Experimental Models of Brugada syndrome

Sendfeld, Franziska; Selga, Elisabet; Scornik, Fabiana S.; Pérez, Guillermo J.; Mills, Nicholas L; Brugada, Ramón

doi:10.3390/ijms20092123

Cited by 35 publications

(29 citation statements)

References 88 publications

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“…In epicardial myocytes in the RVOT, the loss-of-dome AP followed by marked shortening of APD, i.e., repolarization abnormality 7,26 , is considered to be one of the mechanisms of coved-type ST-segment elevation (Brugada-type ECG) 2,6 . One of the factors causing the loss-of-dome is thought to be the ventricular gradient of I to through the RV wall, as well as endogenously heterogeneous I to in the RV epicardial layers 7,26 .…”

Section: Discussionmentioning

confidence: 99%

“…BrS is characterized by the electrocardiograms with both a right bundle-branch block pattern and ST-segment elevation in the right precordial leads (V 1 –V 3 ) and by the higher incidence of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) 5 , 6 . It is commonly believed that VT/VF is elicited by the closely coupled premature ventricular contractions via the phase-2 reentry (P2R) mechanism 6 . This mechanism is that APs with phase-2 dome in some sites of the tissue re-excite neighboring repolarized sites via electrotonic interaction to evoke an additional conductive AP (triggered activity) (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

Tsumoto

Ashihara

Naito

et al. 2020

Sci Rep

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Reduced cardiac sodium (Na+) channel current (INa) resulting from the loss-of-function of Na+ channel is a major cause of lethal arrhythmias in Brugada syndrome (BrS). Inspired by previous experimental studies which showed that in heart diseases INa was reduced along with expression changes in Na+ channel within myocytes, we hypothesized that the local decrease in INa caused by the alteration in Na+ channel expression in myocytes leads to the occurrence of phase-2 reentry, the major triggering mechanism of lethal arrhythmias in BrS. We constructed in silico human ventricular myocardial strand and ring models, and examined whether the Na+ channel expression changes in each myocyte cause the phase-2 reentry in BrS. Reducing Na+ channel expression in the lateral membrane of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients. Furthermore, the selective reduction in Na+ channels on the lateral membrane of each myocyte together with spatial tissue heterogeneity of Na+ channel expression caused the phase-2 reentry and phase-2 reentry-mediated reentrant arrhythmias. Our data suggest that the BrS phenotype is strongly influenced by expression abnormalities as well as genetic abnormalities of Na+ channels.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

Tsumoto

Ashihara

Naito

et al. 2020

Sci Rep

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“…Over the last few years, hiPSCs have been increasingly employed to elucidate pathophysiological mechanisms of various cardiovascular diseases (reviewed in Giacomelli et al, 2017) [41]. They have been shown to be effective for phenotype and drug response studies in diseases with genetic mutations such as long QT syndrome [42], short QT syndrome [43], catecholaminergic polymorphic ventricular tachycardia (CPVT) [44], atrial fibrillation [45], dilated cardiomyopathy (DCM) as well as hypertrophic cardiomyopathy (HCM) [5,46], arrhythmogenic right ventricular dysplasia (ARVD) [47], Brugada syndrome [48], Timothy syndrome [49], and Duchenne muscular dystrophy [50]. Another area of application of hiPSC-based technologies has been the modelling of diseases with early-onset symptoms, in particular cardiometabolic diseases (Fabry's disease [51], Pompe disease [52], Danon disease [53], Barth syndrome [54]).…”

Section: Approaches To Model Heart Failure In a Dish Using Hipsc-cmsmentioning

confidence: 99%

“…Besides low cardiac output due to reduced contractility, patients with heart failure are threatened by malignant arrhythmias like ventricular tachycardia or fibrillation. As mentioned above, several studies have been reported using hiPSC-CMs to model channelopathies, namely long QT [42], short QT [43], and Brugada syndrome [48], but also arrhythmic diseases like CPVT [44].…”

Section: Analysis Of Hipsc-cm Modelsmentioning

confidence: 99%

Human Induced Pluripotent Stem Cells as a Disease Model System for Heart Failure

Deicher

Seeger

2020

Curr Heart Fail Rep

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Purpose of Review Heart failure is among the most prevalent disease complexes overall and is associated with high morbidity and mortality. The underlying aetiology is manifold including coronary artery disease, genetic alterations and mutations, viral infections, adverse immune responses, and cardiac toxicity. To date, no specific therapies have been developed despite notable efforts. This can especially be attributed to hurdles in translational research, mainly due to the lack of proficient models of heart failure limited translation of therapeutic approaches from bench to bedside. Recent Findings Human induced pluripotent stem cells (hiPSCs) are rising in popularity, granting the ability to divide infinitely, to hold human, patient-specific genome, and to differentiate into any human cell, including cardiomyocytes (hiPSC-CMs). This brings magnificent promise to cardiological research, providing the possibility to recapitulate cardiac diseases in a dish. Advances in yield, maturity, and in vivo resemblance due to straightforward, low-cost protocols, high-throughput approaches, and complex 3D cultures have made this tool widely applicable. In recent years, hiPSC-CMs have been used to model a wide variety of cardiac diseases, bringing along the possibility to not only elucidate molecular mechanisms but also to test novel therapeutic approaches in the dish. Summary Within the last decade, hiPSC-CMs have been exponentially employed to model heart failure. Constant advancements are aiming at improvements of differentiation protocols, hiPSC-CM maturity, and assays to elucidate molecular mechanisms and cellular functions. However, hiPSC-CMs are remaining relatively immature, and in vitro models can only partially recapitulate the complex interactions in vivo. Nevertheless, hiPSC-CMs have evolved as an essential model system in cardiovascular research.

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“…BrS is characterized by the ECGs with both a right bundle-branch block pattern and ST-segment elevation in the right precordial leads (V 1 -V 3 ) and by the higher incidence of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) (4,5). It is commonly believed that VT/VF is elicited by the closely coupled premature ventricular contractions via the phase-2 reentry (P2R) mechanism (6).…”

Section: Introductionmentioning

confidence: 99%

Specific decreasing of Na⁺ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

Tsumoto

Ashihara

Naito

et al. 2019

Preprint

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Non-standard Abbreviations and Acronyms: LM: lateral membrane of cardiomyocytes; JM: junctional membrane of cardiomyocytes; pre-JM: pre-junctional membrane of cardiomyocytes; post-JM: post-junctional membrane of cardiomyocyte; I Na,LM : I Na across the LM; I Na,pre-JM : I Na across the pre-JM; I Na,post-JM : I Na across the post-JM; V m,pre-JM : membrane potential of the pre-JM; V m,post-JM : membrane potential of the post-JM 1 ABSTRACT One phenotypic feature of Brugada syndrome (BrS) is slowed conduction due to the reduction (loss-of-function) of Na + channels. In contrast, recent clinical observations in BrS patients highlighted the poor correlation between the phenotype (typical ECG change or lethal arrhythmia) and the genotype (SCN5A mutation). Inspired by our previous theoretical study which showed that reduced Na + channels in the lateral membrane (LM) of ventricular myocytes caused the slowing of conduction under myocardial ischemia, we hypothesized that a loss-of-function of Na + channels caused by the decreases in Na + channel expression within myocytes leads to phase-2 reentry (P2R), the major triggering mechanism of lethal arrhythmias in BrS. We constructed an in silico human ventricular myocardial strand and ring models, and investigated the relationship between the subcellular Na + channel distribution and P2R. Reducing Na + channel expression in the LM of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients. Furthermore, we showed that both the reduction in Na + channels on the LM of each myocyte and tissue-level heterogeneity of Na + channel expression were essential for P2R as well as P2R-mediated reentrant excitation. Our data suggest that the alteration in subcellular Na + channel distribution together with a tissue-level heterogeneity of Na + channels can cause arrhythmogenesis in BrS.

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Experimental Models of Brugada syndrome

Cited by 35 publications

References 88 publications

Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

Human Induced Pluripotent Stem Cells as a Disease Model System for Heart Failure

Specific decreasing of Na⁺ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

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