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Background: Short-term variability (STV) of repolarization of the monophasic action potential duration (MAPD) or activation recovery interval (ARI) on the intracardiac electrogram (EGM) increases abruptly prior to the occurrence of ventricular arrhythmias in the chronic AV-block (CAVB) dog model. Therefore, this parameter might be suitable for continuous monitoring of imminent arrhythmias using the EGM stored on an implanted device. However, 24/7 monitoring would require automatic STVARI measurement by the device. Objective: To evaluate a newly developed automatic measurement of STVARI for prediction of dofetilide-induced torsade de pointes (TdP) arrhythmias in the CAVB-dog. Methods: Two retrospective analyses were done on data from recently performed dog experiments. (1) In seven anesthetized CAVB-dogs, the new automatic STVARI method was compared with the gold standard STVMAPD at baseline and after dofetilide administration (0.025 mg/kg in 5 min). (2) The predictive value of the automatic method was compared to currently used STVARI methods, i.e., slope method and fiducial segment averaging (FSA) method, in 11 inducible (≥3 TdP arrhythmias) and 10 non-inducible CAVB-dogs. Results: (1) The automatic measurement of STVARI had good correlation with STVMAPD (r2 = 0.89; p < 0.001). Bland-Altman analysis showed a small bias of 0.06 ms with limits of agreement between −0.63 and 0.76 ms. (2) STVARI of all three methods was significantly different between inducible and non-inducible dogs after dofetilide. The automatic method showed the highest predictive performance with an area under the ROC-curve of 0.93, compared to 0.85 and 0.87 of the slope and FSA methods, respectively. With a threshold of STV set at 1.69 ms, STVARI measured with the automatic method had a sensitivity of 0.91 and specificity of 0.90 in differentiating inducible from non-inducible subjects. Conclusion: We developed a fully-automatic method for measurement of STVARI on the intracardiac EGM that can accurately predict the occurrence of ventricular arrhythmias in the CAVB-dog. Future integration of this method into implantable devices could provide the opportunity for 24/7 monitoring of arrhythmic risk.

Kv11.1 (hERG) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g. dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use due to their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue WT or G601S Kv11.1 trafficking as shown by western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S Kv11.1 cells, dofetilide (10 μM) or dofetilide+LUF7244 (10+5 μM) restored Kv11.1 trafficking also, as demonstrated by western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased IKv11.1 despite the presence of dofetilide (1 μM) in WT Kv11.1 cells. In G601S expressing cells, long-term treatment (24-48 h) with LUF7244 (10 μM) and dofetilide (1 μM) increased IKv11.1 compared to non-treated, or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1. Thus, combined administration of LUF7244 and an IKV11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced Kv11.1 trafficking defects.

Background: Dofetilide is one of the only anti-arrhythmic agents approved for atrial fibrillation (AF) in patients with reduced left ventricular ejection fraction (LVEF). However, postapproval data and safety outcomes are limited. In this study, we assessed the incidence and predictors of LVEF improvement, safety, and outcomes in patients with AF with LVEF ≤35% without prior implantable cardioverter defibrillator, cardiac resynchronization therapy, or AF ablation. Methods: An analysis of 168 consecutive patients from 2007 to 2016 was performed. Incidences of adverse events, drug continuation, implantable cardioverter defibrillator and cardiac resynchronization therapy implantation, LVEF improvement (>35%) and recovery (≥50%), AF recurrence, and AF ablation were determined. Multivariable regression analysis to identify predictors of LVEF improvement/recovery was performed. Results: The mean age was 64±12 years. Dofetilide was discontinued before hospital discharge in 46 (27%) because of QT prolongation (14%), torsades de pointe or polymorphic ventricular tachycardia/fibrillation (6% [sustained 3%, nonsustained 3%]), ineffectiveness (5%), or other causes (3%). At 1 year, 43% remained on dofetilide. Freedom from AF was 42% at 1 year, and 40% underwent future AF ablation. LVEF recovered (≥50%) in 45% and improved to >35% in 73%. Predictors of LVEF improvement included presence of AF during echocardiogram (odds ratio, 4.22 [95% CI, 1.71–10.4], P =0.002), coronary artery disease (odds ratio, 0.35 [95% CI, 0.16–0.79], P =0.01), left atrial diameter (odds ratio, 0.52 per 1 cm increase [95% CI, 0.30–0.90], P =0.01), and LVEF (odds ratio, per 1% increase, 1.09 [95% CI, 1.02–1.16], P =0.006). The C statistic was 0.78. Conclusions: In patients with LVEF ≤35%, who are potential implantable cardioverter defibrillator candidates, treated with dofetilide as an initial anti-arrhythmic strategy for AF, drug discontinuation rates were high, and many underwent future AF ablation. However, most patients had improvement in LVEF, obviating the need for primary prevention implantable cardioverter defibrillator.

Using animal cells and tissues as precise measuring devices for developing new drugs presents a long-standing challenge for the pharmaceutical industry. Despite the very significant resources that continue to be dedicated to animal testing of new compounds, only qualitative results can be obtained. This often results in both false positives and false negatives. Here, we show how the effect of drugs applied to animal ventricular myocytes can be translated, quantitatively, to estimate a number of different effects of the same drug on human cardiomyocytes. We illustrate and validate our methodology by translating, from animal to human, the effect of dofetilide applied to dog cardiomyocytes, the effect of E-4031 applied to zebrafish cardiomyocytes, and, finally, the effect of sotalol applied to rabbit cardiomyocytes. In all cases, the accuracy of our quantitative estimates are demonstrated. Our computations reveal that, in principle, electrophysiological data from testing using animal ventricular myocytes, can give precise, quantitative estimates of the effect of new compounds on human cardiomyocytes.

Background The anesthetized, complete chronic atrioventricular block (CAVB) dog model allows reproducible inducibility of torsades de pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr blocker. High-rate pacing (HRP) prevents ventricular arrhythmias but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases before ventricular arrhythmias and has been proposed as a marker to guide HRP. Objective The purpose of this proof-of-principle study was to show that automatically determined STV can guide HRP to prevent imminent ventricular arrhythmias. Methods Eight CAVB dogs were implanted with an implantable cardioverter-defibrillator (ICD) with software to automatically determine STV (STVICD) in real time. During HRP, STV was measured offline from right ventricular (RV) electrograms (EGMs) and left ventricular (LV) monophasic action potential durations (MAPDs) (STVRV,EGM/LV,MAPD). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg intravenously over 5 minutes or until the first TdP). In experiment 1, the individual STVICD threshold before the first arrhythmic event was determined and programmed into the ICD. In experiment 2, HRP with 100 bpm was initiated automatically once the STVICD threshold was reached. Results In experiment 1, 8 of 8 dogs had repetitive TdP, and STVICD increased from 0.96 ± 0.42 ms to 2.10 ± 1.26 ms (P Conclusion STV can guide HRP automatically by an ICD to prevent ventricular arrhythmias.

Background Dofetilide is an antiarrhythmic medication that has the potential to cause life threatening arrhythmias, such as Torsade de pointes. The 2014 ACC/AHA/HRS guidelines for the management of patients with atrial fibrillation state that patients need to meet certain criteria to be initiated on dofetilide. Patients who are not initiated on this therapy according to the guideline criteria are likely to be at higher risk of adverse reactions. Methods This is a single center, retrospective chart review of patients who were initiated on dofetilide from July 2016-December 2019. Patients included in the study were initiated on dofetilide as a new antiarrhythmic and monitored inpatient for three days. The primary outcome was a composite of incidence of cardiac arrhythmias, cardiac arrest, cardiac death, and cardiac related hospital readmission. Results There were 224 patients included in the analysis: 190 patients who were initiated on dofetilide inappropriately and 34 that were initiated appropriately. The primary outcome (composite of cardiac arrhythmia, cardiac arrest, cardiac death, and hospital readmission) was statistically significant with more patients experiencing an outcome in the group initiated inappropriately. Discussion Patients are placed at a higher risk of adverse reactions when this potentially dangerous antiarrhythmic medication is not used according to the protocol set forth by the guidelines. Conclusion Practitioners should use caution when prescribing dofetilide. Other antiarrhythmic medications or non-pharmacologic options should be considered due to the incidence of these dangerous adverse reactions.

NEW FINDINGS What is the central question of this study? Can antiarrhythmic drug effects on repolarization, conduction time and excitation wavelength in premature beats be determined by prior cardiac activation frequency? What is the main finding and its importance? In premature beats induced after a series of cardiac activations at a slow rate, antiarrhythmics prolong repolarization but evoke little or no conduction delay, thus increasing the excitation wavelength, which indicates an antiarrhythmic effect. Fast prior activation rate attenuates prolongation of repolarization, while amplifying the conduction delay induced by drugs, which translates into the reduced excitation wavelength, indicating proarrhythmia. These findings suggest that a sudden increase in heart rate can shape adverse pharmacological profiles in patients with ventricular ectopy. ABSTRACT Antiarrhythmic drugs used to treat atrial fibrillation can occasionally induce ventricular tachyarrhythmia, which is typically precipitated by a premature ectopic beat through a mechanism related, in part, to the shortening of the excitation wavelength (EW). The arrhythmia is likely to occur when a drug induces a reduction, rather than an increase, in the EW of ectopic beats. In this study, I examined whether the arrhythmic drug profile is shaped by the increased cardiac activation rate before ectopic excitation. Ventricular monophasic action potential durations, conduction times and EW values were assessed during programmed stimulations applied at long (S1 -S1 [basic drive cycle length] = 550 ms) and short (S1 -S1 = 200 ms) cycle lengths in perfused guinea-pig hearts. The premature activations were induced with extrastimulus application immediately upon termination of the refractory period. With dofetilide, a class III antiarrhythmic agent, a prolongation in action potential duration and the resulting increase in the EW obtained at S1 -S1 = 550 ms were significantly attenuated at S1 -S1 = 200 ms, in both the regular (S1 ) and the premature (S2 ) beats. With class I antiarrhythmic agents (quinidine, procainamide and flecainide), fast S1 -S1 pacing was found to attenuate the drug-induced increase in action potential duration, while amplifying drug-induced conduction slowing, in both S1 and S2 beats. As a result, although the EW was increased (quinidine and procainamide) or not changed (flecainide) at the long S1 -S1 intervals, it was invariably reduced by these agents at the short S1 -S1 intervals. These findings indicate that the increased heart rate before ectopic activation shapes the arrhythmic profiles by facilitating drug-induced EW reduction.

Background: Patients initiated on sotalol and dofetilide require inpatient monitoring and dose adjustments due to risks of corrected QT (QTc) prolongation and Torsades de pointes (TdP). Patients may receive higher initial doses than recommended due to close monitoring by specialized practitioners. The objective of this study was to describe prescribing practices of sotalol and dofetilide and to compare safety outcomes between standard and nonstandard dosing strategies. Methods: This was a single-center retrospective analysis of adult inpatients who underwent sotalol or dofetilide initiation between June 1, 2015, and August 1, 2018. The end points of this study included the percentage of patients who received standard and nonstandard dosing, incidence of QTc prolongation (≥500 milliseconds or ≥15% from baseline), incidence of TdP, and dose reduction or medication discontinuation. Results: A total of 379 patients (195 sotalol and 184 dofetilide) were included in this analysis. There were 110 (56.4%) patients in the sotalol group and 111 (58.4%) patients in the dofetilide group that received nonstandard initial dosing. Nonstandard dosing was associated with a greater incidence of QTc prolongation compared to standard dosing (57.5% vs 43.0%, P = .005). Only one patient in the nonstandard dosing group experienced TdP. Patients initiated on nonstandard dosing required dose reduction or therapy discontinuation (37.6% vs 23.4%, P = .003) more frequently. Conclusion: Higher than recommended initial doses of sotalol or dofetilide were associated with higher incidence of QTc prolongation and more frequent therapy modification.

Background Hypokalemia reduces the cardiac repolarization reserve. This prolongs the QT-interval and increases the risk of ventricular arrhythmia; a risk that is exacerbated by administration of classical class 3 anti-arrhythmic agents. Small conductance Ca2+-activated K+-channels (KCa2) are a promising new atrial selective target for treatment of atrial fibrillation. Under physiological conditions KCa2 plays a minor role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in ventriculay -60r intracellur Ca2+. Purpose To study the effects of pharmacological KCa2 channel inhibition by the compounds AP14145, ICA, or AP30663 under hypokalemic conditions as compared to dofetilide and hypokalemia alone time-matched controls (TMC). Methods The current at +10 mV was compared in HEK293 cells stably expressing KCa2.3 perfused first with normo- and then hypokalemic solutions (4 mM K+ and 2.5 mM K+, respectively). Guinea pig hearts were isolated and perfused with normokalemic (4 mM K+) Krebs-Henseleit solution, followed by perfusion with drug or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K+) in presence of drug. 30 animals were randomly assigned to 5 groups: ICA, AP14145, AP30663, dofetilide, or TMC. QT-interval, the interval from the peak to the end of the T wave (Tp–Te), ventricular effective refractory period (VERP), arrhythmia score, and ventricular fibrillation (VF) incidence were recorded. Results Hypokalemia slightly increased KCa2.3 current compared to normokalemia. Application of KCa2 channel inhibitors and dofetilide prolonged the QT interval corrected for heart rate. Dofetilide, but none of the KCa2 channel inhibitors increased Tp–Te during hypokalemia. During hypokalemia 4/6 hearts in the TMC group developed VF (two spontaneously, two by S1S2 stimulation) whereas 5/6 hearts developed VF in the dofetilide group (two spontaneously, three by S1S2 stimulation). In comparison, 0/6, 1/6, and 1/6 hearts developed VF when treated with the KCa2 channel inhibitors AP30663, ICA, or AP14145, respectively. Conclusion Hypokalemia was associated with an increased incidence of VF, an effect that also seen in the presence of dofetilide. In comparison, the structurally and functionally different KCa2 channel inhibitors, ICA, AP14145, and AP30663 protected the heart from hypokalemia induced VF. These results support that KCa2 inhibition may be associated with a better safety and tolerability profile than dofetilide.

Introduction: Both heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation (AF) independently cause significant morbidity and mortality. The two conditions commonly coexist and AF in the setting of HFrEF is associated with worse mortality, hospitalizations, and quality of life compared to HFrEF without AF. Despite the large burden of these conditions, there is no clear optimal management strategy for when they occur together.Areas covered: This review focuses on the pharmacological management of AF in HFrEF. Studies were identified through PubMed search of relevant keywords. The authors review key clinical trials that have influenced management strategies and guidelines. The authors focus on the classes of drugs used to treat AF for both rate and rhythm control strategies including beta-blockers, digoxin, amiodarone, and dofetilide. Additionally, the authors discuss select non-antiarrhythmic medications that affect AF in HFrEF. The authors highlight the strengths and weakness of the data supporting the use of these medications and suggest future directions.Expert opinion: The pharmacological treatment of AF in HFrEF will need further refinement alongside the emerging role of catheter ablation. Novel HF medications and antiarrhythmics offer new tools to prevent the development of AF, as well as for rate and rhythm control strategies.

Dofetilide is an antiarrhythmic drug that selectively inhibits the rapid component of the delayed rectifier potassium current. The administration of dofetilide may cause ventricular arrhythmias and torsade de pointes. Electrocardiographic (ECG) microvolt T-wave alternans (TWA), an electrophysiologic phenomenon consisting in the beat-to-beat alternation of the T-wave amplitude requiring computerized algorithms to be detected, has also been associated to malignant ventricular arrhythmias. Aim of the present study was to evaluate if dofetilide induces TWA during the 24 hours following administration. The study population consisted of 22 healthy subjects ("ECG Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects" database by Physionet) to whom a 500 μg-dose of dofetilide was administered. For each subject, 10 s ECG were acquired at baseline (0.5 hour before dofetilide administration) and at 15 time points during the 24 hours following the drug administration. ECG were then processed for automatic TWA detection by correlation method. In 21 subjects out of 22, after dofetilide administration, TWA significantly increased to a peak value (median TWA values went from 6 μV at baseline to a max 32 μV; p; 0.05), on average after 5 hours, to then come back to values closer to baseline. Thus, in healthy subjects, dofetilide increases occurrence and levels (6 times baseline value on average) of TWA in the hours following its administration.

Class III antiarrhythmic drugs (AADs) predominantly block outward-repolarizing potassium currents and prolong cardiac action potential duration (APD) and refractoriness at concentrations at which they do not affect the sodium channels and, therefore, intracardiac conduction velocity is not significantly affected. The prolongation of the APD and refractoriness, combined with the maintenance of normal conduction velocity, leads to an increase in the wavelength of the cardiac impulse, defined as the distance travelled by the depolarization wave during the functional refractory period, closes the excitable gap in the reentrant circuit and suppresses reentry. Class III AADs include: amiodarone, dofetilide, dronedarone, ibutilide and sotalol.

Introduction: Body surface characterization of repolarization gradient substrates for ventricular fibrillation (VF) is still poor. We investigated if VF propensity can be assessed from surface T-wave in an ex-vivo model of purely electrical repolarization dispersion. Methods: To create repolarization gradients, dofetilide and/or pinacidil were separately infused in N=7 isolated pig hearts in a human-shaped torso tank. At each drug state, VF inducibility was quantified by the vulnerability window (VW), i.e. the interval during which VF was triggered by S1 (atrium) S2 (ventricle) stimulation. T-wave duration (the peak-to-end interval, T PEAK -T END ), and shape, i.e., symmetry (the ratio of the areas under the peak-to-end and onset-to-peak frames, Asy), and flatness (kurtosis, Kurt) were computed from 256 tank potentials. We fitted a linear mixed-effect (LMM) model to link T-wave markers (fixed effects) with VW (response), with random effects on drug states and hearts. Results: VF was induced in 14/23 drug states from at least one ventricle. In vulnerable substrates (higher VW), T-waves were longer (T PEAK -T END , p=0.0004), less symmetric (Asy, p

Dofetilide is an antiarrhythmic drug with dosing based on the Cockcroft-Gault formula using total body weight (TBW). We investigated the impact of calculating dofetilide dose using adjusted body weight (ABW) or ideal body weight (IBW) on subsequent dose reduction or discontinuation. We conducted a retrospective review of 265 patients admitted to an academic medical center for initiation of dofetilide using TBW. Dosing was recalculated using ABW or IBW. Patients who would have received a reduced dose using ABW or IBW (reduced dose group) were compared with patients whose dose would not have changed (same dose group). Manual measurement of QT intervals was performed. We found that Forty-one of 265 patients (15%) would have received a lower initial dose of dofetilide based on ABW. Patients in this reduced dose group had 2.95 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 1.47-5.90; P < 0.01) compared with the same dose group. Seventy-seven of 265 patients (29%) would have received a lower initial dose of dofetilide based on IBW. Patients in this reduced dose group had 1.78 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 0.98-3.21; P = 0.056) compared with the same dose group. These data suggest that caution should be used when dosing dofetilide using TBW, as it may lead to a greater frequency of dose reduction or discontinuation compared with dosing using ABW or IBW.

Background Manufacturer/federal drug administration (FDA) recommends inpatient initiation of dofetilide with the manufacturer providing an initiation algorithm. The outcomes of algorithm deviation have not been reported outside of clinical trials. Objective We sought to perform a chart review of all the patients admitted for inpatient initiation of dofetilide to report on the incidence of protocol deviations and their implications. Methods We performed a retrospective review of all patients over a 15-month periodwho were initiated on dofetilide for the very first time or reinitiated on dofetilide after a break of three months or more at our institution. We assessed data about patients who were given dofetilide without adherence to the protocol (i.e. protocol deviation). Results A total of 189 patients were included in the study with a median age of 66 ± 9 years. Mean baseline QTc interval was 436 ± 32 msec, and 61% (116/189) were in atrial fibrillation (AF) at the time of dofetilide initiation. In 9% (17/189) of patients, the drug was discontinued due to intolerance or inefficacy. Therapy in 49% (93/189) of patients was noted to deviate from manufacturer recommended protocol with deviations more than once in some patients during the same hospitalization. Baseline QTc exceeding 440 msec(>500msec in conduction abnormalities) was the most frequent deviation (25%; 47/189).Ventricular tachyarrhythmia occurred in 4% (7/189) of patients, did not differ between patients, and occurred with and without protocol deviations (5% vs 2%; p = 0.27). Conclusions In our retrospective study, there were frequent deviations from the manufacturer-recommended algorithm guidelines for dofetilideinitation, primarily due to prolonged baseline QTc interval. The impact of these protocol deviations on drug discontinuation was uncertain; however, significant adverse events were higher in the deviation group compared to the group that fully adhered to the protocol. Further multicenter studies are warranted to clarify our findings.

Dofetilide is a class III antiarrhythmic agent approved by the Food and Drug Administration for the conversion of atrial fibrillation and atrial flutter and maintenance of sinus rhythm in symptomatic patients with persistent arrhythmia. Drug trials showed neutral mortality in post–myocardial infarction patients and those with heart failure. This is a review of postmarket data, including real-world efficacy and safety in a variety of populations. Dofetilide has been used off-label with success in patients with paroxysmal atrial fibrillation and atrial flutter, as well as atrial tachycardia and ventricular tachycardia. The real-world acute conversion rate of atrial fibrillation and atrial flutter is higher than that reported in clinical trials. Dofetilide has an acceptable safety profile when initiated (or reloaded) under hospital monitoring and dosed according to creatinine clearance. Dofetilide is well tolerated and a good choice for patients with acceptable renal function and a normal QT interval, especially if atrioventricular nodal blockade needs to be avoided.

BACKGROUND: Dofetilide is a class III antiarrhythmic drug effective for the treatment of atrial fibrillation (AF). Dofetilide initiation (DI) associates with corrected QT interval (QTc) prolongation. Significant QTc prolongation during DI mandates dose adjustment or discontinuation of the drug. Microsatellite DNA are novel genetic markers associated with congenital and acquired health conditions. HYPOTHESIS. DNA microsatellite polymorphism may associate with QTc response to dofetilide initiation in patients with persistent AF. METHODS: We performed whole‐exome sequencing in a cohort of patients with persistent AF undergoing DI. Electrocardiographic variables and clinical data were assessed. We defined patients as eligible for DI when no significant QTc prolongation (>20% compared with baseline) was seen with a 500‐μg dose. We defined patients as ineligible for DI when significant QTc prolongation was seen during DI with 500 μg. We investigated polymorphisms for 11 919 DNA microsatellite loci in relation to QTc response to DI. RESULTS: During the study, 14 consecutive patients with persistent AF presenting for DI were enrolled. Whole‐exome sequencing revealed 14 different microsatellite loci in the 2 groups. All genes or proximal genes that harbor these loci are known to have expression in the human heart. Two genes, MYH6 and TRAK2, are known to have expression in the atria. TRAK2 is known to interact with KCNJ2, the inward‐rectifier potassium channel 1. CONCLUSIONS: Microsatellite DNA polymorphisms seem to associate with QTc response to DI therapy in patients with persistent AF who are deemed otherwise eligible for dofetilide therapy.

Background Limited medical options are available for rhythm control in patients with atrial fibrillation (AF) and hypertrophic cardiomyopathy (HCM). There are no published reports of dofetilide use in this population. Methods A retrospective chart review was conducted on 1,404 patients loaded on dofetilide for AF suppression at the Cleveland Clinic from 2008 to 2012, 25 of whom were found to have HCM. Results The HCM cohort was 32% female, 76% with persistent AF, mean age of 59 ± 10 years, and mean ejection fraction of 54 ± 9 %. Of the 25 patients, 21 were discharged on dofetilide, three discontinued during loading due to QTc prolongation, and one due to inefficacy. There were no adverse events during loading. Of those discharged on dofetilide, 11/21 (52%) were still on it at a median follow-up of 396 (198, 699) days at the time of the chart review. For those in whom it was discontinued, the median time on the drug was 301 (111, 738) days. Of the 10 patients who discontinued dofetilide during follow-up, six were due to inefficacy, one postablation, one postheart transplant, one due to death secondary to lung cancer, and one due to worsening edema. Conclusions Dofetilide was well tolerated in this group of patients with AF and HCM and it facilitated management of AF in 21/25 (84%) patients. Further research is needed to assess the safety and efficacy of dofetilide in order to develop evidence-based guidelines for the pharmacological management of AF in this population.

Background In the chronic atrioventricular block (CAVB) dog model, beat-to-beat variation of repolarization in the left ventricle (LV) quantified as short-term variability of the left monophasic action potential duration (STV LVMAPD ) increases abruptly upon challenge with a proarrhythmic drug. This increase occurs before the first ectopic beat (EB), specifically in subjects who demonstrate subsequent repetitive torsades de pointes arrhythmias (TdP). Objective The purpose of this study was to demonstrate that STV is feasible to monitor arrhythmic risk through use of the intracardiac electrogram (EGM) derived from the right ventricular (RV) lead from pacemakers or implantable cardioverter–defibrillators. Methods In 30 anaesthetized, inducible (≥3 TdP) CAVB dogs, STV between LV and RV monophasic action potential duration (STV LVMAPD and STV RVMAPD ) was compared. In prospectively enrolled CAVB dogs, STV of the activation-recovery interval (ARI) derived from the RV EGM (STV RVARI ) was measured before and after a challenge with dofetilide under anesthesia (2a; n=10) and cisapride under awake conditions (2b; n=8). Results Both STV LVMAPD and STV RVMAPD increased before the first EB (1.29 ± 0.58 ms to 3.05 ± 1.70 ms and 1.11 ± 0.53 ms to 2.18 ± 1.43 ms, respectively; P = 0.001). STV RVARI increased from 2.82 ± 0.33 ms to 3.77 ± 0.69 ms ( P = .001). Inducible subjects (4/8) showed an increase in STV RVARI from 2.65 ± 0.55 ms to 3.45 ± 0.33 ms (in the first hour; P = .02) and 4.20 ± 1.33 ms (before the first EB; P = .04). Conclusion Behavior of STV from the RV and LV is comparable. STV RVARI increases significantly before the occurrence of an arrhythmia in awake and anaesthetized conditions. This finding can be integrated into devices to monitor arrhythmic risk.

Introduction The anaesthetised guinea pig is a well characterised assay for early assessment of drug effects on ventricular repolarisation and risk of Torsade de Pointes (TdP). We assessed whether a selective hERG blocker with known TdP risk could be differentiated from lower risk, balanced ion channel blockers in the guinea pig, using corrected QT (QTc) interval alongside novel electrocardiogram (ECG) biomarkers J-Tpeakc and Tpeak-Tend. Effects were compared with previous clinical investigations at similar plasma concentrations and with another index of TdP risk, the electromechanical window (EMW). Methods Twenty-two Dunkin Hartley guinea pigs anaesthetised with sodium pentobarbitone were instrumented for haemodynamic measurement and ECG recording. Three ascending doses of vehicle (n = 6), dofetilide (2, 6 or 20 μg/kg; n = 7), ranolazine (2, 6 or 20 mg/kg; n = 5) or verapamil (0.1, 0.3 or 1.0 mg/kg; n = 4) were administered intravenously. Results As reported in previous clinical studies, dofetilide induced dose-dependent increases in QTc interval, with increases in both J-TpeakC or Tpeak-Tend, while verapamil caused no significant increase in QTc interval, J-TpeakC or Tpeak-Tend. Ranolazine caused dose-dependent increases in QTc interval and corrected J-Tpeakc, but had no effect on Tpeak-Tend, which is in contrast to the effects reported in humans at similar concentrations. Only dofetilide caused a clear, dose-related decrease in the EMW. Discussion These findings suggest that measurements of J-Tpeakc and Tpeak-Tend in addition to QT interval, may help differentiate pure hERG channel blockers with high risk of TdP from lower risk, multichannel blockers.