Drug-induced atrial fibrillation

Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with severe consequences, including symptoms, haemodynamic instability, increased cardiovascular mortality and stroke. While other arrhythmias such as torsades de pointes and sinus bradycardia are more typically thought of as drug induced, AF may also be precipitated by drug therapy, although ascribing causality to drug-associated AF is more difficult than with other drug-induced arrhythmias. Drug-induced AF is more likely to occur in patients with risk factors and co-morbidities that commonly co-exist with AF, such as advanced age, alcohol consumption, family history of AF, hypertension, thyroid dysfunction, sleep apnoea and heart disease. New-onset AF has been associated with cardiovascular drugs such as adenosine, dobutamine and milrinone. In addition, medications such as corticosteroids, ondansetron and antineoplastic agents such as paclitaxel, mitoxantrone and doxorubicin have been reported to induce AF. Whether bisphosphonate drugs are associated with new-onset AF remains controversial and requires further study. The potential contribution of specific drug therapy should be considered when patients present with new-onset AF

Neurohormonal Regulation of IKs in Heart Failure: Implications for Ventricular Arrhythmogenesis and Sudden Cardiac Death

Heart failure (HF) results in sustained alterations in neurohormonal signaling, including enhanced signaling through the sympathetic nervous system and renin-angiotensin-aldosterone system pathways. While enhanced sympathetic nervous system and renin-angiotensin-aldosterone system activity initially help compensate for the failing myocardium, sustained signaling through these pathways ultimately contributes to HF pathophysiology. HF remains a leading cause of mortality, with arrhythmogenic sudden cardiac death comprising a common mechanism of HF-related death. The propensity for arrhythmia development in HF occurs secondary to cardiac electrical remodeling that involves pathological regulation of ventricular ion channels, including the slow component of the delayed rectifier potassium current, that contribute to action potential duration prolongation. To elucidate a mechanistic explanation for how HF-mediated electrical remodeling predisposes to arrhythmia development, a multitude of investigations have investigated the specific regulatory effects of HF-associated stimuli, including enhanced sympathetic nervous system and renin-angiotensin-aldosterone system signaling, on the slow component of the delayed rectifier potassium current. The objective of this review is to summarize the current knowledge related to the regulation of the slow component of the delayed rectifier potassium current in response to HF-associated stimuli, including the intracellular pathways involved and the specific regulatory mechanisms

Influence of Zoledronic Acid on Atrial Electrophysiological Parameters and Electrocardiographic Measurements

INTRODUCTION: Our objective was to determine effects of zoledronic acid (ZA) on atrial electrophysiological parameters and electrocardiographic measurements. METHODS AND RESULTS: Ex vivo perfusion study: Isolated guinea pig hearts were perfused with modified Krebs-Henseleit (K-H) buffer with or without ZA 0.07 mg/kg/L (each n = 6). In ZA-perfused hearts, atrial action potential at 90% repolarization (APD90 ) decreased more from baseline than in controls (-23.2% ± -5.1% vs. -2.1% ± -8.1%, P < 0 .0001), as did APD30 (-28.8% ± -3.8% vs. -2.1% ± -2.1%, P < 0.0001). In vivo dose-response study: Guinea pigs underwent intraperitoneal injections every 2 weeks in 1 of 4 groups (each n = 8): ZA 0.007 mg/kg (low-dose), ZA 0.07 mg/kg (medium-dose), ZA 0.7 mg/kg (high-dose), or placebo. Hearts were excised at 8 weeks and perfused with modified K-H. Atrial effective refractory period (ERP) was lower with medium- and high-dose ZA versus placebo (P = 0.004). Atrial APD30 was lower with high-dose ZA versus placebo, low and medium doses (P < 0.001). Canine ECG study: Mature female beagles received intravenous ZA 0.067 mg/kg or saline (placebo; each n = 6) every 2 weeks for 12 weeks. P wave dispersion was greater in the ZA group (7.7 ± 3.7 vs. 3.4 ± 2.6 ms, P = 0.04). There were no significant differences in P wave index, maximum or minimum P wave duration, or PR interval. CONCLUSION: ZA shortens left atrial APD and ERP and increases P wave dispersion

Influence of Oral Progesterone Administration on Drug-Induced QT Interval Lengthening: A Randomized, Double-Blind, Placebo-Controlled Crossover Study

Objectives We tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening. Background Evidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. Methods In this prospective, double-blind, crossover study, 19 healthy female volunteers (21-40 years) were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 49 days). On day 7, ibutilide 0.003 mg/kg was infused over 10 minutes, after which QT intervals were recorded and blood samples collected for 12 hours. Prior to the treatment phases, subjects underwent ECG monitoring for 12 hours to calculate individualized heart rate-corrected QT intervals (QTcI). Results Fifteen subjects completed all study phases. Maximum serum ibutilide concentrations in the progesterone and placebo phases were similar (1247±770 vs 1172±709 pg/mL, p=0.43). Serum progesterone concentrations were higher during the progesterone phase (16.2±11.0 vs 1.2±1.0 ng/mL, p<0.0001), while serum estradiol concentrations in the two phases were similar (89.3±62.8 vs 71.8±31.7 pg/mL, p=0.36). Pre-ibutilide lead II QTcI was significantly lower in the progesterone phase (412±15 vs 419±14 ms, p=0.04). Maximum ibutilide-associated QTcI (443±17 vs 458±19 ms, p=0.003), maximum percent increase in QTcI from pretreatment value (7.5±2.4 vs 9.3±3.4%, p=0.02) and area under the effect (QTcI) curve during the first hour post-ibutilide (497±13 vs 510±16 ms-hr, p=0.002) were lower during the progesterone phase. Progesterone-associated adverse effects included fatigue/malaise and vertigo. Conclusions Oral progesterone administration attenuates drug-induced QTcI lengthening

Effectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patients

BACKGROUND: We evaluated the effectiveness of a computer clinical decision support system (CDSS) for reducing the risk of QT interval prolongation in hospitalized patients. METHODS AND RESULTS: We evaluated 2400 patients admitted to cardiac care units at an urban academic medical center. A CDSS incorporating a validated risk score for QTc prolongation was developed and implemented using information extracted from patients' electronic medical records. When a drug associated with torsades de pointes was prescribed to a patient at moderate or high risk for QTc interval prolongation, a computer alert appeared on the screen to the pharmacist entering the order, who could then consult the prescriber on alternative therapies and implement more intensive monitoring. QTc interval prolongation was defined as QTc interval >500 ms or increase in QTc of ≥60 ms from baseline; for patients who presented with QTc >500 ms, QTc prolongation was defined solely as increase in QTc ≥60 ms from baseline. End points were assessed before (n=1200) and after (n=1200) implementation of the CDSS. CDSS implementation was independently associated with a reduced risk of QTc prolongation (adjusted odds ratio, 0.65; 95% confidence interval, 0.56-0.89; P<0.0001). Furthermore, CDSS implementation reduced the prescribing of noncardiac medications known to cause torsades de pointes, including fluoroquinolones and intravenous haloperidol (adjusted odds ratio, 0.79; 95% confidence interval, 0.63-0.91; P=0.03). CONCLUSIONS: A computer CDSS incorporating a validated risk score for QTc prolongation influences the prescribing of QT-prolonging drugs and reduces the risk of QTc interval prolongation in hospitalized patients with torsades de pointes risk factors

1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP-glucuronosyltransferases 1A8 and 1A10

Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1-alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT-116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity

Calcium/Calmodulin-Dependent Protein Kinase II Regulation of IKs during Sustained Beta-Adrenergic Receptor Stimulation

Background Sustained β-adrenergic receptor (β-AR) stimulation causes pathophysiological changes during heart failure (HF), including inhibition of the slow component of the delayed rectifier potassium current (IKs). Aberrant calcium handling, including increased activation of calcium/calmodulin-dependent protein kinase II (CaMKII), contributes to arrhythmia development during HF. Objective The purpose of this study was to investigate CaMKII regulation of KCNQ1 (pore-forming subunit of IKs) during sustained β-AR stimulation and associated functional implications on IKs. Methods KCNQ1 phosphorylation was assessed using LCMS/MS after sustained β-AR stimulation with isoproterenol (ISO). Peptide fragments corresponding to KCNQ1 residues were synthesized to identify CaMKII phosphorylation at the identified sites. Dephosphorylated (alanine) and phosphorylated (aspartic acid) mimics were introduced at identified residues. Whole-cell, voltage-clamp experiments were performed in human endothelial kidney 293 cells coexpressing wild-type or mutant KCNQ1 and KCNE1 (auxiliary subunit) during ISO treatment or lentiviral δCaMKII overexpression. Results Novel KCNQ1 carboxy-terminal sites were identified with enhanced phosphorylation during sustained β-AR stimulation at T482 and S484. S484 peptides demonstrated the strongest δCaMKII phosphorylation. Sustained β-AR stimulation reduced IKs activation (P = .02 vs control) similar to the phosphorylated mimic (P = .62 vs sustained β-AR). Individual phosphorylated mimics at S484 (P = .04) but not at T482 (P = .17) reduced IKs function. Treatment with CN21 (CaMKII inhibitor) reversed the reductions in IKs vs CN21-Alanine control (P < .01). δCaMKII overexpression reduced IKs similar to ISO treatment in wild type (P < .01) but not in the dephosphorylated S484 mimic (P = .99). Conclusion CaMKII regulates KCNQ1 at S484 during sustained β-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF

Novel associations between CYP2B6 polymorphisms, perioperative methadone metabolism and clinical outcomes in children

Aim: Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics. Methods: This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV). Results:CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadone metabolism compared with normal/rapid metabolizers. The incidence of PONV was 4.7× greater with CYP2B6 rs1038376 variant. AG/GG variants of rs2279343 SNP had 2.86-fold higher incidence of PONV compared with the wild variant (AA). Nominal associations between rs10500282, rs11882424, rs4803419 and pain scores were observed. Conclusion: We have described novel associations between CYP2B6 genetic variants and perioperative methadone metabolism, and associations with pain scores and PONV

Efavirenz inhibits the human ether-a-go-go related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele carriers

Background Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. Objective The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. Methods EFV was administered to healthy volunteers (n=57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. Results EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ΔΔQTcF were observed at 6 hrs (14 ms; 95% CI [1; 27]), 12 hrs (18 ms; 95% CI [−4; 40] and 18 hrs (6 ms; 95% CI [−1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 µg/mL significantly inhibited outward hERG tail currents (P<0.05). Conclusions This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG