Ever since the first case was reported at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19) has become a serious ...threat to public health globally in short time. At this point in time, there is no proven effective therapy. The interactions with concomitant disease are largely unknown, and that may be particularly pertinent to inherited arrhythmia syndrome. An arrhythmogenic effect of COVID-19 can be expected, potentially contributing to disease outcome. This may be of importance for patients with an increased risk of cardiac arrhythmias, either secondary to acquired conditions or comorbidities or consequent to inherited syndromes. Management of patients with inherited arrhythmia syndromes such as long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia in the setting of the COVID-19 pandemic may prove particularly challenging. Depending on the inherited defect involved, these patients may be susceptible to proarrhythmic effects of COVID-19-related issues such as fever, stress, electrolyte disturbances, and use of antiviral drugs. Here, we describe the potential COVID-19-associated risks and therapeutic considerations for patients with distinct inherited arrhythmia syndromes and provide recommendations, pending local possibilities, for their monitoring and management during this pandemic.
Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.
This study sought to perform a retrospective ...analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.
Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.
A total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions.
This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death ...(SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
Worldwide, the Brugada syndrome has been recognized as an important cause of sudden cardiac death in individuals at a relatively young age. Importantly, many drugs have been reported to induce the ...characteristic Brugada syndrome-linked ECG abnormalities and/or (fatal) ventricular tachyarrhythmias.
The purpose of this study was to review the literature on the use of drugs in Brugada syndrome patients, to make recommendations based on the literature and on expert opinion regarding drug safety, and to ensure worldwide online and up-to-date availability of this information to all physicians who treat Brugada syndrome patients.
We performed an extensive review of the literature, formed an international expert panel to produce a consensus recommendation to each drug, and initiated a website (www.brugadadrugs.org).
The literature search yielded 506 reports for consideration. Drugs were categorized into one of four categories: (1) drugs to be avoided (n = 18); (2) drugs preferably avoided (n = 23); (3) antiarrhythmic drugs (n = 4); and (4) diagnostic drugs (n = 4). Level of evidence for most associations was C (only consensus opinion of experts, case studies, or standard-of-care) as there are no randomized studies and few nonrandomized studies in Brugada syndrome patients.
Many drugs have been associated with adverse events in Brugada syndrome patients. We have initiated a website (www.brugadadrugs.org) to ensure worldwide availability of information on safe drug use in Brugada syndrome patients.
Risk stratification in Brugada syndrome (BS) remains controversial. The time interval between the peak and the end of the T wave (Tpe interval), a marker of transmural dispersion of repolarization, ...has been linked to malignant ventricular arrhythmias in various settings but leads to discordant results in BS.
We study the correlation of the Tpe interval with arrhythmic events in a large cohort of patients with BS.
A total of 325 consecutive patients with BS (mean age 47±13 years, 259 men-80%) with spontaneous (n=143, 44%) or drug-induced (n=182, 56%) type 1 electrocardiogram were retrospectively included. 235 were asymptomatic (70%), 80 presented with unexplained syncope (22%), and 10 presented with sudden death (SD) or appropriate implantable cardioverter-defibrillator therapy (AT) (8%) at diagnosis or over a mean follow-up of 48 ± 34 months. The Tpe interval was calculated as the difference between the QT interval and the QT peak interval as measured in each of the precordial leads.
The Tpe interval from lead V1 to lead V4, maximum value of the Tpe interval (max Tpe), and Tpe dispersion in all precordial leads were significantly higher in patients with SD/AT or in patients with syncope than in asymptomatic patients (P < .001). A max Tpe of ≥100 ms was present in 47 of 226 asymptomatic patients (21%), in 48 of 73 patients with syncope (66%), and in 22 of 26 patients with SD/AT (85%) (P < .0001). In multivariate analysis, a max Tpe of ≥100 ms was independently related to arrhythmic events (odds ratio 9.61; 95% confidence interval 3.13-29.41; P < .0001).
The Tpe interval in the precordial leads is highly related to malignant ventricular arrhythmias in this large cohort of patients with BS. This simple electrocardiographic parameter could be used to refine risk stratification.
Objectives The aim of this study was to identify families affected by early repolarization syndrome (ERS) and to determine the mode of transmission of the disease. Background Early repolarization ...(ER) has recently been linked to idiopathic ventricular fibrillation. Familial inheritance of the disease has been suggested but not demonstrated. Methods We screened relatives of 4 families affected by ERS. ER was defined as a distinct J-wave in at least 2 consecutive leads and a 1-mm amplitude above baseline. The Valsalva maneuver was performed in affected and unaffected family members to decrease heart rate and thus increase or reveal an ER pattern. Results Twenty-two sudden cardiac deaths occurred in the 4 families including 10 before 35 years of age. In the 4 families, the prevalence of ER was 56%, 34%, 61%, and 33% of, respectively, 30, 82, 29, and 30 screened relatives. In these families, transmission of an ER pattern is compatible with an autosomal dominant mode of inheritance. All probands were screened for genes identified in ERS, and no mutation was found. The Valsalva maneuver was performed in 80 relatives, resulting in increased J-wave amplitude for 17 of 20 affected patients and revealing an ER pattern in 17 relatives in whom 5 are obligate transmitters of an ER pattern. Conclusions ERS can be inherited through autosomal dominant transmission and should be considered a real inherited arrhythmia syndrome. Familial investigation can be facilitated by using the Valsalva maneuver to reveal the electrocardiographic pattern in family members. The prognosis value of this test remains to be assessed.
Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome ...(BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.
We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes—rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.
Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10−18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10−13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.
Large case–control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
Long-Term Follow-Up of Patients With Short QT Syndrome Giustetto, Carla, MD; Schimpf, Rainer, MD; Mazzanti, Andrea, MD ...
Journal of the American College of Cardiology,
08/2011, Letnik:
58, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Objectives The aim of this study was to investigate the clinical characteristics and the long-term course of a large cohort of patients with short QT syndrome (SQTS). Background SQTS is a rare ...channelopathy characterized by an increased risk of sudden death. Data on the long-term outcome of SQTS patients are not available. Methods Fifty-three patients from the European Short QT Registry (75% males; median age: 26 years) were followed up for 64 ± 27 months. Results A familial or personal history of cardiac arrest was present in 89%. Sudden death was the clinical presentation in 32%. The average QTc was 314 ± 23 ms. A mutation in genes related to SQTS was found in 23% of the probands; most of them had a gain of function mutation in HERG (SQTS1). Twenty-four patients received an implantable cardioverter defibrillator, and 12 patients received long-term prophylaxis with hydroquinidine (HQ), which was effective in preventing the induction of ventricular arrhythmias. Patients with a HERG mutation had shorter QTc at baseline and a greater QTc prolongation after treatment with HQ. During follow-up, 2 already symptomatic patients received appropriate implantable cardioverter defibrillator shocks and 1 had syncope. Nonsustained polymorphic ventricular tachycardia was recorded in 3 patients. The event rate was 4.9% per year in the patients without antiarrhythmic therapy. No arrhythmic events occurred in patients receiving HQ. Conclusions SQTS carries a high risk of sudden death in all age groups. Symptomatic patients have a high risk of recurrent arrhythmic events. HQ is effective in preventing ventricular tachyarrhythmia induction and arrhythmic events during long-term follow-up.
Brugada syndrome (BrS) is a condition defined by ST-segment alteration in right precordial leads and a risk of sudden death. Because BrS is often associated with right bundle branch block and the ...TRPM4 gene is involved in conduction blocks, we screened TRPM4 for anomalies in BrS cases. The DNA of 248 BrS cases with no SCN5A mutations were screened for TRPM4 mutations. Among this cohort, 20 patients had 11 TRPM4 mutations. Two mutations were previously associated with cardiac conduction blocks and 9 were new mutations (5 absent from ~14'000 control alleles and 4 statistically more prevalent in this BrS cohort than in control alleles). In addition to Brugada, three patients had a bifascicular block and 2 had a complete right bundle branch block. Functional and biochemical studies of 4 selected mutants revealed that these mutations resulted in either a decreased expression (p.Pro779Arg and p.Lys914X) or an increased expression (p.Thr873Ile and p.Leu1075Pro) of TRPM4 channel. TRPM4 mutations account for about 6% of BrS. Consequences of these mutations are diverse on channel electrophysiological and cellular expression. Because of its effect on the resting membrane potential, reduction or increase of TRPM4 channel function may both reduce the availability of sodium channel and thus lead to BrS.
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