Assessing the Malignant Ventricular Arrhythmic Substrate in Patients With Brugada Syndrome

Pappone, Carlo; Ciconte, Giuseppe; Manguso, Francesco; Vicedomini, Gabriele; Mecarocci, Valerio; Conti, Manuel; Giannelli, Luigi; Pozzi, Paolo; Borrelli, Valeria; Menicanti, Lorenzo; Ćalović, Žarko; Rattá, G.; Brugada, Josép; Santinelli, Vincenzo

doi:10.1016/j.jacc.2018.02.022

Cited by 73 publications

(61 citation statements)

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“…It is interesting that, again, none of the SNPs studied, including that in the SCN5A gene, were found to be predisposing to syncope, atrial fibrillation, or total mortality. However, again, the electrocardiographic data may be misleading, as in the prior study, because it relies on spontaneously collected electrocardiograms, which are well known to be unreliable in the diagnosis of BrS, even for about 80% of patients who have experienced cardiac arrest or syncope because of documented ventricular fibrillation [5,26]. A study by a different group [27] studying the same genetic variation (rs9388451) adjacent to the HEY2 gene reported its role in the alteration of ion channel expression across the cardiac ventricular wall and its possible association with BrS.…”

Section: The Challenges Surrounding Brs Geneticsmentioning

confidence: 88%

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: The Challenges Surrounding Brs Geneticsmentioning

confidence: 88%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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“…In the 2017 AHA/ACC/HRS guideline for ventricular arrhythmias and SCD, an EPS with programmed ventricular stimulation using single or double extrastimuli may be considered for further risk stratification in asymptomatic and spontaneous type 1patients (Kusumoto et al, 2017 ). Newly studies suggested that extent of substrate is the only independent predictor of inducibility of VT or VF and may contribute to a new marker for risk stratification and therapy (Pappone et al, 2018 ). The differences of sex-related cardiac electrophysiological characteristics may be the main reason contributing to the result, that women have lower expression of KChIP2 which is the main accessory subunit of transient outward current in right ventricular epicardium (Tadros et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Gender Differences in Prognosis and Risk Stratification of Brugada Syndrome: A Pooled Analysis of 4,140 Patients From 24 Clinical Trials

Yuan

Tian

et al. 2018

Front. Physiol.

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Background: Male gender has been consistently shown to be a risk factor for a greater number of arrhythmic events in patients with Brugada Syndrome (BrS). However, there have been no large-scale comprehensive pooled analyses to statistically and systematically verify this association. Therefore, we conducted a pooled analysis on gender differences in prognosis and risk stratification of BrS with a largest sample capacity at present.Methods: We searched PubMed, Embase, Medline, Cochrane Library databases, Chinese National Knowledge Infrastructure, and Wanfang Data for relevant studies published from 2002 to 2017. The prognosis and risk stratification of BrS and risk factors were then investigated and evaluated according to gender.Results: Twenty-four eligible studies involving 4,140 patients were included in the analysis. Male patients (78.1%) had a higher risk of arrhythmic events than female patients (95% confidence interval: 1.46–2.91, P < 0.0001). Among the male population, there were statistical differences between symptomatic patients and asymptomatic patients (95% CI: 2.63–7.86, P < 0.00001), but in the female population, no statistical differences were found. In the female subgroup, electrophysiological study (EPS) positive patients had a tendency toward a higher risk of arrhythmic events than EPS-negative patients (95% CI: 0.93–29.77, P = 0.06).Conclusions: Male patients are at a higher risk of arrhythmic events than female patients. Within the male population, symptomatic patients have a significantly higher risk profile compared to asymptomatic patients, but no such differences are evident within the female population. Consequently, in the female population, the risk of asymptomatic patterns cannot be underestimated.

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“…This is remarkable because, in view of the risks involved (see below) and perceived lack of diagnostic added‐value, this test is generally considered contraindicated for patients who already have documentation of a type‐I Brugada pattern on a resting ECG 7. That “orthodox” view of the test, however, is evolving: SCB tests have been performed in patients with documentation of a type‐I pattern during fever8 or to better delineate the arrhythmogenic substrate during radiofrequency ablation 9…”

Section: The Present Study: a Shift From Diagnostic To Prognostic Test?mentioning

confidence: 99%

“…Patients diagnosed with Brugada syndrome who are then left untreated may develop unbearable anxiety that could lead to therapeutic interventions with limited proof of benefit 22. In a recent study,9 84 asymptomatic patients with only drug‐induced type‐I ECG first underwent a prophylactic implantable cardioverter defibrillator implantation and, after remaining free of arrhythmias for an undisclosed time period, underwent prophylactic epicardial ablation of extensive areas of their right ventricle. If the second explanation for the type‐I paradox is correct, it is possible that some of the patients undergoing these 2 invasive procedures do not even have the disease we call Brugada syndrome.…”

Section: Asymptomatic Patients Without a Spontaneous Type‐imentioning

confidence: 99%

“…7 That "orthodox" view of the test, however, is evolving: SCB tests have been performed in patients with documentation of a type-I pattern during fever 8 or to better delineate the arrhythmogenic substrate during radiofrequency ablation. 9 The appearance of ≥2 mm coved ST-segment elevation in response to a SCB challenge is generally accepted as the test end point, leading to an immediate halt of the drug infusion. 10 Here, Ueoka et al speculated that ECG changes of greater magnitude would identify patients at higher risk of spontaneous arrhythmias, and the infusion was continued irrespective of the ST-segment elevation height.…”

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confidence: 99%

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