Abnormal Repolarization as the Basis for Late Potentials and Fractionated Electrograms Recorded From Epicardium in Experimental Models of Brugada Syndrome

Abstract Introduction The sudden cardiac death risk in Brugada Syndrome (BrS) is higher in patients with spontaneous type 1 pattern. Brugada diagnosis is also established in patients with induced type 1 morphology after provocative test with intravenous administration with a sodium blocker channel. Nevertheless, this group of patients is known to be at a lower risk of SCD, and their risk stratification is still a matter of discussion. Late potentials (LP) detected on signal-averaged ECG (SAECG) on the RVOT have been previously proposed as a predictor factor for BrS, even though data is lacking on its value. Purpose To evaluate the association between positive LP (LMS40> 38ms) on SAECG with modified Brugada leads and a positive flecainide test in patients with non-type 1 BrS. Methods Retrospective single-center study of non-type 1 BrS patients referred for the performance of a flecainide provocative test. Patients presenting with spontaneous type 1 morphology were excluded from the study. Study of LP on SAECG with modified leads for Brugada were evaluated before administration of flecainide [2mg/kg (maximum150mg), for 10minutes] with determination of filtered QRS duration (fQRS), root mean square voltage of the last 40ms of the QRS complex (RMS40) and duration of low amplitude signals <40μV of the terminal QRS complex (LMS40). Results 126 patients (47.3 ± 14.1 years, 61.9% males) underwent study with LP SAECG and flecainide test. Among these patients, 7.9% were symptomatic and 16.7% had familiar history of BrS. Flecainide test was positive in 46.8% of patients. In patients with a positive flecainide test, 64.4% presented LMS40 > 38ms whereas LMS40 > 38ms was present in only 46% of those with a negative flecainide test (p = 0.031). The presence of positive LMS40 was a positive predictor for a positive flecainide test, associated with a two-fold increase likelihood in the induction of a Brugada pattern (OR: 2,12; IC95% 1,025-4,392; P = 0,043). There was no association between fQRS or RMS40 and a positive flecainide test (p = NS). fQRS > 114ms and RMS40 <20uV was present in 22% and 61% of patients with a positive flecainide test, respectively. Conclusion In patient with non-type 1 Brugada syndrome, LMS40 > 38ms in SAECG was a predictor for a positive flecainide test, suggesting that this finding could be helpful on the risk stratification of patients undergoing diagnostic study for Brugada syndrome. Abstract Figure. Effect of LMS 40 in flecainide test

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Experimental Models of Brugada syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms20092123 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2123 ◽

Cited By ~ 6

Author(s):

Sendfeld ◽

Selga ◽

Scornik ◽

Pérez ◽

Mills ◽

...

Keyword(s):

Brugada Syndrome ◽

Experimental Models ◽

Model Systems ◽

Patient Specific ◽

Canine Heart ◽

Stem Cell Technology ◽

St Segment Elevation ◽

St Segment ◽

Cardiac Sodium Channel ◽

The Right

Brugada syndrome is an inherited, rare cardiac arrhythmogenic disease, associated with sudden cardiac death. It accounts for up to 20% of sudden deaths in patients without structural cardiac abnormalities. The majority of mutations involve the cardiac sodium channel gene SCN5A and give rise to classical abnormal electrocardiogram with ST segment elevation in the right precordial leads V1 to V3 and a predisposition to ventricular fibrillation. The pathophysiological mechanisms of Brugada syndrome have been investigated using model systems including transgenic mice, canine heart preparations, and expression systems to study different SCN5A mutations. These models have a number of limitations. The recent development of pluripotent stem cell technology creates an opportunity to study cardiomyocytes derived from patients and healthy individuals. To date, only a few studies have been done using Brugada syndrome patient-specific iPS-CM, which have provided novel insights into the mechanisms and pathophysiology of Brugada syndrome. This review provides an evaluation of the strengths and limitations of each of these model systems and summarizes the key mechanisms that have been identified to date.

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Functionally distinct sodium channels in ventricular epicardial and endocardial cells contribute to a greater sensitivity of the epicardium to electrical depression

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01327.2007 ◽

2008 ◽

Vol 295 (1) ◽

pp. H154-H162 ◽

Cited By ~ 36

Author(s):

J. M. Cordeiro ◽

M. Mazza ◽

R. Goodrow ◽

N. Ulahannan ◽

C. Antzelevitch ◽

...

Keyword(s):

Brugada Syndrome ◽

Experimental Models ◽

Acute Ischemia ◽

Tissue Slices ◽

Channel Current ◽

Whole Cell Patch Clamp ◽

St Segment ◽

Before And After ◽

Severe Hyperkalemia ◽

Clinical Conditions

A greater depression of the action potential (AP) of the ventricular epicardium (Epi) versus endocardium (Endo) is readily observed in experimental models of acute ischemia and Brugada syndrome. Endo and Epi differences in transient outward K+ current and/or ATP-sensitive K+ channel current are believed to contribute to the differential response. The present study tested the hypothesis that the greater sensitivity of Epi is due in part to its functionally distinct early fast Na+ current ( INa). APs were recorded from isolated Epi and Endo tissue slices and coronary-perfused wedge preparations before and after exposures to elevated extracellular K+ concentration ([K+]o; 6–12 mM). INa was recorded from Epi and Endo myocytes using whole cell patch-clamp techniques. In tissue slices, increasing [K+]o to 12 mM reduced Vmax to 51.1 ± 5.3% and 26.8 ± 9.6% of control in Endo ( n = 9) and Epi ( n = 14), respectively ( P < 0.05). In wedge preparations ( n = 12), the increase in [K+]o caused selective depression of Epi APs and transmural conduction slowing and block. INa density was not significantly different between Epi ( n = 14) and Endo ( n = 15) cells, but Epi cells displayed a more negative half-inactivation voltage [−83.6 ± 0.1 and −75.5 ± 0.3 mV for Epi ( n = 16) and Endo ( n = 16), respectively, P < 0.05]. Our data suggest that reduced INa availability in ventricular Epi may contribute to its greater sensitivity to electrical depression and thus may contribute to the R-ST segment changes observed under a variety of clinical conditions including acute myocardial ischemia, severe hyperkalemia, and Brugada syndrome.

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Spatial and transmural repolarization, and dispersion of repolarization and late potentials evaluated using signal-averaged vector-projected 187-channel high-resolution electrocardiogram in Brugada syndrome

Journal of Arrhythmia ◽

10.1016/j.joa.2013.10.004 ◽

2014 ◽

Vol 30 (6) ◽

pp. 433-438 ◽

Cited By ~ 1

Author(s):

Kimie Ohkubo ◽

Ichiro Watanabe ◽

Yasuo Okumura ◽

Masayoshi Kofune ◽

Koichi Nagashima ◽

...

Keyword(s):

High Resolution ◽

Brugada Syndrome ◽

Late Potentials ◽

Dispersion Of Repolarization

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P5529Difference of late potentials detected by signal-averaged ECG in patients with spontaneous or drug-induced type 1 electrocardiogram pattern of Brugada syndrome

European Heart Journal ◽

10.1093/eurheartj/ehx493.p5529 ◽

2017 ◽

Vol 38 (suppl_1) ◽

Author(s):

J.A. Ribeiro Agostinho ◽

P. Antonio ◽

N. Cortez Dias ◽

G. Lima Da Silva ◽

T. Guimaraes ◽

...

Keyword(s):

Brugada Syndrome ◽

Late Potentials ◽

Drug Induced

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Non-invasive assessment of the arrhythmogenic substrate in Brugada syndrome using signal-averaged electrocardiogram: clinical implications from a prospective clinical trial

EP Europace ◽

10.1093/europace/euz295 ◽

2019 ◽

Cited By ~ 1

Author(s):

Giuseppe Ciconte ◽

Vincenzo Santinelli ◽

Gabriele Vicedomini ◽

Valeria Borrelli ◽

Michelle M Monasky ◽

...

Keyword(s):

Risk Stratification ◽

Brugada Syndrome ◽

Predictive Value ◽

Area Under The Curve ◽

Late Potentials ◽

Non Invasive ◽

Arrhythmogenic Substrate ◽

Risk Stratification Tool ◽

Group 2 ◽

Group 1

Abstract Aims Brugada syndrome (BrS) represents a major cause of sudden cardiac death in young individuals. The risk stratification to forecast future life-threatening events is still controversial. Non-invasive assessment of late potentials (LPs) has been proposed as a risk stratification tool. However, their nature in BrS is still undetermined. The purpose of this study is to assess the electrophysiological determinants of non-invasive LPs. Methods and Results Two hundred and fifty consecutive patients with (Group 1, n = 96) and without (Group 2, n = 154) BrS-related symptoms were prospectively enrolled in the registry. Signal-averaged electrocardiogram (SAECG) was performed in all subjects before undergoing epicardial mapping. Group 1 patients exhibited larger arrhythmogenic substrates (AS; 5.8 ± 2.8 vs. 2.6 ± 2.1 cm2, P < 0.001) with more delayed potentials (220.4 ± 46.0 vs. 186.7 ± 42.3 ms, P < 0.001). Late potentials were present in 82/96 (85.4%) Group 1 and in 31/154 (20.1%) Group 2 individuals (P < 0.001). Patients exhibiting LPs had more frequently a spontaneous Type 1 pattern (30.1% vs. 10.9%, P < 0.001), SCN5A mutation (34.5% vs. 21.2%, P = 0.02), and exhibited a larger AS with longer potentials (5.8 ± 2.7 vs. 2.2 ± 1.7 cm2; 231.2 ± 37.3 vs. 213.8 ± 39.0 ms; P < 0.001, respectively). Arrhythmogenic substrate dimension was the strongest predictor of the presence of LPs (odds ratio 1.9; P < 0.001). An AS area of at least 3.5 cm2 identified patients with LPs (area under the curve 0.88, 95% confidence interval 0.843–0.931; P < 0.001) with a sensitivity of 86%, specificity 88%, positive predictive value 85%, and negative predictive value 89%. Conclusion The results of this study support the role of the epicardial AS as an electrophysiological determinant of non-invasive LPs, which may serve as a tool in the non-invasive assessment of the BrS substrate, as SAECG-LPs could be considered an expression of the abnormal epicardial electrical activity. ClinicalTrials.gov number (NCT02641431; NCT03106701).

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