Brugada syndrome (BS) is a cardiac disorder characterized by typical ECG alterations, and it is associated with a high risk for sudden cardiac death (SCD), affecting young subjects with structurally ...normal hearts. The prevalence of this disorder is still uncertain, presenting marked geographical differences. The syndrome has a genetic basis, and several mutations have been identified in genes encoding subunits of cardiac sodium, potassium, and calcium channels, as well as in genes involved in the trafficking or regulation of these channels. Most BS patients are asymptomatic, but those who develop symptoms present with syncope and/or SCD secondary to polymorphic ventricular tachycardia and/or ventricular fibrillation. Risk stratification is still challenging, especially in cases of asymptomatic BS patients. This is a brief review of recent advances in our understanding of the genetic and molecular bases of BS, arrhythmogenic mechanisms and clinical course, as well as an update of the tools for risk stratification and treatment of the condition. (Circ J 2012; 76: 1563–1571)
Objectives We sought to assess differences in phenotype and prognosis between men and women in a large population of patients with Brugada syndrome. Background A male predominance has been reported ...in the Brugada syndrome. No specific data are available, however, concerning gender differences in the clinical manifestations and their role in prognosis. Methods Patients with Brugada syndrome were prospectively included in the study. Data on baseline characteristics, electrocardiogram parameters before and after pharmacological test, and events in follow-up were recorded for all patients. Results Among 384 patients, 272 (70.8%) were men and 112 (29.2%) women. At inclusion, men had experienced syncope more frequently (18%) or aborted sudden cardiac death (6%) than women (14% and 1%, respectively, p = 0.04). Men also had greater rates of spontaneous type-1 electrocardiogram, greater ST-segment elevation, and greater inducibility of ventricular fibrillation (p < 0.001 for all). Conversely, conduction parameters and corrected QT intervals significantly increased more in women in response to sodium blockers (p = 0.03 and p = 0.001, respectively). During a mean follow-up of 58 ± 48 months, sudden cardiac death or documented ventricular fibrillation occurred in 31 men (11.6%) and 3 women (2.8%; p = 0.003). The presence of previous symptoms was the most important predictor for cardiac events in men, whereas a longer PR interval was identified among those women with a greater risk in this series. Conclusions Men with Brugada syndrome present with a greater risk clinical profile than women and have a worse prognosis. Although classical risk factors identify male patients with worse outcome, conduction disturbances could be a marker of risk in the female population.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, ...including 36 SCDs during youth.
We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation.
Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload-induced calcium release activity of the mutant channel in HEK293 cells.
We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation-positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload-induced calcium release activity under conditions that mimic catecholaminergic stress.
Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation.
The identification of conducting channels (CCs) based on its relative high voltage or the presence of electrograms with delayed components has been proposed for substrate-guided scar-related ...ventricular tachycardia (VT) ablation. The relationship of these channels with the VT isthmuses remains unclear.
To assess the link between CCs identified during sinus rhythm (SR) and VT isthmuses in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).
Twenty-two consecutive patients with ARVC undergoing substrate-guided VT ablation (scar dechanneling technique) were analyzed. High-density endocardial and epicardial electroanatomic maps were obtained during SR. Standard bipolar cutoff values (0.5-1.5 and <0.5 mV) were used to define border zone and dense scar. The CCs were identified by voltage threshold adjustment (voltage channels) or by tagging the electrograms with delayed components that are sequentially activated (late potential channels).
A total of 87 CCs were identified; 65 (74.7%) of them on the epicardial surface. Twenty-four (27.6%) CCs were voltage channels, and compared with late potential CCs, these had a higher bipolar voltage (0.96 0.48-1.29 mV vs 0.39 0.26-0.50 mV; P < .001 and required more radiofrequency applications (5 4-7 vs 3 2-5; P = .048. Eighteen (90%) of 20 identified VT isthmuses were located on the epicardium. Only 8 (40%) VT isthmuses were related to a voltage CC. The remaining 12 (60%) VT isthmuses were linked to a late potential CC.
Late potential CCs more frequently act as the VT substrate in ARVC and therefore should also be considered to guide SR substrate-guided ablation.
Objectives. The aim of this study was to investigate the outcomes of left atrial appendage occlusion (LAAO) in high bleeding risk patients suffering atrial fibrillation (AF) and to analyze the ...different antithrombotic therapies following the intervention. Background. Methods. This monocentric study included 68 patients with nonvalvular AF with an absolute contraindication to OAT or at high bleeding risk. Follow-up was done with a clinical visit at 3-6-12 months. Results. Successful LAAO was achieved in 67/68 patients. At discharge, 32/68 patients were on dual antiplatelet therapy (APT), 34/68 were without any antithrombotic therapy or with a single antiplatelet drug, and 2/68 were on anticoagulant therapy. At three-month follow-up visit, 73.6% of the patients did not receive dual APT, of whom 14.7% had no thrombotic therapy and 58.9% were on single antiplatelet therapy. During a follow-up of 1.4 ± 0.9 years, 3/62 patients had late adverse effects (2 device-related thrombus without clinical consequences and 1 extracranial bleeding). The device-related thrombosis was not related to the antithrombotic therapy. Conclusions. LAAO is feasible and safe and prevents stroke in patients with AF with contraindication to oral anticoagulant therapy. After LAAO, single antiplatelet therapy seems to be a safe alternative to dual antiplatelet therapy, especially in patients at high bleeding risk. No benefit has been observed with dual APT.
QRS Spatiotemporal Characteristics in Brugada Syndrome
Introduction
The diagnosis of Brugada syndrome based on the ECG is hampered by the dynamic nature of its ECG manifestations. Brugada syndrome ...patients are only 25% likely to present a type 1 ECG. The objective of this study is to provide an ECG diagnostic criterion for Brugada syndrome patients that can be applied consistently even in the absence of a type 1 ECG.
Methods and Results
We recorded 67‐lead body surface potential maps from 94 Brugada syndrome patients and 82 controls (including right bundle branch block patients and healthy individuals). The spatial propagation direction during the last r’ wave and the slope at the end of the QRS complex were measured and compared between patients groups. Receiver‐operating characteristic curves were constructed for half of the database to identify optimal cutoff values; sensitivity and specificity for these cutoff values were measured in the other half of the database. A spontaneous type 1 ECG was present in only 30% of BrS patients. An orientation in the sagittal plane < 101º during the last r’ wave and a descending slope < 9.65 mV/s enables the diagnosis of the syndrome with a sensitivity of 69% and a specificity of 97% in non‐type 1 Brugada syndrome patients.
Conclusion
Spatiotemporal characteristics of surface ECG recordings can enable a robust identification of BrS even without the presence of a type 1 ECG.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease characterized by the presence of fibrofatty replacement of the right ventricular myocardium, which may cause ventricular ...arrhythmias and sudden cardiac death. Pathogenic mutations in several genes encoding mainly desmosomal proteins have been reported. Our aim is to perform genotype-phenotype correlations to establish the diagnostic value of genetics and to assess the role of mutation type in age-related penetrance in ARVC.
Thirty unrelated Spanish patients underwent a complete clinical evaluation. They all were screened for PKP2, DSG2, DSC2, DSP, JUP and TMEM43 genes. A total of 70 relatives of four families were also studied. The 30 patients fulfilled definite disease diagnostic criteria. Genetic analysis revealed a pathogenic mutation in 19 patients (13 in PKP2, 3 in DSG2, 2 in DSP, and 1 in DSC2). Nine of these mutations created a truncated protein due to the generation of a stop codon. Familial assessment revealed 28 genetic carriers among family members. Stop-gain mutations were associated to a later age of onset of ARVC, without differences in the severity of the pathology.
Familial genetic analysis helps to identify the cause responsible for the pathology. In discrepancy with previous studies, the presence of a truncating protein does not confer a worse severity. This information could suggest that truncating proteins may be compensated by the normal allele and that missense mutations may act as poison peptides.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Brugada syndrome (BrS) is a rare genetic cardiac arrhythmia that can lead to sudden cardiac death in patients with a structurally normal heart. Genetic variations in SCN5A can be identified in ...approximately 20-25% of BrS cases. The aim of our work was to determine the spectrum and prevalence of genetic variations in a Spanish cohort diagnosed with BrS.
We directly sequenced fourteen genes reported to be associated with BrS in 55 unrelated patients clinically diagnosed. Our genetic screening allowed the identification of 61 genetic variants. Of them, 20 potentially pathogenic variations were found in 18 of the 55 patients (32.7% of the patients, 83.3% males). Nineteen of them were located in SCN5A, and had either been previously reported as pathogenic variations or had a potentially pathogenic effect. Regarding the sequencing of the minority genes, we discovered a potentially pathogenic variation in SCN2B that was described to alter sodium current, and one nonsense variant of unknown significance in RANGRF. In addition, we also identified 40 single nucleotide variations which were either synonymous variants (four of them had not been reported yet) or common genetic variants. We next performed MLPA analysis of SCN5A for the 37 patients without an identified genetic variation, and no major rearrangements were detected. Additionally, we show that being at the 30-50 years range or exhibiting symptoms are factors for an increased potentially pathogenic variation discovery yield.
In summary, the present study is the first comprehensive genetic evaluation of 14 BrS-susceptibility genes and MLPA of SCN5A in a Spanish BrS cohort. The mean pathogenic variation discovery yield is higher than that described for other European BrS cohorts (32.7% vs 20-25%, respectively), and is even higher for patients in the 30-50 years age range.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background Dilated cardiomyopathy (DCM), a cardiac heterogeneous pathology characterized by left ventricular or biventricular dilatation, is a leading cause of heart failure and heart ...transplantation. The genetic origin of DCM remains unknown in most cases, but >50 genes have been associated with DCM. We sought to identify the genetic implication and perform a genetic analysis in a Spanish family affected by DCM and sudden cardiac death. Methods and Results Clinical assessment and genetic screening were performed in the index case as well as family members. Of all relatives clinically assessed, nine patients showed clinical symptoms related to the pathology. Genetic screening identified 20 family members who carried a novel mutation in LMNA (c.871 G>A, p.E291K). Family segregation analysis indicated that all clinically affected patients carried this novel mutation. Clinical assessment of genetic carriers showed that electrical dysfunction was present previous to mechanical and structural abnormalities. Conclusions Our results report a novel pathogenic mutation associated with DCM, supporting the benefits of comprehensive genetic studies of families affected by this pathology.
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