QT Lengthening Research Articles

Cardiac electrical and functional activity following an outdoor cold-water swimming event

AimsParticipation in outdoor cold-water swimming (OCWS) events combines endurance exercise and cold exposure. Concerns have emerged about the potential risk of acute adverse cardiac events during OCWS, particularly during endurance events. We analysed the effect of prolonged OCWS on cardiac function in trained athletes. MethodsThe swimming event consisted of laps over a 1000-m course, for up to 6 h, in water at 15 °C. Twenty participants (11 males, 47.3 ± 8.6 years old) were included. Core temperature (Tcore) was monitored using an ingestible temperature sensor during and up to 1 h after the swim. Body composition, blood pressure, electrocardiogram (ECG), and transthoracic echocardiography were assessed 1 day before the event and within the first hour upon completion of the swim. ResultsMean body mass index was 27.1 ± 5.1 kg/m2 and fat mass was 25.2 ± 9.1 %. Mean duration of swimming was 214 ± 115 min. Minimum Tcore was 35.6 ± 1.3 °C. A significant lengthening of the QT interval corrected (QTc) for heart rate was observed post-exercise (437.7 ± 27.7 vs. 457.2 ± 35.9 ms, p = 0.012), with 5 participants exhibiting post-exercise QTc >500ms. OCWS did not alter the biventricular systolic function and left ventricular relaxation. No correlation was observed between ΔQTc and ΔTcore. ConclusionOCWS seemed to acutely delay post-exercise cardiac repolarization without alteration of cardiac function in a healthy trained population. Additional investigations would be warranted to explore the clinical implications of QT lengthening and its relationship with autonomic nervous system regulation during OCWS.

Potential Impact of 3% Hypertonic Saline Infusion on Tramadol Poisoning-Induced Electrocardiogram Changes; a Randomized Clinical Trial

Introduction:Tramadol is a synthetic analgesic with weak mu-opioid receptor agonist activity. Tramadol overdose is associated with adverse cardiac effects due to inhibiting cardiac Na+ and K+ channels. This study aimed to investigate the potential ameliorative role of 3% hypertonic saline on the electrocardiogram (ECG) changes in patients presenting with tramadol poisoning.Methods:This was a single-center, controlled, randomized, single-blind clinical trial. Patients were randomized into the case (received hypertonic saline) and control (received placebo) groups. ECG was obtained twice in each group (upon arrival and following the intervention). Response to therapeutic interventions was evaluated using Wilcoxon Signed Ranks Test. Results:A total of 76 patients were included. The mean age of patients was 24.88 ± 4.29 years, and 62 (81.6%) were male. The mean ingested dose of tramadol was 1673.68 ± 608.85 (range: 550-2750) mg. The number needed to treat and the absolute risk reduction of 3% hypertonic saline in the treatment of wide QRS were 1 (95% CI: 1.00 – 1.00) and 100%, respectively. In the treatment of long QTc, these measures were 1.9 (95%CI: 1.2 – 4.5) and 53.85% (95%CI: 22.00 – 85.69), respectively.Conclusion:Given that hypertonic saline infusion can significantly ameliorate tramadol-mediated ECG changes, including QRS prolongation and QT lengthening, it can be regarded as a potential therapeutic strategy to prevent the development of life-threatening ventricular arrhythmias caused by tramadol toxicity.

Enhanced Response to Drug-Induced QT Interval Lengthening in Patients with Heart Failure with Preserved Ejection Fraction

Patients with heart failure (HF) with reduced ejection fraction demonstrate enhanced response to drug-induced QT interval lengthening and are at increased risk for torsades de pointes. The influence of HF with preserved ejection fraction (HFpEF) on response to drug-induced QT lengthening is unknown. We administered intravenous ibutilide 0.003 mg/kg to 10 patients with HFpEF and 10 age- and sex-matched control subjects without HF. Serial 12-lead electrocardiograms were obtained for determination of QT intervals. Demographics, maximum serum ibutilide concentrations, area under the serum ibutilide concentration vs time curves, and baseline Fridericia-corrected QT (QTF) (417 ± 14 vs 413 ± 15 ms, P = .54) were similar in the HFpEF and control groups. Area under the effect (QTFvs time) curve (AUEC) from 0 to 1.17 hours during and following the ibutilide infusion was greater in the HFpEF group (519 ± 19 vs 497 ± 18 ms·h, P= .04), as was AUEC from 0 to 8.17 hours (3576 ± 125 vs 3428 ± 161 ms·h, P = .03) indicating greater QTF interval exposure. Maximum QTF (454 ± 15 vs 443 ± 22 ms, P = .18) and maximum percent increase in QTF from baseline (8.2 ± 2.1 vs 6.7 ± 1.9%, P = .10) in the 2 groups were not significantly different. HFpEF is associated with enhanced response to drug-induced QT interval lengthening.

Treatment of Headache in the Emergency Department: Haloperidol in the Acute Setting (THE-HA Study): A Randomized Clinical Trial.

Headache is a common complaint of emergency department (ED) patients and current treatment varies with significant limitations. Our aim was to evaluate the efficacy and safety of 2.5mg i.v. haloperidol in the treatment of severe benign headache in the ED. A randomized, double-blind, placebo-controlled trial was performed in the ED of a single high-volume teaching hospital. Convenience sampling identified 287 eligible patients 13 to 55years old with benign headache. One hundred and eighteen patients were enrolled to receive either 2.5mg of haloperidol i.v. or placebo. The primary outcome measure was pain reduction at 60min. Patients were evaluated for adverse events and follow-up was conducted after discharge. QT measurement was performed at baseline and discharge. Fifty-eight patients received haloperidol and 60 patients received placebo. Patients in the haloperidol group reported an average 4.77-unit reduction in visual analogue scale score at 60min compared to a 1.87-unit reduction in the control group. Thirty-four patients (58.6%) in the haloperidol group had complete resolution of their headache. Treatment with rescue ketorolac was required in 78.3% of the control group and 31% of the haloperidol group. Adverse events were uncommon, benign, and easily treated. No patients in the haloperidol group were found to have QT lengthening. This study suggests that 2.5mg i.v. haloperidol is a rapid and effective treatment for acute, severe, benign headache in ED patients aged 18 to 55years. Further study is warranted to confirm these results in adolescents. ClinicalTrials.gov Identifier NCT02747511.

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

BackgroundElectrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.Methods and findingsWe conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (−61.77 milliseconds; 95% credible interval [CI]: −80.71 to −42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (−110.89 milliseconds; 95% CI: −140.38 to −81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: −3.17 to −2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.ConclusionsAdjustment for malaria and fever-recovery–related QT lengthening is necessary to avoid misattributing malaria-disease–related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval–prolonging medications are important therapeutic options.

Familial hypercholesterolemia with early coronary atherosclerotic heart disease: A case report.

Patients with familial hypercholesterolemia usually present with high levels of serum low-density lipoprotein, xanthomas and early coronary artery disease. A 13 years old female patient was admitted to Children's Hospital of Chongqing Medical University presenting symptoms of heart failure. Laboratory tests showed that her cholesterol and low-density lipid levels were extremely high. Electrocardiogram test revealed that she had sinus tachycardia, QT lengthening and ST-T change. Multiple cardiac function abnormalities were diagnosed by echocardiogram. Multiple coronary artery stenosis was determined by computed tomography angiography. After the combination of lipid lowering, anti-thrombosis, and cardiac remodeling therapies, the patient's symptoms were significantly improved and the patient was discharged.

Azithromycin is not associated with QT prolongation in hospitalized patients with community-acquired pneumonia.

Large data-based studies have reported excess cardiovascular mortality in high-risk patients treated with azithromycin, but whether or not azithromycin causes QT prolongation remains controversial. The purpose of this study was to examine the association of azithromycin treatment on QT prolongation in a cohort of patients hospitalized with community-acquired pneumonia (CAP) METHODS: One-hundred twenty-two hospitalized patients with CAP were enrolled in the study. We compared the baseline QTc, with daily post antibiotic QTc. Other risk factors for QT prolongation such as medication or electrolyte abnormalities were recorded. Ninety (73.8%) patients were treated with azithromycin (usually in combination with ceftriaxone), and 32 (26.2%) patients with other antibiotics (ampicillin-clavulanate, chloramphenicol, doxcycline, or ceftriaxone); 72.1% (88) of the cohort experienced QT lengthening; 72.7% with QT lengthening had a normal baseline QTc. Azithromycin was not associated with the post-antibiotic QTc. Wide (pathological) post-antibiotic QTc was associated with the pneumonia score. Every 10-point increase in the pneumonia score raised the risk for a pathological post antibiotic QTc by 1.249 (95%CI: 1.050-1.486). Analysis of patients with non-pathological baseline QTc revealed that pathological post-antibiotic QTc was only associated with previous stroke and not with the type of antibiotic. Azithromycin treatment was not associated with QT prolongation in patients with severe CAP. Nonetheless, in a large majority of hospitalized CAP patients, QT prolongation and pathological QTc develop regardless of the antibiotic used, especially in patients with previous stroke or a higher pneumonia score.

Sensitivity and Specificity of the In Vitro Guinea Pig Papillary Muscle Action Potential Duration for the Assessment of Drug-Induced Torsades De Pointes Liability in Humans.

The ICH S7B document, which provides guidance for the preclinical cardiovascular evaluation of pharmaceutical new chemical entities (NCE), is essentially focused on drug-induced QT lengthening, a biomarker for the proarrhythmic adverse drug reaction, torsades de pointes (TdP). In 2005, this guidance recommended the IKr assay and the in vivo QT telemetry study as mandatory assays for detecting potential torsades de pointes liability and relegated the cardiac action potential (AP) assay as a follow-up study. The IKr assay has become a mandatory screening tool in the early development and safety assessment process. Using only the IKr assay as a go/no go decision arbiter is regrettable since, due to the low specificity of the model (positives that are false for proarrhythmia liability, e.g. verapamil), promising, safe NCEs may be inadvertently discarded. Inclusion of additional medium throughput assays should be performed early to confirm or balance the putatively unfavourable IKr result with positive discovery model output (Pugsley et al., J Pharmacol Toxicol Methods 60:24-27, 2009). In the present chapter, the predictive value of in vitro guinea pig papillary muscle action potential assay will be discussed in terms of sensitivity and specificity and compared to currently available preclinical models such as IKr/hERG assay, dog Purkinje fibre action potential and in vivo QT measurements in dog and cynomolgus monkey.

Abstract 9481: The Response of the Qt Interval and the T-wave Morphology to Sudden Tachycardia Provoked by Standing in Young Athletes

Background: the response of the QT interval to the sudden tachycardia provoked by standing can aid in the diagnosis of the long QT syndrome (LQTS). It is therefore important to know what is the normal response to this maneuver. The aim of this study was to characterise the response of the QT interval and the T-wave morphology following this provocation test in young healthy athletes. Methods: ECG was analysed as part of a prospective study about the impact of cardiovascular screening with ECG in young (14-35 years) athletes. ECG was performed after 5 minute of supine resting. Athletes without cardiac abnormalities, not taking drugs and with normal ECG (QTc for men < 450 msec, for women < 460 msec) were asked to stand up quickly with continuous ECG monitoring for 30”. Heart rate, QT, QTc (Bazett) and T-wave morphology [normal, biphasic, notched G1 (T2>T1), notched G2 (T2>>T1)] were analysed at baseline and at maximal tachycardia. Results: ECG of 289 athletes was analysed (76 % men, mean age 18.4 ± 5.6 years). Baseline parameters were following: heart rate 69 ± 11/min, QT 378 ± 27 msec, QTc 401 ± 21 msec. After standing, the maximal heart rate was 101 ± 13/min. QT was 361 ± 28 msec (shortening by 17 ±11 msec). In 4 % of athletes QT increased by 10-20 msec. QTc was 466 ± 30 msec (lengthening of 65 ± 24 msec). In 12 % of athletes QTc was ≥ 500 msec. T-wave morphology during tachycardia were notched G2 in 6% of athletes. During tachycardia, 15 % of athletes displayed a QTc ≥ 500 msec or QT lengthening or notched G2 morphology of T waves. Conclusions: During sudden tachycardia, a significant proportion of healthy young athletes demonstrated QTc interval and changes of T-wave morphology in the magnitude observed in patients with the LQTS. Caution should be applied in interpreting these parameters in ECG tracing and Holter monitoring displaying sudden oscillations of heart rate in this population.

Jacketed external telemetry in the guinea-pig

Among these models, the guinea-pig is now well established as one of the most predictive for the assessment of QT lengthening and arrhythmia inducing potentials of drug candidates, with the following advantages: • Intra-animal variability in terms of ECG parameters (QT, RR) in the guinea-pig is much lower than in the dog or monkey. • With the exception of Ito, cardiac ionic currents are similar to those in humans, resulting in high predictivity for QT prolongation and in identifying arrhythmia potential including Torsades de Pointes (Loenders et al., 2009). • A minimal amount of compound is needed for guinea-pig treatment, making them a convenient choice for early safety pharmacology programmes. • The guinea pig is a well established model for the evaluation of respiratory function.

A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects. This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.

Le syndrome du QT long chez les patients psychiatriques chimiorésistants : prévalence, facteurs de risque, et implications thérapeutiques

Patients with psychiatric illness have an increased cardiovascular mortality, partly due to sudden death and increased by taking certain antipsychotics and other psychotropic drugs. Poor cardiac safety of these drugs is associated with prolongation of the QT interval of the electrocardiogram (ECG), causing an arrhythmia called Torsade de Pointes (TdP). Units for Difficult Patients receive patients whose care is complicated in a usual psychiatric ward, due to agitation or violence. There are currently five of these psychiatric units in France. These units therefore welcome the chemo-resistant patients, that is to say, resistant to many neuroleptics, or associations of major psychotropic drugs. They also accommodate patients whose condition is not compatible with care in prisons. The hospitalization lasts for 10 months on average. The distinctive feature of these units is that they treat patients with reinforced human resources, psychotherapies, and above all psychotropic drugs. ObjectivesA study was conducted at the unit in Villejuif, Paris, to measure the prevalence of long QT syndrome and its risk factors in connection with drug prescription. Material and methodAn ECG and serum electrolytes were made in the same time for each patient. The data collected are: QT, heart rate, QTc by the formulas of Bazett and Fridericia, QTc given by the device. Conduction disorders were sought for exclusion. Prescriptions were analyzed, sorted by drug therapeutic class, according to the risk of QT prolongation, and dosage levels. PatientsThe analysis results of 63 patients aged 19 to 64 years. The average age is 33 years and the sex ratio is 11 women (17%) and 52 men (83%). The most frequent diagnosis was paranoid schizophrenia, representing over 50% of the patients. It is followed by specific disorders of personality. The mood disorders are less frequent. The pervasive developmental disorders are absent. Some patients also have comorbid psychiatric diagnoses. ResultsThese results show: prevalence of long QT syndrome by 40% according to the formula of Bazett (including 6 %>500ms, major risk of TdP); the preponderance of medicinal risk factor, present in all patients. Other risk factors for QT prolongation are rare (hypokalaemia and bradycardia: 1.6%, female: 17%). The risk factors for TdP are frequent (hypomagnesemia: 8%, hypocalcemia: 46%, renal dysfonction 11%), some of which can be corrected; a measurement variability of the QT interval with significant differences (p<0.001) by the operator and the method of calculation used (Bazett, Fridericia…); increase in the number and average values of long QTc with the number of drugs associated with QT lengthening; lastly, an increase of number and average values of long QTc with high doses. ConclusionsThe prevalence of long QT syndrome in our study is higher than that usually found in the literature. The associations of psychotropic drugs are many, evidence that drug resistance is present. These treatments involve many molecules presented as lengthening the QT. Patients with the longest QT, are those having most associated drugs and higher doses. However, despite the proven toxicity of these treatments, it must be remembered that the QT prolongation does not necessarily a negative risk-benefit balance. This is assessed on a case-by-case basis to determine the right practice. These results emphasize the need for increased surveillance of risk associated with long QT patients on psychotropic associations. They now have awareness of carers and the establishment of a protocol for enhanced surveillance in the service.

Abnormal repolarization dynamics revealed in exercise test in long QT syndrome mutation carriers with normal resting QT interval

The identification of affected family members with long QT syndrome (LQTS) is often difficult due to their normal-or only marginally lengthened-QT interval duration. We examined whether physical exercise test could increase the ability to detect the mutation carrier status in phenotypically normal LQTS family members. Sixty-six subjects were included: 15 were carriers of KCNQ1 (LQT1); 15 of KCNH(2) (LQT2); and 9 of SCN5A (LQT3) gene mutations with no, or borderline, QT lengthening; and 27 were healthy controls. Multiple electrograms over the precordial area were recorded during workload and recovery phases of exercise test. QT intervals and T peak to T end intervals (Tpe intervals) were determined using an automatic algorithm at specified heart rates (HR).The LQT1 mutation carriers had QT interval most prolonged during exercise and recovery, whereas the LQT2 carriers had QT interval longest at low exercise HR. The LQT3 carriers had QT interval longest at rest. The Tpe interval remained nearly unchanged during exercise in LQT1, but shortened in LQT2 and in LQT3 carriers. The Tpe interval was longest in LQT2 carriers at the end of the recovery phase. Tentative dichotomizing values of QT and Tpe intervals improved sensitivity and specificity in distinguishing LQTS subtypes, compared with the QT interval duration alone. LQTS mutation carriers lacking diagnostic QT interval prolongation exhibit abnormal QT and Tpe interval adaptations during physical exercise test. Looking for subtype-specific adaptations might facilitate the identification of LQTS mutation carriers when molecular genetic analysis is not available.

Abstract 4401: Two Independent Genetic Variants in NOS1AP are Associated with QT interval in a Multi-Ethnic Population: the Dallas Heart Study

Extremes of QT interval are associated with increased risk for sudden cardiac death (SCD), and thus identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous work revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We thus sought to characterize the effects of NOS1AP genetic variants in the multi-ethnic population-based Dallas Heart Study (DHS). Among 3,557 participants in DHS with available DNA, those without QT interval, heart rate, age, and/or sex information, and those with QRS &gt;120 or undetermined ethnicity were excluded, resulting in 2,949 samples available for analysis (501 Hispanic, 1,506 Black, 942 White). Sex- and ethnicity-stratified linear regression was used to correct QT interval for heart rate and age. Eight SNPs spanning the region previously associated with QT interval were genotyped, and ethnic-specific analyses were performed under an additive genetic model. The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in the White participants (+2.6 ms, P&lt;0.005) as well as in Blacks (+3.2 ms, P&lt;3.6 × 10 –5), with the same direction of effect in Hispanics (+1.5 ms, P&lt;0.17). A second SNP, rs16856785, which was uncorrelated with rs16847548 (r2 &lt; 0.01 in Blacks) was also associated with QT interval in Blacks (+1.6 ms, P&lt;0.01), with qualitatively similar results in Whites (+0.9 ms, P&lt;0.33) and Hispanics (+0.6 ms, P&lt;0.66). Adjusting for local and global ancestry using Ancestry Informative Markers did not significantly alter the results. Comparing Blacks homozygous at both SNPs for the QT lengthening allele to Blacks homozygous for the complementary alleles revealed a 13.9 ms difference in QT interval. These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends in Hispanics. Further, a second, independent site within NOS1AP has been implicated in modulating QT interval, highlighting the importance of NOS1AP genetic variants in regulating QT interval.

Le syndrome de « Tako-Tsubo » : à propos de deux cas

The "tako-tsubo" syndrome, initially described by Japanese authors is an apical akinesis of the left ventricule without significant coronary artery disease, with a moderate elevation of troponine I. We report 2 cases of women (with an average age of 68 years). They were refered for suspected acute coronary syndrome including on admission chest pain and ST segment elevation. Cardiac ultrasonography shew an apical akinesis. Coronary angiography didn't show significant coronary lesion. A moderate elevation of troponine was noted but no significant elevation of CPK. The prognosis has been excellent for these 2 patients. We observed a ventricular tachycardia due to QT lengthening in 1 case treated anteriorly by Flecaïn which spontaneously resolved. The first month, the electrocardiogram and cardiac ultrasonography anomalies disappeared totally. The treatment is based on β-blockers, aspirin, statines, ACE. In the two cases, we didn't find arguments for myocarditis, recanalized thrombosis, coronary spasm, pheochromocytomas, but a risk factor is inboth: emotional stress. Maybe the diagnosis could be easier with the sub-millimeter cardiac computed tomography.

Issue Highlights

HomeCirculationVol. 113, No. 11Issue Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIssue Highlights Originally published21 Mar 2006https://doi.org/10.1161/circ.113.11.1377Circulation. 2006;113:1377EPINEPHRINE QT STRESS TESTING IN THE EVALUATION OF CONGENITAL LONG-QT SYNDROME: DIAGNOSTIC ACCURACY OF THE PARADOXICAL QT RESPONSE, by Vyas et al.The diagnosis of congenital long-QT syndrome (LQTS) may not be entirely clear from a resting ECG. With exercise or catecholaminergic provocation, most healthy individuals have QT interval shortening, whereas patients with type 1 LQTS (LQT1; due to KCNQ1 mutations) may have QT prolongation. In this issue of Circulation, Vyas and colleagues sought to validate the diagnostic accuracy of an epinephrine infusion for paradoxical QT prolongation in LQT1 patients. They studied 125 genotyped untreated patients (40 LQT1, 30 LQT2, 11 LQT3, and 44 genotype-negative) and observed QT shortening with epinephrine provocation in most genotype-negative and LQT3 patients, but QT lengthening in 92% of LQT1 patients (compared with 18% of genotype-negative and 13% of LQT2 patients). The authors conclude that a paradoxical QT prolongation 30 ms in response to epinephrine challenge has a positive predictive value of 76% and negative predictive value of 96% for LQT1. The test characteristics were much poorer if patients were already on β-blocker therapy. This safe, relatively simple test may be of particular value in diagnosing patients with indeterminate LQTS and may unmask “concealed LQTS.” See p 1385.A TALE OF TWO TRIALS: A COMPARISON OF THE POST–ACUTE CORONARY SYNDROME LIPID-LOWERING TRIALS A TO Z AND PROVE IT-TIMI 22, by Wiviott et al.Several trials have reported comparisons of intensive- versus moderate-dose statin therapy in patients who present with an acute coronary syndrome. Although the bulk of the evidence has fallen in favor of early intensive-dose statin therapy, the magnitude of the treatment benefit has varied from trial to trial. To help clinicians through the complex datasets of the Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trials, Wiviott et al analyze the demographics, end point definitions, impact on low-density lipoprotein (LDL), and impact of C-reactive protein (CRP) in those two studies. Potential implications from their analysis include the benefit of early intensive therapy when combined with revascularization. The relationship of reductions in CRP to early benefit provides further support for the antiinflammatory events of statins. This type of synthesis across trials is a welcome addition to the cardiovascular literature and helps focus therapeutic decision making for clinicians. See p 1406.SAFETY OF CORONARY SIROLIMUS-ELUTING STENTS IN DAILY CLINICAL PRACTICE: ONE-YEAR FOLLOW-UP OF THE E-CYPHER REGISTRY, by Urban et al.Over the past several years, drug-eluting stents have become widely utilized in coronary interventional procedures as the revascularization modality of choice. Increased use of these stents, in turn, has markedly reduced restenosis rates as compared to rates seen with bare metal stents, resulting in a decrease in target vessel revascularization rates. A number of randomized clinical trials now have clinical and angiographic follow-up demonstrating the long-term durability of these stents. Interestingly, although these landmark trials studied only highly select patient populations with prespecified lesion characteristics, it remained unknown if these findings would extend to a heterogeneous patient population with higher-risk coronary artery lesions. In this issue of Circulation, Urban et al present data from the e-Cypher registry that examine the safety and efficacy of sirolimus-eluting stents in daily practice. See p 1434.Visit http://circ.ahajournals.org:Clinician UpdateCardiovascular Genomics. See p e450.Images in Cardiovascular MedicineA Left Atrial Appendage Thrombus Mimicking Atrial Myxoma. See p e456.Hereditary Hypertrophic Nonobstructive Cardiomyopathy Seen on Delayed Hyperenhancement Magnetic Resonance Imaging. See p e458. Download figureDownload PowerPointTime-Resolved 3-Dimensional Magnetic Resonance Velocity Mapping at 3 T Reveals Drastic Changes in Flow Patterns in a Partially Thrombosed Aortic Arch. See p e460.CorrespondenceSee p e462. Previous Back to top Next FiguresReferencesRelatedDetails March 21, 2006Vol 113, Issue 11 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.113.11.1377 Originally publishedMarch 21, 2006 PDF download Advertisement

Comparative Evaluation of HERG Currents and QT Intervals following Challenge with Suspected Torsadogenic and Nontorsadogenic Drugs

The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block I(HERG) in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC50 < 0.1 microM) included lidoflazine, terfenadine, and haloperidol; moderate-potency blockers (0.1 microM < IC50 < 1 microM) included sertindole, thioridazine, and prenylamine; low-potency blockers (IC50 > 1 microM) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers (IC50 > 300 microM) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only (<30 min of drug exposure per measurement). Since two of the drugs that were ineffective I(HERG) blockers, arsenic trioxide and pentamidine, have been associated with cardiac repolarization delays (QT interval lengthening) and torsades de pointes ventricular arrhythmias in patients, we chose to evaluate them further using the isolated perfused rabbit heart model. Neither arsenic trioxide nor pentamidine had any significant effect on QT intervals in this model, even at relatively high (micromolar) concentrations. Similar results were obtained for loratadine in this model. When the hearts were challenged with a known torsadogenic drug such as cisapride, significant QT lengthening was rapidly induced. These results demonstrate that arsenic trioxide and pentamidine are essentially devoid of direct acute effects on cardiac repolarization or inhibition of I(HERG).

Brugada‐like ECG abnormalities during thioridazine overdose

A previously healthy 58-year-old woman was comatose when admitted to our emergency department. Physical evaluation showed muscular rigidity, opisthotonus, external-rotation of upper limbs in response to painful stimulation and neck stiffness. Arterial blood pressure (120/80 mmHg) and temperature (36.5 °C) were unremarkable. The ECG showed sinus rhythm with significant QT lengthening (Figure 1A). A CT scan of the brain and evaluation of spinal fluid were normal. The patient was intubated and mechanically ventilated. Figure 1 (A) Sinus rhythm with significant QT lengthening; (B) Brugada-like pattern; (C) Normal ECG A few hours after admission, we learnt that the patient's husband was being treated with haloperidol and risperidone. The ECG recorded the day after evolved into a Brugada-like pattern (Figure 1B). Over the next 72 h, both the ECG and the clinical abnormalities resolved (Figure 1C), and she was extubated on day 3. She denied deliberate ingestion of psychoactive drugs. Later we learned that the patient's husband was also receiving thioridazine. Thioridazine, measured by HPLC-UV and FL, in a blood sample drawn from the patient on day 4 was 1.48 µg ml−1 (therapeutic levels for our laboratory are up to 2 µg dl−1). No haloperidol or risperidone was detectable in the same sample. In the literature there are several reports of Brugada-like ECG abnormalities during tryciclic antidepressant intoxication [1, 2], but such abnormalities have not been reported during neuroleptic overdose.

Torsades de pointes

Torsades de pointes are infrequent ventricular polymorphic tachycardias characterized by a typical twisting morphology, some very specific precipitating factors, and a specific treatment. These arrhythmias of variable durations, are often repeated like a rhythmic storm. Despite their rapidity, they may go unrecognized when they are short-lived, but when sustained they may produce syncope and, eventually, can progress to ventricular fibrillation and sudden death. They occur in a setting of acquired or congenital prolonged QT interval. Acquired forms occur most of the time in the elderly, mainly in women, with a history of cardiovascular disease submitted to multiple treatments. QT lengthening results from a combination of several factors (some medications, bradycardia, hypokalemia.). Treatment associates suppression of the risk factors and i.v. infusion of magnesium. In some cases, temporary ventricular pacing is used to accelerate the heart rate. The benefit/risk ratio must be thoroughly weighted before considering prescription of drugs that lengthen repolarisation in these patients. The congenital forms are related to mutations of genes coding potassium channels (Iks, Ikr and their satellites) or, uncommonly, the gene coding the fast sodium channel. Preventing sudden death in children or young adults is obtained by beta-adrenergic antagonistic drugs but ventricular stimulation or implanted defibrillator may be necessary. Drugs that lengthen repolarisation must be prohibited. Genetic family screening is mandatory to detect silent mutation carriers in order to reduce the incidence of sudden death which can be the first expression of the disease.

Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs.

In recent years there has been a major reorientation of drug therapy for cardiac arrhythmias, its changing role, and above all, a radical change in the class of arrhythmia drugs because of their impact on mortality. The decline in the use of sodium-channel blockers has led to an ex panding use of beta-blockers and simple or complex class III agents for controlling cardiac arrhythmias. Success with these agents in the context of their side effects has spurred the development of compounds with simpler ion-channel blocking properties that have less complex adverse reactions. The resulting so-called pure class III agents, such as dofetilide or ibutilide, were found to have antifibrillatory effects in atrial fibrillation and flutter and in ventricular tachyarrhythmias. Such agents are effective and have diversity, but they have come into therapeutics with a price: the sometimes-fatal torsades de pointes. The drug amiodarone, a complex compound that was synthesized as an antianginal agent, has been an exception in this regard. Its therapeutic use is associated with a negligibly low incidence of torsades de pointes, even though the drug produces significant bradycardia and QT lengthening to 500 to 700 msec. Recent electrophysiologic studies suggest that this paradox is likely due to the differential block of ion channels in endocardium, epicardium, midmyocardial (M) cells, and Purkinje fibers in the ventricular myocardium. There is also clinical evidence suggesting that amiodarone reduces the "torsadogenic" effects of pure class III agents. Ranolazine was also synthesized for the development of antianginal properties that stem from a partial inhibition of fatty acid oxidation; it too has been found to have electrophysioloigic properties. These are somewhat similar to those of amiodarone on ion channels in endocardium, epicardium, M cells, and Purkinje fibers in the ventricular myocardium, but the drug does not prolong the QT interval to the same extent as amiodarone does. Thus, the drug produces modest increases in repolarization as judged by its effects on the action potential duration (APD) without the potential for the development of torsades de pointes. By virtue of its suppressant action on early afterdepolarizations and triggered activity in Purkinje fibers and M cells, the drug appears to have a powerful potential for reducing the torsadogenic proclivity of conventional class III antiarrhythmic compounds. The rationale for the therapeutic niche for amiodarone, and especially in the case of ranolazine, in the prevention of drug-induced torsades de pointes is discussed.