Management of Ventricular Arrhythmias in Suspected Channelopathies

Obeyesekere, Manoj; Antzelevitch, Charles; Krahn, Andrew D.

doi:10.1161/circep.114.002321

Cited by 31 publications

(16 citation statements)

References 77 publications

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“…The phenotype-genotype correlation for patients with definite or probable Brugada syndrome, CPVT, or ARVC in our study was consistent with contemporary literature, whereas the proportion of gene positive LQT patients was lower than previously described. 24,25 Older studies reported positive genetic findings in up to 78% of patients with a clear LQT phenotype. 26 However, those data were derived from highly selected patients with overt LQT syndrome and high Schwartz scores.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Abnormalities in First-Degree Relatives of Unexplained Cardiac Arrest Victims

Steinberg¹,

Padfield²,

Champagne³

et al. 2016

Circ: Arrhythmia and Electrophysiology

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Background— Unexplained cardiac arrest (UCA) may be explained by inherited arrhythmia syndromes. The Cardiac Arrest Survivors With Preserved Ejection Fraction Registry prospectively assessed first-degree relatives of UCA or sudden unexplained death victims to screen for cardiac abnormalities. Methods and Results— Around 398 first-degree family members (186 UCA, 212 sudden unexplained death victims’ relatives; mean age, 44±17 years) underwent extensive cardiac workup, including ECG, signal averaged ECG, exercise testing, cardiac imaging, Holter-monitoring, and selective provocative drug testing with epinephrine or procainamide. Genetic testing was performed when a mutation was identified in the UCA survivor or when the diagnostic workup revealed a phenotype suggestive of a specific inherited arrhythmia syndrome. The diagnostic strength was classified as definite, probable, or possible based on previously published definitions. Cardiac abnormalities were detected in 120 of 398 patients (30.2%) with 67 of 398 having a definite or probable diagnosis (17%), including Long-QT syndrome (13%), catecholaminergic polymorphic ventricular tachycardia (4%), arrhythmogenic right ventricular cardiomyopathy (4%), and Brugada syndrome (3%). The detection yield was similar for family members of UCA and sudden unexplained death victims (31% versus 27%; P =0.59). Genetic testing was performed more often in family members of UCA patients (29% versus 20%; P =0.03). Disease-causing mutations were identified in 20 of 398 relatives (5%). The most common pathogenic mutations were RyR2 (2%), SCN5A (1%), and KNCQ1 (0.8%). Conclusions— Cardiac screening revealed abnormalities in 30% of first-degree relatives of UCA or sudden unexplained death victims, with a clear working diagnosis in 17%. Long-QT, arrhythmogenic right ventricular cardiomyopathy, and catecholaminergic polymorphic ventricular tachycardia were the most common diagnoses. Systematic cascade screening and genetic testing in asymptomatic individuals will lead to preventive lifestyle and medical interventions with potential to prevent sudden cardiac death. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00292032.

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Section: Discussionmentioning

confidence: 99%

Cardiac Abnormalities in First-Degree Relatives of Unexplained Cardiac Arrest Victims

Steinberg¹,

Padfield²,

Champagne³

et al. 2016

Circ: Arrhythmia and Electrophysiology

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“…The sympathetic surge after delivery of a shock is always a risk for recurrence [16]. There are experimental data supporting the use of beta blockers in LQT3 [17] and others contradicting its use [18]. Analysis of 493 LQT3 patients derived from 9 registries supports the use of beta blockers [19].…”

Section: Sudden Cardiac Deathmentioning

confidence: 99%

Inherited Ventricular Arrhythmias, the Channelopathies and SCD: Current Knowledge and Future Speculations - Risk Stratification, Management Plans and Future Speculations

Abdulgader¹

2020

Sudden Cardiac Death

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Channelopathy constitutes significant proportion of SCD worldwide (around 10% or 370,000 deaths annually). It was creating a mysterious group of diseases until the second half of the last century when Anton Jervell and Fred Lange-Nielsen described Jervell Lange-Nielsen syndrome in 1957. It was late until 1995 where genetic characterization commenced. Later on, the massive genetic information with the discovery of genetic heterogeneity and allelic het¬erogeneity was a major victory in the field. The basic sciences in cellular electrophysiology and genetics complemented by meticulous clinical detection and the different clinical trials in the field opened a new era of wide therapeutic choices for clinicians. The knowledge obtained from the different experimental platforms especially the induced pluripotent stem cells is promising. The revolutionary move in SCD and channelopathies is described where correlation between the arrhythmogenesis and fluctuation in SGMA is established and must be investigated. The observation of the arrhythmogenicity of SGMA fluctuation and its effect on HRV together with the differential effect of certain sympathovagal tones (more sympathetic innervation is favoring VT/VF in LQTS1, LQTS2 and SQTS but not BrS or ERS) are all future directions to optimize our preventive, diagnostic as well as therapeutic options of SCD and channelopathy in humans.

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“…Slowed or incomplete inactivation of the Na V 1.5 channel results in an additional inward current, known as late or persistent I Na , during the course of the ventricular action potential and thereby in an increase in action potential duration and prolongation of the QT interval on the ECG. The estimated prevalence of LQT3 among LQTS patients is ≈10% [11,12].…”

Section: Aim Of the Studymentioning

confidence: 99%

Mechanism of Sinus Node Dysfunction in Carriers of the E161K Mutation in the SCN5A Gene

Wilders

2018

2018 Computing in Cardiology Conference (CinC)

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Heterozygous carriers of the E161K mutation in the SCN5A gene, which encodes the Na V 1.5 pore-forming αsubunit of the ion channel carrying the cardiac fast sodium current (I Na), show sinus node dysfunction. We assessed the mechanism by which the E161K mutation causes sinus bradycardia and reduces atrial excitability, as well as the potential role of the common H558R polymorphism. To this end, we incorporated reported mutation-induced changes in I Na into the recently developed Fabbri-Severi model of a single human sinoatrial node (SAN) cell. The threshold current of the Courtemanche-Ramirez-Nattel human right atrial cell model was used as a measure of atrial excitability. The E161K/H558 mutation significantly increased the cycle length of the SAN cell, in particular under vagal tone. The mutant component of I Na was effectively zero, thus slowing diastolic depolarization. Highly similar results were obtained with the E161K/R558 mutation. The E161K mutation increased the threshold stimulus current of the atrial cell by a factor of ≈2.2, virtually independent of the H558 or R558 background. We conclude that the E161K mutation underlies the clinically observed sinus node dysfunction. Furthermore, we conclude that the common H558R polymorphism does not significantly alter the effects of the E161K mutation.

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Management of Ventricular Arrhythmias in Suspected Channelopathies

Cited by 31 publications

References 77 publications

Cardiac Abnormalities in First-Degree Relatives of Unexplained Cardiac Arrest Victims

Cardiac Abnormalities in First-Degree Relatives of Unexplained Cardiac Arrest Victims

Inherited Ventricular Arrhythmias, the Channelopathies and SCD: Current Knowledge and Future Speculations - Risk Stratification, Management Plans and Future Speculations

Mechanism of Sinus Node Dysfunction in Carriers of the E161K Mutation in the SCN5A Gene

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