Torsades De Pointes In Patients Research Articles

Role of Pharmacokinetics and Pharmacogenetics of Antidepressant-Induced Prolongation of the QT Interval and Torsade de Pointes in Patients with Mental Disorders

Antidepressants (ADs) include drugs of various pharmacological groups, which are mainly used for the treatment of mental disorders (major depressive disorder, obsessive-compulsive disorder, social phobia, panic disorder, generalized anxiety disorder, post-traumatic stress disorder), chronic pain and addiction diseases. Chronic use of ADs can lead to the development of cardiotoxic adverse drug reactions (ADRs). The most important cardiotoxic AD-induced ADRs are prolongation of the QT interval, ventricular tachycardia of the "pirouette" type (Torsades de Pointes - TdP). This narrative review analyzes and summarizes the results of studies on pharmacokinecis and pharmacogenetics of ADs on QT interval prolongation and updates physicians' knowledge of the risk of developing AD-induced TdP in patients with psychiatric disorders.

Roles of atrial arrhythmias in triggering torsade de pointes in patients with acquired long QT syndrome

Abstract Background Little is known about a role of atrial arrhythmias (AAs) in triggering Torsade de Pointes (TdP) in patients with long QT syndrome (LQTS). Purpose To determine the prevalence of AAs-induced TdP in acute acquired LQTS patients and to classify the AAs’ roles in the development of TdP. Methods Initiation patterns of 81 episodes of TdP obtained from 34 consecutive acquired LQTS patients (14 men; median age, 69 years; median QTc, 645.5 ms) with documented TdP were analysed. The patients were divided into 2 groups based on the presence or absence of AAs involvement in triggering TdP: AAs-induced and non-AAs-induced groups. Results AAs-induced group comprised 52.9% (18/34) of the patients studied. TdP was preceded by AAs-induced short-long sequences (SLSs) in 41.2% (14/34) of the patients and directly induced by R-on-T AAs (AAs coincidentally encounter a vulnerable repolarizing region during the T wave) in 23.5% (8/34). AAs-induced group experienced TdP after initiating therapy more frequently than non-AAs-induced group (2.5 vs. 1, p=0.008). AAs triggered 48 (59.3%) of the 81 TdP episodes. AAs-induced SLS comprised 67.8% (40 /59) of the SLS-induced TdP episodes. R-on-T AAs accounted for 23.5% (19/81) of the TdP episodes. Conclusions Our observations suggest that AAs are associated with the onset mechanism of TdP in more than half of acute acquired LQTS patients and even increase TdP frequency. Thus, AAs are not benign but rather can be lethal in acute acquired LQTS patients.Representative casesAnalysis of Torsade de Pointes episodes

Mechanisms of fever-induced QT prolongation and torsades de pointes in patients with KCNH2 mutation.

Patients with particular mutations of type-2 long QT syndrome (LQT2) are at an increased risk for malignant arrhythmia during fever. This study aimed to determine the mechanism by which KCNH2 mutations cause fever-induced QT prolongation and torsades de pointes (TdP). We evaluated three KCNH2 mutations, G584S, D609G, and T613M, in the Kv11.1 S5-pore region, identified in patients with marked QT prolongation and TdP during fever. We also evaluated KCNH2 M124T and R269W, which are not associated with fever-induced QT prolongation. We characterized the temperature-dependent changes in the electrophysiological properties of the mutant Kv11.1 channels by patch-clamp recording and computer simulation. The average tail current densities (TCDs) at 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller and less increased with rising temperature from 35°C to 40°C than those for WT, M124T, and R269W. The ratios of the TCDs at 40°C to 35°C for G584S, WT+D609G, and WT+T613M were significantly smaller than for WT, M124T, and R269W. The voltage dependence of the steady-state inactivation curve for WT, M124T, and R269W showed a significant positive shift with increasing temperature; however, that for G584S, WT+D609G, and WT+T613M showed no significant change. Computer simulation demonstrated that G584S, WT+D609G, and WT+T613M caused prolonged action potential durations and early afterdepolarization formation at 40°C. These findings indicate that KCNH2 G584S, D609G, and T613M in the S5-pore region reduce the temperature-dependent increase in TCDs through an enhanced inactivation, resulting in QT prolongation and TdP at a febrile state in patients with LQT2.

Alternating Early Afterdepolarizations Underlying Bradycardia-Dependent Macroscopic T Wave and Discordant Mechanical Alternans.

Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA remain unclear. We examined the cellular and ionic basis for macro-TWA in rabbits with left ventricular hypertrophy (LVH). The renovascular hypertension model was used to induce LVH in rabbits. Action potentials were simultaneously recorded from epicardium and endocardium together with a transmural ECG and isometric contractility in arterially perfused left ventricular wedges. Late sodium current (INa-L) was recorded in single-isolated left ventricular myocytes with the whole cell patch-clamp technique. Macro-TWA and accompanied mechanical alternans occurred spontaneously in 8 of 33 LVH rabbits (P<0.05, versus 0/15 in controls) and were induced by an INa-L enhancer ATX-II at 1 to 3 nM in additional 7. Macro-TWA and mechanical alternans occurred discordantly, that is, that longer QT interval and larger T wave were associated with weaker isometric contvractility. Alternating early afterdepolarizations in the endocardium caused macro-TWA in 12 of 15 LVH rabbits and, therefore, early afterdepolarization-dependent R-from-T extrasystoles and Torsades de Pointes always originated from the beats with longer QT and larger T wave during macro-TWA. INa-L density was significantly larger in LVH myocytes than that of control myocytes. Macro-TWA, mechanical alternans, R-from-T extrasystoles, and Torsades de Pointes were all abolished by INa-L blocker ranolazine or mexiletine. LVH enhances INa-L density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. INa-L blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.

Torsade de pointes caused by citalopram during the pacemaker battery‐depletion phase: A case report

Drug‐induced QT prolongation, primarily antiarrhythmic drugs, is a common cause of torsade de pointes (TdP). Although there have been previous reports of drug‐induced TdP in patients, it has not been well documented when caused by citalopram during the pacemaker battery‐depletion phase. To improve delirium recognition, we report a case of citalopram‐induced TdP during the pacemaker battery‐depletion phase. An 84‐year‐old Chinese female was brought to the hospital presenting recurrent syncope. She lost consciousness and was admitted after her syncope TdP was documented. Her pacemaker was inspected and found to be operating in an extremely ineffective manner. Although she had prolonged QT interval after the pacemaker was replaced, she did not suffer another syncope attack, and ECG monitoring revealed no cardiac arrhythmia or TdP. During her admission, she was treated with citalopram for depression. Citalopram was discontinued when the QT interval shortened progressively. In this study, we described a case of citalopram‐induced TdP during the depletion phase of a pacemaker battery. This case should serve as a cautionary lesson to clinicians to avoid using citalopram during the pacemaker battery‐depletion phase.

Treatment Options for Coronavirus Disease 2019 in Patients With Reduced or Absent Kidney Function.

Coronavirus disease 2019, the disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was first identified in the Hubei Province of China in late 2019. Currently, the only role for therapy is treatment of the disease, as opposed to postexposure prophylaxis, however multiple clinical trials are currently ongoing for both treatment and prophylaxis. Treating coronavirus disease 2019 relies on two components; the first is inhibition of the viral entrance and replication within the body and the second is inhibition of an exacerbated immune response which can be seen in patients with severe disease. Many drugs have shown in vitro antiviral activity; however, clinical trials have not been as promising. This review summarizes the current data for the most commonly used drugs for coronavirus disease 2019 and will cover the unique factors that may affect the dosing of these medications in patients with CKD. While clinical trials are ongoing, most are in patients with normal kidney function. During a pandemic, when patients with CKD are at higher risk of both infection and death, it is imperative to include patients these patients in the clinical trials.

COVID-19 and cardiac arrhythmias: a global perspective on arrhythmia characteristics and management strategies.

BackgroundCardiovascular and arrhythmic events have been reported in hospitalized COVID-19 patients. However, arrhythmia manifestations and treatment strategies used in these patients have not been well-described. We sought to better understand the cardiac arrhythmic manifestations and treatment strategies in hospitalized COVID-19 patients through a worldwide cross-sectional survey.MethodsThe Heart Rhythm Society (HRS) sent an online survey (via SurveyMonkey) to electrophysiology (EP) professionals (physicians, scientists, and allied professionals) across the globe. The survey was active from March 27 to April 13, 2020.ResultsA total of 1197 respondents completed the survey with 50% of respondents from outside the USA, representing 76 countries and 6 continents. Of respondents, 905 (76%) reported having COVID-19-positive patients in their hospital. Atrial fibrillation was the most commonly reported tachyarrhythmia whereas severe sinus bradycardia and complete heart block were the most common bradyarrhythmias. Ventricular tachycardia/ventricular fibrillation arrest and pulseless electrical activity were reported by 4.8% and 5.6% of respondents, respectively. There were 140 of 631 (22.2%) respondents who reported using anticoagulation therapy in all COVID-19-positive patients who did not otherwise have an indication. One hundred fifty-five of 498 (31%) reported regular use of hydroxychloroquine/chloroquine (HCQ) + azithromycin (AZM); concomitant use of AZM was more common in the USA. Sixty of 489 respondents (12.3%) reported having to discontinue therapy with HCQ + AZM due to significant QTc prolongation and 20 (4.1%) reported cases of Torsade de Pointes in patients on HCQ/chloroquine and AZM. Amiodarone was the most common antiarrhythmic drug used for ventricular arrhythmia management.ConclusionsIn this global survey of > 1100 EP professionals regarding hospitalized COVID-19 patients, a variety of arrhythmic manifestations were observed, ranging from benign to potentially life-threatening. Observed adverse events related to use of HCQ + AZM included prolonged QTc requiring drug discontinuation as well as Torsade de Pointes. Large prospective studies to better define arrhythmic manifestations as well as the safety of treatment strategies in COVID-19 patients are warranted.Electronic supplementary materialThe online version of this article (10.1007/s10840-020-00789-9) contains supplementary material, which is available to authorized users.

Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes.

BackgroundMen normally have shorter heart rate-corrected QT interval (QTc) than women, at least in part due to accelerating effects of testosterone on ventricular repolarization. Accumulating data suggest that androgen-deprivation therapy (ADT) used for the treatment of prostatic cancer, may increase Torsades de Pointes (TdP) risk by prolonging QTc. However, the evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases.ObjectiveTo better determine the clinical impact of ADT on TdP development, we examined the prevalence of this therapy in a consecutive cohort of 66 TdP patients, prospectively collected over a ~10 years period.Methods and ResultsWe found and described four patients who were under ADT for prostatic cancer when TdP occurred, and in two cases degenerated to cardiac arrest. Notably, in this unselected population, ADTs unexpectedly represented the second most frequently administered QT-prolonging medication in males (4/24, 17%), after amiodarone. Moreover, in the ADT patients, a blood withdrawal was performed within 24 h from TdP/marked QTc prolongation occurrence and circulating concentration of androgens and gonadothropins were measured. As expected, all cases showed markedly reduced testosterone levels (total, free, and available).ConclusionWe provide evidence that a significant proportion of patients developing TdP were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals. An accurate assessment of the arrhythmic risk profile should be included in the standard of care of prostatic cancer patients before starting ADT.

QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin

BackgroundThere is no known effective therapy for patients with coronavirus disease 2019 (COVID-19). Initial reports suggesting the potential benefit of hydroxychloroquine/azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns about the potential risk of QT interval prolongation and induction of torsade de pointes (TdP).ObjectiveThe purpose of this study was to assess the change in corrected QT (QTc) interval and arrhythmic events in patients with COVID-19 treated with HY/AZ.MethodsThis is a retrospective study of 251 patients from 2 centers who were diagnosed with COVID-19 and treated with HY/AZ. We reviewed electrocardiographic tracings from baseline and until 3 days after the completion of therapy to determine the progression of QTc interval and the incidence of arrhythmia and mortality.ResultsThe QTc interval prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc interval prolongation to >500 ms, a known marker of high risk of TdP, had developed in 23% of patients. One patient developed polymorphic ventricular tachycardia suspected as TdP, requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc interval of patients exhibiting extreme QTc interval prolongation was normal.ConclusionThe combination of HY/AZ significantly prolongs the QTc interval in patients with COVID-19. This prolongation may be responsible for life-threatening arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in light of its unproven efficacy. Strict QTc interval monitoring should be performed if the regimen is given.

Pharmacological β-adrenoceptor blockade can augment torsadogenic action of IKr inhibitor: Comparison of proarrhythmic effects of d-sotalol and dl-sotalol in the chronic atrioventricular block dogs

Information is still limited whether β-blockade may augment or attenuate the onset of torsade de pointes in patients with IKr inhibitor-induced labile repolarization process. We compared the proarrhythmic effects of d-sotalol with those of dl-sotalol using the chronic atrioventricular block dogs, since d- and l-isomers share a similar blocking action on IKr but β-blocking activity resides only in l-isomer. dl-Sotalol (3 mg/kg, p.o.) induced torsade de pointes in 3 out of 4 animals, whereas d-sotalol (3 mg/kg, p.o.) induced it in only 1 out of 4 animals. Thus, β-blockade can augment torsadogenic action of IKr inhibitor.

Proton Pump Inhibitors and Serum Magnesium Levels in Patients With Torsades de Pointes.

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.

Adverse Drug Event Causality Analysis (ADECA): A Process for Evaluating Evidence and Assigning Drugs to Risk Categories for Sudden Death

Growing evidence indicates that many drugs have the ability to cause a potentially lethal cardiac arrhythmia, torsades de pointes (TdP). This necessitates the development of a compilation of drugs that have this potential toxicity. Such a list is helpful in identifying the etiology of TdP in patients taking multiple drugs and assists decision making by those caring for patients at high risk of TdP. The Arizona Center for Education and Research on Therapeutics (AZCERT) has developed a process to standardize the identification of drugs and place them in risk categories for their clinical ability to cause TdP and QT prolongation. AZCERT's Adverse Drug Event Causality Analysis (ADECA) utilizes 16 types of data drawn from four sources to compile an open-source knowledge base, QTdrugs, which is maintained on the CredibleMeds.org website. Because the evidence for most drugs is incomplete, the ADECA process is used to place drugs into one of three categories that represent different levels of certainty: known TdP risk, possible TdP risk, and conditional TdP risk. Each category has strict evidentiary requirements for clinical evidence of TdP and/or QT prolongation. These are described in this paper. Because evidence can evolve over time, the ADECA process includes the continuous gathering and analysis of newly emerging evidence to revise the lists. The QTdrugs lists have proven to be a valued, readily available, commercial influence-free resource for healthcare providers, patients, researchers, and authors of consensus guidelines for the safe use of medicines.

Arrhythmogenicity of Anti-Ro/SSA Antibodies in Patients With Torsades de Pointes.

In patients with autoimmune disease, anti-Ro/SSA antibodies (anti-Ro/SSA) are responsible for a novel autoimmune-associated long-QT syndrome by targeting the hERG potassium channel and inhibiting the related current (IKr). Because anti-Ro/SSA are also present in a significant proportion of healthy subjects and may be associated with torsades de pointes (TdP) arrhythmia, we tested the hypothesis that anti-Ro/SSA may represent a silent risk factor in patients developing TdP. Twenty-five consecutive patients who experienced TdP were prospectively collected independent of ongoing therapies and concomitant diseases. Anti-Ro/SSA were detected by fluoroenzyme immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified IgGs from anti-Ro/SSA-positive and anti-Ro/SSA-negative patients were tested on IKr using HEK293 cells stably expressing the hERG channel. As expected, in TdP patients, many known corrected QT interval-prolonging risk factors were simultaneously present, including hypokalemia that was the most common (52%). Anti-Ro/SSA were present in 60% of the subjects, mostly the anti-Ro/SSA-52-kD subtype detected by immuno-Western blotting only. A history of autoimmune disease was found in only 2 of anti-Ro/SSA-positive patients. Experimental data demonstrated that purified anti-Ro/SSA-positive IgGs significantly inhibited IKr and cross reacted with hERG-channel proteins. Moreover, anti-Ro/SSA-positive sera exhibited high reactivity with a peptide corresponding to the hERG-channel pore-forming region. Anti-Ro/SSA may represent a clinically silent novel risk factor for TdP development via an autoimmune-mediated electrophysiological interference with the hERG channel. We propose that TdP patients may benefit from specific anti-Ro/SSA testing even in the absence of autoimmune diseases as immunomodulating therapies may be effective in shortening corrected QT interval and reducing TdP recurrence risk.

Electrocardiographic predictors of bradycardia-induced torsades de pointes in patients with acquired atrioventricular block.

Predictors of torsades de pointes (TdP) in bradyarrhythmia-induced acquired long QT syndrome are not well defined. The purpose of this study was to search for electrocardiographic (ECG) TdP predictors in patients with acquired atrioventricular block (AVB) and QT prolongation. We analyzed 12-lead ECGs from 20 patients (15 females, age 65.9 ± 15.6 years) with TdP episodes from among 898 AVB patients (2.2%) in 3 tertiary hospitals. The ECG repolarization parameters in TdP patients were compared with those of 80 age- and sex-matched control AVB patients with no TdP episodes. TdP was initiated by premature ventricular complexes with a long-short sequence of activation. The average cycle length of the long sequence was 1289.9 ± 228.9 ms and was 2.3 ± 0.6 times longer than the cycle length of the short sequence. TdP patients had a significantly longer mean QT interval (716.4 ± 98.9 ms vs 523.2 ± 91.3 ms, P = .001), mean T peak to end interval (334.2 ± 59.1 ms vs 144.0 ± 73.7 ms, P = .001) and a higher T peak to end interval/QT ratio (0.49 ± 0.09 vs 0.27 ± 0.11, P = .001) compared with non-TdP controls. TdP patients showed a higher prevalence of notched T waves in which T2 was at least 3 mm taller than T1 (45.0% vs 1.3%, P = .001), triphasic T waves (30.0% vs 1.3%, P = .001), reversed asymmetry (20.0% vs 0%, P = .001), and T-wave alternans (35.0% vs 0%, P = .001). An algorithm combining these morphologic parameters was able to differentiate TdP patients from non-TdP patients with high sensitivity (85.0%) and specificity (97.5%). An algorithm combining specific T-wave morphologies was useful for identifying patients with AVB who are at risk for developing TdP.

Determinants of torsades de pointes in older patients with drug-associated long QT syndrome: a case-control study.

Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS. In this retrospective, case-control study, documented reports of drug-associated LQTS plus TdP (n=125) and LQTS without TdP (n=81) in patients ≥65years of age were retrieved from the French Pharmacovigilance Database over a 10-year period. Available clinical, biological, and drug therapy data were compared in the two groups and logistic regression was performed to identify significant predictors of TdP. The uncorrected QT interval was significantly longer in patients with TdP than in patients without TdP (577±79 vs. 519±68 ms; p=0.0001). The number of drugs with a known risk of TdP administered to each patient was not a predictor of arrhythmia, nor was female gender. Logistic regression analysis identified the uncorrected QT interval as the only significant predictor of TdP. The receiver operating characteristic curve analysis was characterized by an area under the curve of 0.77 (95% confidence interval 0.64-0.88) and a QT cutoff of 550ms. The uncorrected QT interval was significantly associated with the probability of TdP in elderly patients with acquired, drug-associated LQTS.

Effects of ramipril and darbepoetin on electromechanical activity of the heart in doxorubicin-induced cardiotoxicity

Cardiac toxicity is a deadly condition caused by impaired cardiac activity similar to congestive heart failure (CHF). Doxorubicin (DOX) is a potent anticancer drug having a potential of myocardial damage [ [1] Minotti G. Menna P. Salvatorelli E. Cairo G. Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004; 56: 185-229 Crossref PubMed Scopus (2860) Google Scholar ]. Doxorubicin induced experimental toxicity has been characterized by heart failure and anaemia [ [2] Noiri E. Nagano N. Negishi K. et al. Efficacy of darbepoetin in doxorubicin-induced cardiorenal injury in rats. Nephron Exp Nephrol. 2006; 104: e6-e14 Crossref PubMed Scopus (20) Google Scholar ]. In human patients, risks for the use of anthracyclines have been reported associated with cardiac death which is the most prevalent of QT prolongation that triggered Torsades de Pointes [ [3] Arbel Y. Swartzon M. Justo D. QT prolongation and Torsades de Pointes in patients previously treated with anthracyclines. Anticancer Drugs. 2007; 18: 493-498 Crossref PubMed Scopus (31) Google Scholar ]. The anaemia of CHF patient is evidently due to the excessive cytokine production [ [4] Silverberg D. Wexler D. Blum M. Wollman Y. Iaina A. The cardio-renal anaemia syndrome: does it exist?. Nephrol Dial Transplant. 2003; 18: viii7-12 PubMed Google Scholar ]. Pre-treatment with erythropoietin hormone alone protected the myocardium against DOX induced impaired cardiac function and cardiomyocyte apoptosis [ [5] Kim K.H. Oudit G.Y. Backx P.H. Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway. J Pharmacol Exp Ther. 2008; 324: 160-169 Crossref PubMed Scopus (93) Google Scholar ]. Therefore, the present study was designed to investigate the effects of ramipril and darbepoetin alfa, used either alone or together, on electromechanic activity of heart in an experimental toxicity model.

Assessment of Drug-Induced Torsade de Pointes Risk for Hospitalized High-Risk Patients Receiving QT-Prolonging Agents

Although risk factors for torsade de pointes (TdP) are known, identifying hospitalized patients at greatest risk for QTcP who should receive cardiac monitoring is poorly defined. Describe the prevalence of risk for TdP in patients and associations between risk factors and QTc prolongation (QTcP) at a tertiary teaching hospital. This retrospective analysis assessed physiological and pharmacological risk factors for TdP of adult patients receiving ≥1 QTc-prolonging medications (QTcMed) during hospitalization. The QTcMeds were stratified by risk for causing TdP (probable, possible, and conditional). Baseline electrocardiograms (ECGs) were assessed for QTcP associated with risk for TdP. During a 6-month period, 12,401 (51%) hospitalizations received ≥1 QTcMed. A baseline ECG was obtained for 2381 (19%) patients. A total of 386 (16%) patients with a baseline ECG were found to have QTcP. Significant associations for QTcP were found with the following physiological risk factors: female (P = .021), left-ventricular ejection fraction <40% (P < .0001), cardiac arrest (P < .0001), and cardioversion (P = .007). Significantly more patients with QTcP (n = 209, 54%) received probable-risk QTcMeds than those without QTcP (n = 542, 27%; P < .0001). Probable-risk QTcMeds administered alone or concomitantly with other QTcMeds were more frequently associated with QTcP. No documented cases of TdP were identified. Of the population receiving QTcMeds, only a small portion had a baseline ECG, identifying a large population at risk of QTcP without appropriate monitoring. Patients with cardiac disease receiving probable-risk QTcMeds were associated with the highest risk of QTcP and should be monitored closely.

Effects of probucol, a typical hERG expression inhibitor, on in vivo QT interval prolongation in conscious dogs

The cholesterol-lowering drug, probucol, is known to induce QT interval prolongation and torsades de pointes in patients. Recent in vitro studies have indicated that probucol reduces hERG expression in the plasma membrane and does not directly block human ether-a-go-go-related gene (hERG) channels. The present study was performed to investigate the effects of probucol on in vivo QT interval prolongation. Epicardial electrocardiograms were recorded in conscious dogs given oral single or repeated (7 days) doses of probucol (100mg/kg), and in combination with moxifloxacin (20mg/kg). QTc intervals were analyzed by a probabilistic method with individual rate collection formulae. Values of change in QTc (<DELTA>QTc) interval and its integration from 1 to 21h (AUC1–21h) were calculated to evaluate drug-induced QT prolongation. A single dose of probucol slightly but significantly increased the AUC1–21h QTc interval on days 2 and 3. The QT prolongation was markedly augmented by repeated doses of probucol in a time-dependent manner, despite the lack of increase in plasma concentration. The combination of probucol and moxifloxacin produced additive effects on QT interval prolongation. These results suggest that long-term exposure to the hERG expression inhibitor, probucol, is required to evaluate its maximal effects on in vivo QT interval prolongation. A combination of direct and indirect hERG inhibitors may produce simple additive effects on QT interval prolongation.

The electrocardiographic predictors of bradycardia-induced Torsade de Pointes in patients with acquired atrioventricular block

The electrocardiographic predictors of bradycardia-induced Torsade de Pointes in patients with acquired atrioventricular block

Negating the dominant-negative allele: a new treatment paradigm for arrhythmias explored in human induced pluripotent stem cell-derived cardiomyocytes

This editorial refers to ‘Allele-specific RNA interference rescues the long-QT syndrome phenotype in human induced pluripotent stem cell cardiomyocytes’[†][1], by E. Matsa et al. , on page 1078 Congenital long-QT syndrome (LQTS) is a disorder of cardiac repolarization that manifests typically with ventricular arrhythmias such as torsades de pointes in patients with prolonged QT intervals in the ECG and structurally normal hearts. The known mutations affect genes encoding either subunits of cardiac ion channels or proteins involved in their regulation. Matsa and colleagues1 describe how they succeeded in using human induced pluripotent stem cell (hiPSC) technology not only to model a subtype of LQTS (LQT2), but also to evaluate a novel therapeutic approach using human cardiomyocytes derived from patient-specific hiPSCs. The authors generated cardiomyocytes from hiPSCs derived from a patient carrying a heterozygous mutation in the KCNH2 gene, corresponding to an A561T amino acid exchange in the KCNH2 -encoded protein hERG. Four hERG subunits co-assemble to form the pore of the ion channel generating the delayed rectifier potassium current IKr, an important determinant of the cardiac action potential duration. In accordance with the clinical phenotype of the patient, the hiPSC-derived cardiomyocytes displayed prolonged action potentials. The authors further demonstrated that, similar to other LQT2-causing ion channel mutations,2 the A561T mutation results in impaired ion channel trafficking: mutated subunits were not glycosylated properly and thus were retained in a perinuclear compartment instead of being integrated into the plasma membrane. Presumably due to co-assembly, the mutation also interfered with normal trafficking of the wild-type subunits in … [1]: #fn-2