Hypogonadism as a Reversible Cause of Torsades de Pointes in Men.
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ABSTRACT:
SUBMITTER: Salem JE
PROVIDER: S-EPMC6053686 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
Publications
Hypogonadism as a Reversible Cause of Torsades de Pointes in Men.
Salem Joe-Elie JE Waintraub Xavier X Courtillot Carine C Shaffer Christian M CM Gandjbakhch Estelle E Maupain Carole C Moslehi Javid J JJ Badilini Fabio F Haroche Julien J Gougis Paul P Fressart Veronique V Glazer Andrew M AM Hidden-Lucet Francoise F Touraine Philippe P Lebrun-Vignes Benedicte B Roden Dan M DM Bachelot Anne A Funck-Brentano Christian C
Circulation 20180701 1
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Project description:Background Systemic inflammation and male hypogonadism are 2 increasingly recognized "nonconventional" risk factors for long-QT syndrome and torsades de pointes (TdP). Specifically, inflammatory cytokines prolong, while testosterone shortens the heart rate-corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men, testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of inflammation on QTc. Methods and Results We investigated (1) the levels of sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C-reactive protein and interleukin-6 levels. Reduction of testosterone levels, which also inversely correlated with 17-β estradiol over time, significantly contributed to inflammation-induced QTc prolongation. In men with TdP, both active systemic inflammation and hypogonadism were frequently present, with significant correlations between C-reactive protein, testosterone, and 17-β estradiol levels; in these patients, increased C-reactive protein and reduced testosterone were associated with a worse short-term outcome of the arrhythmia. Conclusions During systemic inflammatory activation, interleukin-6 elevation is associated with reduced testosterone levels in males, possibly deriving from an enhanced androgen-to-estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased long-QT syndrome/TdP risk in men.
| S-EPMC9075210 | biostudies-literature
Project description: Not available
| S-EPMC1767957 | biostudies-literature
Project description:BackgroundDrugs belonging to diverse therapeutic classes can prolong myocardial refractoriness or slow conduction. These drugs may be effective and well-tolerated, but the risk of sudden cardiac death from torsades de pointes (TdP) remains a major concern. The corrected QT interval has significant limitations when used for risk stratification. Measurement of global electrical heterogeneity (GEH) could help identify the substrate vulnerable to drug-induced ventricular arrhythmias.ObjectiveThe purpose of this study was to improve risk stratification for drug-induced TdP by measuring GEH on the electrocardiogram (ECG).MethodsWe analyzed ECG data from a case-control study of patients with a history of drug-induced TdP as well as age- and sex-matched controls. Vectorcardiograms were constructed from ECGs. GEH was measured via the spatial ventricular gradient (SVG) vector (magnitude, azimuth, and elevation). Log odds coefficients for TdP were estimated using multivariable logistic regression.ResultsAmong 17 cases (47% male; age 58.9 ± 12.5 years) and 17 controls (29% male; age 61.0 ± 12.2 years), 34 ECGs were analyzed. SVG azimuth was significantly different between cases and controls (3.4 vs 22.0 degrees, respectively; P = 0.02). After adjusting for sex and QTc interval, odds of TdP increased by a factor of 3.2 for each 1 SD change in SVG azimuth from the control group mean (95% confidence interval 1.07-9.14; P = .04). QTc was not significant in the multivariable analysis (P = .20).ConclusionSVG azimuth is correlated with a history of drug-induced TdP independent of QTc. GEH measurement may help identify patients at high risk for drug-induced arrhythmias.
| S-EPMC7796973 | biostudies-literature
Project description: Not available
| S-EPMC7793232 | biostudies-literature
Project description:While pre-clinical Torsades de Pointes (TdP) risk classifiers had initially been based on drug-induced block of hERG potassium channels, it is now well established that improved risk prediction can be achieved by considering block of non-hERG ion channels. The current multi-channel TdP classifiers can be categorized into two classes. First, the classifiers that take as input the values of drug-induced block of ion channels (direct features). Second, the classifiers that are built on features extracted from output of the drug-induced multi-channel blockage simulations in the in-silico models (derived features). The classifiers built on derived features have thus far not consistently provided increased prediction accuracies, and hence casts doubt on the value of such approaches given the cost of including biophysical detail. Here, we propose a new two-step method for TdP risk classification, referred to as Multi-Channel Blockage at Early After Depolarization (MCB@EAD). In the first step, we classified the compound that produced insufficient hERG block as non-torsadogenic. In the second step, the role of non-hERG channels to modulate TdP risk are considered by constructing classifiers based on direct or derived features at critical hERG block concentrations that generates EADs in the computational cardiac cell models. MCB@EAD provides comparable or superior TdP risk classification of the drugs from the direct features in tests against published methods. TdP risk for the drugs highly correlated to the propensity to generate EADs in the model. However, the derived features of the biophysical models did not improve the predictive capability for TdP risk assessment.
| S-EPMC5694470 | biostudies-literature
Project description:Mounting evidence indicates that in chronic inflammatory arthritis (CIA), QTc prolongation is frequent and correlates with systemic inflammatory activation. Notably, basic studies demonstrated that inflammatory cytokines induce profound changes in potassium and calcium channels resulting in a prolonging effect on cardiomyocyte action potential duration, thus on the QT interval on the electrocardiogram. Moreover, it has been demonstrated that in rheumatoid arthritis (RA) patients, the risk of sudden cardiac death is significantly increased when compared to non-RA subjects. Conversely, to date no data are available about torsades de pointes (TdP) prevalence in CIA, and the few cases reported considered CIA only an incidental concomitant disease, not contributing factor to TdP development. We report three patients with active CIA developing marked QTc prolongation, in two cases complicated with TdP degenerating to cardiac arrest. In these patients, a blood sample was obtained within 24?h from TdP/marked QTc prolongation occurrence, and levels of IL-6, TNF?, and IL-1 were evaluated. In all three cases, IL-6 was markedly elevated, ~10 to 100 times more than reference values. Moreover, one patient also showed high circulating levels of TNF? and IL-1. In conclusion, active CIA may represent a currently overlooked QT-prolonging risk factor, potentially contributing in the presence of other "classical" risk factors to TdP occurrence. In particular, a relevant role may be played by elevated circulating IL-6 levels via direct electrophysiological effects on the heart. This fact should be carefully kept in mind, particularly when recognizable risk factors are already present and/or the addition of QT-prolonging drugs is required.
| S-EPMC5029147 | biostudies-literature
Project description:Background: Torsades de pointes (TdP) is a life-threatening ventricular tachycardia occurring in long QT-syndrome patients. It usually develops when multiple QT-prolonging factors are concomitantly present, more frequently drugs and electrolyte imbalances. Since proton-pump inhibitors (PPIs)-associated hypomagnesemia is an increasingly recognized adverse event, PPIs were recently included in the list of drugs with conditional risk of TdP, despite only few cases of TdP in PPI users have been reported so far. Objectives: Aim of the present study is to evaluate whether PPI-induced hypomagnesemia actually has a significant clinical impact on the risk of TdP in the general population. Methods: Forty-eight unselected patients who experienced TdP were consecutively enrolled (2008-2017). Shortly after the first TdP episode, in those patients who did not receive magnesium sulfate and/or potassium or calcium replacement therapy, serum electrolytes were measured and their relationship with PPI usage analyzed. Results: Many patients (28/48, 58%) were under current PPI treatment when TdP occurred. Among TdP patients in whom serum electrolyte determinations were obtained before replacement therapy (27/48), those taking PPIs had significantly lower serum magnesium levels than those who did not. Hypomagnesemia occurred in ~40% of patients receiving PPIs (6/14), in all cases after an extended treatment (>2 weeks). In patients taking PPIs the mean QT-prolonging risk factor number was significantly higher than in those who did not, a difference which was mainly driven by lower magnesium levels. Conclusions: In unselected TdP patients, PPI-induced hypomagnesemia was common and significantly contributed to their cumulative arrhythmic risk. By providing clinical support to current recommendations, our data confirm that more awareness is needed when a PPI is prescribed, specifically as regards the risk of life-threatening arrhythmias.
| S-EPMC5922007 | biostudies-literature
Project description:BackgroundPoly ADP-ribose polymerase (PARP) inhibitors target pathogenic BRCA mutations in chemotherapy-resistant malignancies. PARP inhibitors cause modest dose-dependent QT prolongation in the setting of a normal baseline QT interval.Case summaryWe describe a case of PARP inhibitor-induced torsades de pointes (TdP) in an 86-year-old gentleman prescribed rucaparib due to chemotherapy-resistant, metastatic prostate cancer with pre-existing long QT, with an apparent dose-dependent increase in QT interval. The patient presented with syncope and recurrent TdP requiring direct cardioversion reversion (200 J biphasic) and an isoprenaline infusion (2 μg/min). There were no other QT prolonging agents and no electrolyte or metabolic disturbance to account for this arrhythmia. Improvement in QT interval was observed within 72 h of rucaparib cessation.DiscussionPARP inhibitors cause a modest, dose-dependent increase in QT interval in patients with a normal baseline. The safety of PARP inhibitors in patients with pre-existing long QT has not been evaluated. This is the first reported case of rucaparib-associated TdP in a patient with pre-existing long QT, highlighting the amplified effect of this agent in individuals with pre-existing QT prolongation and the risk of fatal arrhythmias.
| S-EPMC7047052 | biostudies-literature
Project description:Drug-induced torsades de pointes (TdP) remains a significant public health concern that has challenged scientists who have the responsibility of advancing new medicines through development to the patient, while assuring public safety. As a result, from the point of discovering a new molecule to the time of its registration, significant efforts are made to recognize potential liabilities, including the potential for TdP. With this background, the ILSI (HESI) Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. A workshop was therefore convened at which four topics were considered including: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia and Key Considerations for Demonstrating Utility of Pre-Clinical Models. The series of publications in this special edition has established the background, areas of debate and those that deserve scientific pursuit. This is intented to encourage the research community to contribute to these important areas of investigation in advancing the science and our understanding of drug-induced proarrhythmia.
| S-EPMC2492097 | biostudies-other
Project description:BackgroundFemale gender, degree of QT prolongation, and genetic susceptibility are known risk factors for developing torsades de pointes (TdP) during high-grade atrioventricular block (HG-AVB). Our objective was to analyze the prevalence and clinical characteristics of patients presenting with TdP and AVB (TdP [+]) in comparison with non-TdP patients with AVB (TdP [-]).MethodsAll the ECGs from patients prospectively admitted for AVB (2 to 1, HG, and complete) at the University Hospital of Nice were analyzed. Automated corrected QT (QTc), manual measurements of QT and JT intervals, and Tpeak-to-end were performed at the time of the most severe bradycardia.ResultsFrom September 2020 to November 2021, 100 patients were admitted for HG-AVB. Among them, 17 patients with TdP were identified (8 men; 81 ± 10 years). No differences could be identified concerning automated QTc, manual QTc (Bazett correction), baseline QRS width, or mean left ventricular ejection fraction between the two groups. Potassium serum level on admission and mean number of QT-prolonging drugs per patient were not significantly different between the two groups, respectively: 4.34 ± 0.5 mmol/L in TdP [+] versus 4.52 ± 0.6 mmol/L (p = 0.33); and 0.6 ± 0.7 in TdP [+] versus 0.3 ± 0.5 (p = 0.15). In contrast, manual QTcFR (Fridericia correction), JT (Fridericia correction), Tpeak-to-end, and Tpe/QT ratio were significantly increased in the TdP [+] group, respectively: 486 ± 70 ms versus 456 ± 53 ms (p = 0.04); 433 ± 98 ms versus 381 ± 80 ms (p = 0.02); 153 ± 57 ms versus 110 ± 40 ms (p < 0.001); and 0.27 ± 0.08 versus 0.22 ± 0.06 (p < 0.001).ConclusionsThe incidence of TdP complicating acquired AVB was 17%. Longer QTcFR, JT, and Tpeak-to-end were significantly increased in the case of TdP but also in the presence of permanent AVB during the hospitalization.
| S-EPMC9917754 | biostudies-literature