Assuntos
Ajmalina , Síndrome de Brugada , Eletrocardiografia , Humanos , Síndrome de Brugada/fisiopatologia , Ajmalina/farmacologia , Ajmalina/uso terapêutico , Eletrocardiografia/efeitos dos fármacos , Masculino , Adulto , Feminino , Antiarrítmicos/uso terapêutico , Antiarrítmicos/efeitos adversos , Antiarrítmicos/farmacologia , Pessoa de Meia-Idade , Voluntários SaudáveisRESUMO
Brugada syndrome (BrS) is an inherited arrhythmogenic disorder predisposing patients to a high risk of sudden cardiac death. Specific guidelines on the health surveillance of BrS workers are lacking. We report here three cases requiring assessment of specific job capacity, investigated with an interdisciplinary protocol including 24-h Holter electrocardiography with modified precordial leads, pharmacological test with ajmaline, molecular genetic analysis, electrophysiological study with ventricular stimulation, risk stratification, and occupational medicine evaluation: (1) a female 42-yr-old company manager with positive ajmaline test and CACNA1C gene mutation (judged fit for the job with limitations regarding work-related stress); (2) a male 44-yr-old welder with positive ajmaline test, SCN5A gene mutation, and associated OSAS (obstructive sleep apnea syndrome), who was advised to refrain from night shifts and driving company vehicles; (3) a male 45-yr-old electrical technician with inducible ventricular tachyarrhythmia, who was implanted with a biventricular cardioverter defibrillator, and therefore recommended to avoid exposure to electromagnetic fields and working at heights. We conclude that the collaboration between the cardiologist and the occupational physician allows defining the functional capabilities and the arrhythmogenic risk of BrS workers, to optimize job fitness assessment.
Assuntos
Síndrome de Brugada , Humanos , Masculino , Feminino , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Eletrocardiografia/métodos , Ajmalina/farmacologia , Morte Súbita Cardíaca , Eletrocardiografia AmbulatorialRESUMO
PURPOSE: Drug-induced type I Brugada syndrome (BrS) is associated with a ventricular arrhythmia (VA) rate of 1 case per 100 person-years. This study aims to evaluate changes in electrocardiographic (ECG) parameters such as microvolt T wave alternans (mTWA) and heart rate variability (HRV) at baseline and during ajmaline testing for BrS diagnosis. METHODS: Consecutive patients diagnosed with BrS during ajmaline testing with 5-year follow-up were included in this study. For comparison, a negative ajmaline control group and an isoproterenol control group were also included. ECG recordings during ajmaline or isoproterenol test were divided in two timeframes from which ECG parameters were calculated: a 5-min baseline timeframe and a 5-min drug timeframe. RESULTS: A total of 308 patients with BrS were included, 22 (0.7%) of which suffered VAs during follow-up. One hundred patients were included in both isoproterenol and negative ajmaline control groups. At baseline, there was no difference in ECG parameters between control groups and patients with BrS, nor between BrS with and without VAs. During ajmaline testing, BrS with VAs presented longer QRS duration [159 ± 34 ms versus 138 (122-155) ms, p = 0.006], higher maximum mTWA [33.8 (14.0-114) µV versus 8.00 (3.67-28.2) µV, p = 0.001], and lower power in low frequency band [25.6 (5.8-53.8) ms2 versus 129.5 (52.7-286) ms2, p < 0.0001] when compared to BrS without VAs. CONCLUSIONS: Ajmaline induced important HRV changes similar to those observed during isoproterenol. Increased mTWA was observed only in patients with BrS. BrS with VAs during follow-up presented worse changes during ajmaline test, including lower LF power and higher maximum mTWA which were independent predictors of events.
Assuntos
Ajmalina , Síndrome de Brugada , Humanos , Ajmalina/farmacologia , Síndrome de Brugada/diagnóstico , Frequência Cardíaca , Isoproterenol , Arritmias Cardíacas , Eletrocardiografia , PrognósticoRESUMO
BACKGROUND: Brugada syndrome (BrS) is caused by mutations in SCN5A gene in 15%-20% of cases. Previous studies showed worse prognosis in SCN5A mutation carriers (SCN5A+). To date, there are no data on genotype-phenotype correlation with electrocardiographic (ECG) imaging (ECGI) and high-density epicardial electroanatomic map. OBJECTIVE: This study aimed to correlate SCN5A mutation with substrate severity in BrS assessed by ECGI and high-density electroanatomic map. METHODS: All consecutive BrS patients undergoing ECGI and high-density epicardial electroanatomic map with HD Grid Mapping Catheter were retrospectively analyzed. On ECGI, the following parameters were analyzed before and after ajmaline administration: right ventricular outflow tract (RVOT) activation time (RVOT-AT) and RVOT recovery time (RVOT-RT). On electroanatomic map, the parameters analyzed before and after ajmaline were high-frequency potential activation time (HFPat), high-frequency potential duration (HFPd), high-frequency potential amplitude (HFPa), low-frequency potential activation time (LFPat), low-frequency potential duration (LFPd), and low-frequency potential amplitude (LFPa). RESULTS: Thirty-nine BrS patients with ECGI were included. Eight patients (20.5%) were SCN5A+. At baseline ECGI map, mean RVOT-RT was longer in SCN5A+ (P = .024). After ajmaline administration, SCN5A+ patients showed longer RVOT-AT (125.6 vs 100.8 ms; P = .045) and longer RVOT-RT (426.4 vs 397 ms; P = .033). After ajmaline administration, SCN5A+ showed longer HFPat (164.1 vs 119.5 ms; P = .041); longer LFPat (272.7 vs 200.5 ms; P = .018); and longer LFPd (211.9 vs 151.2 ms; P = .033). CONCLUSION: In BrS, SCN5A+ patients compared with SCN5A- patients exhibit marked depolarization and repolarization abnormalities as assessed by ECGI and epicardial high-density electroanatomic map.
Assuntos
Síndrome de Brugada , Ajmalina/farmacologia , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Eletrocardiografia/métodos , Humanos , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5 , Estudos RetrospectivosRESUMO
BACKGROUND: The pathogenesis of Brugada syndrome (BrS) and consequently of abnormal electrograms (aEGMs) found in the epicardium of the right ventricular outflow tract (RVOT-EPI) is controversial. OBJECTIVE: The purpose of this study was to analyze aEGM from high-density RVOT-EPI electroanatomic mapping (EAM). METHODS: All patients undergoing RVOT-EPI EAM with the HD-Grid catheter for BrS were retrospectively included. Maps were acquired before and after ajmaline, and all patients had concomitant noninvasive electrocardiographic imaging with annotation of RVOT-EPI latest activation time (RVOTat). High-frequency potentials (HFPs) were defined as ventricular potentials occurring during or after the far-field ventricular EGM showing a local activation time (HFPat). Low-frequency potentials (LFPs) were defined as aEGMs occurring after near-field ventricular activation showing fractionation or delayed components. Their activation time from surface ECG was defined as LFPat. RESULTS: Fifteen consecutive patients were included in the study. At EAM before ajmaline, 7 patients (46.7%) showed LFPs. All patients showed HFPs before and after ajmaline and LFPs after ajmaline. Mean HFPat (134.4 vs 65.3 ms, P <.001), mean LFPat (224.6 vs 113.6 ms, P <.001), and mean RVOTat (124.8 vs 55.9 ms, P <.001) increased after ajmaline. RVOTat correlated with HFPat before (ρ = 0.76) and after ajmaline (ρ = 0.82), while RVOTat was shorter than LFPat before (P <.001) and after ajmaline (P <.001). BrS patients with history of aborted sudden cardiac death had longer aEGMs after ajmaline. CONCLUSION: Two different types of aEGMs are described from BrS high-density epicardial mapping. This might correlate with depolarization and repolarization abnormalities.
Assuntos
Síndrome de Brugada , Ajmalina/farmacologia , Síndrome de Brugada/diagnóstico , Eletrocardiografia/métodos , Mapeamento Epicárdico/métodos , Humanos , Estudos RetrospectivosRESUMO
BACKGROUND: The mechanisms by which sodium channel blockade and high-rate pacing modify electrogram (EGM) substrates of Brugada syndrome (BrS) have not been elucidated. OBJECTIVE: The purpose of this study was to determine the effect of ajmaline and high pacing rate on the BrS substrates. METHODS: Thirty-two patients with BrS (mean age 40 ± 12 years) and frequent ventricular fibrillation episodes underwent right ventricular outflow tract substrate electroanatomical and electrocardiographic imaging (ECGI) mapping before and after ajmaline administration and during high-rate atrial pacing. In 4 patients, epicardial mapping was performed using open thoracotomy with targeted biopsies. RESULTS: Ajmaline increased the activation time delay in the substrate (33%; P = .002), ST-segment elevation in the right precordial leads (74%; P < .0001), and the area of delayed activation (170%; P < .0001), coinciding with the increased substrate size (75%; P < .0001). High atrial pacing rate increased the abnormal EGM duration at the right ventricular outflow tract areas from 112 ± 48 to 143 ± 66 ms (P = .003) and produced intermittent conduction block and/or excitation failure at the substrate sites, especially after ajmaline administration. Biopsies from the 4 patients with thoracotomy showed epicardial fibrosis where EGMs were normal at baseline but became fractionated after ajmaline administration. In some areas, local activation was absent and unipolar EGMs had a monophasic morphology resembling the shape of the action potential. CONCLUSION: Sodium current reduction with ajmaline severely compromises impulse conduction at the BrS fibrotic substrates by producing fractionated EGMs, conduction block, or excitation failure, leading to the Brugada ECG pattern and favoring ventricular fibrillation genesis.
Assuntos
Síndrome de Brugada , Bloqueadores dos Canais de Sódio , Adulto , Ajmalina/farmacologia , Arritmias Cardíacas , Síndrome de Brugada/diagnóstico , Eletrocardiografia/métodos , Humanos , Pessoa de Meia-Idade , Bloqueadores dos Canais de Sódio/uso terapêutico , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/tratamento farmacológico , Fibrilação Ventricular/etiologiaRESUMO
BACKGROUND: The Brugada pattern manifests as a spontaneous variability of the electrocardiographic marker, suggesting a variability of the underlying electrical substrate. OBJECTIVE: The purpose of this study was to investigate the response of the epicardial substrate of Brugada syndrome (BrS) to programmed ventricular stimulation and to Na blocker infusion. METHODS: We investigated 6 patients (all male; mean age 54 ± 14 years) with BrS and recurrent ventricular fibrillation. Five had no type 1 BrS electrocardiogram pattern at admission. They underwent combined epicardial-endocardial mapping using multielectrode catheters. Changes in epicardial electrograms were evaluated during single endocardial extrastimulation and after low-dose ajmaline infusion (0.5 mg/kg in 5 minutes). RESULTS: All patients had a region in the anterior epicardial right ventricle with prolonged multicomponent electrograms. Single extrastimulation prolonged late epicardial components by 59 ± 31 ms and in 4 patients abolished epicardial components at some sites, without reactivation by surrounding activated sites. These localized blocks occurred at an initial coupling interval of 335 ± 58 ms and then expanded to other sites, being observed in up to 40% of epicardial sites. Ajmaline infusion prolonged electrogram duration in all and produced localized blocks in 62% of sites in the same patients as during extrastimulation. Epicardial conduction recovery after ajmaline occurred intermittently and at discontinuous sites and produced beat-to-beat changes in local repolarization, resulting in an area of marked electrical disparity. These changes were consistent with models based on microstructural alterations under critical propagation conditions. CONCLUSION: In BrS, localized functional conduction blocks occur at multiple epicardial sites and with variable patterns, without being reactivated from the surrounding sites.
Assuntos
Síndrome de Brugada , Potenciais de Ação , Adulto , Idoso , Ajmalina/farmacologia , Arritmias Cardíacas , Síndrome de Brugada/diagnóstico , Eletrocardiografia , Bloqueio Cardíaco , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.
Assuntos
Síndrome de Brugada/genética , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Adolescente , Adulto , Idoso , Ajmalina/farmacologia , Substituição de Aminoácidos , Síndrome de Brugada/complicações , Síndrome de Brugada/metabolismo , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Feminino , Testes Genéticos , Células HEK293 , Heterozigoto , Humanos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Técnicas de Patch-Clamp , Linhagem , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoAssuntos
Ajmalina/farmacologia , Síndrome de Brugada/diagnóstico , Eletrocardiografia , Dispositivos Eletrônicos Vestíveis , Adulto , Antiarrítmicos/farmacologia , Mapeamento Potencial de Superfície Corporal/métodos , Diagnóstico Diferencial , Eletrocardiografia/instrumentação , Eletrocardiografia/métodos , Humanos , Masculino , Reprodutibilidade dos TestesRESUMO
Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient's electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effect in vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSC-CMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC50 values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from pure in vitro measurements of patient derived cell lines.
Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Avaliação Pré-Clínica de Medicamentos/métodos , Sistema de Condução Cardíaco/anormalidades , Cardiopatias Congênitas/tratamento farmacológico , Cardiopatias Congênitas/fisiopatologia , Modelos Cardiovasculares , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Potenciais de Ação/efeitos dos fármacos , Adulto , Ajmalina/farmacologia , Algoritmos , Arritmias Cardíacas/genética , Linhagem Celular , Biologia Computacional , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Canal de Potássio ERG1/genética , Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Cardiopatias Congênitas/genética , Humanos , Técnicas In Vitro , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/fisiologia , Ivabradina/farmacologia , Mexiletina/farmacologia , Mutação , Quinidina/farmacologia , Pesquisa Translacional BiomédicaRESUMO
Patients with Brugada syndrome (BrS) can show a leftward deviation of the frontal QRS-axis upon provocation with sodium channel blockers. The cause of this axis change is unclear. In this study, we aimed to determine (1) the prevalence of this left axis deviation and (2) to evaluate its cause, using the insights that could be derived from vectorcardiograms. Hence, from a large cohort of patients who underwent ajmaline provocation testing (n = 1430), we selected patients in whom a type-1 BrS-ECG was evoked (n = 345). Depolarization and repolarization parameters were analyzed for reconstructed vectorcardiograms and were compared between patients with and without a >30° leftward axis shift. We found (1) that the prevalence of a left axis deviation during provocation testing was 18% and (2) that this left axis deviation was not explained by terminal conduction slowing in the right ventricular outflow tract (4th QRS-loop quartile: +17 ± 14 ms versus +13 ± 15 ms, nonsignificant) but was associated with a more proximal conduction slowing (1st QRS-loop quartile: +12[8;18] ms versus +8[4;12] ms, p < 0.001 and 3rd QRS-loop quartile: +12 ± 10 ms versus +5 ± 7 ms, p < 0.001). There was no important heterogeneity of the action potential morphology (no difference in the ventricular gradient), but a left axis deviation did result in a discordant repolarization (spatial QRS-T angle: 122[59;147]° versus 44[25;91]°, p < 0.001). Thus, although the development of the type-1 BrS-ECG is characterized by a terminal conduction delay in the right ventricle, BrS-patients with a left axis deviation upon sodium channel blocker provocation have an additional proximal conduction slowing, which is associated with a subsequent discordant repolarization. Whether this has implications for risk stratification is still undetermined.
Assuntos
Ajmalina/uso terapêutico , Síndrome de Brugada/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Adulto , Ajmalina/farmacologia , Síndrome de Brugada/fisiopatologia , Eletrocardiografia , Potenciais Evocados/efeitos dos fármacos , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Bloqueadores dos Canais de Sódio/farmacologia , Função Ventricular/efeitos dos fármacosRESUMO
BACKGROUND: Concomitant apamin-sensitive small conductance calcium-activated potassium current (IKAS) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong. OBJECTIVE: The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates IKAS and causes JWS in the presence of ajmaline. METHODS: We performed optical mapping in Langendorff-perfused rabbit hearts and whole-cell voltage clamp to determine IKAS in isolated ventricular cardiomyocytes. RESULTS: ACh (1 µM) + ajmaline (2 µM) induced J-point elevations in all (6 male and 6 female) hearts from 0.01± 0.01 to 0.31 ± 0.05 mV (P<.001), which were reduced by apamin (specific IKAS inhibitor, 100 nM) to 0.14 ± 0.02 mV (P<.001). More J-point elevation was noted in male than in female hearts (P=.037). Patch clamp studies showed that ACh significantly (P<.001) activated IKAS in isolated male but not in female ventricular myocytes (n=8). Optical mapping studies showed that ACh induced action potential duration (APD) heterogeneity, which was more significant in right than in left ventricles. Apamin in the presence of ACh prolonged both APD at the level of 25% (P<.001) and APD at the level of 80% (P<.001) and attenuated APD heterogeneity. Ajmaline further increased APD heterogeneity induced by ACh. Ventricular arrhythmias were induced in 6 of 6 male and 1 of 6 female hearts (P=.015) in the presence of ACh and ajmaline, which was significantly suppressed by apamin in the former. CONCLUSION: ACh activates ventricular IKAS. ACh and ajmaline induce JWS and facilitate the induction of ventricular arrhythmias more in male than in female ventricles.
Assuntos
Acetilcolina/farmacologia , Ajmalina/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Ventrículos do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Canais de Sódio/metabolismo , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Agonistas Colinérgicos/farmacologia , Modelos Animais de Doenças , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Preparação de Coração Isolado/métodos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Imagem Óptica , Técnicas de Patch-Clamp , Canais de Potássio Cálcio-Ativados/metabolismo , Coelhos , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores , Canais de Sódio/efeitos dos fármacos , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologiaRESUMO
BACKGROUND: J wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin. METHODS: The effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin's effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Ito agonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF. RESULTS: Acacetin (5-10 µM) reduced Ito density, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Ito with NS5806, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF. CONCLUSIONS: We present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS.
Assuntos
Síndrome de Brugada , Eletrocardiografia , Flavonas/farmacologia , Miócitos Cardíacos/metabolismo , Pericárdio/metabolismo , Ajmalina/farmacologia , Animais , Síndrome de Brugada/induzido quimicamente , Síndrome de Brugada/tratamento farmacológico , Síndrome de Brugada/metabolismo , Síndrome de Brugada/fisiopatologia , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Hipotermia/metabolismo , Hipotermia/patologia , Hipotermia/fisiopatologia , Compostos de Fenilureia/farmacologia , Tetrazóis/farmacologia , Verapamil/farmacologiaRESUMO
Brugada syndrome (BrS) diagnosis requires the presence of a typical type 1 ECG pattern. Owing to the spontaneous ECG variability, the real BrS prevalence in the general population remains unclear. The aim of the present study was to evaluate the prevalence of positive ajmaline challenge for BrS in a cohort of consecutive patients who underwent electrophysiological evaluation for different clinical reasons. All consecutive patients from 2008 to 2019 who underwent ajmaline testing were prospectively included. A total of 2,456 patients underwent ajmaline testing, 742 (30.2%) in the context of familial screening for BrS. In non-familial screening group (1,714) ajmaline testing resulted positive in 186 (10.9%). Indications for ajmaline testing were: suspicious BrS ECG in 23 cases (12.4%), palpitations in 27 (14.5%), syncope in 71 (38.2%), presyncope in 7 (3.8%), family history of sudden cardiac death in 18 (9.7%), documented ventricular arrhythmias in 12 (6.5%), unexplained cardiac arrest in 4 (2.2%), atrial fibrillation in 16 (8.5%), brady-arrhythmias in 1 (0.5%), and cerebrovascular accidents in 7 (3.7%). Compared with the overall population, ajmaline testing positive patients were younger (42.8 ± 15.5 vs 48.9 ± 20.4; p <0.001) and more frequently male (65.1% vs 56.3%; pâ¯=â¯0.023). Implantable cardioverter defibrillator was implanted in 84 patients (45.2%). During a median follow-up of 42.4 months, 12 appropriate shocks and 13 implantable cardioverter defibrillator related complications were reported. In conclusion, the BrS was diagnosed in an unexpected high proportion of patients that underwent ajmaline testing for a variety of cardiovascular symptoms. This can lead to an adequate counseling and clinical management in BrS patients.
Assuntos
Ajmalina , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/epidemiologia , Eletrocardiografia , Adulto , Idoso , Ajmalina/farmacologia , Eletrocardiografia/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos ProspectivosRESUMO
Class-I-antiarrhythmics like ajmaline are known to alter smooth muscle function, which may cause alterations in gastrointestinal motility. The effects of ajmaline on isolated gastric and portal vein smooth muscle and the underlying mechanisms are unknown. We studied the effects of ajmaline on the contractile patterns of isolated preparations of gastric antrum and portal vein from Wistar rats. The organ bath technique was used to measure spontaneous or pharmacologically induced isometric contractions. Changes in force observed after application of ajmaline or under control conditions are reported as % of the amplitude of an initial K+-induced contraction. Electric field stimulation was used to study neurogenic relaxations of gastric fundus smooth muscle. Ajmaline increased the amplitude of spontaneous contractions of muscle strips (portal vein: control 31.1 ± 15.2%, with 100 µM ajmaline 76.6 ± 32.3%, n = 9, p < 0.01; gastric antrum: control 9.5 ± 1.6%, with 100 µM ajmaline 63.9 ± 9.96%, n = 14, p < 0.01). The frequency of spontaneous activity was reduced in portal vein, but not in gastric antrum strips. The effects of ajmaline were not blocked by tetrodotoxin, L-nitroarginine methyl ester, or atropine. Ajmaline abolished coordinated neurogenic relaxations triggered by electric field stimulation and partly reversed the inhibition of GA spontaneous activity caused by the gap junction blocker carbenoxolone. Ajmaline enhances the amplitude of spontaneous contractions in rat gastric and portal vein smooth muscle. This effect may be accompanied, but not caused by an inhibition of enteric neurotransmission. Enhanced syncytial coupling as indicated by its ability to antagonize the effects of carbenoxolone is likely to underlie the enhancement of contractility.
Assuntos
Ajmalina/farmacologia , Fundo Gástrico/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Veia Porta/efeitos dos fármacos , Antro Pilórico/efeitos dos fármacos , Animais , Atropina/farmacologia , Estimulação Elétrica/métodos , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacos , Tetrodotoxina/farmacologiaRESUMO
AIMS: Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS. CONCLUSION: Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.
Assuntos
Potenciais de Ação/fisiologia , Síndrome de Brugada/genética , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Ajmalina/farmacologia , Síndrome de Brugada/metabolismo , Cardiotônicos/farmacologia , Estudos de Casos e Controles , Técnicas de Reprogramação Celular , Venenos de Cnidários/farmacologia , Morte Súbita Cardíaca , Humanos , Células-Tronco Pluripotentes Induzidas , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacologia , Mutação , Miócitos Cardíacos/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Técnicas de Patch-Clamp , Fenótipo , Taquicardia Ventricular , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologiaRESUMO
OBJECTIVES: The authors studied the response rates and relative sensitivity of the most common agents used in the sodium-channel blocker (SCB) challenge. BACKGROUND: A type 1 Brugada electrocardiographic pattern precipitated by an SCB challenge confers a diagnosis of Brugada syndrome. METHODS: Patients undergoing an SCB challenge were prospectively enrolled across Canada and the United Kingdom. Patients with no prior cardiac arrest and family histories of sudden cardiac death or Brugada syndrome were included. RESULTS: Four hundred twenty-five subjects underwent SCB challenge (ajmaline, n = 331 [78%]; procainamide, n = 94 [22%]), with a mean age of 39 ± 15 years (54% men). Baseline non-type 1 Brugada ST-segment elevation was present in 10%. A total of 154 patients (36%) underwent signal-averaged electrocardiography, with 41% having late potentials. Positive results were seen more often with ajmaline than procainamide infusion (26% vs. 4%, p < 0.001). On multivariate analysis, baseline non-type 1 Brugada ST-segment elevation (odds ratio [OR]: 6.92; 95% confidence interval [CI]: 3.15 to 15.2; p < 0.001) and ajmaline use (OR: 8.76; 95% CI: 2.62 to 29.2; p < 0.001) were independent predictors of positive results to SCB challenge. In the subgroup undergoing signal-averaged electrocardiography, non-type 1 Brugada ST-segment elevation (OR: 9.28; 95% CI: 2.22 to 38.8; p = 0.002), late potentials on signal-averaged electrocardiography (OR: 4.32; 95% CI: 1.50 to 12.5; p = 0.007), and ajmaline use (OR: 12.0; 95% CI: 2.45 to 59.1; p = 0.002) were strong predictors of SCB outcome. CONCLUSIONS: The outcome of SCB challenge was significantly affected by the drug used, with ajmaline more likely to provoke a type 1 Brugada electrocardiographic pattern compared with procainamide. Patients undergoing SCB challenge may have contrasting results depending on the drug used, with potential clinical, psychosocial, and socioeconomic implications.
Assuntos
Ajmalina/farmacologia , Síndrome de Brugada/diagnóstico , Eletrocardiografia/efeitos dos fármacos , Procainamida/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Adulto , Síndrome de Brugada/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Abnormal delayed electrograms (EGMs) from the anterior wall of the right ventricular outflow tract (RVOT) epicardium have become the ablation target in Brugada syndrome (BrS). OBJECTIVE: The aim of this study was to analyze the safety, feasibility, and efficacy of a novel hybrid thoracoscopic approach to perform epicardial RVOT radiofrequency ablation in BrS. METHODS: Thirty-six patients with BrS (26 men (72.2%); mean age 36.6±15.8 years; range 3-63 years) who underwent hybrid thoracoscopic epicardial ablation of RVOT from January 2016 to April 2018 were included in this study. Two expert electrophysiologists analyzed the EGMs during ajmaline challenge and guided the surgeon to perform ablation. Ajmaline challenge was repeated after 1 month to assess the absence of the BrS electrocardiographic pattern. Patients were followed by remote monitoring and outpatient visits every 6 months. RESULTS: The elimination of all abnormal EGMs was achieved in 94.4% of patients. After a mean follow-up of 16 ± 8 months (range 6-30 months), freedom from ventricular arrhythmias was obtained in 7 (77.8%) patients in secondary prevention 9/36 (25%) and in 24 (100%) patients in primary prevention 24/36 (75%). Major complications were observed in 1 patient (2.8%), who experienced late cardiac tamponade. CONCLUSION: Hybrid thoracoscopic epicardial RVOT ablation in BrS is a safe and feasible approach, allowing direct visualization of ablation during radiofrequency delivery. Because of ventricular arrhythmia recurrences, implantable cardioverter-defibrillator implantation is still mandatory in patients treated in secondary prevention and with high risk.
Assuntos
Síndrome de Brugada , Tamponamento Cardíaco , Ablação por Cateter , Técnicas Eletrofisiológicas Cardíacas/métodos , Ventrículos do Coração , Complicações Pós-Operatórias/diagnóstico , Taquicardia Ventricular , Cirurgia Torácica Vídeoassistida/métodos , Adulto , Ajmalina/farmacologia , Antiarrítmicos/farmacologia , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/fisiopatologia , Síndrome de Brugada/cirurgia , Tamponamento Cardíaco/diagnóstico , Tamponamento Cardíaco/etiologia , Ablação por Cateter/efeitos adversos , Ablação por Cateter/instrumentação , Ablação por Cateter/métodos , Estudos de Viabilidade , Feminino , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/cirurgia , Humanos , Masculino , Pericárdio/cirurgia , Recidiva , Risco Ajustado , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/prevenção & controleRESUMO
BACKGROUND: Familial evaluation after a sudden death with negative autopsy (sudden arrhythmic death syndrome; SADS) may identify relatives at risk of fatal arrhythmias. OBJECTIVES: This study aimed to assess the impact of systematic ajmaline provocation testing using high right precordial leads (RPLs) on the diagnostic yield of Brugada syndrome (BrS) in a large cohort of SADS families. METHODS: Three hundred three SADS families (911 relatives) underwent evaluation with resting electrocardiogram using conventional and high RPLs, echocardiography, exercise, and 24-h electrocardiogram monitor. An ajmaline test with conventional and high RPLs was undertaken in 670 (74%) relatives without a familial diagnosis after initial evaluation. Further investigations were guided by clinical suspicion. RESULTS: An inherited cardiac disease was diagnosed in 128 (42%) families and 201 (22%) relatives. BrS was the most prevalent diagnosis (n = 85, 28% of families; n = 140, 15% of relatives). Ajmaline testing was required to unmask the BrS in 97% of diagnosed individuals. The use of high RPLs showed a 16% incremental diagnostic yield of ajmaline testing by diagnosing BrS in an additional 49 families. There were no differences of the characteristics between individuals and families with a diagnostic pattern in the conventional and the high RPLs. On follow-up, a spontaneous type 1 Brugada pattern and/or clinically significant arrhythmic events developed in 17% (n = 25) of the concealed BrS cohort. CONCLUSIONS: Systematic use of ajmaline testing with high RPLs increases substantially the yield of BrS in SADS families. Assessment should be performed in expert centers where patients are counseled appropriately for the potential implications of provocation testing.