Abstract:
AIMS:In mammalian ventricles, electrical gradients establish electrical heterogeneities as essential tissue mechanisms to optimize mechanical efficiency and safeguard electrical stability. Electrical gradients shape mammalian electrocardiographic patterns; disturbance of electrical gradients is proarrhythmic. The zebrafish heart is a popular surrogate model for human cardiac electrophysiology thanks to its remarkable recapitulation of human electrocardiogram and ventricular action potential features. Yet, zebrafish ventricular electrical gradients are largely unexplored. The goal of this study is to define the zebrafish ventricular electrical gradients that shape the QRS complex and T wave patterns at baseline and under oxidative stress. METHODS AND RESULTS:We performed in vivo electrocardiography and ex vivo voltage-sensitive fluorescent epicardial and transmural optical mapping of adult zebrafish hearts at baseline and during acute H2O2 exposure. At baseline, apicobasal activation and basoapical repolarization gradients accounted for the polarity concordance between the QRS complex and T wave. During H2O2 exposure, differential regional impairment of activation and repolarization at the apex and base disrupted prior baseline electrical gradients, resulting in either reversal or loss of polarity concordance between the QRS complex and T wave. KN-93, a specific calcium/calmodulin-dependent protein kinase II inhibitor (CaMKII), protected zebrafish hearts from H2O2 disruption of electrical gradients. The protection was complete if administered prior to oxidative stress. CONCLUSIONS:Despite remarkable apparent similarities, zebrafish and human ventricular electrocardiographic patterns are mirror images supported by opposite electrical gradients. Like mammalian ventricles, zebrafish ventricles are also susceptible to H2O2 proarrhythmic perturbation via CaMKII activation. Our findings suggest that the adult zebrafish heart may constitute a clinically relevant model to investigate ventricular arrhythmias induced by oxidative stress. However, the fundamental ventricular activation and repolarization differences between the two species that we demonstrated in this study highlight the potential limitations when extrapolating results from zebrafish experiments to human cardiac electrophysiology, arrhythmias, and drug toxicities. TRANSLATIONAL PERSPECTIVE:Zebrafish electrocardiograms remarkably recapitulate human electrocardiograms in health and disease. Yet, the underlying tissue mechanisms were unknown. This study provides the first demonstration that the baseline electrical gradients that shape zebrafish ventricular electrocardiograms are opposite human electrical gradients. Additionally, like mammalian hearts, zebrafish hearts are susceptible to CaMKII-mediated H2O2 proarrhythmic perturbations. Despite its vital role in zebrafish cardiac regeneration following injury, H2O2 can disrupt zebrafish sinus node activity, cause all three types of atrioventricular blocks, and reverse ventricular electrical gradients. These findings highlight the clinical relevance, utility, and limitations of the adult zebrafish heart as model for mammalian arrhythmogenesis studies.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Zhao Y,James NA,Beshay AR,Chang EE,Lin A,Bashar F,Wassily A,Nguyen B,Nguyen TPdoi
10.1093/cvr/cvaa238subject
Has Abstractpub_date
2020-07-31 00:00:00eissn
0008-6363issn
1755-3245pii
5879279pub_type
杂志文章abstract:OBJECTIVE:Experimental and clinical studies have shown that administration of insulin during reperfusion is cardioprotective, but the underlying mechanisms are still unknown. In this study, we investigated in isolated rat cardiomyocytes subjected to hypoxia and reoxygenation whether administration of insulin during reo...
journal_title:Cardiovascular research
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abstract:AIMS:SR-B1 is a cholesterol transporter that exerts anti-atherogenic properties in liver and peripheral tissues in mice. Bone marrow (BM) transfer studies suggested an atheroprotective role in cells of haematopoietic origin. Here, we addressed the specific contribution of SR-B1 in the monocyte/macrophage. METHODS AND ...
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journal_title:Cardiovascular research
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更新日期:2004-08-01 00:00:00
abstract::The effect of circulation time on plasma high density lipoprotein cholesterol concentrations was investigated in 20 male Wistar rats injected with alcohol, stressed with lighting, or fed a high fat diet. Circulation time was measured during anaesthesia with a computerised dichromatic earpiece densitometer. Indocyanine...
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更新日期:1988-05-01 00:00:00
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更新日期:1980-02-01 00:00:00
abstract:AIMS:GATA4 is a transcription factor that is up-regulated during cardiac hypertrophy and plays a fundamental role in myocyte growth and survival. In this study, we investigate the transcriptional vs. post-transcriptional mechanisms that are involved in regulating GATA4 in the heart during neonatal and pressure overload...
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doi:10.1093/cvr/cvs001
更新日期:2012-03-15 00:00:00
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doi:10.1016/j.cardiores.2003.09.017
更新日期:2003-12-01 00:00:00
abstract:OBJECTIVE:The multifunctional Ca2+-binding protein S100A4 (also known as Mts1 and Fsp1) is involved in fibrosis and tissue remodeling in several diseases including cancer, kidney fibrosis, central nervous system injury, and pulmonary vascular disease. We previously reported that S100A4 mRNA expression was increased in ...
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doi:10.1016/j.cardiores.2007.03.027
更新日期:2007-07-01 00:00:00
abstract:STUDY OBJECTIVE:Compensatory mechanisms of the left ventricle for volume overloading caused by acute aortic regurgitation and associated changes in physiological properties of the aorta were studied in rabbits. DESIGN:Aortic regurgitation was produced by aortic valve perforation, and haemodynamic measurements were per...
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doi:10.1093/cvr/25.6.463
更新日期:1991-06-01 00:00:00
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更新日期:2014-05-01 00:00:00
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doi:
更新日期:1995-01-01 00:00:00
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更新日期:2019-01-01 00:00:00
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更新日期:1997-07-01 00:00:00
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更新日期:2009-04-01 00:00:00
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doi:10.1016/j.cardiores.2006.10.020
更新日期:2007-01-01 00:00:00
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更新日期:2010-04-01 00:00:00
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