The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
BACKGROUND - Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) compared with other ADTs.
AIM - To determine if abiraterone was associated with an increased proportion of AT and HF reports among all suspected adverse drug reactions (ADRs) reported in several pharmacovigilance databases compared with enzalutamide, other ADTs and all other drugs.
METHODS - In this observational retrospective pharmacovigilance study, we performed a disproportionality analysis of reports of suspected ADRs in men in the French pharmacovigilance database, the European pharmacovigilance database and the international pharmacovigilance database VigiBase, to evaluate the reporting odds ratios (RORs) of AT and HF for abiraterone compared with enzalutamide, other ADTs and all other drugs.
RESULTS - In the 5,759,781 ADR reports in men in VigiBase, 55,070 pertained to ADTs. The RORs for AT for abiraterone versus enzalutamide, other ADTs and all other drugs were 4.1 (95% confidence interval 3.1-5.3), 3.7 (3-4.5) and 3.2 (2.7-3.7), respectively (P<0.0001 for all). The corresponding RORs for HF were 2.5 (2-3), 1.5 (1.3-1.7) and 2 (1.7-2.3), respectively (P<0.0001 for all). These results were concordant with the French and European pharmacovigilance databases. Mean times to AT and HF onset were shorter with abiraterone (5.2±0.8 and 4.5±0.6 months, respectively) versus other ADTs (13.3±3.2 and 9.2±1.1 months, respectively) (both P<0.05). Cases on abiraterone versus other ADTs were more frequently associated with at least two ADR terms, including AT, HF, hypokalaemia, hypertension and oedema (13.6% vs 6%; P<0.0001). For abiraterone, age, but not dose, was associated with reporting of AT and HF versus any other ADR.
CONCLUSIONS - Compared with other ADTs, abiraterone was associated with higher reporting of AT and HF, associated with hypokalaemia, hypertension and oedema. These findings are consistent with the hypermineralocorticism induced by abiraterone, but not by other ADTs.
Copyright © 2019 Elsevier Masson SAS. All rights reserved.
Importance - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with β-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release-the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively.
Objective - To determine whether flecainide dosed to therapeutic levels and added to β-blocker therapy is superior to β-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT.
Design, Setting, and Participants - This investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated β-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing.
Interventions - Patients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels.
Main Outcomes and Measures - The primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia).
Results - Of 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0-4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms.
Conclusions and Relevance - In this randomized clinical trial of patients with CPVT, flecainide plus β-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus β-blocker and β-blocker alone.
Trial Registration - clinicaltrials.gov Identifier: NCT01117454.
BACKGROUND - Calmodulin (CaM) mutations are associated with severe forms of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). CaM mutations are found in 13% of genotype-negative long QT syndrome patients, but the prevalence of CaM mutations in genotype-negative CPVT patients is unknown. Here, we identify and characterize CaM mutations in 12 patients with genotype-negative but clinically diagnosed CPVT.
METHODS AND RESULTS - We performed mutational analysis of CALM1, CALM2, and CALM3 gene-coding regions, in vitro measurement of CaM-Ca(2+) (Ca)-binding affinity, ryanodine receptor 2-CaM binding, Ca handling, L-type Ca current, and action potential duration. We identified a novel CaM mutation-A103V-in CALM3 in 1 of 12 patients (8%), a female who experienced episodes of exertion-induced syncope since age 10, had normal QT interval, and displayed ventricular ectopy during stress testing consistent with CPVT. A103V modestly lowered CaM Ca-binding affinity (3-fold reduction versus WT-CaM), but did not alter CaM binding to ryanodine receptor 2. In permeabilized cardiomyocytes, A103V-CaM (100 nmol/L) promoted spontaneous Ca wave and spark activity, a cellular phenotype of ryanodine receptor 2 activation. Even a 1:3 mixture of A103V-CaM:WT-CaM activated Ca waves, demonstrating functional dominance. Compared with long QT syndrome D96V-CaM, A103V-CaM had significantly less effects on L-type Ca current inactivation, did not alter action potential duration, and caused delayed afterdepolarizations and triggered beats in intact cardiomyocytes.
CONCLUSIONS - We discovered a novel CPVT mutation in the CALM3 gene that shares functional characteristics with established CPVT-associated mutations in CALM1. A small proportion of A103V-CaM is sufficient to evoke arrhythmogenic Ca disturbances via ryanodine receptor 2 dysregulation, which explains the autosomal dominant inheritance.
© 2016 American Heart Association, Inc.
AIMS - Postural Tachycardia Syndrome (POTS) represents an autonomic disorder predominantly affecting females between 15 and 50 years of age. POTS is a chronic disorder (>6 months) characterized by an excessive heart rate increment on standing (>30 beats/min) in the presence of characteristic symptoms of cerebral hypoperfusion or sympathetic activation. Patients have clinically been noted to describe lower urinary tract symptoms (LUTS), although urologic symptoms have not been methodically assessed in the POTS population. Herein, we present data from a pilot study designed to identify and quantitate overactive bladder (OAB) in patients diagnosed with POTS.
METHODS - Patients admitted to the Vanderbilt Autonomic Dysfunction Center between June 2009 and October 2010 for evaluation for the potential diagnosis of POTS completed a validated, standardized questionnaire for OAB (OAB-q) at presentation. Symptom score and subscale analyses were conducted. Subscale health related quality of life (HRQL) scores were transformed into a 0-100 scale, with higher scores reflecting superior HRQL. Data are presented as mean ± SD.
RESULTS - Thirty-two females presented for evaluation of symptoms consistent with POTS. Twenty-nine women were subsequently diagnosed with POTS with 19 of these patients completing the OAB-q questionnaire (65.5% response rate). Average age was 33.5 ± 8.3 years. Symptom severity transformed score was 26.0 ± 16.4, with 13 of 19 patients (68.4%) meeting clinical criteria for diagnosis of probable clinically significant OAB. Nocturia was the most bothersome symptom, followed by increased daytime frequency and urgency.
CONCLUSIONS - This pilot study describes bothersome lower urinary tract dysfunction in patients presenting with POTS as assessed by patient-reported questionnaire data. Nocturia demonstrated the greatest negative impact on health-related quality of life (HRQL), while social interaction was the least affected HRQL domain. In patients with dysautonomia, this data provides a critical baseline for mechanistic insight into both disease-specific and global pathophysiology of nocturia and OAB. Neurourol. Urodynam. 36:610-613, 2017. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
BACKGROUND - Dexmedetomidine is commonly used after congenital heart surgery and may be associated with a decreased incidence of postoperative tachyarrhythmias. Using a large cohort of patients undergoing congenital heart surgery, we examined for an association between dexmedetomidine use in the immediate postoperative period and subsequent arrhythmia development.
METHODS AND RESULTS - A total of 1593 surgical procedures for congenital heart disease were performed. Dexmedetomidine was administered in the immediate postoperative period after 468 (29%) surgical procedures. When compared with 1125 controls, the group receiving dexmedetomidine demonstrated significantly fewer tachyarrhythmias (29% versus 38%; P<0.001), tachyarrhythmias receiving intervention (14% versus 23%; P<0.001), bradyarrhythmias (18% versus 22%; P=0.03), and bradyarrhythmias receiving intervention (12% versus 16%; P=0.04). After propensity score matching with 468 controls, the arrhythmia incidence between groups became similar: tachyarrhythmias (29% versus 31%; P=0.66), tachyarrhythmias receiving intervention (14% versus 17%; P=0.16), bradyarrhythmias (18% versus 15%; P=0.44), and bradyarrhythmias receiving intervention (12% versus 9%; P=0.17). After excluding controls exposed to dexmedetomidine at a later time in the hospitalization, dexmedetomidine was associated with increased odds of bradyarrhythmias receiving intervention (odds ratio, 2.18; 95% confidence interval, 1.02-4.65). Furthermore, there was a dose-dependent increase in the odds of bradyarrhythmias (odds ratio, 1.04; 95% confidence interval, 1.01-1.07) and bradyarrhythmias receiving intervention (odds ratio, 1.05; 95% confidence interval, 1.01-1.08).
CONCLUSIONS - Although dexmedetomidine exposure in the immediate postoperative period is not associated with a clinically meaningful difference in the incidence of tachyarrhythmias after congenital heart surgery, it may be associated with increased odds of bradyarrhythmias.
© 2015 American Heart Association, Inc.
BACKGROUND - Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2), 1q21 (rs13376333 in KCNN3), and 16q22 (rs7193343 in ZFHX3) have consistently been associated with the risk of atrial fibrillation (AF). Single-center studies have shown that 4q25 risk alleles predict recurrence of AF after catheter ablation of AF. Here, we performed a meta-analysis to test the hypothesis that these 4 AF susceptibility SNPs modulate response to AF ablation.
METHODS AND RESULTS - Patients underwent de novo AF ablation between 2008 and 2012 at Vanderbilt University, the Heart Center Leipzig, and Massachusetts General Hospital. The primary outcome was 12-month recurrence, defined as an episode of AF, atrial flutter, or atrial tachycardia lasting >30 seconds after a 3-month blanking period. Multivariable analysis of the individual cohorts using a Cox proportional hazards model was performed. Summary statistics from the 3 centers were analyzed using fixed effects meta-analysis. A total of 991 patients were included (Vanderbilt University, 245; Heart Center Leipzig, 659; and Massachusetts General Hospital, 87). The overall single procedure 12-month recurrence rate was 42%. The overall risk allele frequency for these SNPs ranged from 12% to 35%. Using a dominant genetic model, the 4q25 SNP, rs2200733, predicted a 1.4-fold increased risk of recurrence (adjusted hazard ratio,1.3 [95% confidence intervals, 1.1-1.6]; P=0.011). The remaining SNPs, rs10033464 (4q25), rs13376333 (1q21), and rs7193343 (16q22) were not significantly associated with recurrence.
CONCLUSIONS - Among the 3 genetic loci most strongly associated with AF, the chromosome 4q25 SNP rs2200733 is significantly associated with recurrence of atrial arrhythmias after catheter ablation for AF.
© 2015 American Heart Association, Inc.
Atrial fibrillation (AF) is the most common sustained arrhythmia disease. Current drug- and surgical-based therapies are ineffective in about 40% to 50% of AF patients; therefore, there is a great need to better understand the underlying mechanisms of this disease and identify potential therapeutic targets. In this issue of the JCI, Greiser and coworkers discovered that atrial remodeling in response to sustained tachycardia silences Ca2+ signaling in isolated rabbit and human atrial myocytes. This Ca2+ release silencing was attributable to a failure of subcellular propagated Ca2+ release due to an increased cytosolic buffering strength. The results from this study challenge the current paradigm that Ca2+ release instability underlies AF. Instead, Ca2+ silencing could be protective against the massive cellular Ca2+ loading that occurs during chronic AF.
BACKGROUND - Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations.
METHODS AND RESULTS - We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.
CONCLUSIONS - CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
© 2014 American Heart Association, Inc.
Postural tachycardia syndrome (POTS) is characterized by excessive increases in heart rate (HR) upon standing. Previous studies have shown that standing HR decreases over time in POTS patients given placebo. We hypothesized that this reduction is due to cardiovascular physiological alteration, as opposed to psychological benefit from perceived therapy. To prospectively test this hypothesis, we examined the effects of an open-label 'no treatment' intervention (NoRx) compared with a patient-blinded placebo on standing HR in POTS patients. Twenty-one POTS patients participated in a randomized cross-over trial with oral placebo versus NoRx administered at 0900 h. Seated blood pressure (BP) and HR were measured at baseline and every hour for 4 h. Similarly, BP and HR were measured while patients stood for 10 min at these time points. Standing HR decreased significantly over time with both NoRx (112±13 and 103±16 b.p.m. at baseline and 4 h, respectively) and placebo (112±14 and 102±16 b.p.m. at baseline and 4 h, respectively; Ptime<0.001), but this effect was not different between interventions (Pdrug=0.771). Postural tachycardia syndrome patients have exaggerated orthostatic tachycardia in the morning that decreases over time with either placebo or NoRx interventions, suggesting this phenomenon is due to cardiovascular physiological variation. These data highlight the need for a placebo arm in haemodynamic clinical trials in POTS and may have important implications for the diagnosis of these patients.
© 2014 Wiley Publishing Asia Pty Ltd.