Circulation: Arrhythmia and Electrophysiology On the Beat July 2017

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Dr. Paul Wang: Welcome to the monthly podcast, On The Beat for Circulation: Arrhythmia, and Electrophysiology. I'm Dr. Paul Wang, Editor in Chief, with some of the key highlights from this month's issue. We'll also hear from Dr. Suraj Kapa, reporting on new research from the latest journal articles in the field.

This month's issue of Circulation: Arrhythmia, and Electrophysiology has a number of groundbreaking and fascinating articles. Let's start with the first article by Christopher Andrews and Associates on the novel use of noninvasive electrocardiographic imaging in patients with arrhythmogenic right ventricular cardiomyopathy.

The authors compared 20 genotyped arrhythmogenic right ventricular cardiomyopathy patients to 20 control patients using electrocardiographic imaging, ECGI, a method for noninvasive cardiac electrophysiology mapping. They found that ARVC patients had a longer ventricular activation duration, with a mean of 52 milliseconds versus 42 milliseconds with a p-value of 0.007, as well as a prolonged mean epicardial activation recovery interval, a surrogate for local action potential duration with a median of 275 milliseconds versus 240 milliseconds with a p-value of 0.014.

In addition, the authors observed abnormal epicardial activation breakthrough locations with regions of nonuniform conduction and fractionated electrograms. These abnormal activation patterns correlated with late gadolinium enhancement using cardiac magnetic resonance scar imaging. This study suggests that electrocardiographic imaging may be a promising tool for the diagnosis and follow-up of patients with ARVC.

In the next article, Thomas Fink and Associates report the results of the prospective randomized Alster-Lost AF trial, comparing ablation strategies in patients with symptomatic persistent or long-standing persistent atrial fibrillation. The study compared standalone pulmonary vein isolation, the PVI-only approach, with a stepwise approach of PVI followed by complex fractionated atrial CFAE ablation and linear ablation, the substrate modification approach. Patients were randomized one-to-one to each study group. The primary study endpoint was freedom from recurrence of any atrial tachyarrhythmia at 12 months after a 90-day blanking period. 118 of 124 enrolled patients were analyzed. 61 in the p-value only group and 57 in the substrate modification group. The pulmonary vein isolation only group had a one-year freedom from arrhythmia recurrence of 54%, which was similar to the 57% recurrence rate in the substrate modification group, p = 0.86. Thus, this study confirms in a population of persistent and long-standing persistent atrial fibrillation that there is no significant benefit to the addition of CFAE ablation to pulmonary vein isolation only.

In the next paper, John Papagiannis and associates studied AV nodal reentrant tachycardia in patients with congenital heart disease. In this multi-centered, retrospective study, the authors compared catheter ablation of AV nodal reentrant tachycardia in 51 patients with complex congenital heart disease, with 58 patients with simple congenital heart disease.

There was no significant difference between the groups in terms of growth parameters, the use of 3D imaging, or type of ablation, radio frequency versus cryoablation. The procedure times, fluoroscopy times were longer in the complex group compared to the simple group. There were also significant differences between the groups in terms of acute success of ablation, 82% versus 97%; the risk of AV block, 14% versus 0%; and the need for chronic pacing, all significant in favor of the simple congenital heart disease group. There were no permanent AV block observed in patients who underwent cryoablation.

After a mean, 3.2 years of follow up, the long-term success was 86% in the complex group, and 100% in the simple group, p = 0.004. Thus, the authors concluded that the complexity of congenital heart disease affects the outcome of AV nodal reentrant tachycardia catheter ablation.

In the next paper, Moloy Das and associates studied whether the presence of abnormal intra-QRS peaks would indicate altered activation and might predict ventricular arrhythmias in cardiomyopathy patients. The authors examined the 99 patients with ischemic or nonischemic cardiomyopathy undergoing primary prevention ICD implantation, with a mean left ventricular ejection fraction of 27%. After a median follow up of 24 months, 20% of patients had arrhythmic events. Using a multivariate, Cox regression model that included age, left ventricular ejection fraction, QRS duration, and QRS peaks, only QRS peaks was an independent predictor of arrhythmic events with a hazard ration of 2.1. ROC analysis revealed that a QRS peak value of greater than or equal to 2.25 identified arrhythmic events with a greater sensitivity than QRS duration, 100% versus 70%, with p < 0.05, and a negative predictive value of 100%, compared to 89% for QRS duration, p < 0.05. Thus, the authors concluded that this novel QRS morphology index may be a promising additional tool in sudden death risk stratification.

In our next paper, Yoshiyasu Aizawa and associates studied J wave changes during atrial pacing in patients with and without idiopathic ventricular fibrillation. In eight patients with idiopathic ventricular fibrillation, and 17 patients without idiopathic ventricular fibrillation, having J waves, the J wave amplitude was measured before, during and after atrial pacing. All of the patients with ventricular fibrillation did not have any structural heart disease. The idiopathic ventricular fibrillation patients were younger than the non-idiopathic ventricular fibrillation patients, and had larger J waves with more extensive distribution. The J wave amplitude decreased from 0.35 millivolts to 0.22 millivolts when the R-R intervals shortened, a decrease of greater than, equal to 0.005 millivolts in the J wave amplitude was observed in six of eight idiopathic ventricular fibrillation patients while the J wave amplitudes were augmented in nine out of 17 non-idiopathic ventricular fibrillation subjects. The authors therefore concluded that the different response patterns of J waves to rapid pacing suggested different mechanisms that is early repolarization in idiopathic ventricular fibrillation patients, and conduction delay in non-idiopathic ventricular fibrillation patients.

Our final paper of the month was written by Jim T. Vehmeijer and colleagues, who examined the utility of recent guidelines and consensus documents for ICD implantation for sudden death protection in adults with congenital heart disease. The authors examined an international, multi-center registry, having 25,790 adult congenital heart disease patients, and identified all sudden cardiac death cases, which were then matched to living controls by age, gender, congenital defect and surgical repair. They used conditional logistic regression models to calculate odds ratios, and receiver operating characteristic curves. In their first analysis, they identified 124 cases and 230 controls. In total, 41% of sudden cardiac death cases, and 17% of controls had an ICD recommendation based on the 2014 consensus statement on arrhythmias in adult congenital heart disease, with an odds ratio of 5.9. A similar analysis of the 2015 European Society of Cardiology guidelines showed that 35% of cases and 14% of controls had an ICD recommendation, respectively with an odds ratio of 4.8. The authors concluded that a minority of sudden cardiac death cases had an ICD recommendation according to these guidelines, while the majority of sudden cardiac death victims remained under-recognized, emphasizing the need for continued critical, clinical reasoning when deciding on ICD implantation in adult congenital heart disease patients.

And now, here with the review of the highlights from the articles from journals throughout the world, in the past month is Dr. Suraj Kapa.

Dr. Suraj Kapa: Thank you, Paul. Today we'll be discussing hard-hitting articles that have been published within the last month across the electrophysiologic literature. First, we'll be focusing on the topical area of atrial fibrillation, with an initial foray into the realm of anticoagulation. The first article we will be focusing on was published by Yao, et al., in the Journal of the American College of Cardiology in volume 69, entitled Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients with Atrial Fibrillation and Renal Dysfunction. In the study, Yao, et al, demonstrated that the dosing of direct oral anticoagulants in a real world patient sample, with preexisting renal dysfunction was inappropriately dosed in as many as 43% of patients. Specifically, in these patients, there was overdosing of the direct oral anticoagulants. Moreover, as many as 13% of patients were underdosed.

The overdosing of these patients led to increased bleeding risks, without an incremental stroke benefit compared with cohorts that were appropriately dosed. In turn, underdosing led to increased stroke risk without an incremental reduction in bleeding risk. These results are provocative in that they indicate, in a real life sample of patients, frequent inappropriate dosing of direct oral anticoagulants. This identifies the need for better guidelines, or better adherence to guidelines, in management of these patients to improve clinical outcomes.

In another article with the realm of anticoagulation management of atrial fibrillation patients, was published by Labovitz, et al. in Stroke, in volume 48, entitled Using Artificial Intelligence to Reduce the Risk of Nonadherence in Patients on Anticoagulation Therapy. They demonstrated in a small randomized study that a smart phone based artificial intelligence program could be used to monitor anticoagulation adherence, and in fact, improve it. The program utilized features available on all smart phones to identify the patient, the medication, and active ingestion of the medication by the patient in real time.

With this approach, they noted the plasma drug concentration levels indicated 100% adherence in the intervention group, namely those using the artificial intelligence program, while in the control group, only 50% of patients had adherence to the medications. Overall, there was an absolute improvement in adherence amongst patients on direct oral anticoagulants by as many as 67%. These findings are provocative given data suggestive of the lack of appropriate adherence to anticoagulant therapy amongst patients.

Changing paths from anticoagulation management, the next article we choose to focus on was published within the realm of cardiac mapping in ablation for atrial fibrillation. It was published by Das, et al. in JACC: Clinical Electrophysiology in volume three, entitled Pulmonary Vein Re-Isolation as a Routine Strategy Regardless of Symptoms, The PRESSURE Randomized Controlled Trial. In this randomized trial, Das, et al, demonstrated that aggressive reevaluation of patients undergoing pulmonary vein isolation after index ablation for pulmonary vein reconnection, with the intent to re-ablate, significantly reduced arrhythmia recurrence. In addition, there was a commented improvement in quality of life. It has been well-recognized that even in the absence of clinical recurrence, a large number of patients, after index pulmonary vein isolation, may have pulmonary vein reconnection. However, it has always been unclear whether aggressive reevaluation and re-isolation of reconnected veins holds value, has been unclear. Further study is needed to evaluate the cost effectiveness and the risk-benefit ratio of such an invasive approach to reevaluate pulmonary vein isolation, irrespective of the evidence of clinical atrial fibrillation recurrence, however.

Changing gears, with the realm of atrial fibrillation, we will now focus on risk stratification and management. Pathik, et al, in JACC: Clinical Electrophysiology, published in volume three, have progressed to complement their work on the role of risk stratification, and risk factor management in patients with atrial fibrillation, to evaluate the cost-effectiveness and clinical effectiveness of such risk factor management clinics in atrial fibrillation, that they termed the SENSE Study. They demonstrated that there was significant cost and clinical benefits to aggressive risk factor targeting clinics for patients with atrial fibrillation, specifically, utilizing supervised approaches to weight-loss, improvements in fitness and reduction in other clinical risk factors such as diabetes, hypertension, or other risks. The patients had a significantly decreased risk of arrhythmia occurrence. In addition to this, there was an actual incremental cost benefit of $62,000 for quality adjusted life year saved. These findings suggest that such an aggressive risk factor mediated approach to management of patients with atrial fibrillation holds significant promise, not just in the reduction of arrhythmia occurrence, but also in potential healthcare cost savings.

Our next article within the realm of risk stratification and management relates to identification of patients with atrial fibrillation, in otherwise normal population-wide cohorts. Krivoshei, et al, in Europace volume 19, studied algorithms applied to information gathered on pulse-wave signals via smartphone-based LED light/camera lens. They demonstrated that using such a tool on patients, atrial fibrillation can be discriminated from sinus rhythm with sensitivity specificity of above 95%. We recognize the critical importance of early detection of atrial fibrillation, particularly in high-risk cohorts for stroke. Early identification of patients may identify those patients for initiation of anticoagulation, even if asymptomatic or minimally symptomatic. Our so-termed subclinical atrial fibrillation patients, which we identify by prior clinical trials, have an increased risk of stroke. However, the main hurdle to implementation of such technology has been the high cost, applied to traditional medical interventions. However, use of ever-advancing ambulatory technologies, such as smartphones or in the future, smart watches, may held the promise to identify atrial fibrillation via cheaper mechanisms.

The last article within the realm of atrial fibrillation risk stratification and management that we'll choose to focus on is that by Gaeta, et al, published in Europace in volume 19. They performed a systematic review and meta-analysis of existing trials, regarding whether epicardial fat depot was associated with atrial fibrillation. They demonstrated via their meta-analysis that there is, in fact, a significant association between epicardial fat and atrial fibrillation risk, with more epicardial fat being associated with more persistent, rather than paroxysmal forms of atrial fibrillation, as well as any atrial fibrillation versus none. However, the role of epicardial fat in arrhythmogenesis remains unclear. While many studies suggest an association, causation remains to be proven. A recent review, however, published by Antonopoulos, et al, in the Journal of Physiology in June 2017, has multiple suggestive pathways by which paracrine effects of epicardial fat on the heart and vice versa, may lead to alterations in normal cardiac function. Thus, while this remains an association, there are evolving principles that might further support causation.

Changing topics, we'll next focus on four major articles within the realm of ICDs, pacemakers, and CRT managements. Lyons, et al, in JACC: Heart Failure, volume five, studied the impact of current versus previous cardiac resynchronization therapy guidelines on the proportion of patients with heart failure eligible for therapy. They evaluated the effect of changing guidelines based on increased bodies of evidence, related to indications for resynchronization therapy on real world patient samples. They demonstrated that these further refined guidelines would decrease by as many as 15% those patients eligible for cardiac resynchronization therapy. However, while their study demonstrates that fewer patients may qualify, as far as receiving benefit from resynchronization therapy, at least two studies published in the same month have demonstrated that even amongst patients who meet guidelines, there is severe under-utilization/under-referral for such devices. These studies by Marzec, et al, in JAMA Cardiology, as well as by Randolph, et al, in American Heart Journal, demonstrated that there's frequent under-utilization and under-referral of patients meetings indications for resynchronization therapy.

Keeping on the same topic in resynchronization therapy, Barra, et al, in Heart, volume 103, looked at sex-specific outcomes with addition of defibrillation to resynchronization therapy in patients with heart failure. They demonstrated in a multi-central observational cohort study that the addition of defibrillator resynchronization therapy in patients meeting primary prevention indications for device implant, primarily conferred benefit in men, rather than women. In the same month, Randolph, et al, in the American Heart Journal, demonstrated that resynchronization therapy offered potential greater benefits in women over men. Interestingly, this study by Barra, et al, conversely demonstrates that the concomitant addition of defibrillator therapy does not necessarily further improve outcomes on women, with the primary benefit being conferred to men. Whether this differential is effected by relative rates of arrhythmogenic myopathy is in men versus women remains unclear. However, the findings are provocative.

Keeping within the realm of appropriateness of defibrillator therapies, Luni, et al, performed a meta-analysis of randomized controlled trials published in the Journal of Cardiovascular Physiology, in volume 28, on the mortality effect of ICDs in primary prevention in nonischemic cardiomyopathies, including six studies that met criteria. They found that while there was an overall significant survival benefit in patients receiving ICDs in the setting of nonischemic cardiomyopathy. Once accounting for those on adequate beta-blockade, and ACE or ARP 00:22:56 therapy, there was no statistical difference conferred by primary prevention ICD use.

This complements an article published by Al-Khatib, et al, in JAMA Cardiology, in the same month, which also suggested that the overall mortality benefit was present in nonischemic patients, though in their case, they did not evaluate the granularity of appropriateness based on current management at the time of ICD implant. These findings further previous findings from a Danish study that the survival benefit of primary prevention ICD in nonischemic cardiomyopathy might not be anywhere near the same as those conferred with ischemic cardiomyopathy. However, the perceived lower relative mortality benefit, compared to earlier clinical trials, namely partly due to improvements in the clinical and pharmacologic management of such patients.

The final paper we'll choose to focus on within the realm of device therapies was published by Doppalapudi, in the Journal of Cardiovascular Electrophysiology, in volume 28. They looked at the significant discrepancy between estimated and actual longevity in St. Jude Medical implantable cardioverter defibrillators. While amongst a small number of patients of only 40, they demonstrated that up to 74% of these patients had a significant discrepancy between actual and estimated battery life, specifically amongst current or promotes defibrillator devices. This discrepancy was most significant in the 18 months prior to reaching electrical replacement medication. These findings suggest the need for more frequent monitoring of such devices to look for rapid battery depletion.

Switching topics away from device therapies, we next focus on the realm of sudden death in cardiac arrest. The first paper we'll focus on was published in Circulation, in volume 135, by Halliday, et al, and focused on the association between mid-wall late gadolinium enhancements, and sudden cardiac death in patients with dilated cardiomyopathy in mild and moderate left ventricular systolic dysfunction. In his publication, Halliday demonstrated that the presence of mid-wall late gadolinium enhancements on MRI identified patients at risk of sudden cardiac death, with a hazard ratio up to 35.9 for border sudden cardiac death, amongst dilated cardiomyopathy patients with such mid-wall dilated enhancements. The incremental value of MRI is evolving in the risk stratification of patients, though it has not quite met inclusion in guidelines for decision making regarding those who most benefit from ICDs. However, studies like this are provocative in the sense of identifying those patients most at risk.

Within the realm of cardiac arrest, we next focus on the role of out-of-hospital cardiac arrest, and how to improve management of these patients. Boutilier, et al, published in Circulation, in volume 135, optimization of drone networks to deliver automated external defibrillators. They demonstrated via simulation model that using a drone network system to deliver AEDs to patients suffering sudden cardiac arrest could decrease the time to response by as much as six minutes and 43 seconds compared to traditional approaches, such as 911 in urban areas, or as much as 10 minutes and 34 seconds in rural areas. These findings are highly provocative. However, they need to be applied to clinical real world situations. The first attempt at such was actually published this month as well, by Claesson, et al, in the Journal of the American Medical Association, and demonstrated the feasibility of implementing a drone network within real world case example, and the efficacy of the same. These disruptive technologies have the potential to improve emergency care, and out of hospital cardiac arrest survival.

Next, we move on to studies in electrophysiology. The first article we will focus on is by De Jesus, et al, published in Heart Rhythm, volume 14, on antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. De Jesus, et al, in this study, demonstrated that the use of anakinra and interleukin 1 beta antagonist would improve conduction velocity, calcium handling, spontaneous and inducible ventricular arrhythmias, and action potential duration dispersion, in canine models. These findings of potential antiarrhythmic effects were due to increased expression of connexin 43, and sarcoplasmic reticulum calcium ATPase. While in isolation, this might seem a general article, it complements multiple recent studies that suggest a significant role for targeting inflammatory pathways, not just in infarct pathogenesis, but in arrhythmogenesis.

Lazzerini, et al, this month as well, demonstrated in the European Heart Journal, the link between systemic inflammation and arrhythmic risk based on a review of the existing literature. In addition, Yucel, et al, demonstrated in Nature Scientific Reports the relationship between lipopolysaccharides and electrophysiology dysfunction in stem cell direct cardiomyocytes, which they felt partly may be mediated through interleukin pathways. Finally, though as of yet unpublished, a clinically available interleukin 1 beta inhibitor, canakinumab, has been shown in preliminary data to reduce major cardiovascular events in a randomized, double-blind, placebo-controlled trial, when combined with optimal medical therapy in patients with post myocardial infarction. These potential clinical benefits complement translational benefits seen to date. However, whether these are conferred by primary inflammatory pathways, arrhythmogenic pathways, or interactions between both remains to be seen.

The next article we will focus on is by Chauveau, et al, published in Circulation: Arrhythmia Electrophysiology, volume 10. They looked at induced pluripotent stem cells derived cardiomyocytes in producing in vivo biological pacemaker function. They demonstrated that in canines with atrioventricular block, injection of such derived cardiomyocytes into the epicardial surface of the heart, demonstrated inherent pacemaker activity with global cardiac activation. In fact, this activation in pacemaker activity increased over time, up to four weeks of maturation, and also demonstrated responsiveness to epinephrine and alterations with day and night variation. However, the intrinsic rates tend to be quite low, in the 50 to 60 beat per minute range. The potential to restore pacemaker activity in patients with severe conduction disease, holds the potential to dynamically progress options in care for patients with electrophysiologic disease. However, even though these findings are promising, significant remaining questions include ensuring the robustness of the heart rate conferred by these biologic pacemakers, the durability of pacemaker activity, and the arrhythmogenic potential of such interventions.

Within the realm of cellular electrophysiology, the final article we will choose to focus on was published by Barbic, et al, in American Journal of Physiology, heart and Circulatory Physiology, in volume 312, entitled Detachable Glass Microelectrodes for Recording Action Potentials in Active Moving Organs. They demonstrated that a new glass microelectrode could allow for determinational cellular actional potential duration in actively moving organs. This is a profound potential advance in the physiologic evaluation of both in vitro and in vivo translational cellular models of cardiac activation. Traditional patch clamping action potential studies required immobilization of cells being studied, whether by mechanical or pharmacologic means. However, directed efforts to immobilize cells can alter electrophysiologic parameters. The ability to record cellular action potentials in actively moving cells, for example the beating heart, may offer studies of cellular electrophysiology, that more closely approximate real world physiology.

Our next area of focus will be on genetic channelopathies, including long QT syndrome, Brugada, catecholaminergic polymorphic ventricular tachycardia and others. The article we choose to focus on this month, within this realm, was published by Pappone, et al, in Circulation: Arrhythmia and Electrophysiology, volume 10. They focus on electrical substrate elimination in 135 consecutive patients with Brugada syndrome. They demonstrated in this large cohort of patients that the arrhythmogenic electrical substrate associated with the Brugada syndrome primarily localized to the right ventricular epicardium, and an ablation of such region led to normalization of electrocardiogram and non-inducibility ventricular arrhythmias acutely in all patients, and over a long term in all but two patients.

These findings complement prior work by Nademanee and others that support a role for targeting substrate in the region of the right ventricular epicardium, in preventing recurrent ventricular arrhythmias in patients with Brugada syndrome, and in normalizing the electrocardiographic Brugada pattern. At the translational level, prior work has demonstrated that the same SCN mutations associated with Brugada syndrome confer accentuated transmittal gradients within the realm of the right ventricle, along with preferential prolongations of action potentials in the right ventricular epicardial myocytes. However, it remains to be seen whether the specific genetic cause of individual patient's Brugada pattern or Brugada syndrome is associated with discreet pathologic and inter-ablation findings and success rates.

Next, moving on to the realm of ventricular arrhythmias, we focus on three major articles published in the past month. The first article is published by Vaseghi, et al, in the Journal of the American College of Cardiology, volume 69, entitled Cardiac Sympathetic Denervation for Refractory Ventricular Arrhythmias. They demonstrated that cardiac sympathetic denervation may be an effective therapy in many patients with intractable ventricular arrhythmias, with a greater than 50% reduction in sustained VT, ICD shock, transplant or death over one year follow-up. Not only this but nearly one third of patients no longer required antiarrhythmics. However, bilateral sympathectomy is far superior over left sided only sympathectomy. Furthermore, advanced heart failure and VT cycle length were associated with poor outcomes. These findings suggest a role for bilateral sympathectomy in management of patients presenting with intractable ventricular arrhythmias. However, patient identification and selection in terms of the ideal cohorts for such therapy, and how to identify such cohorts remains to be seen.

Our next article regards advances in attaining epicardial access. Di Biase, et al, published in Heart Rhythm, volume 14, the initial international multi-centered human experience with the novel epicardial access needle embedded with a real time pressure frequency monitor to facilitate epicardial access. They looked specifically at feasibility and safety of this novel approach. While in only 25 patients, they did demonstrate that epicardial access can be successfully obtained with only one complication of a delayed pericardial effusion. With evolving indications for epicardial access, including for left atrial appendage occlusion, epicardial ganglia modulation, and ventricular arrhythmia mapping and ablation, development of novel tools to minimize the risks associated with epicardial ablation, particularly in individuals who do not perform it routinely, is critical. However, whether these variable approaches hold significant advances in randomized trials, beyond traditional approaches, remains to be seen.

Within the realm of ventricular arrhythmias, the last article we will choose to focus on was published by Acosta, et al, in Europace, volume 19. They looked at the long-term benefit of first line peri-implantable cardioverter-defibrillator implant ventricular tachycardia substrate ablation in secondary prevention patients. This study complemented prior data from SMASH-VT supporting a role for early ablation to reduce future arrhythmia events in patients receiving defibrillators. In their study, they demonstrated that early ablation was associated with a decreased recurrence of ventricular arrhythmias and defibrillary shocks over an average of almost four years. However, it addressed patients with lower ejection fractions, namely less than 35%, received less benefit. Though this was mostly conferred by while having similar frequency of VT recurrence, having an overall lower burden compared to those who did not have ablation. Practice patterns continue to vary in the decision making with regards to performing early ablation in such patients. Furthermore, whether or not a mortality benefit exists with early ablation remains relatively unclear and unproven. However, there's an evolving body of evidence to support the notion that aggressive, early intervention with invasive procedures in patients receiving ICDs, and at high risk for ventricular arrhythmias, may make sense.

The final article we will focus on that has been published in the past month, is published by Turagam, et al, in the International Journal of Cardiology, volume 236, entitled Practice Variation in the Re-initiation of Dofetilide: an Observational Study. Turagam, et al, surveyed 347 providers in the U.S. and worldwide, and demonstrate significant practice variability when re-initiating dofetilide. They know that up to 21% of providers always admit patients to the hospital for dofetilide re-initiation, while 37% of physician admit patients less than 10% of the time. Interestingly, the duration off of dofetilide ranging anywhere from three days to more than a year, did not necessarily significantly affect the rate of decision to re-initiate dofetilide, after prior cessation. One key finding of this was the 4% of physicians reporting major adverse events with drug re-initiation in patients. This was despite the vast majority of these patients tolerating de novo initiation. Given the prolific effects of antiarrhythmetic drugs, strategies to reduce those potential risks are critical. In fact, multiple groups such as the Cardiac Safety Research Consortium, within the same month, had sought to publish recommendations for long-term electrocardiographic monitoring, in drug developments. It must be realized the consideration of the impact of antiarhythmetic drug managements may not always be well outlined by existing protocols. And thus, further study is likely required to inform current clinical practice.

It was my pleasure to introduce to you some of the major heart hitting articles published in the part month across the electrophysiologic literature. While none of this is really touching on every single major advance, we hope to identify those that hold potential, measure immediate clinical potential, or those that hold potential for future advancements within our field. Thank you.

Dr. Paul Wang: I hope you enjoyed this month's podcast On the Beat, Circulation: Arrhythmia and Electrophysiology. We've had a number of groundbreaking and fascinating studies. See you next month.

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