cancer Medicine Team, CRUK Manchester Institute, And the Christie NHS Foundation, Manchester, UK.
| | - Leanna Goodwin
- Digital Experimental Cancer Medicine Team, CRUK Manchester Institute, And the Christie NHS Foundation, Manchester, UK.
| | - Katharine Cresswell
- Cancer Precision Medicine and Cancer Prevention and Early Detection, NIHR Manchester Biomedical Research Centre (BRC), Manchester University NHS Foundation Trust, Manchester, UK.
| | - Zahra Arain
- Cancer Precision Medicine and Cancer Prevention and Early Detection, NIHR Manchester Biomedical Research Centre (BRC), Manchester University NHS Foundation Trust, Manchester, UK.
| | - Markel Vigo
- Department of Computer Science, The University of Manchester, Manchester, UK.
| | - Caroline Jay
- Department of Computer Science, The University of Manchester, Manchester, UK.
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Gu K, Qian D, Qin H, Cui C, Fernando WCHA, Wang D, Wang J, Cao K, Chen M. A novel mutation in KCNH2 yields loss-of-function of hERG potassium channel in long QT syndrome 2. Pflugers Arch 2021; 473:219-229. [PMID: 33449212 DOI: 10.1007/s00424-021-02518-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 12/24/2020] [Accepted: 01/07/2021] [Indexed: 12/16/2022]
Abstract
Mutations in hERG (human ether-à-go-go-related gene) potassium channel are closely associated with long QT syndromes. By direct Sanger sequencing, we identified a novel KCNH2 mutation W410R in the patient with long QT syndrome 2 (LQT2). However, the electrophysiological functions of this mutation remain unknown. In comparison to hERGWT channels, hERGW410R channels have markedly decreased total and surface expressions. W410R mutation dramatically reduces hERG channel currents (IKr) and shifts its steady-state activation curve to depolarization. Moreover, hERGW410R channels make dominant-negative effects on hERGWT channels. Significantly, we find hERG channel blocker E-4031 could partially rescue the function of hERGW410R channels by increasing the membrane expression. By using in silico model, we reveal that hERGW410R channels obviously elongate the repolarization of human ventricular myocyte action potentials. Collectively, W410R mutation decreases the currents of hERG channel, because of diminished membrane expression of mutant channels, that subsequently leads to elongated repolarization of cardiomyocyte, which might induce the pathogenesis of LQT2. Furthermore, E-4031 could partially rescue the decreased activity of hERGW410R channels. Thus, our work identifies a novel loss-of-function mutation in KCNH2 gene, which might provide a rational basis for the management of LQT2.
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Affiliation(s)
- Kai Gu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Duoduo Qian
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Huiyuan Qin
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - Chang Cui
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China
| | - W C Hewith A Fernando
- Department of Physiology, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, China
| | - Daowu Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.,State Key Laboratory of Reproductive Medicine, the Centre for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Juejin Wang
- Department of Physiology, Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, China.
| | - Kejiang Cao
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
| | - Minglong Chen
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
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40
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Park KC, Krywawych S, Richard E, Desviat LR, Swietach P. Cardiac Complications of Propionic and Other Inherited Organic Acidemias. Front Cardiovasc Med 2020; 7:617451. [PMID: 33415129 PMCID: PMC7782273 DOI: 10.3389/fcvm.2020.617451] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022] Open
Abstract
Clinical observations and experimental studies have determined that systemic acid-base disturbances can profoundly affect the heart. A wealth of information is available on the effects of altered pH on cardiac function but, by comparison, much less is known about the actions of the organic anions that accumulate alongside H+ ions in acidosis. In the blood and other body fluids, these organic chemical species can collectively reach concentrations of several millimolar in severe metabolic acidoses, as in the case of inherited organic acidemias, and exert powerful biological actions on the heart that are not intuitive to predict. Indeed, cardiac pathologies, such as cardiomyopathy and arrhythmia, are frequently reported in organic acidemia patients, but the underlying pathophysiological mechanisms are not well established. Research efforts in the area of organic anion physiology have increased dramatically in recent years, particularly for propionate, which accumulates in propionic acidemia, one of the commonest organic acidemias characterized by a high incidence of cardiac disease. This Review provides a comprehensive historical overview of all known organic acidemias that feature cardiac complications and a state-of-the-art overview of the cardiac sequelae observed in propionic acidemia. The article identifies the most promising candidates for molecular mechanisms that become aberrantly engaged by propionate anions (and its metabolites), and discusses how these may result in cardiac derangements in propionic acidemia. Key clinical and experimental findings are considered in the context of potential therapies in the near future.
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Affiliation(s)
- Kyung Chan Park
- Department of Anatomy, Physiology and Genetics, Burdon Sanderson Cardiac Science Centre, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
| | - Steve Krywawych
- Department of Chemical Pathology, Great Ormond Street Hospital, London, United Kingdom
| | - Eva Richard
- Centro de Biología Molecular Severo Ochoa, Universidad Autonoma de Madrid-Consejo Superior de Investigaciones Cientificas (UAM-CSIC), Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Lourdes R Desviat
- Centro de Biología Molecular Severo Ochoa, Universidad Autonoma de Madrid-Consejo Superior de Investigaciones Cientificas (UAM-CSIC), Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Pawel Swietach
- Department of Anatomy, Physiology and Genetics, Burdon Sanderson Cardiac Science Centre, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
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Long QT and Silver Russell syndrome: First case report in a 9-year-old girl. HeartRhythm Case Rep 2020; 6:591-595. [PMID: 32983873 PMCID: PMC7498520 DOI: 10.1016/j.hrcr.2020.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Alahmadi A, Davies A, Vigo M, Jay C. Pseudo-colouring an ECG enables lay people to detect QT-interval prolongation regardless of heart rate. PLoS One 2020; 15:e0237854. [PMID: 32853262 PMCID: PMC7451551 DOI: 10.1371/journal.pone.0237854] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 08/04/2020] [Indexed: 01/08/2023] Open
Abstract
Drug-induced long QT syndrome (diLQTS), characterized by a prolongation of the QT-interval on the electrocardiogram (ECG), is a serious adverse drug reaction that can cause the life-threatening arrhythmia Torsade de Points (TdP). Self-monitoring for diLQTS could therefore save lives, but detecting it on the ECG is difficult, particularly at high and low heart rates. In this paper, we evaluate whether using a pseudo-colouring visualisation technique and changing the coordinate system (Cartesian vs. Polar) can support lay people in identifying QT-prolongation at varying heart rates. Four visualisation techniques were evaluated using a counterbalanced repeated measures design including Cartesian no-colouring, Cartesian pseudo-colouring, Polar no-colouring and Polar pseudo-colouring. We used a multi-reader, multi-case (MRMC) receiver operating characteristic (ROC) study design within a psychophysical paradigm, along with eye-tracking technology. Forty-three lay participants read forty ECGs (TdP risk n = 20, no risk n = 20), classifying each QT-interval as normal/abnormal, and rating their confidence on a 6-point scale. The results show that introducing pseudo-colouring to the ECG significantly increased accurate detection of QT-interval prolongation regardless of heart rate, T-wave morphology and coordinate system. Pseudo-colour also helped to reduce reaction times and increased satisfaction when reading the ECGs. Eye movement analysis indicated that pseudo-colour helped to focus visual attention on the areas of the ECG crucial to detecting QT-prolongation. The study indicates that pseudo-colouring enables lay people to visually identify drug-induced QT-prolongation regardless of heart rate, with implications for the more rapid identification and management of diLQTS.
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Affiliation(s)
- Alaa Alahmadi
- Department of Computer Science, The University of Manchester, Manchester, United Kingdom
| | - Alan Davies
- Division of Informatics, Imaging and Data Sciences, School of Health Sciences, The University of Manchester, Manchester, United Kingdom
| | - Markel Vigo
- Department of Computer Science, The University of Manchester, Manchester, United Kingdom
| | - Caroline Jay
- Department of Computer Science, The University of Manchester, Manchester, United Kingdom
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Lammers A, Janssen NAH, Boere AJF, Berger M, Longo C, Vijverberg SJH, Neerincx AH, Maitland-van der Zee AH, Cassee FR. Effects of short-term exposures to ultrafine particles near an airport in healthy subjects. ENVIRONMENT INTERNATIONAL 2020; 141:105779. [PMID: 32402984 DOI: 10.1016/j.envint.2020.105779] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 05/20/2023]
Abstract
BACKGROUND Recent studies reported elevated concentrations of ultrafine particles (UFP) near airports. Little is known about the health effects of UFP from aviation. Since UFP can deposit deep into the lungs and other organs, they may cause significant adverse health effects. OBJECTIVE We investigated health effects of controlled short-term human exposure to UFP near a major airport. METHODS In this study, 21 healthy non-smoking volunteers (age range: 18-35 years) were repeatedly (2-5 visits) exposed for 5 h to ambient air near Schiphol Airport, while performing intermittent moderate exercise (i.e. cycling). Pre- to post-exposure changes in cardiopulmonary outcomes (spirometry, forced exhaled nitric oxide, electrocardiography and blood pressure) were assessed and related to total- and size-specific particle number concentrations (PNC), using linear mixed effect models. RESULTS The PNC was on average 53,500 particles/cm3 (range 10,500-173,200). A 5-95th percentile increase in exposure to UFP (i.e. 125,400 particles/cm3) was associated with a decrease in FVC of -73.8 mL (95% CI -138.8 - -0.4) and a prolongation of the corrected QT (QTc) interval by 9.9 ms (95% CI 2.0 - 19.1). These effects were associated with particles < 20 nm (mainly UFP from aviation), but not with particles > 50 nm (mainly UFP from road traffic). DISCUSSION Short-term exposures to aviation-related UFP near a major airport, was associated with decreased lung function (mainly FVC) and a prolonged QTc interval in healthy volunteers. The effects were relatively small, however, they appeared after single exposures of 5 h in young healthy adults. As this study cannot make any inferences about long-term health impacts, appropriate studies investigating potential health effects of long-term exposure to airport-related UFP, are urgently needed.
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Affiliation(s)
- A Lammers
- Amsterdam UMC, University of Amsterdam, Department of Respiratory Medicine, Meibergdreef 9, Amsterdam, The Netherlands
| | - N A H Janssen
- National Institute for Public Health and the Environment (RIVM), Centre for Sustainability, Environment and Health, Antonie van Leeuwenhoeklaan 9, 3721 MA Bilthoven, The Netherlands
| | - A J F Boere
- National Institute for Public Health and the Environment (RIVM), Centre for Sustainability, Environment and Health, Antonie van Leeuwenhoeklaan 9, 3721 MA Bilthoven, The Netherlands
| | - M Berger
- Amsterdam UMC, University of Amsterdam, Department of Respiratory Medicine, Meibergdreef 9, Amsterdam, The Netherlands
| | - C Longo
- Amsterdam UMC, University of Amsterdam, Department of Respiratory Medicine, Meibergdreef 9, Amsterdam, The Netherlands
| | - S J H Vijverberg
- Amsterdam UMC, University of Amsterdam, Department of Respiratory Medicine, Meibergdreef 9, Amsterdam, The Netherlands
| | - A H Neerincx
- Amsterdam UMC, University of Amsterdam, Department of Respiratory Medicine, Meibergdreef 9, Amsterdam, The Netherlands
| | - A H Maitland-van der Zee
- Amsterdam UMC, University of Amsterdam, Department of Respiratory Medicine, Meibergdreef 9, Amsterdam, The Netherlands
| | - F R Cassee
- National Institute for Public Health and the Environment (RIVM), Centre for Sustainability, Environment and Health, Antonie van Leeuwenhoeklaan 9, 3721 MA Bilthoven, The Netherlands; Institute for Risk Assessment Sciences at the Utrecht University, Yalelaan 2, 3584 CM Utrecht, The Netherlands.
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Wang Y, Eldstrom J, Fedida D. Gating and Regulation of KCNQ1 and KCNQ1 + KCNE1 Channel Complexes. Front Physiol 2020; 11:504. [PMID: 32581825 PMCID: PMC7287213 DOI: 10.3389/fphys.2020.00504] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 04/24/2020] [Indexed: 12/20/2022] Open
Abstract
The IKs channel complex is formed by the co-assembly of Kv7.1 (KCNQ1), a voltage-gated potassium channel, with its β-subunit, KCNE1 and the association of numerous accessory regulatory molecules such as PIP2, calmodulin, and yotiao. As a result, the IKs potassium current shows kinetic and regulatory flexibility, which not only allows IKs to fulfill physiological roles as disparate as cardiac repolarization and the maintenance of endolymph K+ homeostasis, but also to cause significant disease when it malfunctions. Here, we review new areas of understanding in the assembly, kinetics of activation and inactivation, voltage-sensor pore coupling, unitary events and regulation of this important ion channel complex, all of which have been given further impetus by the recent solution of cryo-EM structural representations of KCNQ1 alone and KCNQ1+KCNE3. Recently, the stoichiometric ratio of KCNE1 to KCNQ1 subunits has been confirmed to be variable up to a ratio of 4:4, rather than fixed at 2:4, and we will review the results and new methodologies that support this conclusion. Significant advances have been made in understanding differences between KCNQ1 and IKs gating using voltage clamp fluorimetry and mutational analysis to illuminate voltage sensor activation and inactivation, and the relationship between voltage sensor translation and pore domain opening. We now understand that the KCNQ1 pore can open with different permeabilities and conductance when the voltage sensor is in partially or fully activated positions, and the ability to make robust single channel recordings from IKs channels has also revealed the complicated pore subconductance architecture during these opening steps, during inactivation, and regulation by 1−4 associated KCNE1 subunits. Experiments placing mutations into individual voltage sensors to drastically change voltage dependence or prevent their movement altogether have demonstrated that the activation of KCNQ1 alone and IKs can best be explained using allosteric models of channel gating. Finally, we discuss how the intrinsic gating properties of KCNQ1 and IKs are highly modulated through the impact of intracellular signaling molecules and co-factors such as PIP2, protein kinase A, calmodulin and ATP, all of which modulate IKs current kinetics and contribute to diverse IKs channel complex function.
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Affiliation(s)
- Yundi Wang
- Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, BC, Canada
| | - Jodene Eldstrom
- Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, BC, Canada
| | - David Fedida
- Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, BC, Canada
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Brewer KR, Kuenze G, Vanoye CG, George AL, Meiler J, Sanders CR. Structures Illuminate Cardiac Ion Channel Functions in Health and in Long QT Syndrome. Front Pharmacol 2020; 11:550. [PMID: 32431610 PMCID: PMC7212895 DOI: 10.3389/fphar.2020.00550] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/09/2020] [Indexed: 12/13/2022] Open
Abstract
The cardiac action potential is critical to the production of a synchronized heartbeat. This electrical impulse is governed by the intricate activity of cardiac ion channels, among them the cardiac voltage-gated potassium (Kv) channels KCNQ1 and hERG as well as the voltage-gated sodium (Nav) channel encoded by SCN5A. Each channel performs a highly distinct function, despite sharing a common topology and structural components. These three channels are also the primary proteins mutated in congenital long QT syndrome (LQTS), a genetic condition that predisposes to cardiac arrhythmia and sudden cardiac death due to impaired repolarization of the action potential and has a particular proclivity for reentrant ventricular arrhythmias. Recent cryo-electron microscopy structures of human KCNQ1 and hERG, along with the rat homolog of SCN5A and other mammalian sodium channels, provide atomic-level insight into the structure and function of these proteins that advance our understanding of their distinct functions in the cardiac action potential, as well as the molecular basis of LQTS. In this review, the gating, regulation, LQTS mechanisms, and pharmacological properties of KCNQ1, hERG, and SCN5A are discussed in light of these recent structural findings.
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Affiliation(s)
- Kathryn R. Brewer
- Center for Structural Biology, Vanderbilt University School of Medicine Basic Sciences, Nashville, TN, United States
- Department of Biochemistry, Vanderbilt University, Nashville, TN, United States
| | - Georg Kuenze
- Center for Structural Biology, Vanderbilt University School of Medicine Basic Sciences, Nashville, TN, United States
- Department of Chemistry, Vanderbilt University, Nashville, TN, United States
| | - Carlos G. Vanoye
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Alfred L. George
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Jens Meiler
- Center for Structural Biology, Vanderbilt University School of Medicine Basic Sciences, Nashville, TN, United States
- Department of Chemistry, Vanderbilt University, Nashville, TN, United States
- Department of Pharmacology, Vanderbilt University School of Medicine Basic Sciences, Nashville, TN, United States
- Institute for Drug Discovery, Leipzig University Medical School, Leipzig, Germany
| | - Charles R. Sanders
- Center for Structural Biology, Vanderbilt University School of Medicine Basic Sciences, Nashville, TN, United States
- Department of Biochemistry, Vanderbilt University, Nashville, TN, United States
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Kim SY, Kim KH, Schilling JM, Leem J, Dhanani M, Head BP, Roth DM, Zemljic-Harpf AE, Patel HH. Protective role of cardiac-specific overexpression of caveolin-3 in cirrhotic cardiomyopathy. Am J Physiol Gastrointest Liver Physiol 2020; 318:G531-G541. [PMID: 31961720 PMCID: PMC7099497 DOI: 10.1152/ajpgi.00346.2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by blunted cardiac contractile responses to stress and/or heart rate-corrected QT (QTc) interval prolongation. Caveolin-3 (Cav-3) plays a critical role in cardiac protection and is an emerging therapeutic target for heart disease. We investigated the protective role of cardiac-specific overexpression (OE) of Cav-3 in cirrhotic cardiomyopathy. Biliary fibrosis was induced in male Cav-3 OE mice and transgene negative (TGneg) littermates by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 0.1%) for 3 wk. Liver pathology and blood chemistries were assessed, and stress echocardiography, telemetry, and isolated heart perfusion studies to assess adrenergic responsiveness were performed. Cav-3 OE mice showed a similar degree of hyperdynamic contractility, pulmonary hypertension, and QTc interval prolongation as TGneg mice after 3 wk of DDC diet. Blunted systolic responses were shown in both DDC-fed Cav-3 OE and TGneg hearts after in vivo isoproterenol challenge. However, QTc interval prolongation after in vivo isoproterenol challenge was significantly less in DDC-fed Cav-3 OE hearts compared with DDC-fed TGneg hearts. In ex vivo perfused hearts, where circulatory factors are absent, isoproterenol challenge showed hearts from DDC-fed Cav-3 OE mice had better cardiac contractility and relaxation compared with DDC-fed TGneg hearts. Although Cav-3 OE in the heart did not prevent cardiac alterations in DDC-induced biliary fibrosis, cardiac expression of Cav-3 reduced QTc interval prolongation after adrenergic stimulation in cirrhosis.NEW & NOTEWORTHY Prevalence of cirrhotic cardiomyopathy is up to 50% in cirrhotic patients, and liver transplantation is the only treatment. However, cirrhotic cardiomyopathy is associated with perioperative morbidity and mortality after liver transplantation; therefore, management of cirrhotic cardiomyopathy is crucial for successful liver transplantation. This study shows cardiac myocyte specific overexpression of caveolin-3 (Cav-3) provides better cardiac contractile responses and less corrected QT prolongation during adrenergic stress in a cirrhotic cardiomyopathy model, suggesting beneficial effects of Cav-3 expression in cirrhotic cardiomyopathy.
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Affiliation(s)
- So Yeon Kim
- 1Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kang Ho Kim
- 2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Jan M. Schilling
- 3Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California
| | - Joseph Leem
- 3Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California
| | - Mehul Dhanani
- 3Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California
| | - Brian P. Head
- 3Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California
| | - David M. Roth
- 3Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California
| | - Alice E. Zemljic-Harpf
- 3Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California
| | - Hemal H. Patel
- 3Veterans Administration San Diego Healthcare System and the Department of Anesthesiology, University of California, San Diego, School of Medicine, San Diego, California
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Beard JM, Shockett PE, O'Reilly JP. Substituted cysteine scanning in D1-S6 of the sodium channel hNav1.4 alters kinetics and structural interactions of slow inactivation. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183129. [PMID: 31738900 DOI: 10.1016/j.bbamem.2019.183129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 10/25/2019] [Accepted: 11/08/2019] [Indexed: 10/25/2022]
Abstract
Slow inactivation in voltage-gated Na+ channels (Navs) plays an important physiological role in excitable tissues (muscle, heart, nerves) and mutations that disrupt Nav slow inactivation can result in pathophysiologies (myotonia, arrhythmias, epilepsy). While the molecular mechanisms responsible for slow inactivation remain elusive, previous studies have suggested a role for the pore-lining D1-S6 helix. The goals of this research were to determine if (1) cysteine substitutions in D1-S6 affect gating kinetics and (2) methanethiosulfonate ethylammonium (MTSEA) accessibility changes in different kinetic states. Site-directed mutagenesis in the human skeletal muscle isoform hNav1.4 was used to substitute cysteine for eleven amino acids in D1-S6 from L433 to L443. Mutants were expressed in HEK cells and recorded from with whole-cell patch clamp. All mutations affected one or more baseline kinetics of the sodium channel, including activation, fast inactivation, and slow inactivation. Substitution of cysteine (for nonpolar residues) adjacent to polar residues destabilized slow inactivation in G434C, F436C, I439C, and L441C. Cysteine substitution without adjacent polar residues enhanced slow inactivation in L438C and N440C, and disrupted possible H-bonds involving Y437:D4 S4-S5 and N440:D4-S6. MTSEA exposure in closed, fast-inactivated, or slow-inactivated states in most mutants had little-to-no effect. In I439C, MTSEA application in closed, fast-inactivated, and slow-inactivated states produced irreversible reduction in current, suggesting I439C accessibility to MTSEA in all three kinetic states. D1-S6 is important for Nav gating kinetics, stability of slow-inactivated state, structural contacts, and state-dependent positioning. However, prominent reconfiguration of D1-S6 may not occur in slow inactivation.
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Affiliation(s)
- Jonathan M Beard
- Department of Biological Sciences, Southeastern Louisiana University, Hammond, LA, USA.
| | - Penny E Shockett
- Department of Biological Sciences, Southeastern Louisiana University, Hammond, LA, USA.
| | - John P O'Reilly
- Department of Biological Sciences, Southeastern Louisiana University, Hammond, LA, USA.
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Genova E, Cavion F, Lucafò M, Leo LD, Pelin M, Stocco G, Decorti G. Induced pluripotent stem cells for therapy personalization in pediatric patients: Focus on drug-induced adverse events. World J Stem Cells 2019; 11:1020-1044. [PMID: 31875867 PMCID: PMC6904863 DOI: 10.4252/wjsc.v11.i12.1020] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 09/05/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023] Open
Abstract
Adverse drug reactions (ADRs) are major clinical problems, particularly in special populations such as pediatric patients. Indeed, ADRs may be caused by a plethora of different drugs leading, in some cases, to hospitalization, disability or even death. In addition, pediatric patients may respond differently to drugs with respect to adults and may be prone to developing different kinds of ADRs, leading, in some cases, to more severe consequences. To improve the comprehension, and thus the prevention, of ADRs, the set-up of sensitive and personalized assays is urgently needed. Important progress is represented by the possibility of setting up groundbreaking patient-specific assays. This goal has been powerfully achieved using induced pluripotent stem cells (iPSCs). Due to their genetic and physiological species-specific differences and their ability to be differentiated ideally into all tissues of the human body, this model may be accurate in predicting drug toxicity, especially when this toxicity is related to individual genetic differences. This review is an up-to-date summary of the employment of iPSCs as a model to study ADRs, with particular attention to drugs used in the pediatric field. We especially focused on the intestinal, hepatic, pancreatic, renal, cardiac, and neuronal levels, also discussing progress in organoids creation. The latter are three-dimensional in vitro culture systems derived from pluripotent or adult stem cells simulating the architecture and functionality of native organs such as the intestine, liver, pancreas, kidney, heart, and brain. Based on the existing knowledge, these models are powerful and promising tools in multiple clinical applications including toxicity screening, disease modeling, personalized and regenerative medicine.
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Affiliation(s)
- Elena Genova
- PhD School in Reproduction and Development Sciences, University of Trieste, Trieste 34127, Italy
| | - Federica Cavion
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Marianna Lucafò
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste 34137, Italy
| | - Luigina De Leo
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste 34137, Italy
| | - Marco Pelin
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy.
| | - Giuliana Decorti
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste 34137, Italy
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Ronzier E, Parks XX, Qudsi H, Lopes CM. Statin-specific inhibition of Rab-GTPase regulates cPKC-mediated IKs internalization. Sci Rep 2019; 9:17747. [PMID: 31780674 PMCID: PMC6882895 DOI: 10.1038/s41598-019-53700-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 10/21/2019] [Indexed: 12/18/2022] Open
Abstract
Statins are prescribed for prevention and treatment of coronary artery disease. Statins have different cholesterol lowering abilities, with rosuvastatin and atorvastatin being the most effective, while statins like simvastatin and fluvastatin having lower effectiveness. Statins, in addition to their cholesterol lowering effects, can prevent isoprenylation of Rab-GTPase proteins, a protein family important for the regulation of membrane-bound protein trafficking. Here we show that endosomal localization of Rab-GTPases (Rab5, Rab7 and Rab11) was inhibited in a statin-specific manner, with stronger effects by fluvastatin, followed by simvastatin and atorvastatin, and with a limited effect by rosuvastatin. Fluvastatin inhibition of Rab5 has been shown to mediate cPKC-dependent trafficking regulation of the cardiac delayed rectifier KCNQ1/KCNE1 channels. We observed statin-specific inhibition of channel regulation consistent with statin-specific Rab-GTPase inhibition both in heterologous systems and cardiomyocytes. Our results uncover a non-cholesterol-reducing statin-specific effect of statins. Because Rab-GTPases are important regulators of membrane trafficking they may underlie statin specific pleiotropic effects. Therefore, statin-specificity may allow better treatment tailoring.
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Affiliation(s)
- Elsa Ronzier
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY, 14642, USA
| | - Xiaorong Xu Parks
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY, 14642, USA
| | - Haani Qudsi
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY, 14642, USA
| | - Coeli M Lopes
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY, 14642, USA.
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50
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PKCβII specifically regulates KCNQ1/KCNE1 channel membrane localization. J Mol Cell Cardiol 2019; 138:283-290. [PMID: 31785237 DOI: 10.1016/j.yjmcc.2019.10.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 09/06/2019] [Accepted: 10/09/2019] [Indexed: 01/15/2023]
Abstract
The slow voltage-gated potassium channel (IKs) is composed of the KCNQ1 and KCNE1 subunits and is one of the major repolarizing currents in the heart. Activation of protein kinase C (PKC) has been linked to cardiac arrhythmias. Although PKC has been shown to be a regulator of a number of cardiac channels, including IKs, little is known about regulation of the channel by specific isoforms of PKC. Here we studied the role of different PKC isoforms on IKs channel membrane localization and function. Our studies focused on PKC isoforms that translocate to the plasma membrane in response to Gq-coupled receptor (GqPCR) stimulation: PKCα, PKCβI, PKCβII and PKCε. Prolonged stimulation of GqPCRs has been shown to decrease IKs membrane expression, but the specific role of each PKC isoform is unclear. Here we show that stimulation of calcium-dependent isoforms of PKC (cPKC) but not PKCε mimic receptor activation. In addition, we show that general PKCβ (LY-333531) and PKCβII inhibitors but not PKCα or PKCβI inhibitors blocked the effect of cPKC on the KCNQ1/KCNE1 channel. PKCβ inhibitors also blocked GqPCR-mediated decrease in channel membrane expression in cardiomyocytes. Direct activation of PKCβII using constitutively active PKCβII construct mimicked agonist-induced decrease in membrane expression and channel function, while dominant negative PKCβII showed no effect. This suggests that the KCNQ1/KCNE1 channel was not regulated by basal levels of PKCβII activity. Our results indicate that PKCβII is a specific regulator of IKs membrane localization. PKCβII expression and activation are strongly increased in many disease states, including heart disease and diabetes. Thus, our results suggest that PKCβII inhibition may protect against acquired QT prolongation associated with heart disease.
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