Acacetin suppresses the electrocardiographic and arrhythmic manifestations of the J wave syndromes.

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.

Brugada phenocopy induced by consumption of yellow oleander seeds - A case report.

Brugada phenocopy is a brugada-like pattern in ECG seen in some diseases without an inherited channelopathy. The causes of brugada phenocopy are usually reversible. Once the reversible condition resolves, the ECG pattern disappears. There are many conditions that cause brugada phenocopy like myocardial infarction, hyperkalemia etc. Here we report a case of brugada phenocopy induced by consumption of yellow oleander seeds (T. Peruviana).

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.

Yellow phosphorus-induced Brugada phenocopy.

BACKGROUND: Metallic phosphides (of aluminum and phosphide) and yellow phosphorus are commonly used rodenticide compounds in developing countries. Toxicity of yellow phosphorus mostly pertains to the liver, kidney, heart, pancreas and the brain. Cardiotoxicity with associated Brugada ECG pattern has been reported only in poisoning with metallic phosphides. METHODS AND RESULTS: Brugada phenocopy and hepatic dysfunction were observed in a 29-year-old male following yellow phosphorus consumption. He had both type 1 (day1) and type 2 (day2) Brugada patterns in the electrocardiogram, which resolved spontaneously by the third day without hemodynamic compromise. CONCLUSION: Toxins such as aluminum and zinc phosphide have been reported to induce Brugada ECG patterns due to the generation of phosphine. We report the first case of yellow phosphorus-related Brugada phenocopy, without hemodynamic compromise or malignant arrhythmia.

High prevalence of concealed Brugada syndrome in patients with atrioventricular nodal reentrant tachycardia.

BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) may coexist with Brugada syndrome (BrS). OBJECTIVES: The present study was designed to determine the prevalence of drug-induced type 1 Brugada ECG pattern (concealed BrS) in patients presenting with clinical spontaneous AVNRT and to investigate their electrocardiographic, electrophysiological, and genetic characteristics. METHODS: Ninety-six consecutive patients without any sign of BrS on baseline electrocardiogram undergoing electrophysiological study and ablation for symptomatic, drug-resistant AVNRT and 66 control subjects underwent an ajmaline challenge to unmask BrS. Genetic screening was performed in 17 patients displaying both AVNRT and BrS. RESULTS: A concealed BrS electrocardiogram was uncovered in 26 of 96 patients with AVNRT (27.1%) and in 3 of 66 control subjects (4.5%) (P ≤ .001). Patients with concealed BrS were predominantly female patients (n=23 [88.5%] vs n=44 [62.9%], P = .015), had higher prevalence of chest pain (n=10 [38.5%] vs n=13 [18.6%], p=0.042), migraine headaches (n=10 [38.5%] vs n=10 [14.2%], p=0.008), and drug-induced initiation and/or worsening of duration and/or frequency of AVNRT (n=4 [15.4%] vs n=1 [1.4%], p=0.006) as compared to patients with AVNRT without BrS. Genetic screening identified 19 mutations or rare variants in 13 genes in 13 of 17 patients with both AVNRT and BrS (yield = 76.5%). Ten of these 13 genotype-positive patients (76.9%) harbored genetic variants known or suspected to cause a loss of function of cardiac sodium channel current (SCN5A, SCN10A, SCN1B, GPD1L, PKP2, and HEY2). CONCLUSION: Our results suggest that spontaneous AVNRT and concealed BrS co-occur, particularly in female patients, and that genetic variants that reduce sodium channel current may provide a mechanistic link between AVNRT and BrS and predispose to expression of both phenotypes.