Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through release of neuropeptide Y.

The sympathetic nervous system plays an important role in the occurrence of ventricular tachycardia (VT). Many patients, however, experience VT despite maximal doses of beta blocker therapy, possibly due to the effects of sympathetic cotransmitters such as neuropeptide Y (NPY). The purpose of this study was to determine, in a porcine model, whether propranolol at doses higher than clinically recommended could block ventricular electrophysiological effects of sympathoexcitation via stellate ganglia stimulation, and if any residual effects are mediated by NPY. Greater release of cardiac NPY was observed at higher sympathetic stimulation frequencies (10 and 20 vs. 4 Hz). Despite treatment with even higher doses of propranolol (1.0 mg/kg), electrophysiological effects of sympathetic stimulation remained, with residual shortening of activation recovery interval (ARI), a surrogate of action potential duration (APD). Adjuvant treatment with the NPY Y1 receptor antagonist BIBO 3304, however, reduced these electrophysiological effects while augmenting inotropy. These data demonstrate that high-dose beta blocker therapy is insufficient to block electrophysiological effects of sympathoexcitation, and a portion of these electrical effects in vivo are mediated by NPY. Y1 receptor blockade may represent a promising adjuvant therapy to beta-adrenergic receptor blockade.

An unusual ectopic ventricular rhythm in a young woman.

A case of a 22-year-old young pregnant woman with palpitations and near syncope is presented. Holter monitoring showed very frequent premature beats and runs of wide complex tachycardia, refractory to antiarrhythmic drugs. Electrophysiologic evaluation disclosed spontaneous automatism arising in an atriofascicular pathway. Differential diagnosis is discussed.

Change in QRS morphology as a marker of spontaneous elimination in verapamil-sensitive idiopathic left ventricular tachycardia.

BACKGROUND: Verapamil-sensitive idiopathic left ventricular tachycardia (verapamil-ILVT) is thought to be due to a reentry within the LV fascicular system. Radiofrequency catheter ablation (RFCA) is effective for elimination of the VT; however, a long-term prognosis of patients with verapamil-ILVT is still unclear. METHODS AND RESULTS: Eighty consecutive verapamil-ILVT patients (62 men, 31 ± 12 years of age, LVEF: 65 ± 4%) were enrolled. Seventy-six (95%) cases of VT involved right bundle branch block and left axis deviation. We retrospectively analyzed changes in the QRS duration (ΔQRS-d) and QRS axis (ΔQRS-axis) during follow-up and compared them with recurrence of VT. During a mean follow-up period of 10 years (2-32 years), no sudden death or heart failure occurred. Fifty-one (64%) patients underwent RFCA, and 46 (90%) of them had no VT without any medication after RFCA. The ΔQRS-d (16 ± 2 vs. 8 ± 1 ms, P = 0.24) and ΔQRS-axis (20 ± 4 vs. 4 ± 3 degrees, P = 0.23) were not different in patients with no VT (VT[-]) and those with recurrence of VT (VT[+]). However, in the remaining 29 patients without RFCA, VT was spontaneously eliminated in 16 patients. The ΔQRS-d (30 ± 6 vs. 6 ± 1 ms, P = 0.002) and ΔQRS-axis (23 ± 4 vs. 5 ± 2 degrees, P = 0.001) were significantly larger in VT(-) patients compared to VT(+) patients during follow-up. CONCLUSIONS: Some verapamil-ILVT patients who show QRS morphology changes over the follow-up period may become free from VT without any invasive or pharmacological treatments, suggesting that further altered LV fascicular conduction might eliminate the reentry of verapamil-ILVT.

Effect of supplemented intake of omega-3 fatty acids on arrhythmias in patients with ICD: fish oil therapy may reduce ventricular arrhythmia.

PURPOSE: The aim of this study was to evaluate the effects of fish oils, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on ventricular tachyarrhythmic episodes (VTEs) in implantable cardioverter defibrillator (ICD) recipients with ischemic cardiomyopathy. METHODS: One hundred five ICD recipients with ischemic cardiomyopathy received 3.6 g of EPA and DHA and placebo for 6 months, each at a random order, with a 4-month washout period between treatments. Eighty-seven patients completed the 16-month study protocol. The primary end point was any VTE (including sustained and non-sustained ventricular tachycardias at a rate of >150 bpm) as recorded by the ICDs. Secondary end points included device therapy (anti-tachycardia pacing (ATP) or shocks). RESULTS: During treatment with fish oils, there was a significant increase in EPA and DHA concentrations in red blood cells (RBCs) and subcutaneous fat tissue. Among 87 patients who completed the study protocol, the mean number of VTEs was significantly lower during treatment with fish oil (1.7) vs. placebo (5.6; p = 0.035). Appropriate device therapy for VTE occurred in 18 (21%) patients. Fish oil therapy was associated with a trend toward fewer VTEs terminated with ATP (2.8 ± 13.7 vs. 0.5 ± 2.1, respectively; p = 0.077). VTE terminated by ICD shocks, however, was rare, and rates were similar between both groups (0.11 ± 0.6 vs. 0.10 ± 0.4, p = not significant, respectively). CONCLUSIONS: Our data suggest that fish oil therapy may be associated with a reduction in the frequency of VTE in ICD recipients with ischemic cardiomyopathy.

[Recurrent syncope related to catecholaminergic polymorphic ventricular tachycardia due to de novo RyR2-R2401H mutation].

Objective: To explore the clinical and molecular genetic features of a Chinese patient with catecholaminergic polymorphic ventricular tachycardia (CPVT). Methods: Clinical data including resting electrocardiography, echocardiography and treadmill exercise testing of a patient with CPVT admitted to our department in March 2013 were analyzed, and the peripheral venous blood samples of the patient and his family members and 400 ethnicity-matched healthy controls were obtained. All exons and exon-intron boundaries of the six CPVT-related genes including RYR2, CASQ2, TRDN, CALM1, KCNJ2 and ANKB were sequenced to detect the variants related to CPVT. The relationship between the genotypes and phenotypes was analyzed to direct the target therapy. Results: Recurrent syncope induced either by exercise or extreme frightened fear was observed in this patient. There was no positive family history of syncope or sudden death. The resting electrocardiography and echocardiography of the patient were normal, while the exercise testing revealed bidirectional and polymorphic ventricular tachycardia. A cardiac ryanodine receptor gene mutation (R2401H) was identified in this patient, while this mutation was absent in his parents and sister and 400 controls. No variant was detected in the remaining five candidate genes. Treatment with high dose of metoprolol succinate (118.75 mg/d) was effective and patient was free of syncopal attack during the 2 years follow-up. Conclusion: This is the first report on RyR2-R2401H mutation in Chinese patient with CPVT, and high dose of metoptolol is the effective therapy option for CPVT related to RyR2 mutation.

Exercise-induced syncope in a 22-year-old man.

CLINICAL INTRODUCTION: A 22-year-old man was referred to us for syncope during a game of Captain's ball. There was no prodrome. His friends did not notice any ictal movements. He was otherwise well prior to passing out. He was not taking any medications or supplements. He was not usually physically active, but was otherwise well with no significant medical history. This is his first episode of syncope. There was no history of cardiac arrest or seizures. There is no family history of premature sudden cardiac death.Physical examination was normal. ECG at rest demonstrated sinus rhythm with corrected QT interval of 400 ms. Echocardiography revealed a structurally normal heart. Holter monitoring was normal. Treadmill exercise stress test demonstrated the following rhythm on figure 1 during stage 4 Bruce protocol. Stress test was terminated in view of sustained arrhythmia as illustrated. He felt light-headed during the period, but otherwise felt that he could carry on with the exercise. ECG during recovery was unremarkable.

Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs.

RATIONALE: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal arrhythmic disorder caused by mutations in the type-2 ryanodine receptor (RyR2). Mutant RyR2 cause abnormal Ca2+ leak from the sarcoplasmic reticulum (SR), which is associated with the development of arrhythmias. OBJECTIVE: To determine whether derivatives of tetracaine, a local anesthetic drug with known RyR2 inhibiting action, could prevent CPVT induction by suppression of RyR2-mediated SR Ca2+ leak. METHODS AND RESULTS: Confocal microscopy was used to assess the effects of tetracaine and 9 derivatives (EL1-EL9) on spontaneous Ca2+ sparks in ventricular myocytes isolated from RyR2-R176Q/+ mice with CPVT. Whereas each derivative suppressed the Ca2+ spark frequency, derivative EL9 was most effective at the screening dose of 500nmol/L. At this high dose, the Ca2+ transient amplitude was not affected in myocytes from WT or R176Q/+ mice. The IC50 of EL9 was determined to be 13nmol/L, which is about 400× time lower than known RyR2 stabilizer K201. EL9 prevented the induction of ventricular tachycardia observed in placebo-treated R176Q/+ mice, without affecting heart rate or cardiac contractility. CONCLUSIONS: Tetracaine derivatives represent a novel class of RyR2 stabilizing drugs that could be used for the treatment of the potentially fatal disorder catecholaminergic polymorphic ventricular tachycardia.

Drug-induced post-repolarization refractoriness as an antiarrhythmic principle and its underlying mechanism.

AIMS: We hypothesized that amiodarone (AM), unlike d-sotalol (DS) (a 'pure' Class III agent), not only prolongs the action potential duration (APD) but also causes post-repolarization refractoriness (PRR), thereby preventing premature excitation and providing superior antiarrhythmic efficacy. METHODS AND RESULTS: We tested this hypothesis in 31 patients with inducible ventricular tachycardia (VT) during programmed stimulation with the use of the 'Franz' monophasic action potential (MAP) catheter with simultaneous pacing capability. We determined the effective refractory period (ERP) for each of three extrastimuli (S2-S4) and the corresponding MAP duration at 90% repolarization (APD90), both during baseline and on randomized therapy with either DS (n = 15) or AM (n = 16). We defined ERP > APD90 as PRR and ERP < APD90 as 'encroachment' on repolarization. A revised computer action potential model was developed to help explain the mechanisms of these in-vivo human-heart phenomena. Encroachment but not PRR was present in all patients at baseline and during DS treatment (NS vs. baseline), and VT was non-inducible in only 2 of 15 DS patients. In contrast, in 12 of 16 AM patients PRR was present (P < 0.001 vs. baseline), and VT was no longer inducible. Our model (with revised sodium channel kinetics) reproduced encroachment and drug-induced PRR. CONCLUSION: Both, AM and DS, prolonged APD90 but only AM produced PRR and prevented encroachment of premature extrastimuli. Our computer simulations suggest that PRR is due to altered kinetics of the slow inactivation of the rapid sodium current. This may contribute to the high antiarrhythmic efficacy of AM.

Unifying mechanism of sustained idiopathic atrial and ventricular annular tachycardia.

BACKGROUND: Based on the current understanding of cardiac conduction system development and the observation that arrhythmogenic foci can originate in areas near the atrioventricular annuli, we hypothesized that focal annular tachycardias, whether atrial or ventricular, share a common mechanism. We, therefore, prospectively evaluated this hypothesis in patients with sustained atrial and ventricular tachycardia originating from the peri-tricuspid and mitral annuli. METHODS AND RESULTS: Forty-nine consecutive patients with sustained, focal annular tachycardia comprised the study group. All underwent electrophysiological evaluation and the mode of tachycardia initiation, termination, sensitivity to catecholamine infusion, and response to adenosine/verapamil were evaluated. Electroanatomical activation maps identified the sites of arrhythmia origin. Tachycardias could be initiated or terminated or both with programmed stimulation in 46 of 46 patients and most (70%) were catecholamine facilitated. Of the 9 patients with sustained annular ventricular tachycardia, 3 were localized to the tricuspid annulus, and 6 to the mitral annulus. All the 9 ventricular tachycardias (100%) terminated with adenosine, 2 of 2 terminated with verapamil, and 2 of 2 terminated with Valsalva. Of the 40 patients with annular atrial tachycardia, 4 tachycardias were localized to the mitral annulus and 37 to the tricuspid annulus (including 9 para-Hisian), and all were adenosine sensitive. CONCLUSIONS: Peri-annular atrial and ventricular tissue correspond to a region enriched with arrhythmogenic foci, which may reflect a common developmental origin. Furthermore, the sensitivity of these tachycardias to adenosine provides evidence for a shared arrhythmia mechanism, consistent with intracellular calcium overload and triggered activity.

Flecainide therapy suppresses exercise-induced ventricular arrhythmias in patients with CASQ2-associated catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Calsequestrin-associated catecholaminergic polymorphic ventricular tachycardia (CPVT2) can cause sudden death in young individuals in response to stress. Beta-blockers are the mainstay medical treatment for patients with CPVT2. However, they do not prevent syncope and sudden death in all patients. Flecainide was reported to reduce exercise-induced ventricular arrhythmias (EIVA) in patients with ryanodine receptor-associated CPVT. The role of flecainide in CPVT2 is not known. OBJECTIVE: To summarize our experience in combining flecainide and beta-blockers in high-risk patients with CPVT2. METHODS: All patients with CPVT2 (10 patients) who have high-risk features (syncope, EIVA, or appropriate implantable cardioverter-defibrillator [ICD] shocks) despite beta-blockers with or without calcium channel blockers were treated with a combination of flecainide and beta-blockers. Exercise test was done before and after beginning treatment with flecainide. RESULTS: All patients had EIVA and 4 had appropriate ICD shocks before flecainide treatment. EIVA-included frequent ventricular premature beats and or ventricular tachycardia during the exercise test while on high dose of beta-blockers with or without calcium channel blockers before treatment with flecainide. After combination therapy with flecainide and beta-blockers, EIVA were suppressed completely in all patients. During follow-up of 15.5 ± 10.4 months (range 2-29 months), 8 patients were free of symptoms and free of arrhythmias. Two patients had 1 VT storm episode with recurrent ICD shocks despite repeated normal stress test. CONCLUSIONS: Flecainide can completely prevent ventricular arrhythmia during exercise and partially prevent recurrent ICD shocks in high-risk patients with CPVT2.

[A case of idiopathic ventricular tachycardia in a 14-year-old obese patient due to golden berry fruit extract pills for weight loss]. / Zayiflama amaciyla altin çilek meyve özü hapi kullanan 14 yasinda obez hastada gelisen bir idiyopatik ventriküler tasikardi olgusu.

Several studies have determined an association between obesity and increased risk of cardiac arrhythmia. Currently, due to the increased frequency of obesity, food-, plant-, and drug-based therapies for weight loss have gained great attention. A 14-year-old female patient presented with complaints of palpitation of one-hour onset. Blood pressure was 110/70 mmHg and peripheral pulses were present. She had been using golden berry extract pill three times a day for 10 days. The electrocardiogram showed nonsustained monomorphic ventricular tachycardia (VT). Echocardiographic examination and cardiac magnetic resonance imaging (MRI) were normal. She returned to sinus rhythm following amiodarone infusion. She refused the electrophysiologic study, which plays a vital role in the diagnosis and establishment of the appropriate therapy. Although there was no decrease in body mass index (BMI) of the patient during the two-year follow-up, she had no complaint or evidence of VT on intermittent rhythm Holter studies. This case suggests the primary role of golden berry extract use in the development of VT, rather than obesity.

Noncoronary ST elevation and polymorphic ventricular tachycardia during left-sided accessory pathway ablation.

INTRODUCTION: An early repolarization (ER) pattern on electrocardiogram (ECG) sometimes has the risk of polymorphic ventricular tachycardia (PVT) or ventricular fibrillation (VF). An abnormal ER pattern can develop in various experimental or clinical situations. We experienced 4 cases of abnormal ER pattern with or without PVT during the radiofrequency (RF) ablation of the left accessory pathway. METHODS AND RESULTS: An electrophysiologic study and RF ablation were performed in 4 patients. Four patients had atrioventricular reentrant tachycardia. During RF ablation of the left accessory pathway, severe chest pain developed and was followed by abnormal J-point elevation. During the ongoing chest pain and J-point elevation, coronary angiograms showed normal findings. The chest pain and J-point elevation were followed by PVT or VF that was unresponsive to defibrillation. The PVT was spontaneously terminated and repeated. After 0.5 mg atropin was given, chest pain and ECG change disappeared. CONCLUSION: The mechanisms of ER syndrome during RF ablation might be increased vagal tone due to chest pain or direct vagal stimulation.

Do omega-3 polyunsaturated fatty acids reduce risk of sudden cardiac death and ventricular arrhythmias? A meta-analysis of randomized trials.

INTRODUCTION: Omega-3 polyunsaturated fatty acids (PUFA) have demonstrated to have antiarrhythmic properties. However, randomized studies have shown inconsistent results. OBJECTIVE: We aimed to analyze the effect of omega-3 PUFA on preventing potentially fatal ventricular arrhythmias and sudden cardiac death. METHODS: Randomized trials comparing omega-3 PUFA to placebo and reporting sudden cardiac death (SCD) or first implanted cardioverter-defibrillator (ICD) event for ventricular tachycardia or fibrillation were included in this study. A meta-analysis using a random effects model was performed and results were expressed in terms of Odds Ratio (OR) and 95% Confidence Interval (CI) after evaluating for interstudy heterogeneity using I(2). The reported data were extracted on the basis of the intention-to-treat principle. RESULTS: A total of 32,919 patients were included in nine trials; 16,465 patients received omega-3 PUFA and 16,454 received placebo. When comparing omega-3 PUFA to placebo, there was nonsignificant risk reduction of SCD or ventricular arrhythmias (OR = 0.82 [95% CI: 0.60-1.21], p = 0.21 I(2) = 49.7%). CONCLUSION: Dietary supplementation with omega-3 PUFA does not affect the risk of SCD or ventricular arrhythmias.

Protective effects of saffron (Crocus sativus) against lethal ventricular arrhythmias induced by heart reperfusion in rat: a potential anti-arrhythmic agent.

CONTEXT: Saffron (Crocus sativus L.) has been used as a cuisine spice in eastern and western societies for thousands of years. In traditional medicine, saffron is recommended for the treatment of various kinds of disorders including heart palpitations. OBJECTIVE: We investigated the hypothesis of the protective effect of saffron on lethal cardiac arrhythmias induced by heart ischemia-reperfusion in rat. MATERIALS AND METHODS: Animals were divided into a control (CTL) group that received tap water, Saf50, Saf100 and Saf200 groups that were orally treated with aqueous extracts of saffron, at dosages of 50, 100 and 200 mg/kg/day, respectively, and amiodarone (Amio) group that orally received 30 mg/kg/day for seven days. On day 8, heart ischemia-reperfusion was induced by ligation and releasing of the left anterior descending coronary artery. RESULTS: During reperfusion, the numbers and durations of ventricular fibrillation (VF) decreased in all groups compared to the CTL group (p < 0.05). Ventricular tachycardia (VT)/VF numbers (3.2 ± 1.2), durations (4.9 ± 2.6) and also arrhythmia severity (1.9 ± 0.35) were decreased significantly in the Saf100 group versus CTL group values (18.4 ± 11.6, 52 ± 31 and 3.3 ± 0.3, respectively). The PR and QTcn intervals of ECG were significantly longer in the Saf200 group (p < 0.001 versus CTL). The other doses of saffron only significantly prolonged the QTcn interval. CONCLUSION: The results suggest that pretreatment with saffron, especially at the dosage of 100 mg/kg/day, attenuates the susceptibility and incidence of fatal ventricular arrhythmia during the reperfusion period in the rat. This protective effect is apparently mediated through reduction of electrical conductivity and prolonging the action potential duration.

Clinical spectrum of fascicular tachycardia.

AIMS: Ventricular tachycardia spreading from the anterior or posterior division of the left bundle branch is generally called fascicular tachycardia (FT). We will present our experience with FT, a type of ventricular tachycardia not necessarily implying the absence of heart disease and/or sensitivity to selective antiarrhythmic drugs, but only particular routes of left ventricular depolarization. METHODS: Since 1981 we have had the opportunity to study 10 cases of FT (nine men and one woman; aged 28-77 years, mean ±â€ŠSD 55 ±â€Š18.6 years) by means of echocardiography, coronary angiography (seven cases), endomyocardial biopsy (five cases), signal-averaged electrocardiogram (SAECG, nine patients), electrophysiological and electropharmacological evaluation. RESULTS: Seven patients had paroxystic, extrastimulus inducible FT that was sensitive to verapamil given intravenously (group A); three patients, on the other hand, showed repetitive or incessant FT, not modifiable by stimulation techniques and sensitive to class 1 antiarrhythmic drugs (group B). Patients presented histologic substrates ranging from the absence of heart disease to previous myocardial infarction or myocarditis. FT spontaneously disappeared within 2 years in group B, while frequently persisted in the long term in group A. CONCLUSIONS: FT is not a homogeneous group of ventricular tachycardia, as patients may differ according to clinical presentation, mechanisms that are involved in the genesis of the arrhythmia and natural history; the histologic substrate is highly variable, ranging from the total absence of heart disease to severe forms of myocardial involvement.