Risk Of Torsade De Pointes Research Articles

The In Vitro Pharmacological Profile of Drugs as a Proxy Indicator of Potential In Vivo Organ Toxicities.

The potential of a drug to cause certain organ toxicities is somehow implicitly contained in its full pharmacological profile, provided the drug reaches and accumulates at the various organs where the different interacting proteins in its profile, both targets and off-targets, are expressed. Under this assumption, a computational approach was implemented to obtain a projected anatomical profile of a drug from its in vitro pharmacological profile linked to protein expression data across 47 organs. It was observed that the anatomical profiles obtained when using only the known primary targets of the drugs reflected roughly the intended organ targets. However, when both known and predicted secondary pharmacology was considered, the projected anatomical profiles of the drugs were able to clearly highlight potential organ off-targets. Accordingly, when applied to sets of drugs known to cause cardiotoxicity and hepatotoxicity, the approach is able to identify heart and liver, respectively, as the organs where the proteins in the pharmacological profile of the corresponding drugs are specifically expressed. When applied to a set of drugs linked to a risk of Torsades de Pointes, heart is again the organ clearly standing out from the rest and a potential protein profile hazard is proposed. The approach can be used as a proxy indicator of potential in vivo organ toxicities.

An Integrative Data Science Pipeline to Identify Novel Drug Interactions that Prolong the QT Interval.

IntroductionDrug-induced prolongation of the QT interval on the electrocardiogram (long QT syndrome, LQTS) can lead to a potentially fatal ventricular arrhythmia known as torsades de pointes (TdP). Over 40 drugs with both cardiac and non-cardiac indications are associated with increased risk of TdP, but drug–drug interactions contributing to LQTS (QT-DDIs) remain poorly characterized. Traditional methods for mining observational healthcare data are poorly equipped to detect QT-DDI signals due to low reporting numbers and lack of direct evidence for LQTS.ObjectiveWe hypothesized that LQTS could be identified latently using an adverse event (AE) fingerprint of more commonly reported AEs. We aimed to generate an integrated data science pipeline that addresses current limitations by identifying latent signals for QT-DDIs in the US FDA’s Adverse Event Reporting System (FAERS) and retrospectively validating these predictions using electrocardiogram data in electronic health records (EHRs).MethodsWe trained a model to identify an AE fingerprint for risk of TdP for single drugs and applied this model to drug pair data to predict novel DDIs. In the EHR at Columbia University Medical Center, we compared the QTc intervals of patients prescribed the flagged drug pairs with patients prescribed either drug individually.ResultsWe created an AE fingerprint consisting of 13 latently detected side effects. This model significantly outperformed a direct evidence control model in the detection of established interactions (p = 1.62E−3) and significantly enriched for validated QT-DDIs in the EHR (p = 0.01). Of 889 pairs flagged in FAERS, eight novel QT-DDIs were significantly associated with prolonged QTc intervals in the EHR and were not due to co-prescribed medications.ConclusionsLatent signal detection in FAERS validated using the EHR presents an automated and data-driven approach for systematically identifying novel QT-DDIs. The high-confidence hypotheses flagged using this method warrant further investigation.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-016-0393-1) contains supplementary material, which is available to authorized users.

Effectiveness of Pharmacist-Led Amiodarone Monitoring Services on Improving Adherence to Amiodarone Monitoring Recommendations: A Systematic Review.

Amiodarone remains the mostly frequently used antiarrhythmic in clinical practice and is most often used to maintain normal sinus rhythm in patients with atrial fibrillation who have failed a rate control strategy. Amiodarone has superior efficacy over other antiarrhythmics, a lower risk of torsade de pointes, and a better cardiovascular safety profile in patients with structural heart disease. However, amiodarone is associated with notable noncardiac toxicities affecting the thyroid, lungs, eyes, liver, and central nervous system. Since 2000, clinicians have been advised to follow amiodarone monitoring guidelines provided by the Heart Rhythm Society. Adherence to these recommendations in clinical practice, however, is suboptimal. Pharmacists play a major role in ensuring the safe and effective use of medications, particularly high-risk medications such as amiodarone. This qualitative review details the evidence supporting the role of pharmacist-led amiodarone monitoring services (AMS) in improving adherence to amiodarone monitoring guidelines and identifying adverse effects. Five studies were identified, and, overall, these programs had a favorable impact on improving adherence to guideline-recommended monitoring standards for amiodarone. The available evidence is limited by the significant variations in study designs and outcome definitions, lack of patient randomization, and limited generalizability. Nevertheless, available studies suggest that pharmacist-led AMS may improve adherence to recommended monitoring guidelines and identification of amiodarone-related adverse effects. Further study is warranted to demonstrate whether these services impact the overall quality of care provided to patients receiving amiodarone, which may justify broader implementation.

The high frequency relationship: implications for torsadogenic hERG blockers.

Ventricular arrhythmias induced by human ether-a-go-go related gene (hERG; Kv 11.1 channel) blockers are a consequence of alterations in ventricular repolarisation in association with high-frequency (HF) oscillations, which act as a primary trigger; the autonomic nervous system plays a modulatory role. In the present study, we investigated the role of β1 -adrenoceptors in the HF relationship between magnitude of heart rate and QT interval changes within discrete 10s intervals (sorted into 5bpm heart rate increments) and its implications for torsadogenic hERG blockers. The HF relationship was studied under conditions of autonomic blockade with atenolol (β1 -adrenoceptor blocker) in the absence or presence of five hERG blockers in beagle dogs. In total, the effects of 14 hERG blockers on the HF relationship were investigated. All the torsadogenic hERG blockers tested caused a vertical shift in the HF relationship, while hERG blockers associated with a low risk of Torsades de Pointes did not cause any vertical shift. Atenolol completely prevented the effects four torsadogenic agents (quinidine, thioridazine, risperidone and terfenadine) on the HF relationship, but only partially reduced those of dofetilide, leading to the characterization of two types of torsadogenic agent. Analysis of the vertical shift in the HF relationship demonstrated that signs of transient sympathetic activation during HF oscillations in the presence of torsadogenic hERG blockers are mediated by β1 -adrenoceptors. We suggest the HF relationship as a new biomarker for assessing Torsades de pointes liability, with potential implications in both preclinical studies and the clinic.

Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults - a Swedish nationwide study.

The aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. A matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n = 286,092) and matched controls (n = 1,430,460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds (www.crediblemeds.org) and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. Use of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. The CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with antidepressants and antipsychotics should be taken into consideration when prescribing to the elderly.

Risk management of QTc-prolongation in patients receiving haloperidol: an epidemiological study in a University hospital in Belgium

Many drugs, including haloperidol, are linked with a risk of QTc-prolongation, which can lead to Torsade de Pointes and sudden cardiac death. To investigate the prevalence of concomitant risk factors for QTc-prolongation in patients treated with haloperidol, and the use of safety measures to minimize this risk. University Hospitals of Leuven, Belgium. Methods A retrospective epidemiological study was performed. On 15 consecutive Mondays, all patients with a prescription for haloperidol were included. A risk score for QTc-prolongation, inspired by the pro-QTc score of Haugaa et al., was calculated based on gender, comorbidities, lab results and concomitant QTc-prolonging drugs (each factor counting for one point). Available electrocardiograms before and during the treatment of haloperidol were registered. Management of the risk of QTc-prolongation. Two hundred twenty-two patients were included (59.0 % men, median age 77 years) of whom 26.6 % had a risk score of ≥4 (known to significantly increase the mortality). Overall, 24.3 % received haloperidol in combination with other drugs with a known risk of Torsade de Pointes. Half of the patients had an electrocardiogram in the week before the start of haloperidol; only in one-third a follow-up electrocardiogram during haloperidol treatment was performed. Of the patients with a moderately (n = 41) or severely (n = 14) prolonged QTc-interval before haloperidol, 48.8 % and 42.9 % respectively had a follow-up electrocardiogram. In patients with a risk score ≥4, significantly more electrocardiograms were taken before starting haloperidol (p = 0.020). Although many patients had risk factors for QTc-prolongation (including the use of other QTc-prolonging drugs) or had a prolonged QTc on a baseline electrocardiogram, follow-up safety measures were limited. Persistent efforts should be taken to develop decision support systems to manage this risk.

Presence or Absence of QTc Prolongation in Buprenorphine-Naloxone Among Youth With Opioid Dependence.

The aim of the study was to evaluate buprenorphine-naloxone effects on the QTc in youth with opioid dependence. Buprenorphine is a partial agonist that is an effective treatment for opioid dependence. Compared with methadone, it has a lower risk of QTc prolongation in adults, but is less studied in the youth. It may also reduce the risk of torsades de pointes (TdP)--an uncommon variant of polymorphic ventricular tachycardia--that can result in syncope, ventricular fibrillation, and sudden death. Secondary analysis of the electrocardiogram data from 95 individuals who participated in a multisite trial for youth with opioid dependence. The participants were randomized to a 2-week (DETOX) or a 12-week course of buprenorphine-naloxone (BUP). At baseline, 12-lead electrocardiograms were done at weeks 4 and 12, and QTc intervals were hand-measured and calculated using Bazett formula. Increases above 60 milliseconds were considered clinically significant, and readings above 450 milliseconds (in men) and 470 milliseconds (in women) indicated a prolonged QTc. Mean QTc intervals were higher for BUP than for DETOX participants at baseline, week 4, and week 12 (P = 0.045), and women had longer mean QTc intervals than men (P < 0.0005). Variations in the QTc intervals were observed in some; however, none were above 500 milliseconds--the level at which risk for TdP becomes more significant. In this randomized trial, the mean QTc at baseline, before randomization, was higher in BUP than in DETOX patients. Minimal changes in the QTc were seen at 4 and 12 weeks in a few patients in both groups. There was no evidence that buprenorphine-naloxone alone increased the QTc to a level that increased the risk for TdP.

Prevalence and Risk Factors Associated with Use of QT-Prolonging Drugs in Hospitalized Older People

The objective of this study was to evaluate the prevalence of the prescription of QT-prolonging drugs at hospital admission and discharge and the risk factors associated with their use in older people (aged 65 years and older). Data were obtained from the REPOSI (REgistro POliterapie SIMI [Società Italiana di Medicina Interna]) registry, which enrolled 4035 patients in 2008 (n = 1332), 2010 (n = 1380), and 2012 (n = 1323). Multivariable logistic regression was performed to determine the risk factors independently associated with QT-prolonging drug use. QT-prolonging drugs were classified by the risk of Torsades de Pointes (TdP) (definite, possible, or conditional) according to the Arizona Center for Education and Research on Therapeutics (AzCERT) classification. Specific drug combinations were also assessed. Among 3906 patients prescribed at least one drug at admission, 2156 (55.2%) were taking at least one QT-prolonging drug. Risk factors independently associated with the use of any QT-prolonging drugs were increasing age (odds ratio [OR] 1.02, 95% CI 1.01-1.03), multimorbidity (OR 2.69, 95% CI 2.33-3.10), hypokalemia (OR 2.79, 95% CI 1.32-5.89), atrial fibrillation (OR 1.66, 95% CI 1.40-1.98), and heart failure (OR 3.17, 95% CI 2.49-4.05). Furosemide, alone or in combination, was the most prescribed drug. Amiodarone was the most prescribed drug with a definite risk of TdP. Both the absolute number of QT-prolonging drugs (2890 vs. 3549) and the number of patients treated with them (2456 vs. 2156) increased at discharge. Among 1808 patients not prescribed QT-prolonging drugs at admission, 35.8% were prescribed them at discharge. Despite their risk, QT-prolonging drugs are widely prescribed to hospitalized older persons. The curriculum for both practicing physicians and medical students should be strengthened to provide more education on the appropriate use of drugs in order to improve the management of hospitalized older people.

No Untoward Effect of Long-Term Ketoconazole Administration on Electrocardiographic QT Interval in Patients with Cushing's Disease.

Ketoconazole is listed among drugs that prolong QT interval and may increase the risk of torsade de pointes, a severe ventricular arrhythmia. This compound has recently been approved for treatment of Cushing's syndrome, a severe endocrine disorder. These patients harbour several risk factors for prolonged QT interval, for example hypokalaemia and left ventricular hypertrophy, but no study has evaluated whether administration of ketoconazole affects their QT interval. The aim of this study was to assess the QT interval in patients with Cushing's disease during long-term administration of ketoconazole. Electrocardiograms from 15 patients with Cushing's disease (12 women, 3 men, age: 37.8 ± 2.66 years) on ketoconazole treatment (100 mg-800 mg qd) for 1 month to 12 years were reviewed retrospectively. QT interval was measured and corrected for heart rate (QTc). Measurements before and during ketoconazole treatment were compared and any abnormal QTc value recorded. Concurrent medical therapies were also documented. On average, QTc was superimposable before and during ketoconazole treatment (393.2 ± 7.17 versus 403.3 ± 6.05 msec. in women; 424.3 ± 23.54 versus 398.0 ± 14.93 msec. in men, N.S.). QTc normalized on ketoconazole in one man with prolonged QTc prior to treatment; no abnormal QTc was observed in any other patient during the entire observation period, even during concurrent treatment with other QT-prolonging drugs. In conclusion, long-term ketoconazole administration does not appear to be associated with significant prolongation of QT interval in patients with Cushing's disease. ECG monitoring can follow recommendations drawn for other low-risk QT-prolonging drugs with attention to specific risk factors, for example hypokalaemia and drug interactions.

Electrocardiographic Predictors of Torsadogenic Risk During Dofetilide or Sotalol Initiation: Utility of a Novel T Wave Analysis Program.

Initiation of class III anti-arrhythmic medications requires telemetric monitoring for ventricular arrhythmias and QT prolongation to reduce the risk of torsades de pointes (TdP). Heart rate-corrected QT interval (QTc) is an indicator of risk, however it is imperfect, and subtle abnormalities of repolarization have been linked with arrhythmogenesis. Identification of electrocardiographic predictors of torsadogenic risk through the application of a novel T wave analysis tool. Among all patients admitted to Mayo Clinic for initiation of dofetilide or sotalol, we identified 13 cases who developed drug-induced TdP and 26 age and sex matched controls that did not develop TdP. The immediate pre-TdP ECG of those with TdP was compared to the last ECG performed prior to hospital discharge in controls using a novel T wave program that quantified subtle changes in T wave morphology. The QTc and 12T wave parameters successfully distinguished TdP cases from controls. The top performing parameters were the QTc in lead V3 (mean case vs control 480 vs 420msec, p < 0.001, r = 0.72) and T wave right slope in lead I (mean case vs control -840.29 vs -1668.71mV/s, p = 0.002, r = 0.45). The addition of T wave right slope to QTc improved prediction accuracy from 79 to 88%. Our data demonstrate that, in addition to QTc, the T wave right slope is correlated strongly with TdP risk. This suggests that a computer-based repolarization measurement tool that integrates additional data beyond the QTc may identify patients with the greatest torsadogenic potential.

Increased risk of torsades de pointes in alloxan-induced type-1 diabetic rats

Increased risk of torsades de pointes in alloxan-induced type-1 diabetic rats

10 Electrocardiographic predictors of torsadogenic risk during dofetilide or sotalol initiation: utility of a novel T wave analysis programme

Background Initiation of class III anti-arrhythmic medications requires telemetric monitoring for ventricular arrhythmia and QT prolongation to reduce the risk of torsades de pointes (TdP). Heart rate corrected QT interval (QTc) is an indicator of risk, however it is imperfect and more subtle abnormalities of repolarization have been linked with arrhythmogenesis. We developed and tested a novel T wave analysis tool to identify electrocardiographic predictors of torsadogenic risk. Methods and results We retrospectively identified patients admitted to Mayo Clinic for initiation of dofetilide or sotalol who developed drug induced-TdP. The immediate pre-TdP or hospital discharge surface electrocardiogram (ECG) was compared between cases and controls using a novel T wave program that quantified subtle changes in T wave morphology. We identified 13 TdP cases and 26 matched controls (age and sex matched). The QTc and 12 T wave parameters were able to distinguish TdP cases from controls. The top performing parameters were the QTc in lead V3 (mean case vs control 480 vs 420 msec, p Conclusion Our data demonstrates that, in addition to QTc, the T wave right slope is correlated strongly with TdP risk. This suggests that a computer-based repolarization measurement tool that integrates additional data beyond the QTc may identify patients with the greatest torsadogenic potential.

HERG potassium channel inhibition by ivabradine may contribute to QT prolongation and risk of torsades de pointes.

Deposited with reference to the publisher's Green Open Access policy, available at https://uk.sagepub.com/en-gb/eur/the-green-route-%E2%80%93-open-access-archiving-policy

Safety of oral dofetilide for rhythm control of atrial fibrillation and atrial flutter.

Although dofetilide is widely used in the United States for rhythm control of atrial fibrillation, there is limited postapproval safety data in the atrial fibrillation population despite its known risk of Torsade de pointes (TdP). We conducted a retrospective chart review of a cohort of 1404 patients initially loaded on dofetilide for atrial fibrillation suppression at the Cleveland Clinic from 2008 to 2012 to evaluate the incidence and risk factors for in-hospital adverse events and the long-term safety of continued use. Of the 17 patients with TdP during loading (1.2%), 10 had a cardiac arrest requiring resuscitation (1 death), 5 had syncope/presyncope, and 2 were asymptomatic. Dofetilide loading was stopped for 105 patients (7.5%) because of QTc prolongation or TdP. Variables correlated with TdP were (1) female sex, 2) 500-μg dose, (3) reduced ejection fraction, and (4) increase in QTc from baseline. One-year all-cause mortality was higher in patients who continued dofetilide compared with those who discontinued use (hazard ratio, 2.48; 95% confidence interval, 1.08-5.71; P=0.03). Those patients who had a TdP event had higher one-year all-cause mortality than those who did not (17.6% versus 3% at 1 year; P<0.001). Dofetilide loading has a low but finite risk of TdP and other adverse events that warrant the current Food and Drug Administration-mandated practice of inpatient monitoring during drug loading. In this cohort, all-cause mortality was higher at 1 year in those patients continued on dofetilide and in those patients who experienced TdP while loading.

Computer-assisted interventions to improve QTc documentation in patients receiving QT-prolonging drugs.

Many medications commonly used in hospitals can cause prolonged corrected QT interval (QTc), putting patients at risk for torsade de pointes (TdP), a potentially fatal arrhythmia. However, documentation of QTc for hospitalized patients receiving QT-prolonging medications is often not consistent with American Heart Association standards. To examine effects of education and computerized documentation enhancements on QTc documentation. A quasi-experimental multisite study among 4011 cardiac-monitored patients receiving QTc-prolonging medications within a 10-hospital health care system was conducted to compare QTc documentation before (n=1517), 3 months after (n = 1301), and 4 to 6 months after (n = 1193) an intervention. The intervention included (1) online education for 3232 nurses, (2) electronic notifications to alert nurses when a patient received at least 2 doses of a QT-prolonging medication, and (3) computerized calculation of QTc in electronic health records after nurses had documented heart rate and QT interval. QTc documentation for inpatients receiving QTc-prolonging drugs increased significantly from baseline (17.3%) to 3 months after the intervention (58.2%; P < .001) within the 10 hospitals and had increased further 4 to 6 months after the intervention (62.1%, P = .75). Patients at larger hospitals were significantly more likely to have their QTc documented (46.4%) than were patients at smaller hospitals (26.2%; P < .001). A 3-step system-wide intervention was associated with an increase in QTc documentation for patients at risk for drug-induced TdP, and improvements persisted over time. Further study is needed to assess whether increased QTc documentation decreases occurrence of drug-induced TdP. (American Journal of Critical Care. 2015;24:e6-e15).

Prolonged QT Risk Assessment in Antipsychotic Overdose Using the QT Nomogram

Antipsychotic drugs are frequently reported to cause QT prolongation and torsade de pointes. We aim to investigate the potential risk of torsade de pointes in antipsychotic overdose by assessing the QT interval with the QT nomogram. All presentations to a toxicology service between January 1987 and May 2013 were reviewed. Admissions with single ingestions of an antipsychotic greater than maximum daily dose were extracted. Demographics, dose, ECG, and outcomes (arrhythmias and death) were obtained. QT intervals in multiple leads were manually measured and the median taken. QT-heart rate (QT-HR) pairs were plotted on the QT nomogram and defined as prolonged if above the abnormal line. The QTcF (Fridericia's HR correction) was calculated and compared with dose. From 2,356 antipsychotic overdoses, 494 were included. There were no abnormal QT-HR pairs in 4 aripiprazole, 31 pericyazine, 14 trifluoperazine, and 7 haloperidol overdoses. Abnormal QT intervals occurred in 9 of 16 amisulpride overdoses (56%; 95% confidence interval [CI] 31% to 79%), 16 of 57 thioridazine overdoses (28%; 95% CI 17% to 42%), and 5 of 29 chlorpromazine overdoses (17%; 95% CI 7% to 36%). Abnormal QT intervals occurred in 5 of 41 risperidone overdoses (12%; 95% CI 5% to 27%), 10 of 202 quetiapine overdoses (5%; 95% CI 3% to 9%), and 2 of 76 olanzapine overdoses (3%; 95% CI 0.5% to 10%), but there was no correlation between dose and QTcF, and most abnormal QT intervals were at fast HR. An additional 186 single antipsychotic ingestions with noncardiotoxic coingestants had similar proportions of abnormal QT. There was 1 case of torsade de pointes in a thioridazine overdose. There appeared to be significant risk of QT prolongation with amisulpride and thioridazine overdoses. Although there were abnormal QT intervals for quetiapine, olanzapine, and risperidone overdoses, they were associated with tachycardia and not dose dependent, and so were unlikely to be associated with increased torsade de pointes risk.

Ventricular dysrhythmias associated with poisoning and drug overdose: a 10-year review of statewide poison control center data from California.

Ventricular dysrhythmias are a serious consequence associated with drug overdose and chemical poisoning. The risk factors for the type of ventricular dysrhythmia and the outcomes by drug class are not well documented. The aim of this study was to determine the most common drugs and chemicals associated with ventricular dysrhythmias and their outcomes. We reviewed all human exposures reported to a statewide poison control system between 2002 and 2011 that had a documented ventricular dysrhythmia. Cases were differentiated into two groups by type of arrhythmia: (1) ventricular fibrillation and/or tachycardia (VT/VF); and (2) torsade de pointes (TdP). Among the 300 potential cases identified, 148 cases met the inclusion criteria. Of these, 132 cases (89%) experienced an episode of VT or VF, while the remaining 16 cases (11%) had an episode of TdP. The most commonly involved therapeutic classes of drugs associated with VT/VF were antidepressants (33/132, 25%), stimulants (33/132, 25%), and diphenhydramine (16/132, 12.1%). Those associated with TdP were antidepressants (4/16, 25%), methadone (4/16, 25%), and antiarrhythmics (3/16, 18.75%). Drug exposures with the greatest risk of death in association with VT/VF were antidepressant exposure [odds ratio (OR) 1.71; 95% confidence interval (CI) 0.705-4.181] and antiarrhythmic exposure (OR 1.75; 95% CI 0.304-10.05), but neither association was statistically significant. Drug exposures with a statistically significant risk for TdP included methadone and antiarrhythmic drugs. Antidepressants and stimulants were the most common drugs associated with ventricular dysrhythmias. Patients with suspected poisonings by medications with a high risk of ventricular dysrhythmia warrant prompt ECG monitoring.

Abstract 17726: Comprehensive Evaluation of QT Interval During Abrupt Changes in Heart Rate and Associated Neurohormonal and Inflammatory Markers

Background: QT interval prolongation and risk of torsades de pointes have been associated with abrupt heart rate (HR) slowing after cardioversion from atrial fibrillation (AF) or AV nodal ablation. The degree to which the QT interval prolongs with abrupt changes in HR, and the underlying mechanisms, are poorly understood. We quantified ΔQT interval during cessation of rapid pacing and examined the relationship between QT and circulating neurohormonal and inflammatory markers. Methods: Eleven subjects with dual chamber pacemakers and intact AV conduction were atrially-paced at 90/min for 10 min, 60 min, and 1 week (Figure). Biomarkers were sampled during and after pacing. The relationships between QT, pacing stage, and biomarker levels were analyzed with a mixed effect model. QT intervals were compared for the 20 RR intervals before and 100 RR intervals after each pacing stage. Results: QT intervals prolonged after cessation of rapid pacing: 6.4 ms (95% confidence interval 4.9-7.8 ms) after 10 min (P&lt;0.0001), 6.1ms (4.6-7.5 ms) after 60 min (P&lt;0.0001), and 2.2ms (0.9-3.6 ms) after 1 week (P=0.002). QT interval was significantly associated with angiotensin II (P=0.002), epinephrine (P&lt;0.0001), norepinephrine (P=0.03), dopamine (P&lt;0.0001), C-reactive protein (P=0.0005), and interleukin-6 (P&lt;0.0001), but not associated with atrial natriuretic peptide (P=0.26), B-type natriuretic peptide (P=0.08), renin (P=0.25), or aldosterone (P=0.42). There were no significant inter-individual differences in biomarker levels drawn before and after pacing (P&gt;0.1 for all comparisons). Conclusion: Abrupt decreases in HR were associated with QT prolongation. QT interval changes correlated with several neuroendocrine and inflammatory biomarkers, though there were no inter-individual differences in biomarker levels before and after pacing. These findings may partially explain the increased risk of torsade de points after restoration of sinus rhythm from AF.

Abstract 11940: Mineralocorticoid Receptor Dysregulation by MicroRNA-135a in Bradycardic Arrhythmogenic Remodeling

Introduction: Complete atrioventricular block (CAVB) causes arrhythmogenic remodeling and increases the risk of Torsades de Pointes (TdP) arrhythmias. MicroRNAs (miRs) are key regulators of gene expression that contribute to cardiac remodeling. Here, we assess microRNA changes after CAVB and their potential significance in arrhythmogenic cardiac remodeling. Methods: CAVB was induced in mice via His bundle ablation. Expression of miRs was evaluated by pan-microRNA microarray with qPCR confirmation on samples from controls and at 24 hrs and 4 wks post-CAVB. Arrhythmias were detected by continuous monitoring. MicroRNA target prediction algorithms were used to identify potential target genes. Biological confirmation of targets was by luciferase assay and overexpression (OE) studies in HEK and H9c2 cells respectively. Results: TdP occurred within 24 hrs in 6/17 CAVB mice, vs no controls. Ventricular tachyarrhythmia episodes were frequent at 4 wks CAVB (212±83 per 24 hrs) and were not seen in controls. CAVB was followed by increased left ventricular (LV) dimension (by 31%, ***p&lt;.001), LV mass (by 33%, *p&lt;.05) and LV fractional shortening (by 33%*) at 4 wks. Of &gt;400 miRs assayed, only miR-135a was altered at 24 hrs (downregulated by 96%***, Fig. A), with 70% decrease at 4 wks. TargetScan predicted miR-135a regulation of the mineralocorticoid receptor (MCR), encoded by the NR3C2 gene. miR-135a OE suppressed NR3C2 3’UTR reporter activity 3.2-fold* (n=5, Fig. B). miR-135a OE did not affect NR3C2 mRNA (Fig. C) but significantly reduced NR3C2 protein expression (n=4, Fig. D). Coexpression with anti-miR-135a eliminated the NR3C2 downregulating effect of miR-135a OE. Conclusions: The mineralocorticoid receptor, encoded by the NR3C2 gene, is translationally regulated by miR-135a, a microRNA that is downregulated in the heart following CAVB in mice. These results implicate miR-135a/mineralocorticoid modulation in arrhythmogenic ventricular remodeling caused by CAVB.

Impact of clinical decision support preventing the use of QT-prolonging medications for patients at risk for torsade de pointes

We developed and implemented a 'CPOE-QT Alert' system, that is, clinical decision support integrated in the computerized physician order entry system (CPOE), in 2011. The system identifies any attempts to order medications with risk of torsade de pointes (TdP) for patients with a history of significant QT prolongation (QTc ≥500 ms) and alerts the provider entering the order. We assessed its impact by comparing orders and subsequent medication administration before and after activation of the system. We found a significant decrease in the proportion of completed order per ordering attempt after system activation (94% (1293/1379) vs 77% (1888/2453), difference 16.8%; p<0.001). This resulted in a 13.9% reduction in the administration of those medications to patients. A significant decrease was observed across all provider types, educational levels, and specialties. The CPOE-QT Alert system successfully reduced exposure to QT-prolonging medications in high risk patients.