Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation.

BACKGROUND: QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years. OBJECTIVES: Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs. METHODS: 1.8 million adverse event reports were mined for signals indicating a QT-DDI. Using 1.6 million electrocardiogram results from 380,000 patients in our institutional EHR, these putative interactions were either refuted or corroborated. In the laboratory, we used patch-clamp electrophysiology to measure the human ether-à-go-go-related gene (hERG) channel block (the primary mechanism by which drugs prolong the QT interval) to evaluate our top candidate. RESULTS: Both direct and indirect signals in the adverse event reports provided evidence that the combination of ceftriaxone (a cephalosporin antibiotic) and lansoprazole (a proton-pump inhibitor) will prolong the QT interval. In the EHR, we found that patients taking both ceftriaxone and lansoprazole had significantly longer QTc intervals (up to 12 ms in white men) and were 1.4 times more likely to have a QTc interval above 500 ms. In the laboratory, we found that, in combination and at clinically relevant concentrations, these drugs blocked the hERG channel. As a negative control, we evaluated the combination of lansoprazole and cefuroxime (another cephalosporin), which lacked evidence of an interaction in the adverse event reports. We found no significant effect of this pair in either the EHR or in the electrophysiology experiments. Class effect analyses suggested this interaction was specific to lansoprazole combined with ceftriaxone but not with other cephalosporins. CONCLUSIONS: Coupling data mining and laboratory experiments is an efficient method for identifying QT-DDIs. Combination therapy of ceftriaxone and lansoprazole is associated with increased risk of acquired long QT syndrome.

Differences in continuous spectra of fractionated electrograms in paroxysmal versus persistent atrial fibrillation.

INTRODUCTION: Quantitative measurements are helpful to discern fractionated electrograms in paroxysmal and persistent atrial fibrillation (AF), and may be useful to detect optimal ablation sites. However, electrical activation events can be transient, leading to erroneous estimates of electrogram properties. Measurement of continuous changes in electrogram frequency content may improve analysis. METHOD: Fractionated local electrograms from 10 paroxysmal and 10 persistent AF patients were acquired from outside the pulmonary vein ostia and left atrial free wall using the distal bipolar ablation catheter electrode, and analyzed over continuous 16 second intervals. A New Spectral Estimator (NSE) updated the frequency spectrum and spectral parameters once per millisecond. The tallest spectral peak (dominant frequency or DF) was determined. Statistical tests of variability were used to determine significant differences between paroxysmal and persistent AF. RESULTS: Changes in the value of the DF over 16 seconds were caused by transient drifts in the frequency of the dominant peak, or by changes in which peak had the highest amplitude. The continuous DF and the spectral profile parameters were more highly variable in paroxysmal as compared with persistent AF patients (p<0.001). There was found to be a gradient from high to low variability of DF in paroxysmal AF, from the left superior pulmonary vein antrum to the left atrial free wall. CONCLUSIONS: The results suggest that atrial electrical activation becomes more stable and focused at a narrow frequency range in persistent as compared to paroxysmal AF. The NSE implemented for continuous update of spectral parameters, enables a rapid characterization of fractionated electrograms with high time-frequency resolution and low computational cost.

Bronchial thermoplasty: Where there is smoke, there is fire.

Bronchial thermoplasty (BT) is the first nonpharmacologic interventional therapy approved by the U.S. Food and Drug Administration in 2010 for severe asthma. This approval was based on randomized sham-controlled trial called Asthma Intervention Research (AIR) 2 published in 2010. BT involves the application of radiofrequency energy to airways with an aim to selectively ablate airway smooth muscle. BT is currently marketed for patients with "severe" asthma. Most practicing clinicians apply this severity category to patients with oral corticosteroid dependence, frequent exacerbations, or a significantly reduced forced expiratory volume in 1 second along with a poor quality of life. Did the patients studied in the AIR-2 trial have these clinical features? Was there a reduction in severe asthma exacerbation achieved in the intervention group? Did any of the primary or secondary end points in the AIR-2 trial show a positive signal? There continues to be controversy regarding patient selection and primary outcome. Its efficacy in the management of the patient with difficult-to-manage asthma is uncertain. This review covered pertinent aspects of BT, the design and results of the AIR-2 trial, and provides the practicing allergist with a comprehensive overview of this therapy.

Atrial electrogram discordance during baseline vs reinduced atrial fibrillation: Potential ramifications for ablation procedures.

BACKGROUND: There are scant data comparing the electrogram (EGM) signal characteristics of atrial fibrillation (AF) at baseline vs electrically induced states during ablation procedures. OBJECTIVE: The purpose of this study was to use novel intracardiac signal analysis techniques to gain insights into the effects of catheter ablation and AF reinduction on AF EGMs in patients with persistent AF. METHODS: We collected left atrial EGMs in patients undergoing first ablation for persistent AF at 3 time intervals: (1) AF at baseline; (2) AF after pulmonary vein isolation (PVI); and (3) AF after post-PVI cardioversion and subsequent reinduction. We analyzed 2 EGM spectral characteristics: (1) dominant frequency and (2) spectral complexity; and 2 EGM morphologic characteristics: (1) morphology variation and (2) pattern repetitiveness. RESULTS: There were no differences in AF dominant frequency, dominant amplitude, spectral complexity, or metrics of EGM morphology or repetitiveness at baseline vs after PVI. However, dominant frequency, dominant amplitude, and spectral complexity differed significantly after direct current cardioversion and reinduction of AF. CONCLUSION: The frequency, spectral complexity, and local EGM morphologies of AF do not significantly change over the course of a PVI procedure in patients with persistent AF. However, reinduction of AF after direct current cardioversion results in different dominant frequency and spectral complexity, consistent with a change in the characteristics of the perpetuating source(s) of the newly induced AF. These data suggest that AF properties can vary significantly between baseline and reinduced AF, with potential clinical ramifications for outcomes of catheter ablation procedures.

KCNE1 alters the voltage sensor movements necessary to open the KCNQ1 channel gate.

The delayed rectifier I(Ks) potassium channel, formed by coassembly of α- (KCNQ1) and ß- (KCNE1) subunits, is essential for cardiac function. Although KCNE1 is necessary to reproduce the functional properties of the native I(Ks) channel, the mechanism(s) through which KCNE1 modulates KCNQ1 is unknown. Here we report measurements of voltage sensor movements in KCNQ1 and KCNQ1/KCNE1 channels using voltage clamp fluorometry. KCNQ1 channels exhibit indistinguishable voltage dependence of fluorescence and current signals, suggesting a one-to-one relationship between voltage sensor movement and channel opening. KCNE1 coexpression dramatically separates the voltage dependence of KCNQ1/KCNE1 current and fluorescence, suggesting an imposed requirement for movements of multiple voltage sensors before KCNQ1/KCNE1 channel opening. This work provides insight into the mechanism by which KCNE1 modulates the I(Ks) channel and presents a mechanism for distinct ß-subunit regulation of ion channel proteins.