-
1.
Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan.
Juif, PE, Dingemanse, J, Voors-Pette, C, Ufer, M
The AAPS journal. 2020;(5):103
Abstract
This study investigated the potential QT liability of the selective endothelin-1 A receptor antagonist clazosentan at a therapeutic (20 mg/h) and supratherapeutic (60 mg/h) intravenous (i.v.) dose. A randomized, placebo- and moxifloxacin-controlled, double-blind, 3-period, crossover study was conducted in 36 healthy subjects receiving clazosentan (20 mg/h followed by 60 mg/h i.v. for 3 h each), placebo (i.v. for 6 h), and moxifloxacin (single oral dose of 400 mg concomitantly with placebo i.v. for 6 h). At least three replicate ECGs were extracted from Holter recordings at predefined time points from 1 h pre-dose to 24 h after end of infusion. Pharmacokinetic blood sampling was performed for concentration/QT analysis (primary endpoint). For moxifloxacin, the lower bound of the 90% confidence interval (CI) of baseline- and placebo-corrected QTcF (ΔΔQTcF) was > 5 ms at its maximum plasma concentration together with a positive slope of the concentration/QT regression line demonstrating assay sensitivity. For clazosentan, time of peak exposure preceded maximum ΔΔQTcF by 4 h indicating delayed QT-prolonging effects leading to invalidity of the concentration/QT analysis. The secondary by-time-point analysis revealed QT liability of clazosentan (i.e., upper bound of 90% CI ∆∆QTcF > 10 ms). Delayed QT prolongation (i.e., hysteresis) was predominantly observed in subjects with nausea and vomiting, potentially caused by vagal reaction and/or decreases in potassium concentration. By contrast, there was no association with other adverse events, food intake, or concomitant medication. In conclusion, clazosentan at therapeutic and supratherapeutic doses has QT liability with hysteresis effects being associated with nausea and vomiting.
-
2.
Contemporary Management of Electrical Storm.
Geraghty, L, Santangeli, P, Tedrow, UB, Shivkumar, K, Kumar, S
Heart, lung & circulation. 2019;(1):123-133
Abstract
Cardiac electrical storm (ES) is characterised by three or more discrete episodes of ventricular arrhythmia within 24hours, or incessant ventricular arrhythmia for more than 12hours. ES is a distinct medical emergency that portends a significant increase in mortality risk and often presages progressive heart failure. ES is also associated with psychological morbidity from multiple implanted cardioverter defibrillator (ICD) shocks and exponential health resource utilisation. Up to 30% of ICD recipients may experience storm in follow-up, with the risk higher in patients with a secondary prevention ICD indication. Storm recurs in a high proportion of patients after an initial episode, and multiple storm clusters may occur in follow-up. The mechanism of storm remains elusive but is likely influenced by a complex interplay of inciting triggers (e.g., ischaemia, electrolyte disturbances), with autonomic perturbations acting on a vulnerable structural and electrophysiologic substrate. Triggers can be identified only in a minority of patients. An emergent treatment approach is warranted, if possible with emergent transfer to a high-volume centre for ventricular arrhythmia management with a multi-modality approach including ICD reprogramming, sympathetic blockade (sedation, intubation, ventilation, beta blockers), and anti-arrhythmic drugs, and adjunctive intervention techniques, such as catheter ablation and neuraxial modulation (e.g., thoracic epidural anaesthesia, stellate ganglion block). Outcomes of catheter ablation of ES are excellent with resolution of storm in over 90% of patients at 1year with a low complication rate (∼2%). ES may occur in the absence of structural heart disease in the context of channelopathies, Brugada syndrome, early repolarisation and premature ventricular contraction-induced ventricular fibrillation. There are unique treatment approaches to these conditions that must be recognised. This state-of-the-art review will summarise the incidence, mechanism, and multi-modality treatment of ES in the contemporary era.
-
3.
ST segment depression on 24-hour electrocardiography predicts incident atrial fibrillation in two population-based cohorts.
Johnson, LSB, Berntsson, J, Juhlin, T, Healey, JS, Juul-Möller, S, Wollmer, P, Nilsson, PM, Hedblad, B, Rosenqvist, M, Engström, G
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2018;(3):429-434
Abstract
AIMS: ST-depression at 24hECG has not been studied in relation to atrial fibrillation (AF) risk. We aimed to determine whether ST-depression at 24hECG was associated with incident AF in two Swedish population-based cohorts - a sub-cohort of the Malmö Diet and Cancer study (MDCS), and the cohort 'Men born in 1914', and to determine whether 24hECG could be used to predict AF development. METHODS AND RESULTS There were 378 acceptable 24hECG recordings in the MDCS (mean age 64.5 years, 43% men) and 394 acceptable recordings in 'Men born in 1914' (mean age 68.8 years). Incidence of AF was monitored using national registers of hospitalizations and outpatient visits in Sweden. Mean follow-up ± SD (cumulative incidence) was 10.4 ± 2 years (11.3%) in MDCS, and 10.9 ± 4 years (7.3%) in 'Men born in 1914'. ST-depressions were independently associated with incident AF; hazard ratio (HR) (95% CI) 2.41 (1.29-4.50, P = 0.006) and 2.28 (1.05-4.95, P = 0.038) after adjustment [age, sex, height, weight, systolic blood pressure, smoking, anti-hypertensive drugs, LDL/total cholesterol, and HOMA-IR (in MDCS)]. AF incidence was substantially lower in individuals who had neither ST-depressions or high supraventricular activity (SVA, negative predictive value 0.97 and 0.94, in MDCS and 'Men born in 1914', respectively), and similar in men and women. CONCLUSION ST-depression at 24h-ECG is independently associated with incident AF, and incidence is substantially lower in individuals with neither ST-depression or high SVA. 24hECG can be used not only to diagnose AF but also to identify individuals at high and low AF risk.
-
4.
Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.
Giudicessi, JR, Roden, DM, Wilde, AAM, Ackerman, MJ
Circulation. 2018;(6):619-630
-
-
Free full text
-
Abstract
The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues.
-
5.
Effect of oral fluconazole 1200 mg/day on QT interval in African adults with HIV-associated cryptococcal meningitis.
Molloy, SF, Bradley, J, Karunaharan, N, Mputu, M, Stone, N, Phulusa, J, Chawinga, C, Gaskell, K, Segula, D, Ming, D, et al
AIDS (London, England). 2018;(15):2259-2261
-
-
Free full text
-
Abstract
: We assessed the effect of fluconazole 1200 mg/day on the QT interval in cryptococcal meningitis patients. Mean corrected QT (QTc) change from baseline to day 7 was 10.1 ms (IQR: -28 to 46 ms) in the fluconazole treatment group and -12.6 ms (IQR: -39 to 13.5 ms) in those not taking fluconazole (P = 0.04). No significant increase in QTc measurements over 500 ms was observed with fluconazole. Nevertheless, it remains important to correct any electrolyte imbalance and avoid concomitant drugs that may increase QTc.
-
6.
Predictors of mortality in high-risk patients with QT prolongation in a community hospital.
Gibbs, C, Thalamus, J, Heldal, K, Holla, ØL, Haugaa, KH, Hysing, J
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2018;(FI1):f99-f107
Abstract
AIMS: To determine predictors of mortality in patients with corrected QT interval (QTc) ≥ 500 ms in a community hospital. METHODS AND RESULTS In this retrospective observational study, we searched the electrocardiogram (ECG) database at Telemark Hospital Trust, Norway, from January 2004 to December 2014. Medication, electrolyte abnormalities, and medical conditions known to prolong the QT interval were recorded. From the medical records, we assessed whether the prolonged QTc was noted by the health care providers. We identified 1531 patients (age = 70 ± 15 years, 59% female) with an ECG with QTc ≥ 500 ms. All-cause mortality during 952 (range 0-4161) days of follow-up was 50% (n = 765/1531). Main predictors of mortality were aborted cardiac arrest [hazard ratio (HR) 2.40, 95% confidence interval (CI) 1.44-4.01; P = 0.001], cerebral stroke/head trauma (HR 2.28, 95% CI 1.70-3.05; P < 0.001), and heart failure (HR 1.74, 95% CI 1.43-2.12; P< 0.001). Females with prolonged QTc had better survival compared with males (P = 0.006). We constructed a risk-weighted QTc mortality score. QT prolongation was acknowledged in the medical records in 12% of the cases. CONCLUSIONS QTc ≥ 500 ms was associated with high all-cause mortality with increased mortality in males compared with females. A new QTc mortality score was constructed to predict mortality. Only a minority of cases with prolonged QTc ≥ 500 ms were acknowledged in the medical records.
-
7.
Atrial Fibrillation: Epidemiology, Pathophysiology, and Clinical Outcomes.
Staerk, L, Sherer, JA, Ko, D, Benjamin, EJ, Helm, RH
Circulation research. 2017;(9):1501-1517
-
-
Free full text
-
Abstract
The past 3 decades have been characterized by an exponential growth in knowledge and advances in the clinical treatment of atrial fibrillation (AF). It is now known that AF genesis requires a vulnerable atrial substrate and that the formation and composition of this substrate may vary depending on comorbid conditions, genetics, sex, and other factors. Population-based studies have identified numerous factors that modify the atrial substrate and increase AF susceptibility. To date, genetic studies have reported 17 independent signals for AF at 14 genomic regions. Studies have established that advanced age, male sex, and European ancestry are prominent AF risk factors. Other modifiable risk factors include sedentary lifestyle, smoking, obesity, diabetes mellitus, obstructive sleep apnea, and elevated blood pressure predispose to AF, and each factor has been shown to induce structural and electric remodeling of the atria. Both heart failure and myocardial infarction increase risk of AF and vice versa creating a feed-forward loop that increases mortality. Other cardiovascular outcomes attributed to AF, including stroke and thromboembolism, are well established, and epidemiology studies have championed therapeutics that mitigate these adverse outcomes. However, the role of anticoagulation for preventing dementia attributed to AF is less established. Our review is a comprehensive examination of the epidemiological data associating unmodifiable and modifiable risk factors for AF and of the pathophysiological evidence supporting the mechanistic link between each risk factor and AF genesis. Our review also critically examines the epidemiological data on clinical outcomes attributed to AF and summarizes current evidence linking each outcome with AF.
-
8.
Predictors of permanent pacemaker implantation after transfemoral aortic valve implantation with the Lotus valve.
Keßler, M, Gonska, B, Seeger, J, Rottbauer, W, Wöhrle, J
American heart journal. 2017;:57-63
Abstract
BACKGROUND Permanent pacemaker implantation (PPMI) after transcatheter aortic valve implantation is of high clinical relevance, but PPMI rates differ widely between valve types. Although the Lotus valve can be repositioned, reported rates for PPMI are high. The predictors of PPMI after Lotus valve implantation have not been defined yet. METHODS We analyzed the impact of preexisting conduction disturbances, depth of implantation, oversizing, and amount of calcification on PPMI in 216 patients with severe symptomatic aortic stenosis underdoing Lotus valve implantation. RESULTS PPMI was required in 39.8% of patients. Patients with need for PPMI compared with patients without need for PPMI had more often the following criteria: male gender (P=.035); preprocedural right bundle-branch block (RBBB) (16.3% vs 0, P<.001); atrioventricular (AV) block first degree (26.7% vs 10.1%, P=.004); higher calcium volume of the left coronary cusp (63.1±87.5 mm3 vs 42.8±49.3 mm3, P=.05); and deeper valve implantation at right coronary (P=.011), noncoronary (P=.026), and left coronary (P=.012) position. Oversizing in relation to annulus and left ventricular outflow tract did not have an impact on need for PPMI. By multiple regression analysis, preprocedural AV block first degree (P=.005), RBBB (P<.001), and depth of implantation (P=.006) were independent risk factors for need of PPMI. CONCLUSIONS In patients with severe aortic stenosis receiving transfemoral Lotus valve, preexisting AV block first degree, RBBB, and implantation depth are independent predictors of PPMI, highlighting the importance of careful valve positioning.
-
9.
Normal Ventricular Repolarization and QT Interval: Ionic Background, Modifiers, and Measurements.
Locati, ET, Bagliani, G, Padeletti, L
Cardiac electrophysiology clinics. 2017;(3):487-513
Abstract
The QT interval on surface electrocardiogram represents the sum of depolarization and repolarization process of the ventricles. The ventricular recovery process, reflected by ST segment and T wave, mainly depends on the transmembrane outward transport of potassium ions to reestablish the endocellular electronegativity. Outward potassium channels represent a heterogeneous family of ionic carriers, whose global kinetics is modulated by heart rate and autonomic nervous activity. Several cardiac and noncardiac drugs and disease conditions, and several mutations of genes encoding ionic channels, generating distinct genetic channellopathies, may affect the ventricular repolarization, provoke QT interval prolongation and shortening, and increase the susceptibility to ventricular arrhythmias.
-
10.
In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human atrial arrhythmogenesis.
Colman, MA, Ni, H, Liang, B, Schmitt, N, Zhang, H
PLoS computational biology. 2017;(6):e1005587
Abstract
A recent experimental study investigating patients with lone atrial fibrillation identified six novel mutations in the KCNA5 gene. The mutants exhibited both gain- and loss-of-function of the atrial specific ultra-rapid delayed rectifier K+ current, IKur. The aim of this study is to elucidate and quantify the functional impact of these KCNA5 mutations on atrial electrical activity. A multi-scale model of the human atria was updated to incorporate detailed experimental data on IKur from both wild-type and mutants. The effects of the mutations on human atrial action potential and rate dependence were investigated at the cellular level. In tissue, we assessed the effects of the mutations on the vulnerability to unidirectional conduction patterns and dynamics of re-entrant excitation waves. Gain-of-function mutations shortened the action potential duration in single cells, and stabilised and accelerated re-entrant excitation in tissue. Loss-of-function mutations had heterogeneous effects on action potential duration and promoted early-after-depolarisations following beta-adrenergic stimulation. In the tissue model, loss-of-function mutations facilitated breakdown of excitation waves at more physiological excitation rates than the wild-type, and the generation of early-after-depolarisations promoted unidirectional patterns of excitation. Gain- and loss-of-function IKur mutations produced multiple mechanisms of atrial arrhythmogenesis, with significant differences between the two groups of mutations. This study provides new insights into understanding the mechanisms by which mutant IKur contributes to atrial arrhythmias. In addition, as IKur is an atrial-specific channel and a number of IKur-selective blockers have been developed as anti-AF agents, this study also helps to understand some contradictory results on both pro- and anti-arrhythmic effects of blocking IKur.