Arrhythmogenic Potential Research Articles

Fibrosis and wall thickness affect ventricular repolarization dynamics in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by ventricular repolarization abnormalities and risk of ventricular arrhythmias. Our aim was to study the association between the phenotype and ventricular repolarization dynamics in HCM patients. HCM patients with either the MYBPC3-Q1061X or TPM1-D175N mutation (n=46) and control subjects without mutation and hypertrophy (n=35) were studied with 24-hr ambulatory ECG recordings by measuring time intervals of rate-adapted QT (QTe), maximal QT, and T-wave apex to wave end (TPE) intervals and the QTe/RR slope. Findings were correlated to specified echocardiographic and cardiac magnetic resonance imaging (CMRI) findings. Rate-adapted QTe interval was progressively longer in HCM patients with decreasing heart rates compared to control subjects (p=0.020). The degree of hypertrophy correlated with measured QTe values. HCM patients with maximal wall thickness higher than the mean (20.6mm) had longer maximum QTe and median TPE intervals compared to control subjects and HCM patients with milder hypertrophy (p<0.001 and p=0.014, respectively). HCM patients with late gadolinium enhancement (LGE) on CMRI had steeper QTe/RR slopes compared to HCM patients without LGE and control subjects (p=0.044 and p=0.001, respectively). LGE was an independent predictor of QTe/RR slope (p=0.023, B=0.043). Dynamics of ventricular repolarization in HCM are affected by hypertrophy and fibrosis. LGE may confer an independent effect on QT dynamics which may increase the arrhythmogenic potential in HCM.

Cytosolic increased labile Zn2+ contributes to arrhythmogenic action potentials in left ventricular cardiomyocytes through protein thiol oxidation and cellular ATP depletion

Intracellular labile (free) Zn2+-level ([Zn2+]i) is low and increases markedly under pathophysiological conditions in cardiomyocytes. High [Zn2+]i is associated with alterations in excitability and ionic-conductances while exact mechanisms are not clarified yet. Therefore, we examined the elevated-[Zn2+]i on some sarcolemmal ionic-mechanisms, which can mediate cardiomyocyte dysfunction. High-[Zn2+]i induced significant changes in action potential (AP) parameters, including depolarization in resting membrane-potential and prolongations in AP-repolarizing phases. We detected also the time-dependent effects such as induction of spontaneous APs at the time of ≥ 3 min following [Zn2+]i increases, a manner of cellular ATP dependent and reversible with disulfide-reducing agent dithiothreitol, DTT. High-[Zn2+]i induced inhibitions in voltage-dependent K+-channel currents, such as transient outward K+-currents, Ito, steady-state currents, Iss and inward-rectifier K+-currents, IK1, reversible with DTT seemed to be responsible from the prolongations in APs. We, for the first time, demonstrated that lowering cellular ATP level induced significant decreaeses in both Iss and IK1, while no effect on Ito. However, the increased-[Zn2+]i could induce marked activation in ATP-sensitive K+-channel currents, IKATP, depending on low cellular ATP and thiol-oxidation levels of these channels. The mRNA levels of Kv4.3, Kv1.4 and Kv2.1 were depressed markedly with increased-[Zn2+]i with no change in mRNA level of Kv4.2, while the mRNA level of IKATP subunit, SUR2A was increased significantly with increased-[Zn2+]i, being reversible with DTT. Overall we demonstrated that high-[Zn2+]i, even if nanomolar levels, alters cardiac function via prolonged APs of cardiomyocytes, at most, due to inhibitions in voltage-dependent K+-currents, although activation of IKATP is playing cardioprotective role, through some biochemical changes in cellular ATP- and thiol-oxidation levels. It seems, a well-controlled [Zn2+]i can be novel therapeutic target for cardiac complications under pathological conditions including oxidative stress.

Reduced Arrhythmogenic Potential of Ventricular Paired Pacing During Myocardial Infarction

Since the 1960's, the clinical use of ventricular paired pacing (VPP), a form of continuous postextrasystolic potentiation, to augment cardiac function in cardiogenic shock has been prevented by the stigma of ventricular arrhythmogenesis. Historically, this perception was based on very limited human data on the sickest of the sick when many current medical treatments were long into the future. One such treatment is the use of β‐adrenergic receptor blockade, well accepted now, but antithetical then. A meta‐analysis of canine studies of myocardial infarction was performed to understand the effect β‐blockade had on the incidence of ventricular fibrillation during the VPP treatment

Structural heterogeneity of the rat pulmonary vein myocardium: consequences on intracellular calcium dynamics and arrhythmogenic potential

Mechanisms underlying ectopic activity in the pulmonary vein (PV) which triggers paroxysmal atrial fibrillation are unknown. Although several studies have suggested that calcium signalling might be involved in these arrhythmias, little is known about calcium cycling in PV cardiomyocytes (CM). We found that individual PV CM showed a wide range of transverse tubular incidence and organization, going from their virtual absence, as described in atrial CM, to well transversally organised tubular systems, like in ventricular CM. These different types of CM were found in groups scattered throughout the tissue. The variability of the tubular system was associated with cell to cell heterogeneity of calcium channel (Cav1.2) localisation and, thereby, of Cav1.2-Ryanodine receptor coupling. This was responsible for multiple forms of PV CM calcium transient. Spontaneous calcium sparks and waves were not only more abundant in PV CM than in LA CM but also associated with a higher depolarising current. In conclusion, compared with either the atrium or the ventricle, PV myocardium presents marked structural and functional heterogeneity.

Tropical Coronary Artery Disease and Arrhythmogenic Potentials—The Changing Pattern towards Endomyocardial Fibrosis—An Analysis

Aim: To analyse the increasing burden of coronary artery disease (CAD) in tropical and subtropical belts of the Equator since it remains blurred and carries a grim prognosis. Introduction: Endomyocardial fibrosis [EMF] is a tropical febrile disorder, confined to peculiar and limited geographical areas. Plaque buildup in endocardium and coronary arteries, causing ischemic injury and arrhythmic episodes, is a vanishing mystery in its pathogenesis and emphasizing alternative routes for understanding and treatment of this enigmatic disease. Case Report: 15 cases in various age groups were reported with potential complications of coronary artery disease and arrhythmias, associated with endocardial lesions, the characteristic feature of endomyocardial fibrosis. Conclusion: The narrowing of coronary arteries as a result of thickening of the walls, spasm, inflammation, plaques and its rupture produce ischemic episodes which can occur slowly or suddenly in a devastating pattern with arrhythmogenic potentials. The important steps to prevent and decrease the risk of CAD is to reduce the chance of getting this disorder by epidemiological measures with an advice of blood thinning medications such as small daily dose aspirin, antibiotics in susceptible individuals and revascularization in established myocardial infarction.

Ciprofloxacin, an antibiotic with cardiac actions on isolated rat hearts

Context: Ciprofloxacin is the most commonly used fluoroquinolone and is prescribed as the antibiotic of choice in the treatment of several microbial infections. Some clinical reports have suggested that ciprofloxacin may induce QT-interval prolongation and Torsades de Pointes arrhythmias. This drug is a weak inhibitor of a rapid component of the cardiac delayed rectifier potassium current IKr, but there are few electrophysiological data available to assess whether ciprofloxacin has the potency to provoke QT prolongation and subsequent Torsades de Pointes arrhythmias. Aims: To evaluate the effect of ciprofloxacin on the contractile and electrical activity of isolated rat hearts. Methods: The Langendorff technique was performed in rat hearts, and the effects of ciprofloxacin (0.001 - 100 μM) were measured on the cardiac force of contraction and on the RR, QRS and QTc intervals. The arrhythmogenic potential and the ventricular fibrillation threshold were evaluated with ciprofloxacin. Results: Ciprofloxacin decreased the force of contraction of all hearts studied, in a concentration-dependent manner. The estimated IC50 for the inotropic negative effect was 0.15 ± 0.04 μM. Ciprofloxacin significantly prolonged the QRS complex, QTc and RR interval. Significant arrhythmic effects with ciprofloxacin were shown and the ventricular fibrillation threshold was decreased. Conclusions: These results suggest that ciprofloxacin exerted effects on cardiac Na+, K+ and Ca2+ channels. The actions of ciprofloxacin require further studies at the cellular level. These conclusions may account for clinical data that have been reported previously.

Age-dependent electrocardiographic changes in Pgc-1β deficient murine hearts.

SummaryIncreasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc‐1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12‐16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc‐1β−/− (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1‐adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc‐1β−/− genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino‐atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc‐1β−/− mice. Moreover, Pgc‐1β−/− mice displayed electrocardiographic features consistent with the existence of a pro‐arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc‐1β−/− mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QTc interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc‐1β−/− systems in widespread cardiac regions.

Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches.

Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca2+-activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4. Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed. After rapid desensitization, robust reactivation of TRPM4 channels required high micromolar concentrations of Ca2+. However, upon evaluation with a newly devised, ionomycin-permeabilized cell-attached (Iono-C/A) recording technique, submicromolar concentrations of Ca2+ (apparent Kd = ∼500 nM) were enough to activate this channel. Similar submicromolar Ca2+ dependency was also observed with sharp electrode whole-cell recording and in experiments coexpressing TRPM4 and L-type voltage-dependent Ca2+ channels. Numerical simulations using a number of action potential (AP) models (HL-1, Nygren, Luo-Rudy) incorporating the Ca2+- and voltage-dependent gating parameters of TRPM4, as assessed by Iono-C/A recording, indicated that a few-fold increase in TRPM4 activity is sufficient to delay late AP repolarization and further increases (≥ six-fold) evoke early afterdepolarization. These model predictions are consistent with electrophysiological data from angiotensin II-treated HL-1 cells in which TRPM4 expression and activity were enhanced. These results collectively indicate that the TRPM4 channel is activated by a physiological range of Ca2+ concentrations and its excessive activity can cause arrhythmic changes. Moreover, these results demonstrate potential utility of the first AP models incorporating TRPM4 gating for in silico assessment of arrhythmogenicity in remodelling cardiac tissue.

Early regional wall distension is strongly associated with vulnerability to ventricular fibrillation but not arrhythmia triggers following coronary occlusion in vivo

Wall stress may favor ischemic ventricular arrhythmias, yet its association with ventricular fibrillation (VF) or ventricular ectopy has been inconsistent among studies and its potential arrhythmogenicity across the cardiac cycle is unclear. In 91 open-chest pigs undergoing 40–50 min left anterior descending artery occlusion, we assessed the association between diastolic or systolic distension of the ischemic area and the incidence of ventricular premature beats (VPBs) and VF. End-diastolic segment length (EDL) and systolic bulging ([maximum systolic length–EDL] × 100/EDL) were measured by ultrasonic crystals. Fifteen minutes after occlusion, EDL increased to 112.7 ± 5.6% of baseline (P < 0.001) and systolic bulging averaged 3.4 ± 2.2%. Median VPB number was 52 (IQR, 16–110), 2 (0–7) in phase Ia and 49 (13–94) in phase Ib. VF occurred in 26 animals (28.6%), the first episode appearing 24 ± 6 min after occlusion. EDL increase was associated with subsequent VF (115.9 ± 5.7 and 111.4 ± 5.1% in animals with and without VF, P < 0.001) and with the number of VF episodes (P = 0.001) but not with VPB number, overall (r = 0.028, P = 0.801) or in phases Ia or Ib. Systolic bulging was related neither to VF occurrence (3.2 ± 2.2 and 3.5 ± 2.2%, respectively, P = 0.561) nor to VBP number (r = 0.095, P = 0.397). EDL increase predicted VF after adjusting for ischemic area size and K+ levels (odds ratio for 1% increase: 1.17, 95%CI 1.06–1.29, P = 0.001). Thus, diastolic regional ventricular distension predicts VF occurrence after coronary occlusion whereas neither diastolic nor systolic distension is associated with ventricular ectopy, which suggests that distension favors VF by acting on the arrhythmic substrate but not on arrhythmia triggers.

205 - High arrhythmogenic potential of calcium waves in rat isolated pulmonary vein cardiomyocytes

205 - High arrhythmogenic potential of calcium waves in rat isolated pulmonary vein cardiomyocytes

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis.

The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n = 12) or anterior myocardial infarction (MI, n = 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CVL) was increased by RSGS (0.98 ± 0.11 vs. 1.2 ± 0.14m/s, P < 0.001) but not transverse CV (CVT). This increase was abrogated by β-adrenergic receptor and gap junction (GJ) blockade. Neither CVL nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 ± 37 vs. 322 ± 30 ms, P < 0.001, and 423 ± 36 vs. 398 ± 36 ms, P = 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 ± 1.2 vs. 17.3 ± 1.6 ms, P = 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (P < 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic peri-infarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.NEW & NOTEWORTHY This study demonstrates regional control of conduction velocity in normal hearts by sympathetic nerves. In infarcted hearts, however, not only is modulation of propagation heterogeneous, some regions showed paradoxical conduction slowing. Sympathoexcitation altered propagation in all infarcted hearts studied, and we describe the temporal arrhythmogenic potential of these findings.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/sympathetic-nerves-and-cardiac-propagation/.

Usefulness of cardiotoxicity assessment using calcium transient in human induced pluripotent stem cell-derived cardiomyocytes

Monitoring dramatic changes in intracellular calcium ion levels during cardiac contraction and relaxation, known as calcium transient, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be an attractive strategy for assessing compounds on cardiac contractility. In addition, as arrhythmogenic compounds are known to induce characteristic waveform changes in hiPSC-CMs, it is expected that calcium transient would allow evaluation of not only compound-induced effects on cardiac contractility, but also compound arrhythmogenic potential. Using a combination of calcium transient in hiPSC-CMs and a fast kinetic fluorescence imaging detection system, we examined in this study changes in calcium transient waveforms induced by a series of 17 compounds that include positive/negative inotropic agents as well as cardiac ion channel activators/inhibitors. We found that all positive inotropic compounds induced an increase in peak frequency and/or peak amplitude. The effects of a negative inotropic compound could clearly be detected in the presence of a β-adrenergic receptor agonist. Furthermore, most arrhythmogenic compounds raised the ratio of peak decay time to peak rise time (D/R ratio) in calcium transient waveforms. Compound concentrations at which these parameters exceeded cutoff values correlated well with systemic exposure levels at which arrhythmias were reported to be evoked. In conclusion, we believe that peak analysis of calcium transient and determination of D/R ratio are reliable methods for assessing compounds' cardiac contractility and arrhythmogenic potential, respectively. Using these approaches would allow selection of compounds with low cardiotoxic potential at the early stage of drug discovery.

The effects of zoledronic acid on ECG: a prospective study on patients with bone metastatic cancer.

There are controversial results in the risk of atrial fibrillation as well as arrhythmogenic potential of bis-phosphonates. 37 patients and 40 healthy controls were evaluated prospectively with regard to the cardiac side effects related to the use of zoledronic acid (ZA) and its effects on electrocardiography (ECG) parameters. As the basal ECG results of the patients diagnosed with cancer compared with the control group, it was determined that QT maximum was significantly lower, QT minimum was significantly higher. However; it was determined that QT disp, P max, P min, and P disp values were not significantly different. There was no statistically significant difference in P max, P min, P disp, QT max, QT min, QT disp values of the ECG parameters measured from cancer patients, before and 60 minutes after ZA therapy. There were no significant alterations in ECG in the acute period, indicated that ZA had no arrhythmia potential in the early period in patients with no underlying cardiac disease. However: patients receiving ZA should be monitored more closely because of the risk of arrhythmia which may ensue due to hypocalcemia, hypomagnesemia, or other chemotherapeutics.

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes.

The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for drug-induced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval.

Evaluation system for arrhythmogenic potential of drugs using human-induced pluripotent stem cell-derived cardiomyocytes and gene expression analysis.

In recent years, human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) have been widely used to develop evaluation systems for drug cardiotoxicity, including the arrhythmia caused by QT prolongation. To accurately assess the arrhythmogenic potential of drugs, associated with QT prolongation, we developed an evaluation system using hiPS-CMs and gene expression analysis. hiPS-CMs were treated with 8 arrhythmogenic and 17 non-arrhythmogenic drugs at several concentrations for 24 hr to comprehensively analyze gene expression. The results showed that 19 genes were upregulated in the arrhythmogenic drug-treated cells compared with their expression levels in the non-treated and non-arrhythmogenic drug-treated cells. The arrhythmogenic risks of the drugs were evaluated by scoring gene expression levels. The results indicated that arrhythmogenic risks could be inferred when cells were treated at a concentration 100 times higher than the maximum blood concentration of the drug. Thus, we succeeded in developing a system for evaluation of the arrhythmogenic potential of drugs using gene expression analysis.

Dobutamine Stress Echocardiography Safety in Chagas Disease Patients.

BackgroundA few decades ago, patients with Chagas disease were predominantly rural workers, with a low risk profile for obstructive coronary artery disease (CAD). As urbanization has increased, they became exposed to the same risk factors for CAD of uninfected individuals. Dobutamine stress echocardiography (DSE) has proven to be an important tool in CAD diagnosis. Despite being a potentially arrhythmogenic method, it is safe for coronary patients without Chagas disease. For Chagas disease patients, however, the indication of DSE in clinical practice is uncertain, because of the arrhythmogenic potential of that heart disease.ObjectivesTo assess DSE safety in Chagas disease patients with clinical suspicion of CAD, as well as the incidence of arrhythmias and adverse events during the exam.MethodsRetrospective analysis of a database of patients referred for DSE from May/2012 to February/2015. This study assessed 205 consecutive patients with Chagas disease suspected of having CAD. All of them had their serology for Chagas disease confirmed.ResultsTheir mean age was 64±10 years and most patients were females (65.4%). No patient had significant adverse events, such as acute myocardial infarction, ventricular fibrillation, asystole, stroke, cardiac rupture and death. Regarding arrhythmias, ventricular extrasystoles occurred in 48% of patients, and non-sustained ventricular tachycardia in 7.3%.ConclusionDSE proved to be safe in this population of Chagas disease patients, in which no potentially life-threatening outcome was found.

An unusual case of syncope

Early repolarization syndrome (ERS) is a common electrocardiography (ECG) variant which may prove to be an indicator of increased long-term cardiac mortality in general population. Although the condition is usually considered to be benign, potential arrhythmogenicity of it has been suggested by experimental studies. ERS involving inferolateral leads in the ECG has been seen to be associated with syncopal attacks or sudden cardiac death in young healthy persons. Here, we report a rare case of young asymptomatic healthy male who presented with syncope while at rest and sinus bradycardia with incidental findings of ERS on ECG.

Electrophysiological Characteristics of Human iPSC-Derived Cardiomyocytes for the Assessment of Drug-Induced Proarrhythmic Potential.

The aims of this study were to (1) characterize basic electrophysiological elements of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that correspond to clinical properties such as QT-RR relationship, (2) determine the applicability of QT correction and analysis methods, and (3) determine if and how these in-vitro parameters could be used in risk assessment for adverse drug-induced effects such as Torsades de pointes (TdP). Field potential recordings were obtained from commercially available hiPSC-CMs using multi-electrode array (MEA) platform with and without ion channel antagonists in the recording solution. Under control conditions, MEA-measured interspike interval and field potential duration (FPD) ranged widely from 1049 to 1635 ms and from 334 to 527 ms, respectively and provided positive linear regression coefficients similar to native QT-RR plots obtained from human electrocardiogram (ECG) analyses in the ongoing cardiovascular-based Framingham Heart Study. Similar to minimizing the effect of heart rate on the QT interval, Fridericia’s and Bazett’s corrections reduced the influence of beat rate on hiPSC-CM FPD. In the presence of E-4031 and cisapride, inhibitors of the rapid delayed rectifier potassium current, hiPSC-CMs showed reverse use-dependent FPD prolongation. Categorical analysis, which is usually applied to clinical QT studies, was applicable to hiPSC-CMs for evaluating torsadogenic risks with FPD and/or corrected FPD. Together, this results of this study links hiPSC-CM electrophysiological endpoints to native ECG endpoints, demonstrates the appropriateness of clinical analytical practices as applied to hiPSC-CMs, and suggests that hiPSC-CMs are a reliable models for assessing the arrhythmogenic potential of drug candidates in human.

Targeted Cancer Therapies and QT Interval Prolongation: Unveiling the Mechanisms Underlying Arrhythmic Complications and the Need for Risk Stratification Strategies.

The care and treatment of cancer patients has significantly changed in the last decade with a remarkable shift towards novel targeted therapies. These promising new drugs may represent effective and potentially life-saving therapeutic options in cancer patients, but are also emerging in the cardiotoxicity scenario for their arrhythmogenic potential due to their QT-prolonging activity. In this article we review the mechanisms underlying drug-induced QT interval prolongation and the classes of anticancer-targeted therapies most frequently responsible for this adverse event, with a particular focus on tyrosine kinase-targeting molecules. Since up to 49% of serious adverse drug reactions (ADRs) and 58% of potentially fatal ADRs may not appear on initial drug safety labels, we also review and discuss data from the post-marketing VigiBase® safety reporting system, the World Health Organization's global database of ADRs. Finally, we discuss arrhythmic risk stratification and prevention strategies in the complex multiple-risk setting of cancer patients, paying particular attention to drug-drug interactions with common antimicrobial, psychotropic and antiemetic supportive care, and we also provide an electrocardiographic QT monitoring algorithm for patients who are candidates for targeted cancer therapies.

In vivo Electrophysiological Study of Induced Ventricular Tachycardia in Intact Rat Model of Chronic Ischemic Heart Failure.

The objective of this study was to define the clinical relevance of in vivo electrophysiologic (EP) studies in a rat model of chronic ischemic heart failure (CHF). Electrical activation sequences, voltage amplitudes, and monophasic action potentials (MAPs) were recorded from adult male Sprague-Dawley rats six weeks after left coronary artery ligation. Programmed electrical stimulation (PES) sequences were developed to induce sustained ventricular tachycardia (VT). The inducibility of sustained VT was defined by PES and the recorded tissue MAPs. Rats in CHF were defined ( 0.05) by elevated left ventricular (LV) end-diastolic pressure (5 ± 1 versus 18 ± 2 mmHg), decreased LV + d P/dt (7496 ± 225 versus 5502 [Formula: see text] s), LV - dP/dt (7723 ± 208 versus 3819 [Formula: see text]), LV ejection fraction (79 ± 3 versus [Formula: see text]), peak developed pressure (176 ± 4 versus 145 ± 9 mmHg), and prolonged time constant of LV relaxation Tau (18 ± 1 versus 29 ± 2 ms). The EP data showed decreased ( 0.05) electrogram amplitude in border and infarct zones (Healthy zone (H): 8.7 ± 2.1 mV, Border zone (B): 5.3 ± 1.6 mV, and Infarct zone (I): 2.3 ± 1.2 mV), decreased MAP amplitude in the border zone (H: [Formula: see text] 1.0 mV, B: 9.7 ± 0.5 mV), and increased repolarization heterogeneity in the border zone (H: 8.1 ± 1.5 ms, B: 20.2 ± 3.1 ms). With PES we induced sustained VT (>15 consecutive PVCs) in rats with CHF (10/14) versus Sham (0/8). These EP studies establish a clinically relevant protocol for studying genesis of VT in CHF. The in vivo rat model of CHF combined with EP analysis could be used to determine the arrhythmogenic potential of new treatments for CHF.