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Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients

Published on Jun 20, 2019in European Heart Journal24.889
· DOI :10.1093/eurheartj/ehz326
Haodi Wu20
Estimated H-index: 20
(Stanford University),
Huaxiao Yang10
Estimated H-index: 10
(Stanford University)
+ 10 AuthorsJoseph C. Wu91
Estimated H-index: 91
(Stanford University)
Abstract
  • References (39)
  • Citations (5)
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References39
Newest
#1Ning Ma (Cardiovascular Institute of the South)H-Index: 4
#2Joe Z. Zhang (Cardiovascular Institute of the South)H-Index: 4
Last. Joseph C. Wu (Cardiovascular Institute of the South)H-Index: 91
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Background: The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic “healthy” in...
22 CitationsSource
#1Taylor Howard (OSU: Ohio State University)H-Index: 2
#2Amara Greer-Short (OSU: Ohio State University)H-Index: 1
Last. Thomas J. Hund (OSU: Ohio State University)H-Index: 33
view all 7 authors...
The mechanisms underlying CaMKII-induced arrhythmias in ischemia/reperfusion (I/R) are not fully understood. In this study, we tested the hypothesis that CaMKII increases late Na+ current (INa,L) via phosphorylation of Nav1.5 at Ser571 during I/R, thereby increasing arrhythmia susceptibility. To test our hypothesis, isolated, Langendorff-perfused hearts from wildtype (WT) mice and mice expressing Nav channel variants Nav1.5-Ser571E (S571E) and Nav1.5-Ser571A (S571A) were studied. Wildtype (WT) h...
4 CitationsSource
#1Kishan S. Parikh (Duke University)H-Index: 10
#2Kavita Sharma (Johns Hopkins University)H-Index: 9
Last. G. Michael Felker (Duke University)H-Index: 70
view all 21 authors...
Abstract The number of persons with heart failure has continued to rise over the last several years. Approximately one-half of those living with heart failure have heart failure with preserved ejection fraction, but critical unsolved questions remain across the spectrum of basic, translational, clinical, and population research in heart failure with preserved ejection fraction. In this study, the authors summarize existing knowledge, persistent controversies, and gaps in evidence with regard to ...
14 CitationsSource
#1Chun Liu (Cardiovascular Institute of the South)H-Index: 25
#2Angelos Oikonomopoulos (Cardiovascular Institute of the South)H-Index: 6
Last. Joseph C. Wu (Cardiovascular Institute of the South)H-Index: 91
view all 4 authors...
ABSTRACT The advent of human induced pluripotent stem cells (iPSCs) presents unprecedented opportunities to model human diseases. Differentiated cells derived from iPSCs in two-dimensional (2D) monolayers have proven to be a relatively simple tool for exploring disease pathogenesis and underlying mechanisms. In this Spotlight article, we discuss the progress and limitations of the current 2D iPSC disease-modeling platform, as well as recent advancements in the development of human iPSC models th...
26 CitationsSource
#1Piotr PonikowskiH-Index: 106
#2Adriaan A. VoorsH-Index: 82
Last. P. van der MeerH-Index: 42
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ACC/AHA : American College of Cardiology/American Heart Association ACCF/AHA : American College of Cardiology Foundation/American Heart Association ACE : angiotensin-converting enzyme ACEI : angiotensin-converting enzyme inhibitor ACS : acute coronary syndrome AF : atrial fibrillation
2,864 CitationsSource
#1Ping Liang (ZJU: Zhejiang University)H-Index: 13
#2Karim Sallam (Stanford University)H-Index: 11
Last. Joseph C. Wu (Stanford University)H-Index: 91
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Abstract Background Brugada syndrome (BrS), a disorder associated with characteristic electrocardiogram precordial ST-segment elevation, predisposes afflicted patients to ventricular fibrillation and sudden cardiac death. Despite marked achievements in outlining the organ level pathophysiology of the disorder, the understanding of human cellular phenotype has lagged due to a lack of adequate human cellular models of the disorder. Objectives The objective of this study was to examine single cell ...
54 CitationsSource
#1Piotr PonikowskiH-Index: 106
#2Adriaan A. VoorsH-Index: 82
Last. J.L. ZamoranoH-Index: 82
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2,960 CitationsSource
#1Jennifer Davis (UW: University of Washington)H-Index: 16
#2L. Craig DavisH-Index: 1
Last. Jeffery D. Molkentin (Cincinnati Children's Hospital Medical Center)H-Index: 109
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Summary The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium...
78 CitationsSource
#1Evangeline Tzatzalos (Stanford University)H-Index: 4
#2Oscar J. AbilezH-Index: 24
Last. Joseph C. WuH-Index: 91
view all 4 authors...
Engineered heart tissue has emerged as a personalized platform for drug screening. With the advent of induced pluripotent stem cell (iPSC) technology, patient-specific stem cells can be developed and expanded into an indefinite source of cells. Subsequent developments in cardiovascular biology have led to efficient differentiation of cardiomyocytes, the force-producing cells of the heart. iPSC-derived cardiomyocytes (iPSC-CMs) have provided potentially limitless quantities of well-characterized,...
63 CitationsSource
#1Alexandre J.S. Ribeiro (Cardiovascular Institute of the South)H-Index: 12
#2Yen-Sin Ang (Gladstone Institutes)H-Index: 21
Last. Beth L. Pruitt (Cardiovascular Institute of the South)H-Index: 33
view all 8 authors...
Single cardiomyocytes contain myofibrils that harbor the sarcomere-based contractile machinery of the myocardium. Cardiomyocytes differentiated from human pluripotent stem cells (hPSC-CMs) have potential as an in vitro model of heart activity. However, their fetal-like misalignment of myofibrils limits their usefulness for modeling contractile activity. We analyzed the effects of cell shape and substrate stiffness on the shortening and movement of labeled sarcomeres and the translation of sarcom...
135 CitationsSource
Cited By5
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#1Chrishan J. A. Ramachandra (NUS: National University of Singapore)H-Index: 9
#2Jasper Chua (NUS: National University of Singapore)
Last. Derek J. HausenloyH-Index: 71
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Normal cardiac contractile and relaxation function are critically dependent on a continuous energy supply. Accordingly, metabolic perturbations and impaired mitochondrial bioenergetics with subsequent disruption of ATP production underpin a wide variety of cardiac diseases, including diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, anthracycline cardiomyopathy, peripartum cardiomyopathy, and mitochondrial cardiomyopathies. Crucially, there are no specific treatments ...
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#1Paul J.M. Wijnker (VU: VU University Amsterdam)H-Index: 1
#1Paul J.M. Wijnker (VU: VU University Amsterdam)H-Index: 13
Last. Jolanda van der Velden (VU: VU University Amsterdam)H-Index: 42
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Abstract Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric left ventricular hypertrophy and diastolic dysfunction, and a frequent cause of sudden cardiac death at young age. Pharmacological treatment to prevent or reverse HCM is lacking. This may be partly explained by the variety of underlying disease causes. Over 1500 mutations have been associated with HCM, of which the majority reside in genes encoding sarcomere proteins, the car...
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#1Changwon Kho (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 14
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#1David T. Paik (Cardiovascular Institute of the South)H-Index: 6
#2Mark Chandy (Cardiovascular Institute of the South)H-Index: 7
Last. Joseph C. Wu (Cardiovascular Institute of the South)H-Index: 91
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Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. Despite significan...
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#1Maksymilian Prondzynski (UHH: University of Hamburg)H-Index: 8
#2Marc D. Lemoine (UHH: University of Hamburg)H-Index: 6
Last. Lucie Carrier (UHH: University of Hamburg)H-Index: 44
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Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding alpha-actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient-derived human-induced pluripotent stem cells (hiPSCs) and show that hiPSC-derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks ...
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#1Shambhabi Chatterjee (MHH: Hannover Medical School)H-Index: 3
#2Thomas Thum (MHH: Hannover Medical School)H-Index: 66
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#1Thomas F. Lüscher (Imperial College London)H-Index: 123
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#1Li Pang (FDA: Food and Drug Administration)
#2Philip T. Sager (Stanford University)H-Index: 22
Last. Norman Stockbridge (CDER: Center for Drug Evaluation and Research)H-Index: 30
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Source
In the last few decades, many pathogenic or likely pathogenic genetic mutations in over hundred different genes have been described for non-ischemic, genetic cardiomyopathies. However, the functional knowledge about most of these mutations is still limited because the generation of adequate animal models is time-consuming and challenging. Therefore, human induced pluripotent stem cells (iPSCs) carrying specific cardiomyopathy-associated mutations are a promising alternative. Since the original d...
2 CitationsSource