Assessing the proarrhythmic potential of drugs: current status of models and surrogate parameters of torsades de pointes arrhythmias

Torsades de pointes (TdP) is a potentially lethal cardiac arrhythmia that can occur as an unwanted adverse effect of various pharmacological therapies. Before a drug is approved for marketing, its effects on cardiac repolarisation are examined clinically and experimentally. This paper expresses the opinion that effects on repolarisation duration cannot directly be translated to risk of proarrhythmia. Current safety assessments of drugs only involve repolarisation assays, however the proarrhythmic profile can only be determined in the predisposed model. The availability of these proarrhythmic animal models is emphasised in the present paper. It is feasible for the pharmaceutical industry to establish one or more of these proarrhythmic animal models and large benefits are potentially available if pharmaceutical industries and patient-care authorities embraced these models. Furthermore, suggested surrogate parameters possessing predictive power of TdP arrhythmia are reviewed. As these parameters are not developed to finalisation, any meaningful study of the proarrhythmic potential of a new drug will include evaluation in an integrated model of TdP arrhythmia.     

QT Prolongation Associated with Azithromycin/Amiodarone Combination

Administration of oral azithromycin, in addition to previously well-tolerated long-term amiodarone therapy, was associated with a marked prolongation of QT interval and increased QT dispersion, both substrates for life-threatening ventricular tachyarrhythmia and torsades de pointes. This is a report of QT prolongation and increased QT dispersion associated with the use of azithromycin. The report assumes an added significance, in view of widespread empirical use of this antibiotic for the treatment of lower respiratory infections and belief of its safety in patients with cardiac diseases. Based on the authors' experience, they would like to emphasize that the combination of azithromycin with other drugs known to prolong QT or causing torsades de pointes be used with caution until the question of the proarrhythmic effect of azithromycin is resolved by further studies.     

Effects of the T-type Ca(2+) channel blocker mibefradil on repolarization of guinea pig, rabbit, dog, monkey, and human cardiac tissue

At supratherapeutic doses (2- to 5-fold), the T-type Ca(2+) antagonist mibefradil modifies the T/U wave of the human ECG. In this study, we show that this effect is observed in conscious monkeys and is duplicated by verapamil or diltiazem. We then evaluate the proarrhythmic risk of such alterations of cardiac repolarization by examining the actions of mibefradil on cardiac action potentials (APs). In isolated cardiomyocytes from guinea pigs or humans, mibefradil dose dependently shortens the plateau of the AP; this effect is similar to other Ca(2+) antagonists and opposite to drugs having class III antiarrhythmic properties. The metabolites of mibefradil, singly or in combination, also shorten APs. In isolated rabbit hearts, noncardiodepressant concentrations of mibefradil have no effect on monophasic action potentials (MAPs), whereas cardiodepressant levels produce a slight nonsignificant lengthening. In hearts of open-chest bradycardic dogs, mibefradil has no effect on MAP dispersion or on QT interval and shortens MAPs slightly; although high doses produce atrioventricular block, likely through Ca(2+) antagonism, arrhythmias are never observed. In contrast, d-sotalol lengthens QT interval and MAPs, increases dispersion, and produces arrhythmias. Together, these in vitro and in vivo results suggest that mibefradil carries no proarrhythmic risk despite changes in T/U wave morphology. Although these changes resemble those observed with class III compounds, they also are seen with nonproarrhythmic compounds such as verapamil and diltiazem. In conclusion, the classical models used in the present study could not link the changes in T/U wave morphology produced by mibefradil and verapamil to any experimental marker of proarrhythmic liability.     

Different Effects of Amiodarone and Quinidine on the Homogeneity of Myocardial Refractoriness in Patients With Intraventricular Conduction Delay

BACKGROUND: Increases in QT and JT dispersion have been suggested as indicative of a proarrhythmic potential as a result of heterogeneity in myocardial refractoriness, the reduction of which by antiarrhythmic agents might be associated with a beneficial effect on the development of serious ventricular arrhythmias. METHODS: To test the hypothesis that amiodarone reduces the heter-ogeneity of ventricular refractoriness to a significantly greater extent than quinidine in patients with intraventricular conduction defects under treatment for ventricular arrhythmias, the corrected and uncorrected QT and JT intervals and dispersions from 12-lead surface electrocardiograms were determined in 120 patients with intraventricular conduction defects with cardiac arrhythmias before and during treatment with amiodarone (n = 60) and quinidine (n = 60). RESULTS: Amiodarone increased QT from 403 +/- 50 ms to 459 +/- 47 ms (P <.001), with a similar increase in the corrected QT interval (QTc) (P <.001). Amiodarone reduced QT dispersion by 40% (P <.001), whereas quinidine increased by 18% (P <.001). The net effects of both drugs were similar for OTc. Amiodarone, but not quinidine, reduced heart rate significantly; amiodarone had no effect on the QRS; but quinidine increased if (P <.001). Quinidine as well as amiodarone increased the JT and JTc intervals significantly, but the effect of quinidine was qualitatively less striking. Amiodarone decreased the JT dispersion by 33% (P <.001) and JTc dispersion by 37% (P <.001). On the other hand, quinidine increased the corresponding values for JT and JTc by 18% (P <.001) and 21% (P <.001), respectively. The overall data on QT and JT dispersion indicate an improvement in the homogeneity of myocardial refractoriness with amiodarone treatment and the converse with quinidine treatment; this observation is consistent with a lower proarrhythmic propensity and mortality with amiodarone than with quinidine. Quinidine increased the QRS interval more than amiodarone, and the data indicate that in patients with intraventricular conduction defects, the monitoring of the JT interval might more accurately reflect changes in myocardial repolarization. CONCLUSIONS: Amiodarone and quinidine both increased the corrected and uncorrected QT and JT intervals; amiodarone decreased and quinidine increased the dispersion of these intervals, and these results suggested an improvement in the homogeneity of myocardial refractoriness as a result of amiodarone treatment and the converse as a result of quinidine treatment. Quinidine increased the QTS interval more than amiodarone, and the data indicate that in patients with intraventricular conduction defects, the monitoring of the JT interval might more accurately reflect changes in myocardial repolarization.     

If a drug deemed 'safe' in nonclinical tests subsequently prolongs QT in phase 1 studies, how can its sponsor convince regulators to allow development to proceed?

New drugs are now routinely investigated for their QT-liability in nonclinical studies as well as in a formal Thorough QT Study in man. Data from these studies in man have provided better evidence of the benefits of defining concentration-QT effect relationship of a drug. Therefore, sponsors also frequently monitor electrocardiograms in early phase I clinical pharmacology studies. Although very rare, it is not inconceivable that a drug deemed safe in nonclinical studies may be found to have QT-liability in these early phase clinical studies. Regulatory authorities will no doubt seek a scientific explanation for this discrepancy and as long as the safety of subjects in later phase clinical trials is assured, are content to let the sponsor decide whether to continue or terminate the development of such drugs. Nevertheless, regulatory authorities are prepared provide advice at all the key stages on the optimal way forward so that regulatory concerns likely to arise at evaluation are addressed ahead of submission. Regulatory approval of a drug with QT-liability depends on the comparison of its overall risk/benefit analysis with alternatives available and the morbidity and mortality associated with the disease to be treated. Recent high profile withdrawal of drugs provides a clear signal that cardiac safety is high on the regulatory agenda. An additional regulatory concern is that although QT-related risk can be communicated by appropriate labeling, this may not be enough to mitigate the proarrhythmic risk in clinical practice. A major challenge is to ensure that such drugs are used appropriately.     

Marked QT prolongation and torsades de pointes secondary to acute ischemia in an elderly man taking dofetilide for atrial fibrillation: a cautionary tale

Dofetilide has been shown to be effective and safe in maintaining sinus rhythm in patients with persistent atrial fibrillation and congestive heart failure. Because of serious side effects of an increase in the QT interval causing torsades de pointes, dofetilide must be initiated with close monitoring of the QT interval in an inpatient setting. However, little has been reported about conditions surrounding the change in QT interval after the steady state is achieved that may have implications in the safety and efficacy of the drug. We report marked QT prolongation and torsades de pointes in a setting of flash pulmonary edema resulting from acute myocardial ischemia in a patient who was being treated with dofetilide for atrial fibrillation. Our case reminds the clinicians that the adverse and proarrhythmic effects of dofetilide can occur due to changes in the arrhythmic substrate during acute severe ischemia.     

Molecular determinants of cocaine block of human ether-á-go-go-related gene potassium channels

The use of cocaine causes cardiac arrhythmias and sudden death. Blockade of the cardiac potassium channel human ether-á-go-go-related gene (hERG) has been implicated as a mechanism for the proarrhythmic action of cocaine. hERG encodes the pore-forming subunits of the rapidly activating delayed rectifier K(+) channel (I(Kr)), which is important for cardiac repolarization. Blockade of I(Kr)/hERG represents a common mechanism for drug-induced long QT syndrome. The mechanisms for many common drugs to block the hERG channel are not well understood. We investigated the molecular determinants of hERG channels in cocaine-hERG interactions using site-targeted mutations and patch-clamp method. Wild-type and mutant hERG channels were heterologously expressed in human embryonic kidney 293 cells. We found that there was no correlation between inactivation gating and cocaine block of hERG channels. We also found that consistent with Thr-623, Tyr-652, and Phe-656 being critical for drug binding to hERG channels, mutations in these residues significantly reduced cocaine-induced block, and the hydrophobicity of the residues at position 656 dictated the cocaine sensitivity of the channel. Although the S620T mutation, which removed hERG inactivation, reduced cocaine block by 21-fold, the S620C mutation, which also completely removed hERG inactivation, did not affect the blocking potency of cocaine. Thus, Ser-620 is another pore helix residue whose mutation can interfere with cocaine binding independently of its effect on inactivation.     

Preclinical Torsades-de-Pointes screens: advantages and limitations of surrogate and direct approaches in evaluating proarrhythmic risk

The successful development of novel drugs requires the ability to detect (and avoid) compounds that may provoke Torsades-de-Pointes (TdeP) arrhythmia while endorsing those compounds with minimal torsadogenic risk. As TdeP is a rare arrhythmia not readily observed during clinical or post-marketing studies, numerous preclinical models are employed to assess delayed or altered ventricular repolarization (surrogate markers linked to enhanced proarrhythmic risk). This review evaluates the advantages and limitations of selected preclinical models (ranging from the simplest cellular hERG current assay to the more complex in vitro perfused ventricular wedge and Langendorff heart preparations and in vivo chronic atrio-ventricular (AV)-node block model). Specific attention is paid to the utility of concentration-response relationships and "risk signatures" derived from these studies, with the intention of moving beyond predicting clinical QT prolongation and towards prediction of TdeP risk. While the more complex proarrhythmia models may be suited to addressing questionable or conflicting proarrhythmic signals obtained with simpler preclinical assays, further benchmarking of proarrhythmia models is required for their use in the robust evaluation of safety margins. In the future, these models may be able to reduce unwarranted attrition of evolving compounds while becoming pivotal in the balanced integrated risk assessment of advancing compounds.     

Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine

The Food and Drug Administration recently banned the sale of ephedra alkaloids because of their association with arrhythmic sudden death, myocardial infarction, and stroke. This has resulted in the emergence of formulations marketed for weight loss and performance enhancement that are "ephedra free" but contain other sympathomimetic substances, the safety of which has not been established. We report a case of exercise-induced syncope in a healthy 22-year-old woman that occurred 1 hour after she took the second dose of Xenadrine EFX, an ephedra-free weight-loss supplement. Electrocardiography revealed prolongation of the QT interval (corrected QT, 516 milliseconds); this resolved in 24 hours. Results of echocardiography and exercise stress testing were normal. Nine months of monitoring with an implanted loop recorder revealed no arrhythmias in the absence of Xenadrine EFX. Although this product contains a number of compounds whose pharmacologic effect is poorly characterized, notable quantities of phenylephrine are present, and the proarrhythmic potential of this compound in the setting of exercise is discussed.     

Comprehensive in vitro pro‐arrhythmic assays demonstrate that omecamtiv mecarbil has low pro‐arrhythmic risk

Omecamtiv mecarbil (OM) is a myosin activator (myotrope), developed as a potential therapeutic agent for heart failure with reduced ejection fraction. To characterize the potential pro‐arrhythmic risk of this novel sarcomere activator, we evaluated OM in a series of International Conference on Harmonization S7B core and follow‐up assays, including an in silico action potential (AP) model. OM was tested in: (i) hERG, Nav1.5 peak, and Cav1.2 channel assays; (ii) in silico computation in a human ventricular AP (hVAP) population model; (iii) AP recordings in canine cardiac Purkinje fibers (PF); and (iv) electrocardiography analysis in isolated rabbit hearts (IRHs). OM had low potency in the hERG (half‐maximal inhibitory concentration [IC₅₀] = 125.5 µM) and Nav1.5 and Cav1.2 assays (IC₅₀ > 300 µM). These potency values were used as inputs to investigate the occurrence of repolarization abnormalities (biomarkers of pro‐arrhythmia) in an hVAP model over a wide range of OM concentrations. The outcome of hVAP analysis indicated low pro‐arrhythmia risk at OM concentration up to 30 µM (100‐fold the effective free therapeutic plasma concentration). In the isolated canine PF assay, OM shortened AP duration (APD)₆₀ and APD₉₀ significantly from 3 to 30 µM. In perfused IRH, ventricular repolarization (corrected QT and corrected JT intervals) was decreased significantly at greater than or equal to 1 µM OM. In summary, the comprehensive proarrhythmic assessment in human and non‐rodent cardiac models provided data indicative that OM did not delay ventricular repolarization at therapeutic relevant concentrations, consistent with clinical findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

A new therapeutic agent, omecamtiv mecarbil (OM), increases cardiac contractility by prolonging systolic ejection time, however, there is no published data assessing its pro‐arrhythmic risks.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Pro‐arrhythmic risk assessment of OM in in vitro and ex vivo safety pharmacology models compliant with International Conference on Harmonization S7B guideline and Comprehensive In Vitro Proarrhythmia Assay initiative.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Comprehensive in vitro pro‐arrhythmic risk assays demonstrate that OM has low pro‐arrhythmic risk and translate into clinical safety observations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Low pro‐arrhythmic risks consistently identified in preclinical in vitro models translate well into clinical observations (i.e., negative preclinical pro‐arrhythmic findings can predict negative clinical outcomes).     

Evaluation of moxifloxacin in canine and non‐human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration‐QTc analysis

The in vivo correct QT (QTc) assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in International Conference on Harmonization (ICH) S7B guideline. The typical telemetry study involves a dose‐response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data. An alternative approach has been validated and is used routinely in the clinical setting that pairs pharmacodynamic (PD) responses with PK exposure (e.g., concentration‐QTc (C‐QTc) analysis. The goal of our paper was to compare the QTc sensitivity of two experimental approaches in the conscious dog and non‐human primate (NHP) QTc assays. For timepoint analysis, a conventional design using eight animals (8 × 4 CO) to detect moxifloxacin‐induced QTc prolongation was compared to a PK/PD design in a subset (N = 4) of the same animals. The findings demonstrate that both approaches are equally sensitive in detecting threshold QTc prolongation on the order of 10 ms. Both QTc models demonstrated linearity in the QTc prolongation response to moxifloxacin dose escalation (6 to 46 ms). Further, comparison with human QTc findings with moxifloxacin showed agreement and consistent translation across the three species: C‐QTc slope values were 0.7‐ (dog) and 1.2‐ (NHP) fold of the composite human value. In conclusion, our data show that dog and NHP QTc telemetry with an integrated PK arm (C‐QTc) has the potential to supplement clinical evaluation and improve integrated QTc risk assessment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Typical cardiovascular studies usually employ timepoint analysis. Published in vivo corrected QT (QTc) assay data has exhibited variability in QTc sensitivity that results in challenges in nonclinical‐clinical assessment of translation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Comparison of nonclinical timepoint and concentration QTc (C‐QTc) analyses and how it relates to clinical moxifloxacin data.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Dog and non‐human primate (NHP) QTc timepoint and C‐QTc analyses detect QTc internal prolongation, have equivalent sensitivity, and improve confidence in these models for proarrhythmic risk mitigation.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Risk assessment in nonclinical models translates well to human thorough QT (TQT) data for moxifloxacin. The new data highlights the value of a high‐quality dog or NHP QTc assay to support clinical risk assessment and regulatory decision making.     

Prolongation of the QT interval in palliative care patients

Prolonged QT interval on the electrocardiogram (ECG) is associated with an increased risk of cardiac arrhythmia and sudden death. Many drugs used in palliative medicine increase the QT interval and several have had their licenses withdrawn or severely restricted. The relative importance of prolonged QT interval will increase for palliative medicine physicians when dealing with patients with longer prognoses and especially cardiac disease. Given these safety concerns, the aim of this study was to determine the prevalence of a prolonged QT interval in palliative care patients who were not in the terminal stage and were referred to a specialist service. Of 300 patients, 47 (16%) had prolonged QTc but only two had QT >500ms. The presence of coexistent cardiac disease or high levels of serum alkaline phosphatase appear to be the clinical features most robustly associated with a prolonged QTc. Although prolonged QTc is relatively common in patients referred to a specialist palliative care service, severely prolonged QT is rare.     

In vitro safety “clinical trial” of the cardiac liability of drug polytherapy

Only a handful of US Food and Drug Administration (FDA) Emergency Use Authorizations exist for drug and biologic therapeutics that treat severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection. Potential therapeutics include repurposed drugs, some with cardiac liabilities. We report on a chronic preclinical drug screening platform, a cardiac microphysiological system (MPS), to assess cardiotoxicity associated with repurposed hydroxychloroquine (HCQ) and azithromycin (AZM) polytherapy in a mock phase I safety clinical trial. The MPS contained human heart muscle derived from induced pluripotent stem cells. The effect of drug response was measured using outputs that correlate with clinical measurements, such as QT interval (action potential duration) and drug‐biomarker pairing. Chronic exposure (10 days) of heart muscle to HCQ alone elicited early afterdepolarizations and increased QT interval past 5 days. AZM alone elicited an increase in QT interval from day 7 onward, and arrhythmias were observed at days 8 and 10. Monotherapy results mimicked clinical trial outcomes. Upon chronic exposure to HCQ and AZM polytherapy, we observed an increase in QT interval on days 4–8. Interestingly, a decrease in arrhythmias and instabilities was observed in polytherapy relative to monotherapy, in concordance with published clinical trials. Biomarkers, most of them measurable in patients’ serum, were identified for negative effects of monotherapy or polytherapy on tissue contractile function, morphology, and antioxidant protection. The cardiac MPS correctly predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities. This high content system can help clinicians design their trials, rapidly project cardiac outcomes, and define new monitoring biomarkers to accelerate access of patients to safe coronavirus disease 2019 (COVID‐19) therapeutics.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

As the global pandemic of coronavirus disease 2019 (COVID‐19) expanded, clinicians were pressed to treat patients with new drug combinations, in the absence of regulatory approval. Months after the first cases, the US Food and Drug Administration (FDA)‐approved medicines for the treatment of COVID‐19 have emerged with mixed results and safety concerns. There is a need for tools to rapidly screen for cardiac liability associated with potential COVID‐19 therapeutics.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does hydroxychloroquine (HCQ) and azithromycin (AZM) COVID‐19 polytherapy show synergetic cardiac liability when compared to their monotherapy?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In this in vitro safety “clinical trial,” HCQ or AZM alone showed significant 80% repolarization time (APD₈₀; proxy for QT) prolongation and arrhythmia, whereas their combination polytherapy rescued instances of arrhythmias while increasing APD₈₀.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study demonstrates that a complex in vitro tissue model (cardiac MPS) can predict arrhythmias and rhythm instabilities under experimental conditions mimicking safety clinical trials. We also identified biomarkers associated with cardiac injury, which can be used to design clinical trial monitoring protocols.     

Torsades de pointes liability inter-model comparisons: the experience of the QT PRODACT initiative

Safety pharmacologists from the Japanese pharmaceutical industries and contract laboratories made a database to evaluate drug effects on the QT interval in 2005. This QT PRODACT project was a prospective study of 12 QT-prolonging (positive) drugs and 10 non-prolonging (negative) drugs to evaluate the specificity and sensitivity of several in vivo and in vitro animal models: in vitro guinea pig papillary muscle action potential recordings and in vivo ECG recordings in unanesthetized or anesthetized beagle dogs, cynomolgus monkeys and miniature pigs. In guinea pig papillary muscle action potential recordings, positive drugs showed lengthening of the action potential duration (APD). By using a new measure to detect triangulation of the action potential configuration, an IKr blocking activity of drugs with Ca channel blocking action was detected. All in vivo studies showed a QT-prolonging effect of greater than 10% for the positive drugs. These in vivo models were useful to distinguish positive from negative drugs. The QT PRODACT project showed reliability and sensitivity of the experiments to detect positive drugs. The proarrhythmic effects of these positive drugs could not be detected even though, in some animal models (e.g., unanesthetized monkey), torsades de pointes (TdP)-type arrhythmias were shown by terfenadine. We compared in vivo arrhythmia models for proarrhythmia. The halothane-anesthetized open chest coronary occlusion-reperfusion canine model, the halothane-adrenaline arrhythmia model and the chronic AV block dog models seemed to be useful to detect the arrhythmogenic potential of QT-prolonging drugs.     

Electrophysiologic parameters and predisposing factors in the generation of drug-induced Torsade de Pointes arrhythmias

When a new (cardiovascular) drug shows signs of QT interval prolongation on the ECG (delay in repolarization time), the regulatory agencies demand screening of its possible proarrhythmic potential before approving it for clinical practice. In this review, identified predisposing factors have been related to specific electrophysiological parameters, allowing quantification of their contribution to Torsade de Pointes arrhythmias. In addition, arrhythmogenic mechanisms involved in the initiation and perpetuation of drug-induced Torsade de Pointes are discussed.     

Cardiomyocytes derived from human pluripotent stem cells for drug screening

The attrition rates of drugs in development, many of which attributed to unforeseen cardiotoxic side effects of the drugs being tested in humans that were not realized in preclinical animal models, are a significant problem facing the pharmaceutical industry. Recent advances in human stem cell biology have paved the way for incorporating human cell models into the two key aspects of developing new drugs: discovering new effective entities and screening for their safety. Functional cardiomyocytes can now be derived from human pluripotent stem cells (hPSCs), including both embryonic (hESCs) and induced pluripotent (hiPSCs) stem cells. Moreover, recent studies demonstrate the ability of cardiomyocytes derived from patients' iPSCs to recapitulate the phenotype of several known cardiac diseases. In the present review we describe the knowledge recently gained on this promising human cell source in order to fulfill its potential as a useful tool for drug screening.     

Extreme QT prolongation during therapeutic hypothermia after cardiac arrest due to long QT syndrome

During therapeutic hypothermia, QT interval is prolonged. In patients with congenital long QT syndrome (LQTs), a longer QT interval was associated with significantly increased risk of cardiac arrest (CA). Therefore, therapeutic hypothermia may have proarrhythmic effects in survivors of CA due to congenital LQTs. A 27-year-old man was resuscitated from CA due to congenital LQTs type 3 and Brugada syndrome. Torsade de pointes (TdP) recurred spontaneously on admission (body temperature, 36.9°C). During mild hypothermia therapy, QTc increased from 499 (36.9°C) to 667 milliseconds (33.8°C), although TdP was not induced. A 13-year-old boy with congenital LQTs type 1 underwent therapeutic hypothermia after resuscitation. Short-acting β-blocker was administered intravenously during this treatment. The QTc increased from 534 (36.4°C) to 626 milliseconds (34.3°C). However, TdP did not recur during mild hypothermia therapy. In both patients, electrolyte abnormalities were checked frequently and corrected immediately. QT prolongation remained a couple of days after completion of rewarming. The withdrawal of sedative drugs and extubation were not pursued before QT shortening reached to a plateau. Both patients were fully recovered from neurologic damage. During therapeutic hypothermia, QT interval was extremely prolonged, although TdP did not recur in 2 patients with congenital LQTs. Therapeutic hypothermia may be beneficial for comatose survivors of CA due to LQTs.