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1.
Clinical management of electrical storm: a current overview.
Guarracini, F, Casella, M, Muser, D, Barbato, G, Notarstefano, P, Sgarito, G, Marini, M, Grandinetti, G, Mariani, MV, Boriani, G, et al
Journal of cardiovascular medicine (Hagerstown, Md.). 2021;(9):669-679
Abstract
The number of patients affected by electrical storm has been continuously increasing in emergency departments. Patients are often affected by multiple comorbidities requiring multidisciplinary interventions to achieve a clinical stability. Careful reprogramming of cardiac devices, correction of electrolyte imbalance, knowledge of underlying heart disease and antiarrhythmic drugs in the acute phase play a crucial role. The aim of this review is to provide a comprehensive overview of pharmacological treatment, latest transcatheter ablation techniques and advanced management of patients with electrical storm.
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Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance.
Giudicessi, JR, Lieve, KVV, Rohatgi, RK, Koca, F, Tester, DJ, van der Werf, C, Martijn Bos, J, Wilde, AAM, Ackerman, MJ
Circulation. Genomic and precision medicine. 2019;(5):e002510
Abstract
Background Many rare, potentially pathogenic, RYR2 variants identified in individuals with clinically definite catecholaminergic polymorphic ventricular tachycardia are classified ambiguously as variants of uncertain significance (VUS). We aimed to determine if a phenotype-enhanced variant classification approach could reduce the burden of RYR2 VUS encountered during clinical genetic testing. Methods This retrospective study was conducted in 84 RYR2-positive individuals from the Mayo Clinic (Rochester, MN) and validated in 149 RYR2-positive individuals from Amsterdam University Medical Center (Amsterdam, NL). Using a newly developed diagnostic scorecard, the pretest clinical probability of catecholaminergic polymorphic ventricular tachycardia was determined for all RYR2-positive individuals. Each RYR2 variant was then readjudicated using a phenotype-enhanced American College of Medical Genetics approach that incorporates new criteria that reflect the phenotypic strength associated with each individual RYR2 variant. Results Overall, 72 distinct RYR2 variants were identified among the 84 Mayo Clinic (39 unique) and 149 Amsterdam University Medical Center (30 unique) cases. Three variants were present in both cohorts. American College of Medical Genetics guidelines classified 47% of all RYR2 variants as VUS. In the Mayo Clinic cohort, readjudication using amended phenotype-enhanced American College of Medical Genetics standards dropped the VUS rate significantly (20/42 [48%] versus 3/42 [7%]; P<0.001) with 13/20 (65%) RYR2 VUS promoted to likely pathogenic and 4/20 (20%) demoted to likely benign. A similar drop in VUS rate (14/33 [42%] versus 3/33 [9%]; P=0.001) was observed in the Amsterdam University Medical Center validation cohort with 10/14 (71%) RYR2 VUS promoted to likely pathogenic and 1/14 (7%) demoted to likely benign. Conclusions This multicenter study illustrates the potential utility of phenotype-enhanced variant classification in catecholaminergic polymorphic ventricular tachycardia.
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Antiarrhythmic drug therapy during cardiopulmonary resuscitation: should we use it?
Soar, J
Current opinion in critical care. 2018;(3):138-142
Abstract
PURPOSE OF REVIEW The optimal antiarrhythmic drug therapy (amiodarone or lidocaine) in the treatment of ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT) cardiac arrest that is refractory to defibrillation is uncertain. This article reviews the evidence for and against these drugs, alternatives treatments for refractory VF/pVT and aims to define the role of antiarrhythmic drugs during cardiopulmonary resuscitation (CPR). RECENT FINDINGS A large randomized controlled trial that compared amiodarone, lidocaine and saline 0.9% sodium chloride for the treatment of refractory VF/pVT out-of-hospital cardiac arrest reported no difference in survival to hospital discharge or neurological outcome. In patients with witnessed arrest, survival was improved with antiarrhythmic drugs compared to saline. SUMMARY The benefit of antiarrhythmic drugs appears to be for those patients in whom initial early CPR and defibrillation attempts fail and the antiarrhythmic drug is given early. There does not appear to be any clear survival benefit for any one particular drug and other factors such as availability and cost should be considered when deciding which drug to use. Furthermore, other interventions (e.g. percutaneous coronary intervention and extra-corporeal CPR) may provide additional survival benefit when defibrillation attempts and antiarrhythmic drugs are not effective.
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Response by Kapplinger et al to Letter Regarding Article, "Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation".
Kapplinger, JD, Tester, DJ, Ackerman, MJ
Circulation. Genomic and precision medicine. 2018;(5):e002176
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Desmosterol accumulation in users of amiodarone.
Simonen, P, Lehtonen, J, Lampi, AM, Piironen, V, Stenman, UH, Kupari, M, Gylling, H
Journal of internal medicine. 2018;(1):93-101
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Abstract
BACKGROUND Amiodarone is an effective and widely used antiarrhythmic drug with many possible adverse effects including hypercholesterolaemia and hepatotoxicity. OBJECTIVE Our aim was to evaluate how long-term amiodarone treatment affects cholesterol metabolism. METHODS The study population consisted of 56 cardiac patients, of whom 20 were on amiodarone (amiodarone + group) and 36 did not use the drug (amiodarone - group). We also studied a control group of 124 individuals selected randomly from the population. Cholesterol metabolism was evaluated by analysis of serum noncholesterol sterols by gas-liquid chromatography and gas chromatography-mass spectrometry. RESULTS Comparisons of serum lipids and noncholesterol sterols across the three groups showed increased serum triglyceride in users of amiodarone but no statistically significant group differences in total, LDL or HDL cholesterol or serum proprotein convertase subtilisin/kexin type 9 concentrations. Nor did the groups differ in the ratios of cholestanol or plant sterols to cholesterol in serum, suggesting that cholesterol absorption was unaltered. However, all users of amiodarone had very markedly elevated serum desmosterol concentrations: the desmosterol-to-cholesterol ratio (102 × μmol mmol-1 ) averaged 1030.7 ± 115.7 (mean ± SE) in the amiodarone + group versus 82.7 ± 3.4 and 75.9 ± 1.4 in the amiodarone - and the population control groups (P < 0.001), respectively. CONCLUSION Use of amiodarone was associated with on average 12-fold serum desmosterol concentrations compared with the control groups. This observation is fully novel and suggests that amiodarone interferes with the conversion of desmosterol to cholesterol in the cholesterol synthesis pathway. Whether accumulation of desmosterol plays a role in amiodarone-induced hepatotoxicity deserves to be studied in the future.
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Effects of rosuvastatin and atorvastatin on nonsustained ventricular tachycardia in patients with ST-elevation myocardial infarction: a retrospective analysis.
Hu, X, Cheng, J, Li, C
European journal of clinical pharmacology. 2018;(1):29-35
Abstract
BACKGROUND/AIMS: Early and intensive atorvastatin treatment can decrease nonsustained ventricular tachycardia (nsVT) in patients with ST-segment elevation myocardial infarction (STEMI). The objective of this study was to compare the effects of hydrophilic rosuvastatin and lipophilic atorvastatin on nsVT in STEMI patients treated with primary percutaneous coronary intervention (PCI). METHODS The data from a cohort of patients undergoing primary PCI at Jinhua Municipal Central Hospital from January 1, 2013 through June 30, 2016 were analyzed. The patients were divided into the rosuvastatin group and the atorvastatin group based on which kind of statins that they had received. The endpoint of the study was the occurrence of nsVT on either electrocardiogram monitoring or Holter monitoring. RESULTS A total of 301 patients were enrolled in the study (rosuvastatin group: n = 103; atorvastatin group: n = 198). The baseline and procedural characteristics were similar between the two groups, except that total ischemic time in the rosuvastatin group was markedly longer than that in the atorvastatin group (8 (5-16) h vs. 6 (4-12) h; P = 0.001). The administration of rosuvastatin was significantly associated with lower occurrence of nsVT than that of atorvastatin (9.71 vs. 19.70%; P = 0.026). Multivariable logistic regression analysis suggested that the independent predictors of nsVT included rosuvastatin (odds ratio (OR) 0.397, 95% confidence interval (CI) 0.176-0.894), current smoking (OR 2.307, 95% CI 1.011-5.262), and left ventricular ejection fraction (LVEF) (OR 1.060, 95% CI 1.023-1.098). CONCLUSIONS The effects of rosuvastatin on nsVT might be better than that of atorvastatin in STEMI patients undergoing primary PCI.
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Integration of 60,000 exomes and ACMG guidelines question the role of Catecholaminergic Polymorphic Ventricular Tachycardia-associated variants.
Paludan-Müller, C, Ahlberg, G, Ghouse, J, Herfelt, C, Svendsen, JH, Haunsø, S, Kanters, JK, Olesen, MS
Clinical genetics. 2017;(1):63-72
Abstract
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a highly lethal cardiac arrhythmia disease occurring during exercise or psychological stress. CPVT has an estimated prevalence of 1:10,000 and has mainly been associated with variants in calcium-regulating genes. Identification of potential false-positive pathogenic variants was conducted by searching the Exome Aggregation Consortium (ExAC) database (n = 60,706) for variants reported to be associated with CPVT. The pathogenicity of the interrogated variants was assessed using guidelines from the American College of Medical Genetics and Genomics (ACMG) and in silico prediction tools. Of 246 variants 38 (15%) variants previously associated with CPVT were identified in the ExAC database. We predicted the CPVT prevalence to be 1:132. The ACMG standards classified 29% of ExAC variants as pathogenic or likely pathogenic. The in silico predictions showed a reduced probability of disease-causing effect for the variants identified in the exome database (p < 0.001). We have observed a large overrepresentation of previously CPVT-associated variants in a large exome database. Based on the frequency of CPVT in the general population, it is less likely that the previously proposed variants are associated with a highly penetrant monogenic form of the disease.
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Randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm: RESTORE SR.
Piccini, JP, Pritchett, EL, Davison, BA, Cotter, G, Wiener, LE, Koch, G, Feld, G, Waldo, A, van Gelder, IC, Camm, AJ, et al
Heart rhythm. 2016;(9):1777-83
Abstract
BACKGROUND Vanoxerine is an oral, 1,4-dialkylpiperazine derivative antiarrhythmic drug being evaluated for pharmacological cardioversion of atrial fibrillation (AF). OBJECTIVE The purpose of this study was to evaluate the safety and efficacy of vanoxerine for the restoration of sinus rhythm in subjects with recent onset AF or atrial flutter (AFL). METHODS RESTORE SR (randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm) was a prospective, multinational, randomized, double-blind, placebo-controlled trial that randomized subjects to a single oral dose of vanoxerine 400 mg or placebo (2:1 allocation). RESULTS A total of 41 subjects were randomized in the study (placebo [n = 15] and vanoxerine [n = 26]). The study was terminated prematurely because of safety concerns. Overall, 61% (23 of 38) of the treated cohort had a history of AF/AFL and 66% (27 of 41) had structural heart disease (SHD). The primary efficacy end point-conversion to sinus rhythm through 24 hours-occurred in 20% (3 of 15) in the placebo arm vs 69% (18 of 26) in the vanoxerine arm (P = .0024). The mean length of stay was 4.2 ± 2.9 days in the placebo arm vs 4.7 ± 3.2 days in the vanoxerine arm (P = .6561). The primary safety end point (all-cause death, ventricular fibrillation/tachycardia requiring intervention, or torsades de pointes) occurred in no patient in the placebo arm vs 11.5% (3 of 26) in the vanoxerine arm. All 3 patients had torsades de pointes and underlying SHD. CONCLUSION Vanoxerine is an oral, mixed ion channel blocker with IKr, INa, and L-type calcium channel activity. While oral therapy with 400 mg of vanoxerine appears effective for the termination of recent onset AF/AFL, its use was associated with a significant risk of ventricular proarrhythmia in patients with SHD.
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Advances in the pharmacologic treatment of ventricular arrhythmias.
Schleifer, JW, Sorajja, D, Shen, WK
Expert opinion on pharmacotherapy. 2015;(17):2637-51
Abstract
INTRODUCTION Despite many advances in nonpharmacologic management of ventricular arrhythmias, antiarrhythmic drugs remain important in both the acute conversion and chronic prevention of ventricular arrhythmias. AREAS COVERED Key trials related to antiarrhythmic drug use are reviewed, emphasizing the impact of recent discoveries. Sodium channel blockers are discussed with an emphasis on recently identified specialized uses. Beta blockers, amiodarone, sotalol, and dofetilide are discussed together in the context of structural heart disease, because they do not increase mortality in this group of patients. Other medications found to reduce ventricular arrhythmia burden are discussed last. EXPERT OPINION Since most patients with ventricular arrhythmias have structural heart disease, pharmacologic treatment is limited to amiodarone, d-,l-sotalol, and dofetilide (off-label indication), in conjunction with defibrillator implantation. While amiodarone has superior reduction in arrhythmias, its long-term extracardiac toxicities can cause significant morbidity. A trial of sotalol is reasonable if there are no contraindications, recognizing that over 20% of patients have to discontinue it because of adverse effects. Beta blockers are first line therapy for most patients. Genetic testing is particularly informative regarding treatment approach in long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic VT. Research should continue to focus on developing more effective antiarrhythmic medications with less long-term toxicity.
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Diltiazem vs. Metoprolol in the Management of Atrial Fibrillation or Flutter with Rapid Ventricular Rate in the Emergency Department.
Fromm, C, Suau, SJ, Cohen, V, Likourezos, A, Jellinek-Cohen, S, Rose, J, Marshall, J
The Journal of emergency medicine. 2015;(2):175-82
Abstract
BACKGROUND Diltiazem (calcium channel blocker) and metoprolol (beta-blocker) are both commonly used to treat atrial fibrillation/flutter (AFF) in the emergency department (ED). However, there is considerable regional variability in emergency physician practice patterns and debate among physicians as to which agent is more effective. To date, only one small prospective, randomized trial has compared the effectiveness of diltiazem and metoprolol for rate control of AFF in the ED and concluded no difference in effectiveness between the two agents. OBJECTIVE Our aim was to compare the effectiveness of diltiazem with metoprolol for rate control of AFF in the ED. METHODS A convenience sample of adult patients presenting with rapid atrial fibrillation or flutter was randomly assigned to receive either diltiazem or metoprolol. The study team monitored each subject's systolic and diastolic blood pressures and heart rates for 30 min. RESULTS In the first 5 min, 50.0% of the diltiazem group and 10.7% of the metoprolol group reached the target heart rate (HR) of <100 beats per minute (bpm) (p < 0.005). By 30 min, 95.8% of the diltiazem group and 46.4% of the metoprolol group reached the target HR < 100 bpm (p < 0.0001). Mean decrease in HR for the diltiazem group was more rapid and substantial than that of the metoprolol group. From a safety perspective, there was no difference between the groups with respect to hypotension (systolic blood pressure < 90 mm Hg) and bradycardia (HR < 60 bpm). CONCLUSIONS Diltiazem was more effective in achieving rate control in ED patients with AFF and did so with no increased incidence of adverse effects.