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Schneider L, Begovic M, Zhou X, Hamdani N, Akin I, El-Battrawy I. Catecholaminergic Polymorphic Ventricular Tachycardia: Advancing From Molecular Insights to Preclinical Models. J Am Heart Assoc 2025; 14:e038308. [PMID: 40079282 DOI: 10.1161/jaha.124.038308] [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: 08/14/2024] [Accepted: 12/19/2024] [Indexed: 03/15/2025]
Abstract
Inherited cardiac channelopathies are linked to a heightened risk of sudden cardiac death. Despite evolving knowledge on different genes for these inherited conditions, for certain subtypes, such as catecholaminergic polymorphic ventricular tachycardia syndrome, the specific genetic causes remain unidentified. The research of the pathophysiological mechanisms underlying catecholaminergic polymorphic ventricular tachycardia syndrome has been conducted through different in vitro and in vivo models, including genetically modified animal models, cardiac-specific transgenic models, pharmacological interventions in animal models, human-induced pluripotent stem cell-derived cardiomyocytes in 2- and 3-dimensional cardiac models. Recent research predominantly utilizes human-induced pluripotent stem cell-derived cardiomyocytes, focusing on genotype-phenotype correlations and pharmacological screening. The integration of cutting-edge techniques such as clustered regularly interspaced short palindromic repeats/Cas9 genome editing and 3-dimensional-engineered heart tissues has shed new light on the pathophysiological mechanisms of catecholaminergic polymorphic ventricular tachycardia, potentially enhancing drug therapies as part of personalized medicine approaches. This review emphasizes the diverse insights gained from both in vivo and in vitro studies of catecholaminergic polymorphic ventricular tachycardia, along with the application of these models in various research contexts.
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Affiliation(s)
- Luca Schneider
- Department of Cellular and Translational Physiology, Institute of Physiology Ruhr-University Bochum Bochum Germany
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, St. Josef Hospital Ruhr-University Bochum Bochum Germany
| | - Merima Begovic
- Department of Cellular and Translational Physiology, Institute of Physiology Ruhr-University Bochum Bochum Germany
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, St. Josef Hospital Ruhr-University Bochum Bochum Germany
| | - Xiaobo Zhou
- Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, Medical Centre Mannheim, Medical Faculty Mannheim Heidelberg University Mannheim Germany
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research, Southwest Medical University Luzhou Sichuan China
| | - Nazha Hamdani
- Department of Cellular and Translational Physiology, Institute of Physiology Ruhr-University Bochum Bochum Germany
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, St. Josef Hospital Ruhr-University Bochum Bochum Germany
- Department of Physiology Cardiovascular Research Institute, University Maastricht Maastricht The Netherlands
- HCEMM-SU Cardiovascular Comorbidities Research Group, Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy Intézet címe Semmelweis University Budapest Hungary
- Department of Cardiology and Rhythmology St. Josef Hospital, Ruhr University Bochum Germany
| | - Ibrahim Akin
- Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, Medical Centre Mannheim, Medical Faculty Mannheim Heidelberg University Mannheim Germany
| | - Ibrahim El-Battrawy
- Department of Cellular and Translational Physiology, Institute of Physiology Ruhr-University Bochum Bochum Germany
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, St. Josef Hospital Ruhr-University Bochum Bochum Germany
- Department of Cardiology and Rhythmology St. Josef Hospital, Ruhr University Bochum Germany
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Kim K, Kim S, Katana M, Terentyev D, Radwański PB, Munger MA. Riluzole is associated with reduced risk of heart failure. Eur J Neurol 2025; 32:e70033. [PMID: 39786321 PMCID: PMC11716981 DOI: 10.1111/ene.70033] [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: 09/12/2024] [Accepted: 12/18/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Reduction of intracellular Na+ accumulation through late Na+ current inhibition has been recognized as a target for cardiac Ca2+ handling which underlies myocardial contractility and relaxation in heart failure (HF). Riluzole, an Na+ channel blocker with enhancement of Ca2+-activated K+ channel function, used for management of amyotrophic lateral sclerosis (ALS), is effective in suppressing Ca2+ leak and therefore may improve cardiac function. OBJECTIVES The study aim was to investigate whether riluzole lowers HF incidence. METHODS Rates of HF incident were compared using a commercial insurance and Medicare supplement claims databases. Patients with a filled riluzole prescription (treatment) between 06/2009 and 12/2019 were compared to those with no-riluzole (control). We excluded HF patients during the 180-day baseline period. Study endpoint was the first HF diagnosis from the index riluzole prescription or ALS diagnosis. HF onset was compared between the propensity score matched treatment and control cohorts. RESULTS The matched cohort consisted of 4060 pairs of riluzole/control patients. The 24-month cumulative incidence of HF onset for riluzole versus control patients was 4.96% versus 7.27%, calculating hazard ratio (HR) [95% CI, p-value] of 0.55 [0.40-0.76, p < 0.01]. The HR estimates favoring riluzole over the ALS control were consistent across the 3 months to 2-year follow-up. The clinically and statistically significant effect on HF onset was driven by the lower rate of HFrEF with the 2-year HR [95% CI] of 0.46 [0.21-0.99]. CONCLUSIONS Riluzole is associated with a lower rate of HF onset, suggesting a potential prevention strategy for early management.
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Affiliation(s)
- Kibum Kim
- Department of Pharmacy Systems and Outcomes and PolicyUniversity of Illinois ChicagoChicagoIllinoisUSA
| | - Sodam Kim
- Department of Pharmacy Systems and Outcomes and PolicyUniversity of Illinois ChicagoChicagoIllinoisUSA
| | - Margaret Katana
- Department of Pharmacy Systems and Outcomes and PolicyUniversity of Illinois ChicagoChicagoIllinoisUSA
| | - Dmitry Terentyev
- Department of Physiology and Cell BiologyThe Ohio State UniversityColumbusOhioUSA
- The Frick Center for Heart Failure and ArrhythmiaDorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical CenterColumbusOhioUSA
| | - Przemysław B. Radwański
- The Frick Center for Heart Failure and ArrhythmiaDorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical CenterColumbusOhioUSA
- Division of Pharmaceutics and PharmacologyCollege of Pharmacy, the Ohio State UniversityColumbusOhioUSA
| | - Mark A. Munger
- Department of PharmacotherapyUniversity of Utah HealthSalt Lake CityUtahUSA
- Department of Internal MedicineUniversity of Utah HealthSalt Lake CityUtahUSA
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Begovic M, Schneider L, Zhou X, Hamdani N, Akin I, El-Battrawy I. The Role of Human-Induced Pluripotent Stem Cells in Studying Cardiac Channelopathies. Int J Mol Sci 2024; 25:12034. [PMID: 39596103 PMCID: PMC11593457 DOI: 10.3390/ijms252212034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 10/22/2024] [Accepted: 11/03/2024] [Indexed: 11/28/2024] Open
Abstract
Cardiac channelopathies are inherited diseases that increase the risk of sudden cardiac death. While different genes have been associated with inherited channelopathies, there are still subtypes, e.g., catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome, where the genetic cause remains unknown. Various models, including animal models, heterologous expression systems, and the human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSCs-CMs) model, have been used to study the pathophysiological mechanisms of channelopathies. Recently, researchers have focused on using hiPSCs-CMs to understand the genotype-phenotype correlation and screen drugs. By combining innovative techniques such as Clustered Regularly Interspaced Short Palindromic Repeats/Clustered Regularly Interspaced Short Palindromic Repeats associated protein 9 (CRISPR/Cas9)-mediated genome editing, and three-dimensional (3D) engineered heart tissues, we can gain new insights into the pathophysiological mechanisms of channelopathies. This approach holds promise for improving personalized drug treatment. This review highlights the role of hiPSCs-CMs in understanding the pathomechanism of Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia and how these models can be utilized for drug screening.
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Affiliation(s)
- Merima Begovic
- Institute of Physiology, Department of Cellular and Translational Physiology, Ruhr-University Bochum, 44801 Bochum, Germany; (M.B.); (L.S.); (N.H.)
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Luca Schneider
- Institute of Physiology, Department of Cellular and Translational Physiology, Ruhr-University Bochum, 44801 Bochum, Germany; (M.B.); (L.S.); (N.H.)
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Xiaobo Zhou
- Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China
| | - Nazha Hamdani
- Institute of Physiology, Department of Cellular and Translational Physiology, Ruhr-University Bochum, 44801 Bochum, Germany; (M.B.); (L.S.); (N.H.)
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
- Department of Physiology, Cardiovascular Research Institute, University Maastricht, 6229HX Maastricht, The Netherlands
- HCEMM-SU Cardiovascular Comorbidities Research Group, Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Intézet címe Semmelweis University, 1089 Budapest, Hungary
- Department of Cardiology and Rhythmology, St. Josef Hospital, Ruhr University, 44791 Bochum, Germany
| | - Ibrahim Akin
- Cardiology, Angiology, Haemostaseology, and Medical Intensive Care, Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Ibrahim El-Battrawy
- Institute of Physiology, Department of Cellular and Translational Physiology, Ruhr-University Bochum, 44801 Bochum, Germany; (M.B.); (L.S.); (N.H.)
- Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
- Department of Cardiology and Rhythmology, St. Josef Hospital, Ruhr University, 44791 Bochum, Germany
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Rody E, Zwaig J, Derish I, Khan K, Kachurina N, Gendron N, Giannetti N, Schwertani A, Cecere R. Evaluating the Reparative Potential of Secretome from Patient-Derived Induced Pluripotent Stem Cells during Ischemia-Reperfusion Injury in Human Cardiomyocytes. Int J Mol Sci 2024; 25:10279. [PMID: 39408608 PMCID: PMC11477076 DOI: 10.3390/ijms251910279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/29/2024] [Accepted: 09/03/2024] [Indexed: 10/20/2024] Open
Abstract
During a heart attack, ischemia causes losses of billions of cells; this is especially concerning given the minimal regenerative capability of cardiomyocytes (CMs). Heart remuscularization utilizing stem cells has improved cardiac outcomes despite little cell engraftment, thereby shifting focus to cell-free therapies. Consequently, we chose induced pluripotent stem cells (iPSCs) given their pluripotent nature, efficacy in previous studies, and easy obtainability from minimally invasive techniques. Nonetheless, using iPSC secretome-based therapies for treating injured CMs in a clinical setting is ill-understood. We hypothesized that the iPSC secretome, regardless of donor health, would improve cardiovascular outcomes in the CM model of ischemia-reperfusion (IR) injury. Episomal-generated iPSCs from healthy and dilated cardiomyopathy (DCM) donors, passaged 6-10 times, underwent 24 h incubation in serum-free media. Protein content of the secretome was analyzed by mass spectroscopy and used to treat AC16 immortalized CMs during 5 h reperfusion following 24 h of hypoxia. IPSC-derived secretome content, independent of donor health status, had elevated expression of proteins involved in cell survival pathways. In IR conditions, iPSC-derived secretome increased cell survival as measured by metabolic activity (p < 0.05), cell viability (p < 0.001), and maladaptive cellular remodelling (p = 0.052). Healthy donor-derived secretome contained increased expression of proteins related to calcium contractility compared to DCM donors. Congruently, only healthy donor-derived secretomes improved CM intracellular calcium concentrations (p < 0.01). Heretofore, secretome studies mainly investigated differences relating to cell type rather than donor health. Our work suggests that healthy donors provide more efficacious iPSC-derived secretome compared to DCM donors in the context of IR injury in human CMs. These findings illustrate that the regenerative potential of the iPSC secretome varies due to donor-specific differences.
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Affiliation(s)
- Elise Rody
- Department of Surgery, Division of Cardiac Surgery, McGill University Health Center, Montreal, QC H4A 3J1, Canada
| | - Jeremy Zwaig
- Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada; (J.Z.)
| | - Ida Derish
- Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada; (J.Z.)
- Department of Surgical and Interventional Sciences, McGill University, Montreal, QC H3G 1A4, Canada
| | - Kashif Khan
- Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada; (J.Z.)
- Department of Medicine, Division of Cardiology, McGill University Health Center, Montreal, QC H4A 3J1, Canada (N.G.)
| | - Nadezda Kachurina
- Department of Medicine, Division of Cardiology, McGill University Health Center, Montreal, QC H4A 3J1, Canada (N.G.)
| | - Natalie Gendron
- Department of Medicine, Division of Cardiology, McGill University Health Center, Montreal, QC H4A 3J1, Canada (N.G.)
| | - Nadia Giannetti
- Department of Medicine, Division of Cardiology, McGill University Health Center, Montreal, QC H4A 3J1, Canada (N.G.)
| | - Adel Schwertani
- Department of Medicine, Division of Cardiology, McGill University Health Center, Montreal, QC H4A 3J1, Canada (N.G.)
| | - Renzo Cecere
- Department of Surgery, Division of Cardiac Surgery, McGill University Health Center, Montreal, QC H4A 3J1, Canada
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Sleiman Y, Reisqs JB, Boutjdir M. Differentiation of Sinoatrial-like Cardiomyocytes as a Biological Pacemaker Model. Int J Mol Sci 2024; 25:9155. [PMID: 39273104 PMCID: PMC11394733 DOI: 10.3390/ijms25179155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/16/2024] [Accepted: 08/18/2024] [Indexed: 09/15/2024] Open
Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are widely used for disease modeling and pharmacological screening. However, their application has mainly focused on inherited cardiopathies affecting ventricular cardiomyocytes, leading to extensive knowledge on generating ventricular-like hiPSC-CMs. Electronic pacemakers, despite their utility, have significant disadvantages, including lack of hormonal responsiveness, infection risk, limited battery life, and inability to adapt to changes in heart size. Therefore, developing an in vitro multiscale model of the human sinoatrial node (SAN) pacemaker using hiPSC-CM and SAN-like cardiomyocyte differentiation protocols is essential. This would enhance the understanding of SAN-related pathologies and support targeted therapies. Generating SAN-like cardiomyocytes offers the potential for biological pacemakers and specialized conduction tissues, promising significant benefits for patients with conduction system defects. This review focuses on arrythmias related to pacemaker dysfunction, examining protocols' advantages and drawbacks for generating SAN-like cardiomyocytes from hESCs/hiPSCs, and discussing therapeutic approaches involving their engraftment in animal models.
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Affiliation(s)
- Yvonne Sleiman
- Cardiovascular Research Program, VA New York Harbor Healthcare System, New York, NY 11209, USA
| | - Jean-Baptiste Reisqs
- Cardiovascular Research Program, VA New York Harbor Healthcare System, New York, NY 11209, USA
| | - Mohamed Boutjdir
- Cardiovascular Research Program, VA New York Harbor Healthcare System, New York, NY 11209, USA
- Department of Medicine, Cell Biology and Pharmacology, State University of New York Downstate Health Sciences University, New York, NY 11203, USA
- Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
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Jiang T, Ma C, Wang Z, Miao Y. A review of local anesthetic-induced heart toxicity using human induced pluripotent stem cell-derived cardiomyocytes. Mol Cell Probes 2024; 76:101965. [PMID: 38823509 DOI: 10.1016/j.mcp.2024.101965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 05/11/2024] [Accepted: 05/29/2024] [Indexed: 06/03/2024]
Abstract
Local anesthetic (LA) cardiotoxicity is one of the main health problems in anesthesiology and pain management. This study reviewed the reported LA-induced cardiac toxicity types, risk factors, management, and mechanisms, with attention to the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in heart toxicity research. Important scientific databases were searched to find relevant articles. We briefly assessed the reported cardiotoxic effects of different types of LA drugs, including ester- and amide-linked LA agents. Furthermore, cardiotoxic effects and clinical manifestations, strategies for preventing and managing LA-induced cardiotoxic effects, pharmacokinetics, pharmacodynamics, and sodium channel dynamics regarding individual variability and genetic influences were discussed in this review. The applications and importance of hiPSC-CMs cellular model for evaluating the cardiotoxic effects of LA drugs were discussed in detail. This review also explored hiPSC-CMs' potential in risk assessment, drug screening, and developing targeted therapies. The main mechanisms underlying LA-induced cardiotoxicity included perturbation in sodium channels, ROS production, and disorders in the immune system response due to the presence of LA drugs. Furthermore, drug-specific characteristics including pharmacokinetics and pharmacodynamics are important determinants after LA drug injection. In addition, individual patient factors such as age, comorbidities, and genetic variability emphasize the need for a personalized approach to mitigate risks and enhance patient safety. The strategies outlined for the prevention and management of LA cardiotoxicity underscore the importance of careful dosing, continuous monitoring, and the immediate availability of resuscitation equipment. This comprehensive review can be used to guide future investigations into better understanding LA cardiac toxicities and improving patient safety.
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Affiliation(s)
- Ting Jiang
- Department of Anesthesiology, Xi'an Children's Hospital, Xi'an, 710002, China
| | - Chao Ma
- Department of Anesthesiology, Xi'an Children's Hospital, Xi'an, 710002, China
| | - Zitong Wang
- Health Science Center, Lanzhou University, Lanzhou, 730000, China
| | - Yi Miao
- Department of Anesthesiology, Xi'an Children's Hospital, Xi'an, 710002, China.
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Biswas PK, Park J. Applications, challenges, and prospects of induced pluripotent stem cells for vascular disease. Mol Cells 2024; 47:100077. [PMID: 38825189 PMCID: PMC11260847 DOI: 10.1016/j.mocell.2024.100077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/04/2024] Open
Abstract
Vascular disease, including heart disease, stroke, and peripheral arterial disease, is one of the leading causes of death and disability and represents a significant global health issue. Since the development of human induced pluripotent stem cells (hiPSCs) in 2007, hiPSCs have provided unique and tremendous opportunities for studying human pathophysiology, disease modeling, and drug discovery in the field of regenerative medicine. In this review, we discuss vascular physiology and related diseases, the current methods for generating vascular cells (eg, endothelial cells, smooth muscle cells, and pericytes) from hiPSCs, and describe the opportunities and challenges to the clinical applications of vascular organoids, tissue-engineered blood vessels, and vessels-on-a-chip. We then explore how hiPSCs can be used to study and treat inherited vascular diseases and discuss the current challenges and future prospects. In the future, it will be essential to develop vascularized organoids or tissues that can simultaneously undergo shear stress and cyclic stretching. This development will not only increase their maturity and function but also enable effective and innovative disease modeling and drug discovery.
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Affiliation(s)
- Polash Kumar Biswas
- Department of Physiology, College of Medicine, Hallym University, Chuncheon-si, Gangwon-do 24252, South Korea
| | - Jinkyu Park
- Department of Physiology, College of Medicine, Hallym University, Chuncheon-si, Gangwon-do 24252, South Korea; Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine Yale School of Medicine, New Haven, CT 06511, USA.
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Teles D, Fine BM. Using induced pluripotent stem cells for drug discovery in arrhythmias. Expert Opin Drug Discov 2024; 19:827-840. [PMID: 38825838 PMCID: PMC11227103 DOI: 10.1080/17460441.2024.2360420] [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: 03/18/2024] [Accepted: 05/23/2024] [Indexed: 06/04/2024]
Abstract
INTRODUCTION Arrhythmias are disturbances in the normal rhythm of the heart and account for significant cardiovascular morbidity and mortality worldwide. Historically, preclinical research has been anchored in animal models, though physiological differences between these models and humans have limited their clinical translation. The discovery of human induced pluripotent stem cells (iPSC) and subsequent differentiation into cardiomyocyte has led to the development of new in vitro models of arrhythmias with the hope of a new pathway for both exploration of pathogenic variants and novel therapeutic discovery. AREAS COVERED The authors describe the latest two-dimensional in vitro models of arrhythmias, several examples of the use of these models in drug development, and the role of gene editing when modeling diseases. They conclude by discussing the use of three-dimensional models in the study of arrythmias and the integration of computational technologies and machine learning with experimental technologies. EXPERT OPINION Human iPSC-derived cardiomyocytes models have significant potential to augment disease modeling, drug discovery, and toxicity studies in preclinical development. While there is initial success with modeling arrhythmias, the field is still in its nascency and requires advances in maturation, cellular diversity, and readouts to emulate arrhythmias more accurately.
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Affiliation(s)
- Diogo Teles
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Barry M. Fine
- Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
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Maizels L, Heller E, Landesberg M, Glatstein S, Huber I, Arbel G, Gepstein A, Aronson D, Sharabi S, Beinart R, Segev A, Maor E, Gepstein L. Utilizing Human-Induced Pluripotent Stem Cells to Study Cardiac Electroporation Pulsed-Field Ablation. Circ Arrhythm Electrophysiol 2024; 17:e012278. [PMID: 38344845 PMCID: PMC10949974 DOI: 10.1161/circep.123.012278] [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: 07/10/2023] [Accepted: 01/16/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND Electroporation is a promising nonthermal ablation method for cardiac arrhythmia treatment. Although initial clinical studies found electroporation pulsed-field ablation (PFA) both safe and efficacious, there are significant knowledge gaps concerning the mechanistic nature and electrophysiological consequences of cardiomyocyte electroporation, contributed by the paucity of suitable human in vitro models. Here, we aimed to establish and characterize a functional in vitro model based on human-induced pluripotent stem cells (hiPSCs)-derived cardiac tissue, and to study the fundamentals of cardiac PFA. METHODS hiPSC-derived cardiomyocytes were seeded as circular cell sheets and subjected to different PFA protocols. Detailed optical mapping, cellular, and molecular characterizations were performed to study PFA mechanisms and electrophysiological outcomes. RESULTS PFA generated electrically silenced lesions within the hiPSC-derived cardiac circular cell sheets, resulting in areas of conduction block. Both reversible and irreversible electroporation components were identified. Significant electroporation reversibility was documented within 5 to 15-minutes post-PFA. Irreversibly electroporated regions persisted at 24-hours post-PFA. Per single pulse, high-frequency PFA was less efficacious than standard (monophasic) PFA, whereas increasing pulse-number augmented lesion size and diminished reversible electroporation. PFA augmentation could also be achieved by increasing extracellular Ca2+ levels. Flow-cytometry experiments revealed that regulated cell death played an important role following PFA. Assessing for PFA antiarrhythmic properties, sustainable lines of conduction block could be generated using PFA, which could either terminate or isolate arrhythmic activity in the hiPSC-derived cardiac circular cell sheets. CONCLUSIONS Cardiac electroporation may be studied using hiPSC-derived cardiac tissue, providing novel insights into PFA temporal and electrophysiological characteristics, facilitating electroporation protocol optimization, screening for potential PFA-sensitizers, and investigating the mechanistic nature of PFA antiarrhythmic properties.
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Affiliation(s)
- Leonid Maizels
- Division of Cardiology, Leviev Center of Cardiovascular Medicine, Sheba Medical Center, Ramt Gan, Israel (L.M., E.H., R.B., A.S., E.M.)
- Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel (L.M., R.B., A.S., E.M.)
- Talpiot Sheba Medical Leadership Program, Sheba Medical Center, Ramat Gan, Israel (L.M., E.M.)
- Department of Cardiology, Royal Melbourne Hospital, Australia (L.M.)
| | - Eyal Heller
- Division of Cardiology, Leviev Center of Cardiovascular Medicine, Sheba Medical Center, Ramt Gan, Israel (L.M., E.H., R.B., A.S., E.M.)
| | - Michal Landesberg
- Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine, Technion, Haifa, Israel (M.L., S.G., I.H., G.A., A.G., L.G.)
| | - Shany Glatstein
- Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine, Technion, Haifa, Israel (M.L., S.G., I.H., G.A., A.G., L.G.)
| | - Irit Huber
- Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine, Technion, Haifa, Israel (M.L., S.G., I.H., G.A., A.G., L.G.)
| | - Gil Arbel
- Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine, Technion, Haifa, Israel (M.L., S.G., I.H., G.A., A.G., L.G.)
| | - Amira Gepstein
- Division of Cardiology, Leviev Center of Cardiovascular Medicine, Sheba Medical Center, Ramt Gan, Israel (L.M., E.H., R.B., A.S., E.M.)
- Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine, Technion, Haifa, Israel (M.L., S.G., I.H., G.A., A.G., L.G.)
| | - Doron Aronson
- Division of Cardiology, Rambam Health Care Campus, Haifa, Israel (D.A., L.G.)
| | - Shirley Sharabi
- Advanced Technology Center and Department of Radiology, Sheba Medical Center, Ramat Gan, Israel (S.S.)
| | - Roy Beinart
- Division of Cardiology, Leviev Center of Cardiovascular Medicine, Sheba Medical Center, Ramt Gan, Israel (L.M., E.H., R.B., A.S., E.M.)
- Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel (L.M., R.B., A.S., E.M.)
| | - Amit Segev
- Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel (L.M., R.B., A.S., E.M.)
| | - Elad Maor
- Division of Cardiology, Leviev Center of Cardiovascular Medicine, Sheba Medical Center, Ramt Gan, Israel (L.M., E.H., R.B., A.S., E.M.)
- Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel (L.M., R.B., A.S., E.M.)
- Talpiot Sheba Medical Leadership Program, Sheba Medical Center, Ramat Gan, Israel (L.M., E.M.)
| | - Lior Gepstein
- Sohnis Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Rappaport Faculty of Medicine, Technion, Haifa, Israel (M.L., S.G., I.H., G.A., A.G., L.G.)
- Division of Cardiology, Rambam Health Care Campus, Haifa, Israel (D.A., L.G.)
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Shiti A, Arbil G, Shaheen N, Huber I, Setter N, Gepstein L. Utilizing human induced pluripotent stem cells to study atrial arrhythmias in the short QT syndrome. J Mol Cell Cardiol 2023; 183:42-53. [PMID: 37579942 PMCID: PMC10589759 DOI: 10.1016/j.yjmcc.2023.08.003] [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: 08/24/2022] [Revised: 07/17/2023] [Accepted: 08/11/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND Among the monogenic inherited causes of atrial fibrillation is the short QT syndrome (SQTS), a rare channelopathy causing atrial and ventricular arrhythmias. One of the limitations in studying the mechanisms and optimizing treatment of SQTS-related atrial arrhythmias has been the lack of relevant human atrial tissues models. OBJECTIVE To generate a unique model to study SQTS-related atrial arrhythmias by combining the use of patient-specific human induced pluripotent stem cells (hiPSCs), atrial-specific differentiation schemes, two-dimensional tissue modeling, optical mapping, and drug testing. METHODS AND RESULTS SQTS (N588K KCNH2 mutation), isogenic-control, and healthy-control hiPSCs were coaxed to differentiate into atrial cardiomyocytes using a retinoic-acid based differentiation protocol. The atrial identity of the cells was confirmed by a distinctive pattern of MLC2v downregulation, connexin 40 upregulation, shorter and triangular-shaped action potentials (APs), and expression of the atrial-specific acetylcholine-sensitive potassium current. In comparison to the healthy- and isogenic control cells, the SQTS-hiPSC atrial cardiomyocytes displayed abbreviated APs and refractory periods along with an augmented rapidly activating delayed-rectifier potassium current (IKr). Optical mapping of a hiPSC-based atrial tissue model of the SQTS displayed shortened APD and altered biophysical properties of spiral waves induced in this model, manifested by accelerated spiral-wave frequency and increased rotor curvature. Both AP shortening and arrhythmia irregularities were reversed by quinidine and vernakalant treatment, but not by sotalol. CONCLUSIONS Patient-specific hiPSC-based atrial cellular and tissue models of the SQTS were established, which provide examples on how this type of modeling can shed light on the pathogenesis and pharmacological treatment of inherited atrial arrhythmias.
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Affiliation(s)
- Assad Shiti
- Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel
| | - Gil Arbil
- Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel
| | - Naim Shaheen
- Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel
| | - Irit Huber
- Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel
| | - Noga Setter
- Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel
| | - Lior Gepstein
- Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel; Cardiolology Department, Rambam Health Care Campus, Haifa, Israel.
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11
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Sleiman Y, Reiken S, Charrabi A, Jaffré F, Sittenfeld LR, Pasquié JL, Colombani S, Lerman BB, Chen S, Marks AR, Cheung JW, Evans T, Lacampagne A, Meli AC. Personalized medicine in the dish to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes. Stem Cell Res Ther 2023; 14:266. [PMID: 37740238 PMCID: PMC10517551 DOI: 10.1186/s13287-023-03502-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/14/2023] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Polymorphic ventricular tachycardia (PMVT) is a rare genetic disease associated with structurally normal hearts which in 8% of cases can lead to sudden cardiac death, typically exercise-induced. We previously showed a link between the RyR2-H29D mutation and a clinical phenotype of short-coupled PMVT at rest using patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs). In the present study, we evaluated the effects of clinical and experimental anti-arrhythmic drugs on the intracellular Ca2+ handling, contractile and molecular properties in PMVT hiPSC-CMs in order to model a personalized medicine approach in vitro. METHODS Previously, a blood sample from a patient carrying the RyR2-H29D mutation was collected and reprogrammed into several clones of RyR2-H29D hiPSCs, and in addition we generated an isogenic control by reverting the RyR2-H29D mutation using CRIPSR/Cas9 technology. Here, we tested 4 drugs with anti-arrhythmic properties: propranolol, verapamil, flecainide, and the Rycal S107. We performed fluorescence confocal microscopy, video-image-based analyses and biochemical analyses to investigate the impact of these drugs on the functional and molecular features of the PMVT RyR2-H29D hiPSC-CMs. RESULTS The voltage-dependent Ca2+ channel inhibitor verapamil did not prevent the aberrant release of sarcoplasmic reticulum (SR) Ca2+ in the RyR2-H29D hiPSC-CMs, whereas it was prevented by S107, flecainide or propranolol. Cardiac tissue comprised of RyR2-H29D hiPSC-CMs exhibited aberrant contractile properties that were largely prevented by S107, flecainide and propranolol. These 3 drugs also recovered synchronous contraction in RyR2-H29D cardiac tissue, while verapamil did not. At the biochemical level, S107 was the only drug able to restore calstabin2 binding to RyR2 as observed in the isogenic control. CONCLUSIONS By testing 4 drugs on patient-specific PMVT hiPSC-CMs, we concluded that S107 and flecainide are the most potent molecules in terms of preventing the abnormal SR Ca2+ release and contractile properties in RyR2-H29D hiPSC-CMs, whereas the effect of propranolol is partial, and verapamil appears ineffective. In contrast with the 3 other drugs, S107 was able to prevent a major post-translational modification of RyR2-H29D mutant channels, the loss of calstabin2 binding to RyR2. Using patient-specific hiPSC and CRISPR/Cas9 technologies, we showed that S107 is the most efficient in vitro candidate for treating the short-coupled PMVT at rest.
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Affiliation(s)
- Yvonne Sleiman
- PhyMedExp, University of Montpellier, CNRS, INSERM, Montpellier , France
| | - Steven Reiken
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Azzouz Charrabi
- PhyMedExp, University of Montpellier, CNRS, INSERM, Montpellier , France
| | - Fabrice Jaffré
- Department of Surgery, Weill Cornell Medical College, New York, NY, USA
| | - Leah R Sittenfeld
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Jean-Luc Pasquié
- PhyMedExp, University of Montpellier, CNRS, INSERM, Montpellier , France
- Department of Cardiology, CHRU of Montpellier, Montpellier, France
| | - Sarah Colombani
- PhyMedExp, University of Montpellier, CNRS, INSERM, Montpellier , France
| | - Bruce B Lerman
- Division of Cardiology, Weill Cornell Medical College, New York, NY, USA
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medical College, New York, NY, USA
| | - Andrew R Marks
- Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
| | - Jim W Cheung
- Division of Cardiology, Weill Cornell Medical College, New York, NY, USA
| | - Todd Evans
- Department of Surgery, Weill Cornell Medical College, New York, NY, USA
| | - Alain Lacampagne
- PhyMedExp, University of Montpellier, CNRS, INSERM, Montpellier , France
| | - Albano C Meli
- PhyMedExp, University of Montpellier, CNRS, INSERM, Montpellier , France.
- CNRS, INSERM, Montpellier Organoid Platform, Biocampus, University of Montpellier, Montpellier, France.
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12
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iPSC-Derived Cardiomyocytes in Inherited Cardiac Arrhythmias: Pathomechanistic Discovery and Drug Development. Biomedicines 2023; 11:biomedicines11020334. [PMID: 36830871 PMCID: PMC9953535 DOI: 10.3390/biomedicines11020334] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 01/20/2023] [Accepted: 01/22/2023] [Indexed: 01/26/2023] Open
Abstract
With the discovery of induced pluripotent stem cell (iPSCs) a wide range of cell types, including iPSC-derived cardiomyocytes (iPSC-CM), can now be generated from an unlimited source of somatic cells. These iPSC-CM are used for different purposes such as disease modelling, drug discovery, cardiotoxicity testing and personalised medicine. The 2D iPSC-CM models have shown promising results, but they are known to be more immature compared to in vivo adult cardiomyocytes. Novel approaches to create 3D models with the possible addition of other (cardiac) cell types are being developed. This will not only improve the maturity of the cells, but also leads to more physiologically relevant models that more closely resemble the human heart. In this review, we focus on the progress in the modelling of inherited cardiac arrhythmias in both 2D and 3D and on the use of these models in therapy development and drug testing.
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13
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Ernst P, Bidwell PA, Dora M, Thomas DD, Kamdar F. Cardiac calcium regulation in human induced pluripotent stem cell cardiomyocytes: Implications for disease modeling and maturation. Front Cell Dev Biol 2023; 10:986107. [PMID: 36742199 PMCID: PMC9889838 DOI: 10.3389/fcell.2022.986107] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 12/23/2022] [Indexed: 01/19/2023] Open
Abstract
Human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) are based on ground-breaking technology that has significantly impacted cardiovascular research. They provide a renewable source of human cardiomyocytes for a variety of applications including in vitro disease modeling and drug toxicity testing. Cardiac calcium regulation plays a critical role in the cardiomyocyte and is often dysregulated in cardiovascular disease. Due to the limited availability of human cardiac tissue, calcium handling and its regulation have most commonly been studied in the context of animal models. hiPSC-CMs can provide unique insights into human physiology and pathophysiology, although a remaining limitation is the relative immaturity of these cells compared to adult cardiomyocytes Therefore, this field is rapidly developing techniques to improve the maturity of hiPSC-CMs, further establishing their place in cardiovascular research. This review briefly covers the basics of cardiomyocyte calcium cycling and hiPSC technology, and will provide a detailed description of our current understanding of calcium in hiPSC-CMs.
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Affiliation(s)
- Patrick Ernst
- Cardiovascular Division, University of Minnesota, Minneapolis, MN, United States
| | - Philip A. Bidwell
- Cardiovascular Division, University of Minnesota, Minneapolis, MN, United States
| | - Michaela Dora
- College of Biological Sciences, University of Minnesota, Minneapolis, MN, United States
| | - David D. Thomas
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, United States
| | - Forum Kamdar
- Cardiovascular Division, University of Minnesota, Minneapolis, MN, United States
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14
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Hopton C, Tijsen AJ, Maizels L, Arbel G, Gepstein A, Bates N, Brown B, Huber I, Kimber SJ, Newman WG, Venetucci L, Gepstein L. Characterization of the mechanism by which a nonsense variant in RYR2 leads to disordered calcium handling. Physiol Rep 2022; 10:e15265. [PMID: 35439358 PMCID: PMC9017975 DOI: 10.14814/phy2.15265] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/19/2022] [Accepted: 03/25/2022] [Indexed: 06/14/2023] Open
Abstract
Heterozygous missense variants of the cardiac ryanodine receptor gene (RYR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These missense variants of RYR2 result in a gain of function of the ryanodine receptors, characterized by increased sensitivity to activation by calcium that results in an increased propensity to develop calcium waves and delayed afterdepolarizations. We have recently detected a nonsense variant in RYR2 in a young patient who suffered an unexplained cardiac arrest. To understand the mechanism by which this variant in RYR2, p.(Arg4790Ter), leads to ventricular arrhythmias, human induced pluripotent stem cells (hiPSCs) harboring the novel nonsense variant in RYR2 were generated and differentiated into cardiomyocytes (RYR2-hiPSC-CMs) and molecular and calcium handling properties were studied. RYR2-hiPSC-CMs displayed significant calcium handling abnormalities at baseline and following treatment with isoproterenol. Treatment with carvedilol and nebivolol resulted in a significant reduction in calcium handling abnormalities in the RYR2-hiPSC-CMs. Expression of the mutant RYR2 allele was confirmed at the mRNA level and partial silencing of the mutant allele resulted in a reduction in calcium handling abnormalities at baseline. The nonsense variant behaves similarly to other gain of function variants in RYR2. Carvedilol and nebivolol may be suitable treatments for patients with gain of function RYR2 variants.
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Affiliation(s)
- Claire Hopton
- Division of Evolution and Genomic SciencesFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Manchester Centre for Genomic MedicineManchester University NHS Foundation TrustHealth Innovation ManchesterManchesterUK
- Division of Cardiovascular SciencesFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - Anke J. Tijsen
- The Rappaport Faculty of Medicine and Research InstituteTechnion‐Institute of TechnologyHaifaIsrael
- Amsterdam UMCDepartment of Experimental CardiologyAmsterdam Cardiovascular SciencesUniversity of AmsterdamAmsterdamThe Netherlands
| | - Leonid Maizels
- The Rappaport Faculty of Medicine and Research InstituteTechnion‐Institute of TechnologyHaifaIsrael
- Division of CardiologySheba Medical Center HospitalTel HashomerIsrael
- The Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
- The Talpiot Sheba Medical Leadership ProgramIsrael
| | - Gil Arbel
- The Rappaport Faculty of Medicine and Research InstituteTechnion‐Institute of TechnologyHaifaIsrael
| | - Amira Gepstein
- The Rappaport Faculty of Medicine and Research InstituteTechnion‐Institute of TechnologyHaifaIsrael
| | - Nicola Bates
- Division of Cell Matrix Biology and Regenerative MedicineFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - Benjamin Brown
- Department of CardiologyWythenshawe HospitalManchester University NHS Foundation TrustManchesterUK
| | - Irit Huber
- The Rappaport Faculty of Medicine and Research InstituteTechnion‐Institute of TechnologyHaifaIsrael
| | - Susan J. Kimber
- Division of Cell Matrix Biology and Regenerative MedicineFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
| | - William G. Newman
- Division of Evolution and Genomic SciencesFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Manchester Centre for Genomic MedicineManchester University NHS Foundation TrustHealth Innovation ManchesterManchesterUK
| | - Luigi Venetucci
- Division of Cardiovascular SciencesFaculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
- Manchester Heart CentreManchester University NHS Foundation TrustHealth Innovation ManchesterManchesterUK
| | - Lior Gepstein
- The Rappaport Faculty of Medicine and Research InstituteTechnion‐Institute of TechnologyHaifaIsrael
- Cardiology DepartmentRambam Health Care CampusHaifaIsrael
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15
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Harnessing the Power of Stem Cell Models to Study Shared Genetic Variants in Congenital Heart Diseases and Neurodevelopmental Disorders. Cells 2022; 11:cells11030460. [PMID: 35159270 PMCID: PMC8833927 DOI: 10.3390/cells11030460] [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: 11/16/2021] [Revised: 01/03/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
Advances in human pluripotent stem cell (hPSC) technology allow one to deconstruct the human body into specific disease-relevant cell types or create functional units representing various organs. hPSC-based models present a unique opportunity for the study of co-occurring disorders where “cause and effect” can be addressed. Poor neurodevelopmental outcomes have been reported in children with congenital heart diseases (CHD). Intuitively, abnormal cardiac function or surgical intervention may stunt the developing brain, leading to neurodevelopmental disorders (NDD). However, recent work has uncovered several genetic variants within genes associated with the development of both the heart and brain that could also explain this co-occurrence. Given the scalability of hPSCs, straightforward genetic modification, and established differentiation strategies, it is now possible to investigate both CHD and NDD as independent events. We will first overview the potential for shared genetics in both heart and brain development. We will then summarize methods to differentiate both cardiac & neural cells and organoids from hPSCs that represent the developmental process of the heart and forebrain. Finally, we will highlight strategies to rapidly screen several genetic variants together to uncover potential phenotypes and how therapeutic advances could be achieved by hPSC-based models.
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16
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Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform-A Cardiac Perspective. Cells 2021; 10:cells10123483. [PMID: 34943991 PMCID: PMC8699880 DOI: 10.3390/cells10123483] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023] Open
Abstract
A comprehensive understanding of the pathophysiology and cellular responses to drugs in human heart disease is limited by species differences between humans and experimental animals. In addition, isolation of human cardiomyocytes (CMs) is complicated because cells obtained by biopsy do not proliferate to provide sufficient numbers of cells for preclinical studies in vitro. Interestingly, the discovery of human-induced pluripotent stem cell (hiPSC) has opened up the possibility of generating and studying heart disease in a culture dish. The combination of reprogramming and genome editing technologies to generate a broad spectrum of human heart diseases in vitro offers a great opportunity to elucidate gene function and mechanisms. However, to exploit the potential applications of hiPSC-derived-CMs for drug testing and studying adult-onset cardiac disease, a full functional characterization of maturation and metabolic traits is required. In this review, we focus on methods to reprogram somatic cells into hiPSC and the solutions for overcome immaturity of the hiPSC-derived-CMs to mimic the structure and physiological properties of the adult human CMs to accurately model disease and test drug safety. Finally, we discuss how to improve the culture, differentiation, and purification of CMs to obtain sufficient numbers of desired types of hiPSC-derived-CMs for disease modeling and drug development platform.
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17
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Sleiman Y, Lacampagne A, Meli AC. "Ryanopathies" and RyR2 dysfunctions: can we further decipher them using in vitro human disease models? Cell Death Dis 2021; 12:1041. [PMID: 34725342 PMCID: PMC8560800 DOI: 10.1038/s41419-021-04337-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 10/08/2021] [Accepted: 10/14/2021] [Indexed: 12/23/2022]
Abstract
The regulation of intracellular calcium (Ca2+) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest intracellular calcium release channel located on the sarco/endoplasmic reticulum (SR/ER), plays a key role in the intracellular Ca2+ handling. Abnormal type 2 ryanodine receptor (RyR2) function, associated to mutations (ryanopathies) or pathological remodeling, has been reported, not only in cardiac diseases, but also in neuronal and pancreatic disorders. While animal models and in vitro studies provided valuable contributions to our knowledge on RyR2 dysfunctions, the human cell models derived from patients’ cells offer new hope for improving our understanding of human clinical diseases and enrich the development of great medical advances. We here discuss the current knowledge on RyR2 dysfunctions associated with mutations and post-translational remodeling. We then reviewed the novel human cellular technologies allowing the correlation of patient’s genome with their cellular environment and providing approaches for personalized RyR-targeted therapeutics.
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Affiliation(s)
- Yvonne Sleiman
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Alain Lacampagne
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Albano C Meli
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
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18
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Andrysiak K, Stępniewski J, Dulak J. Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac structures, and heart-on-a-chip as tools for drug research. Pflugers Arch 2021; 473:1061-1085. [PMID: 33629131 PMCID: PMC8245367 DOI: 10.1007/s00424-021-02536-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/01/2021] [Accepted: 02/03/2021] [Indexed: 12/13/2022]
Abstract
Development of new drugs is of high interest for the field of cardiac and cardiovascular diseases, which are a dominant cause of death worldwide. Before being allowed to be used and distributed, every new potentially therapeutic compound must be strictly validated during preclinical and clinical trials. The preclinical studies usually involve the in vitro and in vivo evaluation. Due to the increasing reporting of discrepancy in drug effects in animal and humans and the requirement to reduce the number of animals used in research, improvement of in vitro models based on human cells is indispensable. Primary cardiac cells are difficult to access and maintain in cell culture for extensive experiments; therefore, the human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) became an excellent alternative. This technology enables a production of high number of patient- and disease-specific cardiomyocytes and other cardiac cell types for a large-scale research. The drug effects can be extensively evaluated in the context of electrophysiological responses with a use of well-established tools, such as multielectrode array (MEA), patch clamp, or calcium ion oscillation measurements. Cardiotoxicity, which is a common reason for withdrawing drugs from marketing or rejection at final stages of clinical trials, can be easily verified with a use of hiPSC-CM model providing a prediction of human-specific responses and higher safety of clinical trials involving patient cohort. Abovementioned studies can be performed using two-dimensional cell culture providing a high-throughput and relatively lower costs. On the other hand, more complex structures, such as engineered heart tissue, organoids, or spheroids, frequently applied as co-culture systems, represent more physiological conditions and higher maturation rate of hiPSC-derived cells. Furthermore, heart-on-a-chip technology has recently become an increasingly popular tool, as it implements controllable culture conditions, application of various stimulations and continuous parameters read-out. This paper is an overview of possible use of cardiomyocytes and other cardiac cell types derived from hiPSC as in vitro models of heart in drug research area prepared on the basis of latest scientific reports and providing thorough discussion regarding their advantages and limitations.
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Affiliation(s)
- Kalina Andrysiak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Jacek Stępniewski
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
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Gnecchi M, Sala L, Schwartz PJ. Precision Medicine and cardiac channelopathies: when dreams meet reality. Eur Heart J 2021; 42:1661-1675. [PMID: 33686390 PMCID: PMC8088342 DOI: 10.1093/eurheartj/ehab007] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/10/2020] [Accepted: 01/12/2021] [Indexed: 12/17/2022] Open
Abstract
Precision Medicine (PM) is an innovative approach that, by relying on large populations’ datasets, patients’ genetics and characteristics, and advanced technologies, aims at improving risk stratification and at identifying patient-specific management through targeted diagnostic and therapeutic strategies. Cardiac channelopathies are being progressively involved in the evolution brought by PM and some of them are benefiting from these novel approaches, especially the long QT syndrome. Here, we have explored the main layers that should be considered when developing a PM approach for cardiac channelopathies, with a focus on modern in vitro strategies based on patient-specific human-induced pluripotent stem cells and on in silico models. PM is where scientists and clinicians must meet and integrate their expertise to improve medical care in an innovative way but without losing common sense. We have indeed tried to provide the cardiologist’s point of view by comparing state-of-the-art techniques and approaches, including revolutionary discoveries, to current practice. This point matters because the new approaches may, or may not, exceed the efficacy and safety of established therapies. Thus, our own eagerness to implement the most recent translational strategies for cardiac channelopathies must be tempered by an objective assessment to verify whether the PM approaches are indeed making a difference for the patients. We believe that PM may shape the diagnosis and treatment of cardiac channelopathies for years to come. Nonetheless, its potential superiority over standard therapies should be constantly monitored and assessed before translating intellectually rewarding new discoveries into clinical practice.
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Affiliation(s)
- Massimiliano Gnecchi
- Department of Cardiothoracic and Vascular Sciences-Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy.,Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy.,Department of Medicine, University of Cape Town, J-Floor, Old Main Building, Groote Schuur Hospital, Observatory, 7925 Cape Town, South Africa
| | - Luca Sala
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22 - 20135 Milan, Italy
| | - Peter J Schwartz
- Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Via Pier Lombardo 22 - 20135 Milan, Italy
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20
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Micheu MM, Rosca AM. Patient-specific induced pluripotent stem cells as "disease-in-a-dish" models for inherited cardiomyopathies and channelopathies - 15 years of research. World J Stem Cells 2021; 13:281-303. [PMID: 33959219 PMCID: PMC8080539 DOI: 10.4252/wjsc.v13.i4.281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/11/2021] [Accepted: 03/29/2021] [Indexed: 02/06/2023] Open
Abstract
Among inherited cardiac conditions, a special place is kept by cardiomyopathies (CMPs) and channelopathies (CNPs), which pose a substantial healthcare burden due to the complexity of the therapeutic management and cause early mortality. Like other inherited cardiac conditions, genetic CMPs and CNPs exhibit incomplete penetrance and variable expressivity even within carriers of the same pathogenic deoxyribonucleic acid variant, challenging our understanding of the underlying pathogenic mechanisms. Until recently, the lack of accurate physiological preclinical models hindered the investigation of fundamental cellular and molecular mechanisms. The advent of induced pluripotent stem cell (iPSC) technology, along with advances in gene editing, offered unprecedented opportunities to explore hereditary CMPs and CNPs. Hallmark features of iPSCs include the ability to differentiate into unlimited numbers of cells from any of the three germ layers, genetic identity with the subject from whom they were derived, and ease of gene editing, all of which were used to generate "disease-in-a-dish" models of monogenic cardiac conditions. Functionally, iPSC-derived cardiomyocytes that faithfully recapitulate the patient-specific phenotype, allowed the study of disease mechanisms in an individual-/allele-specific manner, as well as the customization of therapeutic regimen. This review provides a synopsis of the most important iPSC-based models of CMPs and CNPs and the potential use for modeling disease mechanisms, personalized therapy and deoxyribonucleic acid variant functional annotation.
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Affiliation(s)
- Miruna Mihaela Micheu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014452, Romania.
| | - Ana-Maria Rosca
- Cell and Tissue Engineering Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest 050568, Romania
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James EC, Tomaskovic-Crook E, Crook JM. Bioengineering Clinically Relevant Cardiomyocytes and Cardiac Tissues from Pluripotent Stem Cells. Int J Mol Sci 2021; 22:ijms22063005. [PMID: 33809429 PMCID: PMC8001925 DOI: 10.3390/ijms22063005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/11/2021] [Accepted: 03/12/2021] [Indexed: 12/23/2022] Open
Abstract
The regenerative capacity of cardiomyocytes is insufficient to functionally recover damaged tissue, and as such, ischaemic heart disease forms the largest proportion of cardiovascular associated deaths. Human-induced pluripotent stem cells (hiPSCs) have enormous potential for developing patient specific cardiomyocytes for modelling heart disease, patient-based cardiac toxicity testing and potentially replacement therapy. However, traditional protocols for hiPSC-derived cardiomyocytes yield mixed populations of atrial, ventricular and nodal-like cells with immature cardiac properties. New insights gleaned from embryonic heart development have progressed the precise production of subtype-specific hiPSC-derived cardiomyocytes; however, their physiological immaturity severely limits their utility as model systems and their use for drug screening and cell therapy. The long-entrenched challenges in this field are being addressed by innovative bioengingeering technologies that incorporate biophysical, biochemical and more recently biomimetic electrical cues, with the latter having the potential to be used to both direct hiPSC differentiation and augment maturation and the function of derived cardiomyocytes and cardiac tissues by mimicking endogenous electric fields.
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Affiliation(s)
- Emma Claire James
- ARC Centre of Excellence for Electromaterials Science, Intelligent Polymer Research Institute, AIIM Facility, University of Wollongong, Wollongong 2500, Australia;
| | - Eva Tomaskovic-Crook
- ARC Centre of Excellence for Electromaterials Science, Intelligent Polymer Research Institute, AIIM Facility, University of Wollongong, Wollongong 2500, Australia;
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2500, Australia
- Correspondence: (E.T.-C.); (J.M.C.)
| | - Jeremy Micah Crook
- ARC Centre of Excellence for Electromaterials Science, Intelligent Polymer Research Institute, AIIM Facility, University of Wollongong, Wollongong 2500, Australia;
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2500, Australia
- Department of Surgery, St Vincent’s Hospital, The University of Melbourne, Fitzroy 3065, Australia
- Correspondence: (E.T.-C.); (J.M.C.)
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22
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Iop L. Toward the Effective Bioengineering of a Pathological Tissue for Cardiovascular Disease Modeling: Old Strategies and New Frontiers for Prevention, Diagnosis, and Therapy. Front Cardiovasc Med 2021; 7:591583. [PMID: 33748193 PMCID: PMC7969521 DOI: 10.3389/fcvm.2020.591583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 12/08/2020] [Indexed: 12/18/2022] Open
Abstract
Cardiovascular diseases (CVDs) still represent the primary cause of mortality worldwide. Preclinical modeling by recapitulating human pathophysiology is fundamental to advance the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and treatment. In silico, in vivo, and in vitro models have been applied to dissect many cardiovascular pathologies. Computational and bioinformatic simulations allow developing algorithmic disease models considering all known variables and severity degrees of disease. In vivo studies based on small or large animals have a long tradition and largely contribute to the current treatment and management of CVDs. In vitro investigation with two-dimensional cell culture demonstrates its suitability to analyze the behavior of single, diseased cellular types. The introduction of induced pluripotent stem cell technology and the application of bioengineering principles raised the bar toward in vitro three-dimensional modeling by enabling the development of pathological tissue equivalents. This review article intends to describe the advantages and disadvantages of past and present modeling approaches applied to provide insights on some of the most relevant congenital and acquired CVDs, such as rhythm disturbances, bicuspid aortic valve, cardiac infections and autoimmunity, cardiovascular fibrosis, atherosclerosis, and calcific aortic valve stenosis.
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Affiliation(s)
- Laura Iop
- Department of Cardiac Thoracic Vascular Sciences, and Public Health, University of Padua Medical School, Padua, Italy
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23
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Arrhythmia Mechanisms in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. J Cardiovasc Pharmacol 2020; 77:300-316. [PMID: 33323698 DOI: 10.1097/fjc.0000000000000972] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/08/2020] [Indexed: 12/30/2022]
Abstract
ABSTRACT Despite major efforts by clinicians and researchers, cardiac arrhythmia remains a leading cause of morbidity and mortality in the world. Experimental work has relied on combining high-throughput strategies with standard molecular and electrophysiological studies, which are, to a great extent, based on the use of animal models. Because this poses major challenges for translation, the progress in the development of novel antiarrhythmic agents and clinical care has been mostly disappointing. Recently, the advent of human induced pluripotent stem cell-derived cardiomyocytes has opened new avenues for both basic cardiac research and drug discovery; now, there is an unlimited source of cardiomyocytes of human origin, both from healthy individuals and patients with cardiac diseases. Understanding arrhythmic mechanisms is one of the main use cases of human induced pluripotent stem cell-derived cardiomyocytes, in addition to pharmacological cardiotoxicity and efficacy testing, in vitro disease modeling, developing patient-specific models and personalized drugs, and regenerative medicine. Here, we review the advances that the human induced pluripotent stem cell-derived-based modeling systems have brought so far regarding the understanding of both arrhythmogenic triggers and substrates, while also briefly speculating about the possibilities in the future.
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24
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El-Battrawy I, Albers S, Cyganek L, Zhao Z, Lan H, Li X, Xu Q, Kleinsorge M, Huang M, Liao Z, Zhong R, Rudic B, Müller J, Dinkel H, Lang S, Diecke S, Zimmermann WH, Utikal J, Wieland T, Borggrefe M, Zhou X, Akin I. A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes. Europace 2020; 21:1410-1421. [PMID: 31106349 DOI: 10.1093/europace/euz122] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 04/03/2019] [Indexed: 11/15/2022] Open
Abstract
AIMS Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS. CONCLUSION Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.
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Affiliation(s)
- Ibrahim El-Battrawy
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany
| | - Sebastian Albers
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany
| | - Lukas Cyganek
- DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany.,Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
| | - Zhihan Zhao
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany
| | - Huan Lan
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany.,Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Xin Li
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany
| | - Qiang Xu
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany
| | - Mandy Kleinsorge
- DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany.,Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
| | - Mengying Huang
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany
| | - Zhenxing Liao
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany
| | - Rujia Zhong
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany
| | - Boris Rudic
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany
| | - Jonas Müller
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany
| | - Hendrik Dinkel
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany
| | - Siegfried Lang
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany
| | | | - Wolfram-Hubertus Zimmermann
- DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany.,Institute of Pharmacology and Toxicology, University of Göttingen, Göttingen, Germany
| | - Jochen Utikal
- DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany.,Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Thomas Wieland
- DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany.,Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Martin Borggrefe
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany
| | - Xiaobo Zhou
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany.,Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Ibrahim Akin
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg-Mannheim and Göttingen, Göttingen, Germany
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25
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Ng K, Titus EW, Lieve KV, Roston TM, Mazzanti A, Deiter FH, Denjoy I, Ingles J, Till J, Robyns T, Connors SP, Steinberg C, Abrams DJ, Pang B, Scheinman MM, Bos JM, Duffett SA, van der Werf C, Maltret A, Green MS, Rutberg J, Balaji S, Cadrin-Tourigny J, Orland KM, Knight LM, Brateng C, Wu J, Tang AS, Skanes AC, Manlucu J, Healey JS, January CT, Krahn AD, Collins KK, Maginot KR, Fischbach P, Etheridge SP, Eckhardt LL, Hamilton RM, Ackerman MJ, Noguer FRI, Semsarian C, Jura N, Leenhardt A, Gollob MH, Priori SG, Sanatani S, Wilde AAM, Deo RC, Roberts JD. An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation 2020; 142:932-947. [PMID: 32693635 PMCID: PMC7484339 DOI: 10.1161/circulationaha.120.045723] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Genetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter collaboration. METHODS Genotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. RESULTS A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P<0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. CONCLUSIONS This international multicenter study of CASQ2-CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
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Affiliation(s)
- Kevin Ng
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
- Cairns Hospital, Queensland, Australia
| | - Erron W. Titus
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
| | - Krystien V. Lieve
- Amsterdam University Medical Centre, University of Amsterdam, Heart Centre, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
| | - Thomas M. Roston
- Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrea Mazzanti
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
- Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico and Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Frederick H. Deiter
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
| | - Isabelle Denjoy
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
- Service de Cardiologie et CNMR Maladies Cardiacques Héréditaires Rares, Hôpital Bichat, Paris, France
| | - Jodie Ingles
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia
| | - Jan Till
- Department of Cardiology, Royal Brompton Hospital, London, United Kingdom
| | - Tomas Robyns
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
- Department of Cardiovascular Disease, University Hospitals Leuven, Leuven, Belgium
| | - Sean P. Connors
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Memorial University, St. John’s, Newfoundland and Labrador, Canada
| | | | - Dominic J. Abrams
- Inherited Cardiac Arrhythmia Program, Boston Children’s Hospital, Harvard Medical School, Massachusetts, USA
| | - Benjamin Pang
- Arrhythmia Service, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Melvin M. Scheinman
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA
| | - J. Martijn Bos
- 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, Minnesota, USA
| | - Stephen A. Duffett
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Memorial University, St. John’s, Newfoundland and Labrador, Canada
| | - Christian van der Werf
- Amsterdam University Medical Centre, University of Amsterdam, Heart Centre, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
| | - Alice Maltret
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
- Service de Cardiologie et CNMR Maladies Cardiacques Héréditaires Rares, Hôpital Bichat, Paris, France
| | - Martin S. Green
- Arrhythmia Service, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Julie Rutberg
- Arrhythmia Service, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Seshadri Balaji
- Department of Pediatrics, Division of Cardiology, Oregon Health & Science University, Portland, Oregon, USA
| | - Julia Cadrin-Tourigny
- Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, Montréal, Canada
| | - Kate M. Orland
- University of Wisconsin-Madison Inherited Arrhythmia Clinic, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Linda M. Knight
- Children’s Healthcare of Atlanta, Sibley Heart Center Cardiology, Atlanta, Georgia, USA
| | - Caitlin Brateng
- Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Jeremy Wu
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
| | - Anthony S. Tang
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
| | - Allan C. Skanes
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
| | - Jaimie Manlucu
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
| | - Jeff S. Healey
- Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Craig T. January
- University of Wisconsin-Madison Inherited Arrhythmia Clinic, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Cellular and Molecular Arrhythmia Research Program, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Andrew D. Krahn
- Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kathryn K. Collins
- Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Kathleen R. Maginot
- Department of Pediatrics, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin, USA
| | - Peter Fischbach
- Children’s Healthcare of Atlanta, Sibley Heart Center Cardiology, Atlanta, Georgia, USA
| | - Susan P. Etheridge
- Department of Pediatrics, University of Utah, and Primary Children’s Hospital, Salt Lake City, Utah, USA
| | - Lee L. Eckhardt
- University of Wisconsin-Madison Inherited Arrhythmia Clinic, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Cellular and Molecular Arrhythmia Research Program, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Robert M. Hamilton
- The Labatt Family Heart Centre (Department of Pediatrics) and Translational Medicine, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
| | - 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, Minnesota, USA
| | | | - Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia
| | - Natalia Jura
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
- Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA
| | - Antoine Leenhardt
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
- Service de Cardiologie et CNMR Maladies Cardiacques Héréditaires Rares, Hôpital Bichat, Paris, France
| | - Michael H. Gollob
- Department of Physiology and Department of Medicine, Toronto General Hospital, University of Toronto, Ontario, Canada
| | - Silvia G. Priori
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
- Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico and Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Shubhayan Sanatani
- Department of Pediatrics, Children’s Heart Centre, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Arthur A. M. Wilde
- Amsterdam University Medical Centre, University of Amsterdam, Heart Centre, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
| | - Rahul C. Deo
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
- One Brave Idea and Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Harvard University, Boston, Massachusetts, USA
| | - Jason D. Roberts
- Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada
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26
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Luo X, Li W, Künzel K, Henze S, Cyganek L, Strano A, Poetsch MS, Schubert M, Guan K. IP3R-Mediated Compensatory Mechanism for Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Cardiac Ryanodine Receptor Deficiency. Front Cell Dev Biol 2020; 8:772. [PMID: 32903370 PMCID: PMC7434870 DOI: 10.3389/fcell.2020.00772] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 07/22/2020] [Indexed: 02/03/2023] Open
Abstract
In adult cardiomyocytes (CMs), the type 2 ryanodine receptor (RYR2) is an indispensable Ca2+ release channel that ensures the integrity of excitation-contraction coupling, which is fundamental for every heartbeat. However, the role and importance of RYR2 during human embryonic cardiac development are still poorly understood. Here, we generated two human induced pluripotent stem cell (iPSC)-based RYR2 knockout (RYR2–/–) lines using the CRISPR/Cas9 gene editing technology. We found that RYR2–/–-iPSCs could differentiate into CMs with the efficiency similar to control-iPSCs (Ctrl-iPSCs); however, the survival of iPSC-CMs was markedly affected by the lack of functional RYR2. While Ctrl-iPSC-CMs exhibited regular Ca2+ handling, we observed significantly reduced frequency and intense abnormalities of Ca2+ transients in RYR2–/–-iPSC-CMs. Ctrl-iPSC-CMs displayed sensitivity to extracellular Ca2+ ([Ca2+ ]o) and caffeine in a concentration-dependent manner, while RYR2–/–-iPSC-CMs showed inconsistent reactions to [Ca2+ ]o and were insensitive to caffeine, indicating there is no RYR2-mediated Ca2+ release from the sarcoplasmic reticulum (SR). Instead, compensatory mechanism for calcium handling in RYR2–/–-iPSC-CMs is partially mediated by the inositol 1,4,5-trisphosphate receptor (IP3R). Similar to Ctrl-iPSC-CMs, SR Ca2+ refilling in RYR2–/–-iPSC-CMs is mediated by SERCA. Additionally, RYR2–/–-iPSC-CMs showed a decreased beating rate and a reduced peak amplitude of L-type Ca2+ current. These findings demonstrate that RYR2 is not required for CM lineage commitment but is important for CM survival and contractile function. IP3R-mediated Ca2+ release is one of the major compensatory mechanisms for Ca2+ cycling in human CMs with the RYR2 deficiency.
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Affiliation(s)
- Xiaojing Luo
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Wener Li
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Karolina Künzel
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Sarah Henze
- Clinic for Cardiology and Pneumology, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Lukas Cyganek
- Clinic for Cardiology and Pneumology, Universitätsmedizin Göttingen, Göttingen, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany
| | - Anna Strano
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Mareike S Poetsch
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Mario Schubert
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Kaomei Guan
- Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany.,Clinic for Cardiology and Pneumology, Universitätsmedizin Göttingen, Göttingen, Germany
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27
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Ostrominski JW, Yada RC, Sato N, Klein M, Blinova K, Patel D, Valadez R, Palisoc M, Pittaluga S, Peng KW, San H, Lin Y, Basuli F, Zhang X, Swenson RE, Haigney M, Choyke PL, Zou J, Boehm M, Hong SG, Dunbar CE. CRISPR/Cas9-mediated introduction of the sodium/iodide symporter gene enables noninvasive in vivo tracking of induced pluripotent stem cell-derived cardiomyocytes. Stem Cells Transl Med 2020; 9:1203-1217. [PMID: 32700830 PMCID: PMC7519772 DOI: 10.1002/sctm.20-0019] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 05/10/2020] [Accepted: 05/24/2020] [Indexed: 12/31/2022] Open
Abstract
Techniques that enable longitudinal tracking of cell fate after myocardial delivery are imperative for optimizing the efficacy of cell‐based cardiac therapies. However, these approaches have been underutilized in preclinical models and clinical trials, and there is considerable demand for site‐specific strategies achieving long‐term expression of reporter genes compatible with safe noninvasive imaging. In this study, the rhesus sodium/iodide symporter (NIS) gene was incorporated into rhesus macaque induced pluripotent stem cells (RhiPSCs) via CRISPR/Cas9. Cardiomyocytes derived from NIS‐RhiPSCs (NIS‐RhiPSC‐CMs) exhibited overall similar morphological and electrophysiological characteristics compared to parental control RhiPSC‐CMs at baseline and with exposure to physiological levels of sodium iodide. Mice were injected intramyocardially with 2 million NIS‐RhiPSC‐CMs immediately following myocardial infarction, and serial positron emission tomography/computed tomography was performed with 18F‐tetrafluoroborate to monitor transplanted cells in vivo. NIS‐RhiPSC‐CMs could be detected until study conclusion at 8 to 10 weeks postinjection. This NIS‐based molecular imaging platform, with optimal safety and sensitivity characteristics, is primed for translation into large‐animal preclinical models and clinical trials.
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Affiliation(s)
- John W Ostrominski
- Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Ravi Chandra Yada
- Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Noriko Sato
- Molecular Imaging Program, Laboratory of Cellular Therapeutics, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Michael Klein
- Division of Cardiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | - Ksenia Blinova
- Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Dakshesh Patel
- Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Racquel Valadez
- Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
| | - Maryknoll Palisoc
- Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
| | - Stefania Pittaluga
- Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
| | - Kah-Whye Peng
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Hong San
- Animal Surgery and Resources Core, NHLBI, NIH, Bethesda, Maryland, USA
| | | | - Falguni Basuli
- Chemistry and Synthesis Center, NHLBI, NIH, Bethesda, Maryland, USA
| | - Xiang Zhang
- Chemistry and Synthesis Center, NHLBI, NIH, Bethesda, Maryland, USA
| | - Rolf E Swenson
- Chemistry and Synthesis Center, NHLBI, NIH, Bethesda, Maryland, USA
| | - Mark Haigney
- Division of Cardiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | - Peter L Choyke
- Molecular Imaging Program, Laboratory of Cellular Therapeutics, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Jizhong Zou
- iPSC Core, NHLBI, NIH, Bethesda, Maryland, USA
| | - Manfred Boehm
- Laboratory of Cardiovascular Regenerative Medicine, NHLBI, NIH, Bethesda, Maryland, USA
| | - So Gun Hong
- Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Cynthia E Dunbar
- Translational Stem Cell Biology Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA
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28
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Lemme M, Braren I, Prondzynski M, Aksehirlioglu B, Ulmer BM, Schulze ML, Ismaili D, Meyer C, Hansen A, Christ T, Lemoine MD, Eschenhagen T. Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue. Cardiovasc Res 2020; 116:1487-1499. [PMID: 31598634 PMCID: PMC7314638 DOI: 10.1093/cvr/cvz245] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 07/31/2019] [Accepted: 10/04/2019] [Indexed: 01/01/2023] Open
Abstract
AIMS Chronic tachypacing is commonly used in animals to induce cardiac dysfunction and to study mechanisms of heart failure and arrhythmogenesis. Human induced pluripotent stem cells (hiPSC) may replace animal models to overcome species differences and ethical problems. Here, 3D engineered heart tissue (EHT) was used to investigate the effect of chronic tachypacing on hiPSC-cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS To avoid cell toxicity by electrical pacing, we developed an optogenetic approach. EHTs were transduced with lentivirus expressing channelrhodopsin-2 (H134R) and stimulated by 15 s bursts of blue light pulses (0.3 mW/mm2, 30 ms, 3 Hz) separated by 15 s without pacing for 3 weeks. Chronic optical tachypacing did not affect contractile peak force, but induced faster contraction kinetics, shorter action potentials, and shorter effective refractory periods. This electrical remodelling increased vulnerability to tachycardia episodes upon electrical burst pacing. Lower calsequestrin 2 protein levels, faster diastolic depolarization (DD) and efficacy of JTV-519 (46% at 1 µmol/L) to terminate tachycardia indicate alterations of Ca2+ handling being part of the underlying mechanism. However, other antiarrhythmic compounds like flecainide (69% at 1 µmol/L) and E-4031 (100% at 1 µmol/L) were also effective, but not ivabradine (1 µmol/L) or SEA0400 (10 µmol/L). CONCLUSION We demonstrated a high vulnerability to tachycardia of optically tachypaced hiPSC-CMs in EHT and the effective termination by ryanodine receptor stabilization, sodium or hERG potassium channel inhibition. This new model might serve as a preclinical tool to test antiarrhythmic drugs increasing the insight in treating ventricular tachycardia.
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Affiliation(s)
- Marta Lemme
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
| | - Ingke Braren
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
| | - Maksymilian Prondzynski
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
- Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, USA
| | - Bülent Aksehirlioglu
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Bärbel M Ulmer
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
| | - Mirja L Schulze
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
| | - Djemail Ismaili
- Department of Cardiology-Electrophysiology, University Heart Center, 20246 Hamburg, Germany
| | - Christian Meyer
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
- Department of Cardiology-Electrophysiology, University Heart Center, 20246 Hamburg, Germany
| | - Arne Hansen
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
| | - Torsten Christ
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
| | - Marc D Lemoine
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
- Department of Cardiology-Electrophysiology, University Heart Center, 20246 Hamburg, Germany
| | - Thomas Eschenhagen
- Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany
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29
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Rossi D, Gamberucci A, Pierantozzi E, Amato C, Migliore L, Sorrentino V. Calsequestrin, a key protein in striated muscle health and disease. J Muscle Res Cell Motil 2020; 42:267-279. [PMID: 32488451 DOI: 10.1007/s10974-020-09583-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/22/2020] [Accepted: 05/26/2020] [Indexed: 10/24/2022]
Abstract
Calsequestrin (CASQ) is the most abundant Ca2+ binding protein localized in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle. The genome of vertebrates contains two genes, CASQ1 and CASQ2. CASQ1 and CASQ2 have a high level of homology, but show specific patterns of expression. Fast-twitch skeletal muscle fibers express only CASQ1, both CASQ1 and CASQ2 are present in slow-twitch skeletal muscle fibers, while CASQ2 is the only protein present in cardiomyocytes. Depending on the intraluminal SR Ca2+ levels, CASQ monomers assemble to form large polymers, which increase their Ca2+ binding ability. CASQ interacts with triadin and junctin, two additional SR proteins which contribute to localize CASQ to the junctional region of the SR (j-SR) and also modulate CASQ ability to polymerize into large macromolecular complexes. In addition to its ability to bind Ca2+ in the SR, CASQ appears also to be able to contribute to regulation of Ca2+ homeostasis in muscle cells. Both CASQ1 and CASQ2 are able to either activate and inhibit the ryanodine receptors (RyRs) calcium release channels, likely through their interactions with junctin and triadin. Additional evidence indicates that CASQ1 contributes to regulate the mechanism of store operated calcium entry in skeletal muscle via a direct interaction with the Stromal Interaction Molecule 1 (STIM1). Mutations in CASQ2 and CASQ1 have been identified, respectively, in patients with catecholamine-induced polymorphic ventricular tachycardia and in patients with some forms of myopathy. This review will highlight recent developments in understanding CASQ1 and CASQ2 in health and diseases.
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Affiliation(s)
- Daniela Rossi
- Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro, 2, 53100, Siena, Italy.
| | - Alessandra Gamberucci
- Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro, 2, 53100, Siena, Italy
| | - Enrico Pierantozzi
- Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro, 2, 53100, Siena, Italy
| | - Caterina Amato
- Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro, 2, 53100, Siena, Italy
| | - Loredana Migliore
- Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro, 2, 53100, Siena, Italy
| | - Vincenzo Sorrentino
- Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro, 2, 53100, Siena, Italy
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30
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Nakao S, Ihara D, Hasegawa K, Kawamura T. Applications for Induced Pluripotent Stem Cells in Disease Modelling and Drug Development for Heart Diseases. Eur Cardiol 2020; 15:1-10. [PMID: 32180835 PMCID: PMC7066852 DOI: 10.15420/ecr.2019.03] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 08/09/2019] [Indexed: 12/22/2022] Open
Abstract
Induced pluripotent stem cells (iPSCs) are derived from reprogrammed somatic cells by the introduction of defined transcription factors. They are characterised by a capacity for self-renewal and pluripotency. Human (h)iPSCs are expected to be used extensively for disease modelling, drug screening and regenerative medicine. Obtaining cardiac tissue from patients with mutations for genetic studies and functional analyses is a highly invasive procedure. In contrast, disease-specific hiPSCs are derived from the somatic cells of patients with specific genetic mutations responsible for disease phenotypes. These disease-specific hiPSCs are a better tool for studies of the pathophysiology and cellular responses to therapeutic agents. This article focuses on the current understanding, limitations and future direction of disease-specific hiPSC-derived cardiomyocytes for further applications.
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Affiliation(s)
- Shu Nakao
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Japan.,Global Innovation Research Organization, Ritsumeikan University, Kusatsu, Japan.,Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan
| | - Dai Ihara
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Japan.,Global Innovation Research Organization, Ritsumeikan University, Kusatsu, Japan
| | - Koji Hasegawa
- Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan
| | - Teruhisa Kawamura
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Japan.,Global Innovation Research Organization, Ritsumeikan University, Kusatsu, Japan.,Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan
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31
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Garg P, Garg V, Shrestha R, Sanguinetti MC, Kamp TJ, Wu JC. Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Models for Cardiac Channelopathies: A Primer for Non-Electrophysiologists. Circ Res 2019; 123:224-243. [PMID: 29976690 DOI: 10.1161/circresaha.118.311209] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Life threatening ventricular arrhythmias leading to sudden cardiac death are a major cause of morbidity and mortality. In the absence of structural heart disease, these arrhythmias, especially in the younger population, are often an outcome of genetic defects in specialized membrane proteins called ion channels. In the heart, exceptionally well-orchestrated activity of a diversity of ion channels mediates the cardiac action potential. Alterations in either the function or expression of these channels can disrupt the configuration of the action potential, leading to abnormal electrical activity of the heart that can sometimes initiate an arrhythmia. Understanding the pathophysiology of inherited arrhythmias can be challenging because of the complexity of the disorder and lack of appropriate cellular and in vivo models. Recent advances in human induced pluripotent stem cell technology have provided remarkable progress in comprehending the underlying mechanisms of ion channel disorders or channelopathies by modeling these complex arrhythmia syndromes in vitro in a dish. To fully realize the potential of induced pluripotent stem cells in elucidating the mechanistic basis and complex pathophysiology of channelopathies, it is crucial to have a basic knowledge of cardiac myocyte electrophysiology. In this review, we will discuss the role of the various ion channels in cardiac electrophysiology and the molecular and cellular mechanisms of arrhythmias, highlighting the promise of human induced pluripotent stem cell-cardiomyocytes as a model for investigating inherited arrhythmia syndromes and testing antiarrhythmic strategies. Overall, this review aims to provide a basic understanding of the electrical activity of the heart and related channelopathies, especially to clinicians or research scientists in the cardiovascular field with limited electrophysiology background.
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Affiliation(s)
- Priyanka Garg
- From the Stanford Cardiovascular Institute (P.G., R.S., J.C.W.).,Department of Medicine, Division of Cardiology (P.G., R.S., J.C.W.).,Institute for Stem Cell Biology and Regenerative Medicine (P.G., R.S., J.C.W.)
| | - Vivek Garg
- Stanford University School of Medicine, CA; Department of Physiology, University of California San Francisco (V.G.)
| | - Rajani Shrestha
- From the Stanford Cardiovascular Institute (P.G., R.S., J.C.W.).,Department of Medicine, Division of Cardiology (P.G., R.S., J.C.W.).,Institute for Stem Cell Biology and Regenerative Medicine (P.G., R.S., J.C.W.)
| | | | - Timothy J Kamp
- Department of Medicine, University of Wisconsin-Madison (T.J.K.)
| | - Joseph C Wu
- From the Stanford Cardiovascular Institute (P.G., R.S., J.C.W.) .,Department of Medicine, Division of Cardiology (P.G., R.S., J.C.W.).,Institute for Stem Cell Biology and Regenerative Medicine (P.G., R.S., J.C.W.)
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32
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Lee J, Termglinchan V, Diecke S, Itzhaki I, Lam CK, Garg P, Lau E, Greenhaw M, Seeger T, Wu H, Zhang JZ, Chen X, Gil IP, Ameen M, Sallam K, Rhee JW, Churko JM, Chaudhary R, Chour T, Wang PJ, Snyder MP, Chang HY, Karakikes I, Wu JC. Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature 2019; 572:335-340. [PMID: 31316208 PMCID: PMC6779479 DOI: 10.1038/s41586-019-1406-x] [Citation(s) in RCA: 156] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 06/19/2019] [Indexed: 12/11/2022]
Abstract
Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-β (PDGFRB) as a potential therapeutic target.
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MESH Headings
- Arrhythmias, Cardiac/metabolism
- Arrhythmias, Cardiac/pathology
- Calcium/metabolism
- Cardiomyopathy, Dilated/genetics
- Cells, Cultured
- Chromatin/chemistry
- Chromatin/genetics
- Chromatin/metabolism
- Chromatin Assembly and Disassembly/genetics
- Haploinsufficiency/genetics
- Homeostasis
- Humans
- In Vitro Techniques
- Induced Pluripotent Stem Cells/pathology
- Lamin Type A/genetics
- Models, Biological
- Mutation
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Nonsense Mediated mRNA Decay
- Platelet-Derived Growth Factor/metabolism
- RNA, Messenger/analysis
- RNA, Messenger/genetics
- Receptor, Platelet-Derived Growth Factor beta/metabolism
- Signal Transduction
- Single-Cell Analysis
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Affiliation(s)
- Jaecheol Lee
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
| | - Vittavat Termglinchan
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Sebastian Diecke
- Berlin Institute of Health, Berlin, Germany
- Max Delbrueck Center, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
| | - Ilanit Itzhaki
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Chi Keung Lam
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Priyanka Garg
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Edward Lau
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Matthew Greenhaw
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Timon Seeger
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Haodi Wu
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Joe Z Zhang
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Xingqi Chen
- Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA
| | - Isaac Perea Gil
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA
| | - Mohamed Ameen
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Karim Sallam
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - June-Wha Rhee
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Jared M Churko
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Rinkal Chaudhary
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Tony Chour
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA
| | - Paul J Wang
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA
| | - Michael P Snyder
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Howard Y Chang
- Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
| | - Ioannis Karakikes
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
- Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
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33
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Goldfracht I, Efraim Y, Shinnawi R, Kovalev E, Huber I, Gepstein A, Arbel G, Shaheen N, Tiburcy M, Zimmermann WH, Machluf M, Gepstein L. Engineered heart tissue models from hiPSC-derived cardiomyocytes and cardiac ECM for disease modeling and drug testing applications. Acta Biomater 2019; 92:145-159. [PMID: 31075518 DOI: 10.1016/j.actbio.2019.05.016] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 04/23/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023]
Abstract
Cardiac tissue engineering provides unique opportunities for cardiovascular disease modeling, drug testing, and regenerative medicine applications. To recapitulate human heart tissue, we combined human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with a chitosan-enhanced extracellular-matrix (ECM) hydrogel, derived from decellularized pig hearts. Ultrastructural characterization of the ECM-derived engineered heart tissues (ECM-EHTs) revealed an anisotropic muscle structure, with embedded cardiomyocytes showing more mature properties than 2D-cultured hiPSC-CMs. Force measurements confirmed typical force-length relationships, sensitivity to extracellular calcium, and adequate ionotropic responses to contractility modulators. By combining genetically-encoded calcium and voltage indicators with laser-confocal microscopy and optical mapping, the electrophysiological and calcium-handling properties of the ECM-EHTs could be studied at the cellular and tissue resolutions. This allowed to detect drug-induced changes in contraction rate (isoproterenol, carbamylcholine), optical signal morphology (E-4031, ATX2, isoproterenol, ouabin and quinidine), cellular arrhythmogenicity (E-4031 and ouabin) and alterations in tissue conduction properties (lidocaine, carbenoxolone and quinidine). Similar assays in ECM-EHTs derived from patient-specific hiPSC-CMs recapitulated the abnormal phenotype of the long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. Finally, programmed electrical stimulation and drug-induced pro-arrhythmia led to the development of reentrant arrhythmias in the ECM-EHTs. In conclusion, a novel ECM-EHT model was established, which can be subjected to high-resolution long-term serial functional phenotyping, with important implications for cardiac disease modeling, drug testing and precision medicine. STATEMENT OF SIGNIFICANCE: One of the main objectives of cardiac tissue engineering is to create an in-vitro muscle tissue surrogate of human heart tissue. To this end, we combined a chitosan-enforced cardiac-specific ECM hydrogel derived from decellularized pig hearts with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from healthy-controls and patients with inherited cardiac disorders. We then utilized genetically-encoded calcium and voltage fluorescent indicators coupled with unique optical imaging techniques and force-measurements to study the functional properties of the generated engineered heart tissues (EHTs). These studies demonstrate the unique potential of the new model for physiological and pathophysiological studies (assessing contractility, conduction and reentrant arrhythmias), novel disease modeling strategies ("disease-in-a-dish" approach) for studying inherited arrhythmogenic disorders, and for drug testing applications (safety pharmacology).
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Affiliation(s)
- Idit Goldfracht
- Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Israel; Interdisciplinarry Biotechnology Program. Technion - Israel Institute of Technology, Israel
| | - Yael Efraim
- Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Israel
| | - Rami Shinnawi
- Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Israel
| | - Ekaterina Kovalev
- Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Israel
| | - Irit Huber
- Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Israel
| | - Amira Gepstein
- Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Israel
| | - Gil Arbel
- Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Israel
| | - Naim Shaheen
- Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Israel
| | - Malte Tiburcy
- Institute of Pharmacology and Toxicology, University Medical Center, Goettingen, Germany; DZHK (German Center for Cardiovascular Research), Partner Site, Goettingen, Germany
| | - Wolfram H Zimmermann
- Institute of Pharmacology and Toxicology, University Medical Center, Goettingen, Germany; DZHK (German Center for Cardiovascular Research), Partner Site, Goettingen, Germany
| | - Marcelle Machluf
- Faculty of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Israel
| | - Lior Gepstein
- Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Israel; Cardiology Department, Rambam Health Care Campus, Israel.
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Liang W, Gasparyan L, AlQarawi W, Davis DR. Disease modeling of cardiac arrhythmias using human induced pluripotent stem cells. Expert Opin Biol Ther 2019; 19:313-333. [PMID: 30682895 DOI: 10.1080/14712598.2019.1575359] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
INTRODUCTION Inherited arrhythmias are an uncommon, but malignant family of cardiac diseases that result from genetic abnormalities in the ion channels and/or structural proteins within cardiomyocytes. Given the inherent differences between species and the limited reproducibility of in vitro heterologous cell models, progress in understanding the mechanisms underlying these malignant diseases has always languished far behind the clinical science and need. The ability to study human induced pluripotent stem cells (iPSCs) derived cardiomyocytes promises to change this paradigm as patient cells have the potential to become testing platforms for disease phenotyping or therapeutic discovery. AREAS COVERED This review will outline methods developed to genetically reprogram adult cells into iPSCs, differentiate iPSCs into ex vivo models of adult cardiac tissue and iPSCs-based progress in exploring the mechanisms underlying pro-arrhythmic disease phenotypes. EXPERT OPINION Despite being discovered less than 15 years ago, several studies have successfully leveraged iPSCs-derived cardiomyocytes to study malignant arrhythmogenic diseases. These models promise to increase our understanding of the pathophysiology underlying these complex diseases and may identify personalized approaches to treatment.
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Affiliation(s)
- Wenbin Liang
- a Division of Cardiology, Department of Medicine , University of Ottawa Heart Institute , Ottawa , Canada.,b Department of Cellular and Molecular Medicine , University of Ottawa , Ottawa , Canada
| | - Lilit Gasparyan
- a Division of Cardiology, Department of Medicine , University of Ottawa Heart Institute , Ottawa , Canada
| | - Wael AlQarawi
- a Division of Cardiology, Department of Medicine , University of Ottawa Heart Institute , Ottawa , Canada
| | - Darryl R Davis
- a Division of Cardiology, Department of Medicine , University of Ottawa Heart Institute , Ottawa , Canada.,b Department of Cellular and Molecular Medicine , University of Ottawa , Ottawa , Canada
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van Mil A, Balk GM, Neef K, Buikema JW, Asselbergs FW, Wu SM, Doevendans PA, Sluijter JPG. Modelling inherited cardiac disease using human induced pluripotent stem cell-derived cardiomyocytes: progress, pitfalls, and potential. Cardiovasc Res 2018; 114:1828-1842. [PMID: 30169602 PMCID: PMC6887927 DOI: 10.1093/cvr/cvy208] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/06/2018] [Accepted: 08/28/2018] [Indexed: 12/17/2022] Open
Abstract
In the past few years, the use of specific cell types derived from induced pluripotent stem cells (iPSCs) has developed into a powerful approach to investigate the cellular pathophysiology of numerous diseases. Despite advances in therapy, heart disease continues to be one of the leading causes of death in the developed world. A major difficulty in unravelling the underlying cellular processes of heart disease is the extremely limited availability of viable human cardiac cells reflecting the pathological phenotype of the disease at various stages. Thus, the development of methods for directed differentiation of iPSCs to cardiomyocytes (iPSC-CMs) has provided an intriguing option for the generation of patient-specific cardiac cells. In this review, a comprehensive overview of the currently published iPSC-CM models for hereditary heart disease is compiled and analysed. Besides the major findings of individual studies, detailed methodological information on iPSC generation, iPSC-CM differentiation, characterization, and maturation is included. Both, current advances in the field and challenges yet to overcome emphasize the potential of using patient-derived cell models to mimic genetic cardiac diseases.
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Affiliation(s)
- Alain van Mil
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Geerthe Margriet Balk
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Klaus Neef
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Jan Willem Buikema
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Folkert W Asselbergs
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Faculty of Population Health Sciences, Institute of Cardiovascular Science, University College London, London, UK
- Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands
- Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK
| | - Sean M Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Pieter A Doevendans
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Joost P G Sluijter
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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Christidi E, Huang HM, Brunham LR. CRISPR/Cas9-mediated genome editing in human stem cell-derived cardiomyocytes: Applications for cardiovascular disease modelling and cardiotoxicity screening. DRUG DISCOVERY TODAY. TECHNOLOGIES 2018; 28:13-21. [PMID: 30205876 DOI: 10.1016/j.ddtec.2018.06.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 05/31/2018] [Accepted: 06/07/2018] [Indexed: 12/18/2022]
Abstract
Cardiovascular diseases (CVDs) are leading causes of death worldwide, and drug-induced cardiotoxicity is among the most common cause of drug withdrawal from the market. Improved models of cardiac tissue are needed to study the mechanisms of CVDs and drug-induced cardiotoxicity. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) have provided a major advance to our ability to study these conditions. Combined with efficient genome editing technologies, such as CRISPR/Cas9, we now have the ability to study with greater resolution the genetic causes and underlying mechanisms of inherited and drug-induced cardiotoxicity, and to investigate new treatments. Here, we review recent advances in the use of hPSC-CMs and CRISPR/Cas9-mediated genome editing to study cardiotoxicity and model CVD.
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Affiliation(s)
- Effimia Christidi
- Centre for Heart Lung Innovation, Department of Medicine, University of British Columbia, Vancouver, Canada
| | - Haojun Margaret Huang
- Centre for Heart Lung Innovation, Department of Medicine, University of British Columbia, Vancouver, Canada
| | - Liam R Brunham
- Centre for Heart Lung Innovation, Department of Medicine, University of British Columbia, Vancouver, Canada; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore; Department of Medicine, National University of Singapore, Singapore.
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Brandão KO, Tabel VA, Atsma DE, Mummery CL, Davis RP. Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies. Dis Model Mech 2018; 10:1039-1059. [PMID: 28883014 PMCID: PMC5611968 DOI: 10.1242/dmm.030320] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
It is now a decade since human induced pluripotent stem cells (hiPSCs) were first described. The reprogramming of adult somatic cells to a pluripotent state has become a robust technology that has revolutionised our ability to study human diseases. Crucially, these cells capture all the genetic aspects of the patient from which they were derived. Combined with advances in generating the different cell types present in the human heart, this has opened up new avenues to study cardiac disease in humans and investigate novel therapeutic approaches to treat these pathologies. Here, we provide an overview of the current state of the field regarding the generation of cardiomyocytes from human pluripotent stem cells and methods to assess them functionally, an essential requirement when investigating disease and therapeutic outcomes. We critically evaluate whether treatments suggested by these in vitro models could be translated to clinical practice. Finally, we consider current shortcomings of these models and propose methods by which they could be further improved.
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Affiliation(s)
- Karina O Brandão
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Viola A Tabel
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Douwe E Atsma
- Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Christine L Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | - Richard P Davis
- Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients. Stem Cells Int 2018; 2018:9109503. [PMID: 29760739 DOI: 10.1155/2018/9109503] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 02/02/2018] [Accepted: 02/15/2018] [Indexed: 12/18/2022] Open
Abstract
Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and L4115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to this study, the arrhythmia-abolishing effect of neither of the drugs is optimal. iPSC-CMs provide a unique platform for testing drugs for CPVT.
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Baruteau AE, Abrams DJ, Ho SY, Thambo JB, McLeod CJ, Shah MJ. Cardiac Conduction System in Congenitally Corrected Transposition of the Great Arteries and Its Clinical Relevance. J Am Heart Assoc 2017; 6:JAHA.117.007759. [PMID: 29269355 PMCID: PMC5779063 DOI: 10.1161/jaha.117.007759] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Alban-Elouen Baruteau
- Department of Congenital Cardiology, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom .,M3C CHU de Nantes, Fédération des Cardiopathies Congénitales, Nantes, France
| | - Dominic J Abrams
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Siew Yen Ho
- Cardiac Morphology, Royal Brompton Hospital and Harefield NHS Foundation Trust, Imperial College London, London, United Kingdom
| | - Jean-Benoit Thambo
- Department of Paediatric Cardiology, CHU Bordeaux, Pessac, France.,IHU LIRYC, Electrophysiology and Heart Modeling Institute, Bordeaux, France
| | - Christopher J McLeod
- Department of Cardiovascular Diseases, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN
| | - Maully J Shah
- Division of Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
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Ross SB, Fraser ST, Semsarian C. Induced pluripotent stem cell technology and inherited arrhythmia syndromes. Heart Rhythm 2017; 15:137-144. [PMID: 28823602 DOI: 10.1016/j.hrthm.2017.08.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Indexed: 01/13/2023]
Abstract
Inherited arrhythmia syndromes, including familial long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden deaths in the young. Identification of genetic mutations and pathophysiological changes that underlie disease development can inform clinical practice and guide novel drug development. However, disease mechanisms in a large number of patients remain elusive and pharmacologic treatment is suboptimal, so many patients rely on implantable cardioverter-defibrillator therapy. Induced pluripotent stem cell models of disease facilitate analysis of disease mechanisms in patient-specific cardiomyocytes, overcoming limitations of animal models and human tissue restrictions. This review outlines how studies using induced pluripotent stem cell-derived cardiomyocytes are contributing to our understanding of the mechanisms that underpin disease pathogenesis and their potential to facilitate new pharmacologic therapies and personalized medicine.
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Affiliation(s)
- Samantha Barratt Ross
- Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia; Sydney Medical School, University of Sydney, Sydney, Australia
| | - Stuart T Fraser
- School of Medical Sciences, University of Sydney, Sydney, Australia
| | - Christopher Semsarian
- Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
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Li Y, Sallam K, Schwartz PJ, Wu JC. Patient-Specific Induced Pluripotent Stem Cell-Based Disease Model for Pathogenesis Studies and Clinical Pharmacotherapy. Circ Arrhythm Electrophysiol 2017; 10:e005398. [PMID: 28630175 PMCID: PMC5517015 DOI: 10.1161/circep.117.005398] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Affiliation(s)
- Yingxin Li
- From the Stanford Cardiovascular Institute, Departments of Medicine and Radiology, Institute of Stem Cell Biology & Regenerative Medicine (Y.L., K.S., J.C.W.), Stanford University, School of Medicine, CA; and Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.J.S.)
| | - Karim Sallam
- From the Stanford Cardiovascular Institute, Departments of Medicine and Radiology, Institute of Stem Cell Biology & Regenerative Medicine (Y.L., K.S., J.C.W.), Stanford University, School of Medicine, CA; and Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.J.S.)
| | - Peter J Schwartz
- From the Stanford Cardiovascular Institute, Departments of Medicine and Radiology, Institute of Stem Cell Biology & Regenerative Medicine (Y.L., K.S., J.C.W.), Stanford University, School of Medicine, CA; and Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.J.S.)
| | - Joseph C Wu
- From the Stanford Cardiovascular Institute, Departments of Medicine and Radiology, Institute of Stem Cell Biology & Regenerative Medicine (Y.L., K.S., J.C.W.), Stanford University, School of Medicine, CA; and Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milano, Italy (P.J.S.).
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