Effect of moderate potassium-elevating treatment in long QT syndrome: the TriQarr Potassium Study.

BACKGROUND: In long QT syndrome (LQTS), beta blockers prevent arrhythmias. As a supplement, means to increase potassium has been suggested. We set to investigate the effect of moderate potassium elevation on cardiac repolarisation. METHODS: Patients with LQTS with a disease-causing KCNQ1 or KCNH2 variant were included. In addition to usual beta-blocker treatment, patients were prescribed (1) 50 mg spironolactone (low dose) or (2) 100 mg spironolactone and 3 g potassium chloride per day (high dose+). Electrocardiographic measures were obtained at baseline and after 7 days of treatment. RESULTS: Twenty patients were enrolled (10 low dose and 10 high dose+). One patient was excluded due to severe influenza-like symptoms, and 5 of 19 patients completing the study had mild side effects. Plasma potassium in low dose did not increase in response to treatment (4.26±0.22 to 4.05±0.19 mmol/L, p=0.07). Also, no change was observed in resting QTcF (QT interval corrected using Fridericia's formula) before versus after treatment (478±7 vs 479±7 ms, p=0.9). In high dose+, potassium increased significantly from 4.08±0.29 to 4.48±0.54 mmol/L (p=0.001). However, no difference in QTcF was observed comparing before (472±8 ms) versus after (469±8 ms) (p=0.66) high dose+ treatment. No patients developed hyperkalaemia. CONCLUSION: In patients with LQTS, high dose+ treatment increased plasma potassium by 0.4 mmol/L without cases of hyperkalaemia. However, the potassium increase did not shorten the QT interval and several patients had side effects. Considering the QT interval as a proxy for arrhythmic risk, our data do not support that potassium-elevating treatment has a role as antiarrhythmic prophylaxis in patients with LQTS with normal-range potassium levels. TRIAL REGISTRATION NUMBER: NCT03291145.

Impact of Dietary Factors on Brugada Syndrome and Long QT Syndrome.

A healthy regime is fundamental for the prevention of cardiovascular diseases (CVD). In inherited channelopathies, such as Brugada syndrome (BrS) and Long QT syndrome (LQTS), unfortunately, sudden cardiac death could be the first sign for patients affected by these syndromes. Several known factors are used to stratify the risk of developing cardiac arrhythmias, although none are determinative. The risk factors can be affected by adjusting lifestyle habits, such as a particular diet, impacting the risk of arrhythmogenic events and mortality. To date, the importance of understanding the relationship between diet and inherited channelopathies has been underrated. Therefore, we describe herein the effects of dietary factors on the development of arrhythmia in patients affected by BrS and LQTS. Modifying the diet might not be enough to fully prevent arrhythmias, but it can help lower the risk.

Flavonoids and hERG channels: Friends or foes?

The cardiac action potential is regulated by several ion channels. Drugs capable to block these channels, in particular the human ether-à-go-go-related gene (hERG) channel, also known as KV11.1 channel, may lead to a potentially lethal ventricular tachyarrhythmia called "Torsades de Pointes". Thus, evaluation of the hERG channel off-target activity of novel chemical entities is nowadays required to safeguard patients as well as to avoid attrition in drug development. Flavonoids, a large class of natural compounds abundantly present in food, beverages, herbal medicines, and dietary food supplements, generally escape this assessment, though consumed in consistent amounts. Continuously growing evidence indicates that these compounds may interact with the hERG channel and block it. The present review, by examining numerous studies, summarizes the state-of-the-art in this field, describing the most significant examples of direct and indirect inhibition of the hERG channel current operated by flavonoids. A description of the molecular interactions between a few of these natural molecules and the Rattus norvegicus channel protein, achieved by an in silico approach, is also presented.

Long QT syndrome type 1 and 2 patients respond differently to arrhythmic triggers: The TriQarr in vivo study.

BACKGROUND: In patients with long QT syndrome (LQTS), swimming and loud noises have been identified as genotype-specific arrhythmic triggers in LQTS type 1 (LQTS1) and LQTS type 2 (LQTS2), respectively. OBJECTIVE: The purpose of this study was to compare LQTS group responses to arrhythmic triggers. METHODS: LQTS1 and LQTS2 patients were included. Before and after beta-blocker intake, electrocardiograms were recorded as participants (1) were exposed to a loud noise of ∼100 dB; and (2) had their face immersed into cold water. RESULTS: Twenty-three patients (9 LQTS1, 14 LQTS2) participated. In response to noise, LQTS groups showed similarly increased heart rate, but LQTS2 patients had corrected QT interval (Fridericia formula) (QTcF) prolonged significantly more than LQTS1 patients (37 ± 8 ms vs 15 ± 6 ms; P = .02). After intake of beta-blocker, QTcF prolongation in LQTS2 patients was significantly blunted and similar to that of LQTS1 patients (P = .90). In response to simulated diving, LQTS groups experienced a heart rate drop of ∼28 bpm, which shortened QTcF similarly in both groups. After intake of beta-blockers, heart rate dropped to 28 ± 2 bpm in LQTS1 patients and 20 ± 3 bpm in LQTS2, resulting in a slower heart rate in LQTS1 compared with LQTS2 (P = .01). In response, QTcF shortened similarly in LQTS1 and LQTS2 patients (57 ± 9 ms vs 36 ± 7 ms; P = .10). CONCLUSION: When exposed to noise, LQTS2 patients had QTc prolonged significantly more than did LQTS1 patients. Importantly, beta-blockers reduced noise-induced QTc prolongation in LQTS2 patients, thus demonstrating the protective effect of beta-blockers. In response to simulated diving, LQTS groups responded similarly, but a slower heart rate was observed in LQTS1 patients during simulated diving after beta-blocker intake.

Experimental analysis of the onset mechanism of TdP reported in an LQT3 patient during pharmacological treatment with serotonin-dopamine antagonists against insomnia and nocturnal delirium.

Torsade de pointes (TdP) occurred in a long QT syndrome type 3 (LQT3) patient after switching perospirone to blonanserin. We studied how their electropharmacological effects had induced TdP in the LQT3 patient. Perospirone hydrochloride (n = 4) or blonanserin (n = 4) of 0.01, 0.1, and 1 mg/kg, i.v. was cumulatively administered to the halothane-anesthetized dogs over 10 min. The low dose of perospirone decreased total peripheral vascular resistance, but increased heart rate and cardiac output, facilitated atrioventricular conduction, and prolonged J-Tpeakc. The middle dose decreased mean blood pressure and prolonged repolarization period, in addition to those observed after the low dose. The high dose further decreased mean blood pressure with the reduction of total peripheral vascular resistance; however, it did not increase heart rate or cardiac output. It tended to delay atrioventricular conduction and further delayed repolarization with the prolongation of Tpeak-Tend, whereas J-Tpeakc returned to its baseline level. Meanwhile, each dose of blonanserin decreased total peripheral vascular resistance, but increased heart rate, cardiac output and cardiac contractility in a dose-related manner. J-Tpeakc was prolonged by each dose, but Tpeak-Tend was shortened by the middle and high doses. These results indicate that perospirone and blonanserin may cause the hypotension-induced, reflex-mediated increase of sympathetic tone, leading to the increase of inward Ca2+ current in the heart except that the high dose of perospirone reversed them. Thus, blonanserin may have more potential to produce intracellular Ca2+ overload triggering early afterdepolarization than perospirone, which might explain the onset of TdP in the LQT3 patient.

Arrhythmogenic foods - A growing medical problem.

Arrhythmogenic ingredients in our diet such as mushrooms, licorice, toxic honey, liquid protein drinks, etc. have long been recognized as rare but important considerations in the differential diagnosis of arrhythmias. Anecdotal reports of torsades de pointes (TdP), arrhythmias and/or sudden death and small studies in normal subjects have suggested that simple ingredients such as grapefruit juice or ingredients in energy drinks marketed as dietary supplements could have direct arrhythmogenic actions, especially in patients with congenital long QT syndrome (cLQTS). Two recent studies that employed the industry-standard "thorough QT" trial design leave no doubt that grapefruit juice and some energy drinks can prolong the QTc interval and to exceed 500 msec. in some patients with cLQTS, a threshold known to signal imminent danger. These reports raise numerous clinically important questions such as which other patients may be at risk of arrhythmias. For example, patients with multiple clinical risk factors for TdP (hypokalemia, bradycardia, female sex, etc.) may be at risk from these and possibly other dietary ingredients ingested by millions of people each day. It is essential that further research evaluate the safety of these and similar food products and that vulnerable patients, especially those with cLQTS, be warned of this serious and emerging threat.

Multi-dry-electrode plate sensor for non-invasive electrocardiogram and heart rate monitoring for the assessment of drug responses in freely behaving mice.

Monitoring of electrocardiogram (ECG) and heart rate (HR) is essential in a wide range of experiments. For conscious animal studies, telemetry is the preferred approach; however, it requires 1-3 weeks of recovery after surgical device-implantation. The present paper describes a novel multi-dry-electrode plate (MDEP) sensor system to monitor ECG/HR in freely behaving mice without the need for surgery for device/electrode implantation. The MDEP sensor is a rectangular plate with 15 gold-plated stripe pattern electrodes, on which a mouse can walk around freely, and detects ECG whenever ≥2 paws (footpads) come in contact with the electrodes. Here we show that the MDEP sensor detected distinct QRS complexes which, were fragmented due to locomotion and insufficient perspiration on the footpads. Nonetheless, the HR calculated from the QRS complexes were similar to the HR calculated from R-R intervals simultaneously recorded from lead-II ECG (difference = 0.0 ±â€¯0.16 ms) as part of the validation exercise. Also, the archetypal responses to isoproterenol and metoprolol injections were successfully detected as a significantly elevation (+151 ±â€¯15 bpm) and reduction (-77 ±â€¯6 bpm) in HR, respectively, compared to vehicle at 20-60 min postdose. Conversely, the P wave was rarely identifiable unless signal averaging was undertaken. These results indicate a potential utility for the MDEP-sensor system for cardiac pharmacological studies. In addition, signal averaging appeared to be effective for detection of ECG intervals such as PR and QT, although the QT cannot be measured in the mouse heart as there is no T wave.

Arrhythmogenicity Test Based on a Human-Induced Pluripotent Stem Cell (iPSC)-Derived Cardiomyocyte Layer.

In vitro screening for potential side effects of drugs on human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) is a cutting-edge technology in pharmaceutical industry. International groups are currently considering using iPSC-CM as a part of comprehensive battery for an accurate and complex mechanistic-based assessment of the proarrhythmic potential of drugs. Despite iPSC-CMs expression and phenotype differences from mature adult CMs screening for drug-induced prolonged QT interval is now routinely carried and also recommended by ICH. The revelation of the mechanism of how the elongation of the QT interval is associated with the occurrence of an arrhythmia should extend the prospects of screening. To address this problem, a comprehensive tissue-based test for arrhythmogenicity is needed. Induced pluripotent stem (iPS) cells from a healthy individual were differentiated into a CM monolayer that was identified by immunocytochemistry and the patch-clamp technique also considering of the potential impact of the developing phenotype of the iPSC-CMs. To study the occurrence of reentry as a precursor to arrhythmias, a standard obstacle was created in the cell layer. With the aid of optical mapping, the measure of arrhythmogenicity was determined, as defined by the probability of a reentry occurrence for the particular frequency of stimulation. A change in the potassium current corresponding to LQTS type 2 at frequencies matching high heart rates was demonstrated visually and quantitatively. Also, the efficiency of this method for quantifying both the effectiveness and ineffectiveness of drugs for a particular donor and for determining the donor's cardiovascular disease risk zone was tested.

Long QT Syndrome: A Comprehensive Review of the Literature and Current Evidence.

Long QT syndrome (LQT) represents a heterogeneous family of cardiac electrophysiologic disorders characterized by QT prolongation and T-wave abnormalities on the electrocardiogram. It is commonly associated with syncope, however, sudden cardiac death can occur due to torsades de pointes. LQT is a clinical diagnosis and should be suspected in individuals on the basis of clinical presentation, family history and ECG characteristics. Management is focused on the prevention of syncope and ultimately sudden death. Complete cessation of symptoms is the goal. Life-style modification, beta blockers and ICD implantation are the most important therapeutic modalities in proper management of patients with LQT. Awareness should be raised regarding possible circumstances that could increase the risk of QT prolongation. Advanced age, hypokalemia, a history of heart failure, and structural heart disease are often mentioned in this context. Prudent consideration is needed before making a decision to recommend an ICD implantation in a young, active patient. Medical and/or device therapy still represent important therapeutic modalities in the management of patients with LQT with careful clinical judgement for the substrate of patients who will benefit. Insights from benchside to bedside have facilitated progress toward better therapeutic strategies, there also remains a need for tailoring management toward individuals in a mechanism-specific manner to optimize care. In addition, continued progress toward fundamental understanding of mechanisms of ion channel function and drug-channel interaction will guide the development of more effective, mechanism-based molecular agents in the treatment of LQT.

CiPA challenges and opportunities from a non-clinical, clinical and regulatory perspectives. An overview of the safety pharmacology scientific discussion.

The Safety Pharmacology Society organized a scientific session at its annual conference in 2017 to discuss the challenges and opportunities of the Comprehensive In-Vitro Proarrhythmia Assay (CiPA) paradigm. Our intention was to raise awareness of this initiative with its members and also to gauge the extent to which safety pharmacologists have incorporated the CiPA testing strategy within the pharmaceutical industry. CiPA offers many potential opportunities including 1) a focus on proarrhythmic risk (as opposed to QTc prolongation), 2) providing scientific rationale to support the continued development of compounds that may have a poor selectivity over hERG whilst also blocking other inward currents and 3) reducing the extent of ECG monitoring in clinical trials with a greater influence of the non-clinical studies. Such opportunities may speed drug development and reduce costs. However, there are also challenges for CiPA implementation. For example, the mixed ion channel paradigm does not easily lend itself to a prospective drug discovery strategy although testing for such effects can be achieved with assays with good throughput. However, it should also be recognized that compounds with a mixed ion channel profile might also have properties that are undesirable to treat non-life threatening indications. All components of CiPA (nonclinical and clinical) require validation, particularly as a composite package to impact drug development and evaluation. One of the significant discussion points was that the existing regulatory guidance supports the use of components of CiPA through follow-up studies. A survey of the conference audience showed that the level of awareness of CiPA is quite high and that companies are already conducting some testing against a wider panel of cardiac ion channels beyond hERG. However, the adoption of other technologies (stem cell derived cardiac myocytes and in silico modeling) is less well developed. Taken together, the session demonstrated the potential advantages of CiPA, but also some significant challenges.

Inappropriate automatic mode switching episodes: What's the mechanism?

We present a case series of five patients reporting abnormal automatic mode switching (AMS) episodes during routinary cardiac defibrillator (ICD) and pacemaker (PM) follow-up. This non-previously described phenomenon was reported to St. Jude Medical (Abbott) Technical Support that confirmed the inappropriate automatic mode switching.

Can non-clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium.

BACKGROUND AND PURPOSE: Translation of non-clinical markers of delayed ventricular repolarization to clinical prolongation of the QT interval corrected for heart rate (QTc) (a biomarker for torsades de pointes proarrhythmia) remains an issue in drug discovery and regulatory evaluations. We retrospectively analysed 150 drug applications in a US Food and Drug Administration database to determine the utility of established non-clinical in vitro IKr current human ether-à-go-go-related gene (hERG), action potential duration (APD) and in vivo (QTc) repolarization assays to detect and predict clinical QTc prolongation. EXPERIMENTAL APPROACH: The predictive performance of three non-clinical assays was compared with clinical thorough QT study outcomes based on free clinical plasma drug concentrations using sensitivity and specificity, receiver operating characteristic (ROC) curves, positive (PPVs) and negative predictive values (NPVs) and likelihood ratios (LRs). KEY RESULTS: Non-clinical assays demonstrated robust specificity (high true negative rate) but poor sensitivity (low true positive rate) for clinical QTc prolongation at low-intermediate (1×-30×) clinical exposure multiples. The QTc assay provided the most robust PPVs and NPVs (ability to predict clinical QTc prolongation). ROC curves (overall test accuracy) and LRs (ability to influence post-test probabilities) demonstrated overall marginal performance for hERG and QTc assays (best at 30× exposures), while the APD assay demonstrated minimal value. CONCLUSIONS AND IMPLICATIONS: The predictive value of hERG, APD and QTc assays varies, with drug concentrations strongly affecting translational performance. While useful in guiding preclinical candidates without clinical QT prolongation, hERG and QTc repolarization assays provide greater value compared with the APD assay.

Assessment of extracellular field potential and Ca2+ transient signals for early QT/pro-arrhythmia detection using human induced pluripotent stem cell-derived cardiomyocytes.

Cardiovascular toxicity is a prominent reason for failures in drug development, resulting in the demand for assays that can predict this liability in early drug discovery. We investigated whether iCell® cardiomyocytes have utility as an early QT/TdP screen. Thirty clinical drugs with known QT/TdP outcomes were evaluated blind using label-free microelectrode array (parameters measured were beating period (BP), field potential duration (FPD), fast Na+ amplitude and slope) and live cell, fast kinetic fluorescent Ca2+ transient FLIPR® Tetra (parameters measured were peak count, width, amplitude) systems. Many FPD-altering drugs also altered BP. Correction for BP, using a Log-Log (LL) model, was required to appropriately interpret direct drug effects on FPD. In comparison with human QT effects and when drug activity was to be predicted at top test concentration (TTC), LL-corrected FPD and peak count had poor assay sensitivity and specificity values: 13%/64% and 65%/11%, respectively. If effective free therapeutic plasma concentration (EFTPC) was used instead of TTC, the values were 0%/100% and 6%/100%, respectively. When compared to LL-corrected FPD and peak count, predictive values of uncorrected FPD, BP, width and amplitude were not much different. If pro-arrhythmic risk was to be predicted using Ca2+ transient data, the values were 67%/100% and 78%/53% at EFTPC and TTC, respectively. Thus, iCell® cardiomyocytes have limited value as an integrated QT/TdP assay, highlighting the urgent need for improved experimental alternatives that may offer an accurate integrated cardiomyocyte safety model for supporting the development of new drugs without QT/TdP effects.

Shortening of the electromechanical window in the ketamine/xylazine-anesthetized guinea pig model to assess pro-arrhythmic risk in early drug development.

BACKGROUND: A negative electromechanical window (EMw) was recently proposed as a better preclinical tool than QTc interval to predict clinical pro-arrhythmic potential. As such, we utilized the ketamine/xylazine anesthetized guinea pig to characterize the EMw and QTc interval for a diverse set of reference agents with known clinical pro-arrhythmic potential. Then we determined the clinical proarrhythmia predictive capacity of EMw shortening compared to hERG inhibition or QTc interval prolongation alone. METHODS: Changes in EMw and QTc interval by 26 reference agents were evaluated in the ketamine/xylazine-anesthetized guinea pig. Confusion matrix analysis using the hERG, QTc and EMw indexes (hERG IC50, QTc EC5 or the EMw EC-10 divided by their respective free therapeutic maximal plasma concentration) at various folds the therapeutic concentrations was conducted to assess the concordance of each index to predict clinical pro-arrhythmic risk. RESULTS: Shortening of the EMw concomitant to an increase in QTc interval was observed in the GP with known pro-arrhythmic drugs. Non-torsadogenic compounds did not cause EMw shortening, although some prolonged the QTc interval. The preclinical:clinical concordance of the EMw index (88%) was similar (p>0.05) to using QTc interval prolongation alone (85%) but significantly greater (p<0.05) than using hERG inhibition alone (69%). In addition, the specificity when using the EMw (87%) was largely greater (p<0.05) than using QTc interval (73%) or hERG inhibition (60%) alone. When the components of the response (duration of left ventricular pressure (LVP) cycle (QLVPend) or QT interval) that caused EMw shortening were considered, the concordance is further improved (>95%). CONCLUSION: EMw shortening improves QTc interval prolongation recording in early drug development and increases the translatability over existing preclinical tools in predicting clinical arrhythmias.

Points to consider for a validation study of iPS cell-derived cardiomyocytes using a multi-electrode array system.

Human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) provide a novel assay system to assess cardiac safety in drug development to overcome a problem of species difference in non-clinical testing during drug development. Using the multi-electrode array (MEA) platform, electrophysiological activities of iPS-CMs can be recorded easily to assess QT prolongation and proarrhythmic potential of drug candidates. Here we have established a standardized protocol to evaluate the possibility of iPS-CMs, and shared the protocol with an international consortium. To obtain reproducible and reliable experimental data from these cells, we determined the optimal experimental conditions, such as cell density, MEA coating, culture conditions, high-pass filter frequency, definition of early afterdepolarization or triggered activity, and calibration compounds. Based on the protocol, our validation study using 60 compounds is in progress. Thus, MEA-based experiments using iPS-CMs would be a standard testing method to evaluate QT prolongation and proarrhythmic potentials.

Which QT Correction Formulae to Use for QT Monitoring?

BACKGROUND: Drug safety precautions recommend monitoring of the corrected QT interval. To determine which QT correction formula to use in an automated QT-monitoring algorithm in our electronic medical record, we studied rate correction performance of different QT correction formulae and their impact on risk assessment for mortality. METHODS AND RESULTS: All electrocardiograms (ECGs) in patients >18 years with sinus rhythm, normal QRS duration and rate <90 beats per minute (bpm) in the University Hospitals of Leuven (Leuven, Belgium) during a 2-month period were included. QT correction was performed with Bazett, Fridericia, Framingham, Hodges, and Rautaharju formulae. In total, 6609 patients were included (age, 59.8±16.2 years; 53.6% male and heart rate 68.8±10.6 bpm). Optimal rate correction was observed using Fridericia and Framingham; Bazett performed worst. A healthy subset showed 99% upper limits of normal for Bazett above current clinical standards: men 472 ms (95% CI, 464-478 ms) and women 482 ms (95% CI 474-490 ms). Multivariate Cox regression, including age, heart rate, and prolonged QTc, identified Framingham (hazard ratio [HR], 7.31; 95% CI, 4.10-13.05) and Fridericia (HR, 5.95; 95% CI, 3.34-10.60) as significantly better predictors of 30-day all-cause mortality than Bazett (HR, 4.49; 95% CI, 2.31-8.74). In a point-prevalence study with haloperidol, the number of patients classified to be at risk for possibly harmful QT prolongation could be reduced by 50% using optimal QT rate correction. CONCLUSIONS: Fridericia and Framingham correction formulae showed the best rate correction and significantly improved prediction of 30-day and 1-year mortality. With current clinical standards, Bazett overestimated the number of patients with potential dangerous QTc prolongation, which could lead to unnecessary safety measurements as withholding the patient of first-choice medication.

ECG telemetry in conscious guinea pigs.

INTRODUCTION: During preclinical drug development, monitoring of the electrocardiogram (ECG) is an important part of cardiac safety assessment. To detect potential pro-arrhythmic liabilities of a drug candidate and for internal decision-making during early stage drug development an in vivo model in small animals with translatability to human cardiac function is required. METHODS: Over the last years, modifications/improvements regarding animal housing, ECG electrode placement, and data evaluation have been introduced into an established model for ECG recordings using telemetry in conscious, freely moving guinea pigs. Pharmacological validation using selected reference compounds affecting different mechanisms relevant for cardiac electrophysiology (quinidine, flecainide, atenolol, dl-sotalol, dofetilide, nifedipine, moxifloxacin) was conducted and findings were compared with results obtained in telemetered Beagle dogs. RESULTS AND CONCLUSION: Under standardized conditions, reliable ECG data with low variability allowing largely automated evaluation were obtained from the telemetered guinea pig model. The model is sensitive to compounds blocking cardiac sodium channels, hERG K(+) channels and calcium channels, and appears to be even more sensitive to ß-blockers as observed in dogs at rest. QT interval correction according to Bazett and Sarma appears to be appropriate methods in conscious guinea pigs. Overall, the telemetered guinea pig is a suitable model for the conduct of early stage preclinical ECG assessment.

Finding the rhythm of sudden cardiac death: new opportunities using induced pluripotent stem cell-derived cardiomyocytes.

Sudden cardiac death is a common cause of death in patients with structural heart disease, genetic mutations, or acquired disorders affecting cardiac ion channels. A wide range of platforms exist to model and study disorders associated with sudden cardiac death. Human clinical studies are cumbersome and are thwarted by the extent of investigation that can be performed on human subjects. Animal models are limited by their degree of homology to human cardiac electrophysiology, including ion channel expression. Most commonly used cellular models are cellular transfection models, which are able to mimic the expression of a single-ion channel offering incomplete insight into changes of the action potential profile. Induced pluripotent stem cell-derived cardiomyocytes resemble, but are not identical, adult human cardiomyocytes and provide a new platform for studying arrhythmic disorders leading to sudden cardiac death. A variety of platforms exist to phenotype cellular models, including conventional and automated patch clamp, multielectrode array, and computational modeling. Induced pluripotent stem cell-derived cardiomyocytes have been used to study long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and other hereditary cardiac disorders. Although induced pluripotent stem cell-derived cardiomyocytes are distinct from adult cardiomyocytes, they provide a robust platform to advance the science and clinical care of sudden cardiac death.

Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.

BACKGROUND AND PURPOSE: Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans. EXPERIMENTAL APPROACH: We derived typical ΔQTc predictions at therapeutic exposure (ΔQTcTHER ) with 95% confidence intervals (95%CI) for 3 Kv 11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2-6 studies including 10-32 dogs per compound) to derive meta-predictions of typical ΔQTcTHER . Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature. KEY RESULTS: The 95%CIs of study-predicted ΔQTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1-69%). Meta-ΔQTcTHER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline. CONCLUSIONS AND IMPLICATIONS: Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical-clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments.