New electromechanical substrate abnormalities in high-risk patients with Brugada syndrome

Pappone, Carlo; Mecarocci, Valerio; Manguso, Francesco; Ciconte, Giuseppe; Vicedomini, Gabriele; Sturla, Francesco; Votta, Emiliano; Mazza, B.; Pozzi, Paolo; Borrelli, Valeria; Anastasia, Luigi; Micaglio, Emanuele; Locati, Emanuela H.; Monasky, Michelle M.; Lombardi, Massimo; Ćalović, Žarko; Santinelli, Vincenzo

doi:10.1016/j.hrthm.2019.11.019

Cited by 31 publications

(20 citation statements)

References 31 publications

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“…While BrS has been classically regarded as a channelopathy caused by variants in genes encoding for channel proteins on the cellular membrane, recent studies have identified non-channel genes associated with the syndrome. Also, although BrS was for a long time considered a "purely electrical disease without structural abnormalities", recent studies have now reported epicardial surface and interstitial fibrosis, reduced gap junction expression, and increased collagen, as well as reduced contractility and RV structural abnormalities consistent with ARVC involving predominantly the RV anterior wall [2,35,112]. Along these lines, a study by Mango et al described the finding of a mutation in the TPM1 gene, encoding the sarcomeric α-tropomyosin, as causative of an overlap syndrome resulting in both hypertrophic cardiomyopathy and BrS phenotypes [34].…”

Section: Sarcomeropathiesmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype-phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

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Section: Sarcomeropathiesmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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“…To date, the current view based on accumulating evidence from clinical studies using electric mapping and body surface mapping strategies indicates that in Brugada syndrome patients with a type 1 ECG, (I) conduction in the RV/RVOT is slowed concomitant with significant activation delay, (II) there is an increase in the number of late potentials in the area of the RV/RVOT, and (III) changes in repolarization duration are not different compared to in healthy controls [ 93 , 94 , 95 , 96 , 97 , 98 ]. However, we think that in Brugada syndrome, genetic predisposition in the form of ion channel mutations involved in ventricular conduction does not solely determine arrhythmic risk but would rather modulate arrhythmic risk in the presence of 1 or more additional factors.…”

Section: Mechanisms Underlying Arrhythmias In Brugada Syndromementioning

confidence: 99%

“…More recently, the SCN5A 1798insD/+ mutation was demonstrated to cause structural abnormalities in the mouse embryo, thereby impairing ventricular activation before the onset of I Na [ 122 ]. In Brugada syndrome patients, RV ejection fraction was recently found significantly lower compared to control subjects [ 98 ]. Furthermore, the same study showed that RV/RVOT areas with abnormal electrograms significantly correlated with the occurrence of mechanical dysfunction reflected by abnormal motion and deformation leading to wall stress [ 98 ].…”

Section: Towards a Molecular Understanding Of Brugada Syndromementioning

confidence: 99%

“…In Brugada syndrome patients, RV ejection fraction was recently found significantly lower compared to control subjects [ 98 ]. Furthermore, the same study showed that RV/RVOT areas with abnormal electrograms significantly correlated with the occurrence of mechanical dysfunction reflected by abnormal motion and deformation leading to wall stress [ 98 ]. Over time, such wall stress may facilitate the formation of structural abnormalities [ 98 , 102 ].…”

Section: Towards a Molecular Understanding Of Brugada Syndromementioning

confidence: 99%

“…Furthermore, the same study showed that RV/RVOT areas with abnormal electrograms significantly correlated with the occurrence of mechanical dysfunction reflected by abnormal motion and deformation leading to wall stress [ 98 ]. Over time, such wall stress may facilitate the formation of structural abnormalities [ 98 , 102 ]. Collectively, these findings support an important contribution of cardiac aging to the formation of structural abnormalities in myocardial areas when the electromechanical coupling between cardiomyocytes is impaired, a notion that agrees with the conduction hypothesis postulating that structural abnormalities in Brugada syndrome are acquired throughout life explaining why the Brugada syndrome ECG is rare in children and more often manifests later in life [ 16 , 18 , 19 , 102 ].…”

Section: Towards a Molecular Understanding Of Brugada Syndromementioning

confidence: 99%

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Mechanisms of Arrhythmias in the Brugada Syndrome

Blok

Boukens

2020

IJMS

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Arrhythmias in Brugada syndrome patients originate in the right ventricular outflow tract (RVOT). Over the past few decades, the characterization of the unique anatomy and electrophysiology of the RVOT has revealed the arrhythmogenic nature of this region. However, the mechanisms that drive arrhythmias in Brugada syndrome patients remain debated as well as the exact site of their occurrence in the RVOT. Identifying the site of origin and mechanism of Brugada syndrome would greatly benefit the development of mechanism-driven treatment strategies.

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