Developmental Basis for Electrophysiological Heterogeneity in the Ventricular and Outflow Tract Myocardium As a Substrate for Life-Threatening Ventricular Arrhythmias

Boukens, Bastiaan J.; Christoffels, Vincent M.; Coronel, Ruben; Moorman, Antoon F.M.

doi:10.1161/circresaha.108.188698

Cited by 132 publications

(110 citation statements)

References 173 publications

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“…Each cell type (e.g., pacemaker cell, atrioventricular nodal cell, Purkinje fiber, atrial myocyte, ventricular myocyte) is characterized by a distinctive expression pattern of genes encoding a variety of ion channels that determine their specific electrophysiological profile. These electrophysiological properties of the heart develop during embryogenesis and further mature postnatally; accordingly, embryonic and fetal cells do not exhibit the same electrical behavior seen in adult myocytes (21).…”

Section: Do Ips-derived Myocytes Reliably Model the Complexity Of Thementioning

confidence: 97%

Induced pluripotent stem cell–derived cardiomyocytes in studies of inherited arrhythmias

et al. 2013

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The discovery of the genetic basis of inherited arrhythmias has paved the way for an improved understanding of arrhythmogenesis in a wide spectrum of life-threatening conditions. In vitro expression of mutations and transgenic animal models have been instrumental in enhancing this understanding, but the applicability of results to the human heart remains unknown. The ability to differentiate induced pluripotent stem cells (iPSs) into cardiomyocytes enables the potential to generate patient-specific myocytes, which could be used to recapitulate the features of inherited arrhythmias in the context of the patient's genetic background. Few studies have been reported on iPS-derived myocytes obtained from patients with heritable arrhythmias, but they have demonstrated the applicability of this innovative approach to the study of inherited arrhythmias. Here we review the results achieved by iPS investigations in arrhythmogenic syndromes and discuss the existing challenges to be addressed before the use of iPS-derived myocytes can become a part of personalized management of inherited arrhythmias.

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Section: Do Ips-derived Myocytes Reliably Model the Complexity Of Thementioning

confidence: 97%

Induced pluripotent stem cell–derived cardiomyocytes in studies of inherited arrhythmias

et al. 2013

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“…9,10 Cardiac myocytes of the RVOT in a normal heart can be arrhythmogenic and the embryonic outflow tract consists of slow conducting tissue. 23 Recently, Nademanee et al demonstrated in patients with BrS that fractionated electrograms were recorded at the epicardial side of the RVOT and that catheter ablation of these electrograms eliminated type 1 ECG and VF. 24 These results may provide strong support for the depolarization theory.…”

Section: Discussionmentioning

confidence: 99%

Life-Threatening Ventricular Arrhythmia and Brugada-Type ST-Segment Elevation Associated With Acute Ischemia of the Right Ventricular Outflow Tract

Nakamura

Nishizaki

Lee

et al. 2017

Circ J

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phase 2 re-entry (the repolarization theory); 7,8 and the other involves the development of abnormality leading to conduction disturbance and arrhythmogenesis (the depolarization theory). 9,10 Both theories assume that the site of origin of ECG changes and the focus of ventricular arrhythmia is the right ventricular outflow tract (RVOT).An abnormal delayed potential was recorded from the epicardium of the RVOT in patients with BrS through the electrode inserted into the conus branch of the right coronary artery (RCA). 11 Individuals with a normal ECG at baseline occasionally display Br-ECG during acute myocardial ischemia of the RVOT. 12, 13 The RVOT mainly supplies blood through the conus and/or the right ventricular (RV) branch of the RCA. Di Diego et al demonstrated using canine models that global ischemia of the RVOT could accentuate a heterogeneity of repolarization between the epicardium and the endocardium, and lead to augmented ST-T changes similar to those seen in BrS. 14 While a similar phenomenon has been described in case P atients with Brugada syndrome (BrS) have unique electrocardiographic (ECG) changes of ST-segment elevation in the right precordial leads, V1-V3, and are at high risk for sudden cardiac death due to the development of ventricular fibrillation (VF). 1-4 The unique ECG features of BrS (i.e., ST-segment elevation and ST-T wave morphology in leads V1-V3) are defined as type 1 (coved type), type 2, and type 3 (saddle-back type) according to the consensus report. 5 The 3 types of ECG are regarded as Brugada-type ECG (Br-ECG), and type 1 is considered an important diagnostic sign for BrS. Br-ECG, however, is not a specific feature of BrS but is often observed in various physiological and pathological conditions including myocardial ischemia. 2,3 With regard to the mechanism of ST-segment elevation in the right precordial leads and subsequent development of ventricular tachyarrhythmias in BrS, there are 2 proposed theories that are still controversial: 6 one involves the transmural heterogeneity of ventricular repolarization and subsequent development of

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“…Depolarization theory [15] focuses on conduction slowing in the right ventricular outflow tract (RVOT), leading to ST segment elevation in right precordial leads. Recently, a third hypothesis has been proposed, suggesting that the embryological development of the RV could explain the electrophysiological heterogeneity in the ventricular myocardium, including the RV outflow tract, which could provide the arrhythmogenic substrate [16]. These models are not mutually exclusive, and it is possible that BrS could be a mechanistically heterogeneous disease [17].…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Genetic Basis of Brugada Syndrome

Campuzano¹,

Allegue²,

Iglesias³

et al. 2013

J Genet Syndr Gene Ther

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Brugada syndrome is a rare cardiac disorder described as a clinical entity in 1992. It is characterized by typical electrocardiographic alteration in a structurally normal heart, and associated with a high risk of sudden cardiac death. Brugada syndrome affects mainly young adult males and patients can present a wide range of symptoms or even remain asymptomatic. The first genetic basis responsible for the syndrome was described in 1998 in SCN5A. Since then, several pathogenic mutations have been identified in 16 genes, encoding mainly subunits of cardiac sodium, potassium, and calcium channels, or genes involved in the trafficking/regulation of these channels. All these genes together are responsible for 35% of total cases, remaining 2/3 parts of Brugada syndrome cases without genetic cause identified. In this review, we focus on recent advances in genetics of Brugada Syndrome.

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Developmental Basis for Electrophysiological Heterogeneity in the Ventricular and Outflow Tract Myocardium As a Substrate for Life-Threatening Ventricular Arrhythmias

Cited by 132 publications

References 173 publications

Induced pluripotent stem cell–derived cardiomyocytes in studies of inherited arrhythmias

Induced pluripotent stem cell–derived cardiomyocytes in studies of inherited arrhythmias

Life-Threatening Ventricular Arrhythmia and Brugada-Type ST-Segment Elevation Associated With Acute Ischemia of the Right Ventricular Outflow Tract

Genetic Basis of Brugada Syndrome

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