Electrocardiographic variables associated with underlying Brugada syndrome or drug-induced Type 1 Brugada pattern in patients with slow/fast atrioventricular nodal reentrant tachycardia.

Background: The coexistence of clinical atrioventricular nodal reentrant tachycardia (AVNRT) and drug-induced type 1 Brugada pattern (DI-Type 1 BrP) has been previously reported. The present study was designed to determine the 12-lead ECG characteristics at baseline and during AVNRT and to identify a subset of 12-lead ECG variables of benefit associated with underlying Brugada syndrome (BrS)/DI-Type 1 BrP among patients with slow/fast AVNRT. Methods: A total of 40 (11 numerical/29 categorical) 12-lead ECG parameters were analyzed and compared between patients with (n = 69) and without (n = 104) BrS/DI-Type1-BrP matched for age, female gender, body mass index, left ventricular ejection fraction and comorbid conditions. Five distinct types of ECG pattern (Type A/B/C/D/E) in V1-V2 leads during AVNRT were defined. Results: A total of nine electrocardiographic variables, four at baseline, and five during AVNRT were identified. At baseline, patients with BrS/DI-Type 1 BrP had higher prevalence of interatrial block, leftward shift of frontal plane QRS axis, the absence of normal QRS pattern (the presence of rSr' pattern or type 2/3 Brugada pattern) in V1-V2 and QRS fragmentation in inferior leads compared to patients without BrS/DI-Type 1 BrP. During AVNRT, patients with BrS/DI-Type 1 BrP had higher prevalence of Type A ECG pattern ("coved-type" ST-segment elevation) in V1-V2, Type C ECG pattern (pseudo-r' deflection in V1 and "RBBB-like" pattern in V2), pseudo-r' deflection in V1, QRS fragmentation in inferior leads and "isolated" QRS fragmentation/notching/slurring in aVL compared to patients without BrS/DI-Type 1 BrP. Conclusions: We identify several electrocardiographic variables that point to an underlying type 1 BrP among patients with slow/fast AVNRT.

Frequency of Irritable Bowel Syndrome in Patients with Brugada Syndrome and Drug-Induced Type 1 Brugada Pattern.

Irritable bowel syndrome (IBS) is one of the most widely recognized functional bowel disorders (FBDs) with a genetic component. SCN5A gene and SCN1B loci have been identified in population-based IBS cohorts and proposed to have a mechanistic role in the pathophysiology of IBS. These same genes have been associated with Brugada syndrome (BrS). The present study examines the hypothesis that these two inherited syndromes are linked. Prevalence of FBDs over a 12 months period were compared between probands with BrS/drug-induced type 1 Brugada pattern (DI-Type 1 BrP) (n = 148) and a control group (n = 124) matched for age, female sex, presence of arrhythmia and co-morbid conditions. SCN5A/SCN1B genes were screened in 88 patients. Prevalence of IBS was 25% in patients with BrS/DI-Type 1 BrP and 8.1% in the control group (p = 2.34 × 10-4). On stepwise logistic regression analysis, presence of current and/or history of migraine (OR of 2.75; 95% CI: 1.08 to 6.98; p = 0.033) was a predictor of underlying BrS/DI-Type 1 BrP among patients with FBDs. We identified 8 putative SCN5A/SCN1B variants in 7 (12.3%) patients with BrS/DI-Type 1 BrP and 1 (3.2%) patient in control group. Five out of 8 (62.5%) patients with SCN5A/SCN1B variants had FBDs. In conclusion, IBS is a common co-morbidity in patients with BrS/DI-Type 1 BrP. Presence of current and/or history of migraine are a predictor of underlying BrS/DI-Type 1 BrP among patients with FBDs. Frequent co-existence of IBS and BrS/DI-Type 1 BrP necessitates cautious use of certain drugs among the therapeutic options for IBS that are known to exacerbate the Brugada phenotype.

Therapeutic Inefficacy and Proarrhythmic Nature of Metoprolol Succinate and Carvedilol Therapy in Patients With Idiopathic, Frequent, Monomorphic Premature Ventricular Contractions.

BACKGROUND: Antiarrhythmic drugs remain the first-line therapy for treatment of idiopathic ventricular arrhythmias. STUDY QUESTION: The aim of this study was to assess the therapeutic efficacy of extended-release metoprolol succinate (MetS) and carvedilol for idiopathic, frequent, monomorphic premature ventricular contractions (PVCs). STUDY DESIGN: Study population consisted of 114 consecutive patients: 71 received MetS and 43 received carvedilol. MEASURES AND OUTCOMES: All patients underwent 24-hour Holter monitoring at baseline and during drug therapy. PVC-burden response to drug therapy was categorized as "good" (≥80% reduction), "poor" (either <80% reduction or ≤50% increase), and "proarrhythmic" responses (>50% increase) based on change in PVC burden compared with baseline. RESULTS: Most common presenting symptom was palpitations (65.8%), followed by coincidental discovery (29%). The mean MetS and carvedilol dosages were 65.57 ± 30.67 mg/d and 23.66 ± 4.26 mg/d, respectively. "Good," "poor," and "proarrhythmic" responses were observed in 11.3% and 16.3%, 63.4% and 67.4%, and 25.3% and 16.3% of patients treated with MetS and carvedilol, respectively. In patients with relatively high (≥16%) PVC burden, the sum of "poor"/"proarrhythmic" response was observed in 95.5% and 86.4% of patients treated with MetS and carvedilol, respectively. "Proarrhythmic" response was observed in 21.9% of the patients, particularly in the presence of relatively lower (≤10%) baseline PVC burden. Patients with "good" response during beta-blocker therapy had higher baseline daily average intrinsic total heart beats compared with patients with "poor"/"proarrhythmic" response combined (96,437 ± 26,488 vs. 86,635 ± 15,028, P = 0.047, respectively). Side effects and intolerance were observed in 5.6% and 18.6% of patients treated with MetS and carvedilol, respectively. CONCLUSIONS: MetS and carvedilol for idiopathic, frequent, monomorphic PVCs are frequently inefficient. Therapeutic efficacy decreases further in patients with relatively high (≥16%) PVC burden. Relatively higher baseline daily intrinsic total heart beats may be used to predict "good" response before beta-blocker therapy.

Assessment of atrial functional remodeling in patients with atrioventricular nodal reentrant tachycardia with and without drug-induced type 1 Brugada pattern: A case-control study.

PURPOSE: The time interval between the onset of the P-wave on electrocardiogram (ECG) and peak A' velocity of the lateral left atrial wall assessed by tissue Doppler imaging (PA-TDI interval) determine total atrial conduction time (TACT) which reflects atrial remodeling and arrhythmic substrate. In this retrospective study, we aimed to assess TACT in patients with atrioventricular nodal reentrant tachycardia (AVNRT) with and without drug-induced type 1 Brugada electrocardiogram ECG pattern (DI-Type 1 BrP) and control subjects. METHODS: Study population consisted of 62 consecutive patients (46 women; mean age 44 ± 12 years) undergoing electrophysiological study and ablation for symptomatic, drug-resistant AVNRT, and 42 age-matched and sex-matched control subjects. All patients and control subjects underwent ajmaline challenge test and tissue Doppler imaging. RESULTS: A DI-Type 1 BrP was uncovered in 24 of 62 patients with AVNRT (38.7%). PA-TDI interval was similar among AVNRT patients with and without DI-Type 1 BrP (124 ± 12 ms vs 119 ± 14 ms, respectively, P = .32), but significantly longer in patients with AVNRT with as well as without DI-Type 1 BrP than in control subjects (124 ± 12 ms and 119 ± 14 ms vs 105 ± 11 ms, respectively, P < .001). CONCLUSION: The TACT assessed by PA-TDI interval is longer in patients with AVNRT with and without DI-Type 1 BrP than in age-matched and sex-matched healthy control subjects.

Recognition and clinical implications of high prevalence of migraine in patients with Brugada syndrome and drug-induced type 1 Brugada pattern.

INTRODUCTION: We have previously reported high 1-year prevalence of migraine in patients with atrial arrhythmias associated with DI-type 1 BrP. The present study was designed to determine the lifetime prevalence of migraine in patients with Brugada syndrome (BrS) or drug-induced type 1 Brugada pattern (DI-type 1 BrP) and control group, to investigate the demographic and clinical characteristics, and to identify clinical variables to predict underlying BrS/DI-type 1 BrP among migraineurs. METHODS AND RESULTS: Lifetime prevalence of migraine and migraine characteristics were compared between probands with BrS/DI-type 1 BrP (n = 257) and control group (n = 370). Lifetime prevalence of migraine was 60.7% in patients with BrS/DI-type 1 BrP and 30.3% in control group (p = 3.6 × 10-14 ). On stepwise regression analysis, familial migraine (odds ratio [OR] of 4.4; 95% confidence interval [CI]: 2.0-9.8; p = 1.3 × 10-4 ), vestibular migraine (OR of 5.4; 95% CI: 1.4-21.0); p = .013), migraine with visual aura (OR of 1.8; 95% CI: 1.0-3.4); p = .04) and younger age-at-onset of migraine (OR of 0.95; 95% CI: 0.93-0.98); p = .004) were predictors of underlying BrS/DI-type 1 BrP among migraineurs. Use of anti-migraine drugs classified as "to be avoided" or "preferably avoided" in patients with BrS and several other anti-migraine drugs with potential cardiac INa /ICa channel blocking properties was present in 25.6% and 26.9% of migraineurs with BrS/DI-type 1 BrP, respectively. CONCLUSION: Migraine comorbidity is common in patients with BrS/DI-type 1 BrP. We identify several clinical variables that point to an underlying type-1 BrP among migraineurs, necessitating cautious use of certain anti-migraine drugs.

Susceptibility to Ventricular Arrhythmias Resulting from Mutations in FKBP1B, PXDNL, and SCN9A Evaluated in hiPSC Cardiomyocytes.

BACKGROUND: We report an inherited cardiac arrhythmia syndrome consisting of Brugada and Early Repolarization Syndrome associated with variants in SCN9A, PXDNL, and FKBP1B. The proband inherited the 3 mutations and exhibited palpitations and arrhythmia-mediated syncope, whereas the parents and sister, who carried one or two of the mutations, were asymptomatic. METHODS AND RESULTS: We assessed the functional impact of these mutations in induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) derived from the proband and an unaffected family member. Current and voltage clamp recordings, as well as confocal microscopy analysis of Ca2+ transients, were evaluated in hiPSC-CMs from the proband and compared these results with hiPSC-CMs from undiseased controls. Genetic analysis using next-generation DNA sequencing revealed heterozygous mutations in SCN9A, PXDNL, and FKBP1B in the proband. The proband displayed right bundle branch block and exhibited episodes of syncope. The father carried a mutation in FKBP1B, whereas the mother and sister carried the SCN9A mutation. None of the 3 family members screened developed cardiac events. Action potential recordings from control hiPSC-CM showed spontaneous activity and a low upstroke velocity. In contrast, the hiPSC-CM from the proband showed irregular spontaneous activity. Confocal microscopy of the hiPSC-CM of the proband revealed low fluorescence intensity Ca2+ transients that were episodic in nature. Patch-clamp measurements in hiPSC-CM showed no difference in I Na but reduced I Ca in the proband compared with control. Coexpression of PXDNL-R391Q with SCN5A-WT displayed lower I Na density compared to PXDNL-WT. In addition, coexpression of PXDNL-R391Q with KCND3-WT displayed significantly higher I to density compared to PXDNL-WT. CONCLUSION: SCN9A, PXDNL, and FKBP1B variants appeared to alter spontaneous activity in hiPSC-CM. Only the proband carrying all 3 mutations displayed the ERS/BrS phenotype, whereas one nor two mutations alone did not produce the clinical phenotype. Our results suggest a polygenic cause of the BrS/ERS arrhythmic phenotype due to mutations in these three gene variants caused a very significant loss of function of I Na and I Ca and gain of function of I to.

Coexistence of atrioventricular accessory pathways and drug-induced type 1 Brugada pattern.

BACKGROUND: Atrial arrhythmias, particularly atrioventricular nodal reentrant tachycardia, can coexist with drug-induced type 1 Brugada electrocardiogram (ECG) pattern (DI-Type1-BrP). The present study was designed to determine the prevalence of DI-Type1-BrP in patients with atrioventricular accessory pathways (AV-APs) and to investigate the clinical, electrocardiographic, electrophysiologic, and genetic characteristics of these patients. METHODS: One-hundred twenty-four consecutive cases of AV-APs and 84 controls underwent an ajmaline challenge test to unmask DI-Type1-BrP. Genetic screening and analysis was performed in 55 of the cases (19 with and 36 without DI-Type1-BrP). RESULTS: Patients with AV-APs were significantly more likely than controls to have a Type1-BrP unmasked (16.1 vs 4.8%, P = 0.012). At baseline, patients with DI-Type1-BrP had higher prevalence of chest pain, QR/rSr' pattern in V1 and QRS notching/slurring in V2 and aVL during preexcitation, rSr' pattern in V1 -V2 , and QRS notching/slurring in aVL during orthodromic atrioventricular reentrant tachycardia (AVRT) compared to patients without DI-Type1-BrP. Abnormal QRS configuration (QRS notching/slurring and/or fragmentation) in V2 during preexcitation was present in all patients with DI-Type1 BrP. The prevalence of spontaneous preexcited atrial fibrillation (AF) and history of AF were similar (15% vs 18.3%, P = 0.726) in patients with and without DI-Type1-BrP, respectively. The prevalence of mutations in Brugada-susceptibility genes was higher (36.8% vs 8.3%, P = 0.02) in patients with DI-Type1-BrP compared to patients without DI-Type1-BrP. CONCLUSIONS: DI-Type1-BrP is relatively common in patients with AV-APs. We identify 12-lead ECG characteristics during preexcitation and orthodromic AVRT that point to an underlying type1-BrP, portending an increased probability for development of malignant arrhythmias.

Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants.

BACKGROUND: There is limited evidence that Brugada Syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or Sudden Arrhythmic Death Syndrome (SADS). OBJECTIVE: We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity. METHODS: Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed. Clinical characteristics including relevant history, electrocardiographic parameters and drug provocation testing results were studied. SCN1B genetic testing results were reclassified using American College of Medical Genetics criteria. RESULTS: A total of 23 SCN1B genotype-positive individuals were identified from 8 families. Four probands (17%) experienced ventricular fibrillation or sudden cardiac death at the time of presentation. All family members were free from syncope or ventricular arrhythmias. Only 2 of 23 genotype-positive individuals (9%) demonstrated a spontaneous BrS electrocardiographic pattern. Drug challenge testing for BrS in 87% (13 of 15) was negative. There was no difference in PR interval (161 ± 7 ms vs 165 ± 9 ms; P = .83), QRS duration (101 ± 6 ms vs 89 ± 5 ms; P = .35), or corrected QT interval (414 ± 35 ms vs 405 ± 8 ms; P = .7) between genotype-positive and genotype-negative family members. The overall frequency of previously implicated SCN1B variants in the Genome Aggregation Database browser is 0.004%, exceeding the estimated prevalence of BrS owing to SCN1B (0.0005%), including 15 of 23 individuals (65%) who had the p.Trp179X variant. CONCLUSION: The lack of genotype-phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS.

Swallow-induced syncope in 5 patients: Electrophysiologic evaluation during swallowing.

BACKGROUND: We sought to characterize a cohort of participants with swallow-induced syncope (SIS) with clinical and electrophysiologic evaluations. METHODS: Using electrocardiographic monitoring and neurophysiologic methods of swallowing, we evaluated a cohort of 5 patients with SIS, 4 of whom had longitudinal follow-up. RESULTS: We determined electrophysiologically that the duration between the onset of swallow and a bradyarrhythmia or asystole is extremely short (2-3 seconds) in SIS. Most participants with SIS do not have a neurologic or esophageal disorder. SIS can occur with different food types, in sitting or standing position, and has varying frequency in different participants. Permanent pacemaker placement is a curative measure in SIS. CONCLUSIONS: Our findings suggest that SIS is elicited by reflex afferent pathways originating in the oropharynx, rather than an esophageal origin, as previously proposed. Our longitudinally followed cohort with detailed clinical and electrophysiologic characterization should aid the clinician in the diagnosis and treatment of this potentially life-threatening condition.

Brugada syndrome, Brugada phenocopy or none?

Brugada syndrome is a form of inherited arrhythmia syndrome characterized by a distinct ST-segment elevation in the right precordial leads. Brugada phenocopies are clinical entities that present with an electrocardiographic pattern identical to Brugada syndrome and may obey to various clinical conditions. We present a case of a suicidal attempt using a high dose of propafenone causing a Brugada-type electrocardiographic pattern. Is this a Brugada syndrome case, a Brugada phenocopy or something else?

Andersen-Tawil syndrome: Clinical presentation and predictors of symptomatic arrhythmias - Possible role of polymorphisms K897T in KCNH2 and H558R in SCN5A gene.

BACKGROUND: Andersen-Tawil syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5. It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS. METHODS: This study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0±17.3 years, female n=31). Additional genetic screening of 3 LQTS genes (KCNQ1, KCNH2, SCN5A) was performed in 9 families. Predictors of arrhythmias [premature ventricular beats>2000/24h, biventricular and polymorphic ventricular tachycardia (VT)], syncope, and/or cardiac arrest (CA) were evaluated. RESULTS: In KCNJ2 mutation carriers vs non-carriers (n=25 vs n=19) significant differences were observed in U-wave manifestations in V2-V4, Tpeak-Tend duration, QTUc duration (p<0.0001), dysmorphic features, and neurological symptoms. Compared to asymptomatic carriers (n=9), in those with arrhythmias and/or syncope and/or CA (n=16) micrognathia (p=0.004), periodic paralysis (p=0.019), palpitation (p=0.005), U-wave n V2-V4 (p=0.049) were more frequent; QTU (p=0.045) and Tpeak-Tend (p=0.014) were also longer (n=9). In the subgroup of carriers with syncope and/or cardiac arrest (n=10, 90% women), K897T-KCNH2 polymorphism (p=0.02), periodic paralysis (p=0.004), muscle weakness (p=0.04), palpitations (p=0.04), arrhythmias (biventricular VT, p=0.003; polymorphic VT, p=0.009) were observed more frequently. Tpeak-Tend duration was longer (p=0.007) and the percentage of patients with premature ventricular contraction >2000/24h was higher (p=0.005). CONCLUSION: A higher risk of arrhythmia, syncope, and/or CA is associated with the presence of micrognathia, periodic paralysis, and prolonged Tpeak-Tend time. Our findings suggest that K897T may contribute to the occurrence of syncope.

Female gender as independent risk factor of torsades de pointes during acquired atrioventricular block.

BACKGROUND: Female gender increases the risk of torsades de pointes (TdP) in the long QT syndrome, and this increased risk is assumed to be due to their longer QT interval. OBJECTIVE: The purpose of this study was to study the interplay between gender, duration of the QT interval, and risk of TdP during AV block. METHODS: We studied 250 patients (48% women) with AV block. QT interval was measured at the time of most severe bradycardia. We then constructed different receiver operating characteristic curves for the QTc of males and females for predicting TdP. RESULTS: As expected, patients with TdP had longer QTc intervals than did patients with uncomplicated AV block (564 ± 81 ms vs 422 ± 62 ms, P < .001). This correlation between longer QTc and higher risk of TdP was true for both genders. However, the QT of females with TdP was shorter than the respective value for males with TdP. Despite similar severity of bradycardia, the QT was shorter for females (QT 672 ± 88 ms vs 727 ± 57 ms for females with TdP vs males with TdP, P = .022). The QTc/TdP risk curve for females was shifted to the left in comparison to the pertinent graph for males. Female gender was an independent predictor of TdP. CONCLUSION: Women are at increased risk for developing TdP during AV block, but this increased risk is independent of their longer QT interval. Females develop TdP with QT intervals that are not necessarily arrhythmogenic for males.

Disappearance of Idiopathic Outflow Tract Premature Ventricular Contractions After Catheter Ablation of Overt Accessory Pathways.

BACKGROUND: Multiple mechanisms have been proposed for idiopathic premature ventricular contractions (PVCs) originating from the outflow tracts (OTs). Recent observations such as the coexistence of these arrhythmias with atrioventricular nodal reentrant tachycardias and the association between discrete prepotentials and successful ablation sites of ventricular arrhythmias (VAs) from the OTs suggest a common link. OBJECTIVE: In this case series we draw attention to a unique association between accessory pathways (APs) and idiopathic PVCs from the OTs, disappearing after AP ablation. METHODS: We identified 6 cases in collaboration with several international electrophysiology centers, which presented with pre-excitation in association with OT, and in 1 case inflow tract (IT), PVCs on 12-lead surface ECG. RESULTS: Six cases displayed pre-excitation and PVCs, in 5 cases originating from the right ventricular outflow tract (RVOT) and in 1 case from the right ventricular inflow tract (RVIT). In all patients, PVCs were monomorphic and had fixed coupling intervals, in 3 cases presenting in bigeminy. Catheter ablation of the AP led to the simultaneous disappearance of PVCs in 5 of 6 cases. The sites of ablation were remote from the OTs in all these cases. In most cases, the occurrence of OT PVCs was closely associated with the presence of pre-excitation. CONCLUSION: The coexistence of pre-excitation and PVCs from the OTs and the fact that in 5 of 6 cases PVCs disappeared after AP ablation suggests a common mechanism for arrhythmia genesis.

Atrial arrhythmias in inherited arrhythmogenic disorders.

Atrial arrhythmias are being increasingly recognized in inherited arrhythmogenic disorders particularly in patients with Brugada syndrome and short QT syndrome. Atrial arrhythmias in inherited arrhythmogenic disorders have significant epidemiologic, clinical, and prognostic implications. There has been progress in the understanding of underlying genetic characteristics and the mechanistic link between atrial arrhythmias and inherited arrhythmogenic disorders. Appropriate management of these patients is of paramount importance.