Circulation: Arrhythmia and Electrophysiology On the Beat November 2017

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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 journals in the field.

In our first article, Elyar Ghafoori and associates examined the ability of late gadolinium enhancement MRI done immediately after ablation to predict edema and chronically even size. In a canine model, the authors created ventricular radiofrequency ablation lesions. All animals underwent MRI immediately after ablation. After one, two, four and eight weeks, edema and microvascular obstruction MVO, in enhanced volumes were identified in MRI. Immediately after contrast administration, the microvascular obstruction region was 3.2 times larger than the chronic lesion volume size in acute MRI. The authors found that microvascular obstruction region on acute late gadolinium enhancement images acquired 26 minutes after contrast administration most accurately predicts chronic lesion volume.

In the next article, Elad Anter and associates characterized the atrial substrate in patients with paroxysmal atrial fibrillation and obstructive sleep apnea. The authors examined 86 patients with paroxysmal atrial fibrillation, 43 with moderate obstructive sleep apnea and 43 without obstructive sleep apnea. The right atrial and left atrial voltage distribution conduction velocities in electrogram characteristics were examined. The authors found that patients with obstructive sleep apnea had lower atrial voltage amplitude, slower conduction velocities, and higher prevalence of electrogram fractionation. Most commonly, the left atrial septum was an area of atrial abnormality while at baseline the pulmonary veins with the most frequent triggers for atrial fibrillation in both groups after pulmonary vein isolation in patients with obstructive sleep apnea had an increased incidence of extrapulmonary vein triggers, 41.8% versus 11.6%, p=0.003. The one year arrhythmia-free survival are similar between patients with and without obstructive sleep apnea, 83.7% and 81.4%, respectively.

In comparison, control patients with paroxysmal atrial fibrillation and obstructive sleep apnea who underwent pulmonary vein isolation alone without ablation of extrapulmonary vein triggers had an increased risk of arrhythmia recurrence, 83.7% versus 64.0%, p=0.03, suggesting that ablation of these triggers resulted in improved arrhythmia-free survival. A randomized trial would be needed to prove this relationship.

In the next article, Iolanda Feola and associates demonstrated that optogenetics may be used to induce and locally target a rotor in atrial monolayers. The authors used neonatal rat atrial cardiomyocyte monolayers expressing a depolarizing light-gated ion channel, calcium-translocating channelrhodopsin. These monolayers were subjected to patterned illumination to induce the single, stable, and centralized rotor by optical S1-S2 cross-field stimulation. Next, the core region of these rotors was specifically and precisely targeted by light to induce local conduction blocks of circular or linear shapes. Conduction blocks crossing the core region, but not reaching an unexcitable boundary, did not lead to termination. Instead, electrical waves started to propagate along the circumference of block. If, however, core-spanning lines of block reached at least one unexcitable boundary, reentrant activity was consistently terminated by wave collision, suggesting that this may be a key mechanism for rotor elimination.

In our next study, Adam Barnett and associates used data from the outcomes registry for better informed treatment of atrial fibrillation ORBIT-AF to determine how frequently patients receive care that was concordant with 11 recommendations of the 2014 AHA, ACC, HRS A-fib guidelines pertaining to antithrombotic therapy rate control in anti-arrhythmic medications. The authors also analyzed the association between guideline concordant care and clinical outcomes at both the patient's level and center level. The authors study 9,570 patients with the median A 275, median CHA2DS2-VASc score of 4. A total of 62.5% or 5,5977 patients received care that was concordant with all guideline recommendations for which they were eligible. Rates of guideline concordant care was higher in patients treated with providers, with greater specialization in arrhythmias; 60.0%, 62.4%, 67.0% for primary care physicians, cardiologists and electrophysiologist, respectively; p less than 0.001. During a median of 30 months of follow up, patients treated with guideline concordant care had a higher risk of bleeding hospitalization; hazard ratio, 1.21. Similar risk of death, stroke, major bleeding can all cause hospitalization.

In our next article, Hui-Chen Han and associates conducted electronic search of PubMed and Embase for English scientific literature articles to characterize the clinical presentation, procedural characteristics, diagnostic investigations and treatment outcomes of all reported cases of atrioesophageal fistula. Out of 588 references, 120 cases of atrioesophageal fistula were identified. Clinical presentation occurred between 0 and 60 days postablation with a median of 21 days. The most common presentations were fever 73%, neurological 72%, gastrointestinal 41%, and cardiac 40% symptoms. Computed tomography of the chest was the commonest mode of diagnosis, 68% although six cases required repeat testing. Overall mortality was 55%. In conclusion, the authors reported that atrioesophageal fistula complicating atrial fibrillation is associated with a very high mortality 55% with significantly reduced mortality in patients undergoing surgical repair 33% compared to endoscopic treatment 65%, and conservative management 97%. Odds ratio adjusted 24.9; p less than 0.01 compared to surgery. Neurological symptoms adjusted odd ratio 16.0. In GI bleed, adjusted odds ratio 4.2, were the best predictors of mortality.

In the next article, Wei Ma and associates reported that the site origin of left posterior fascicular ventricular tachycardia may be predicted using 12-lead EC morphology in the HIS-ventricular or H-V interval. The authors studied 41 patients who underwent successful catheter ablation of left posterior fascicular ventricular tachycardia. The location of the site of origin was separated into proximal, middle, and distal groups with H-V being greater than zero milliseconds in the proximal group, H-V zero to minus 15 milliseconds in the middle group, and H-V less than negative 15 milliseconds in the distal group. The earliest presystolic potential ratio that is PP-QRS interval during VT divided by the H-V interval during sinus rhythm was statistically significantly different between the three groups, 0.59, 0.45 and 0.31, respectively. In addition, the QRS ratio in the proximal group 114 milliseconds was significant nearer compared to the middle group 128 milliseconds and the distal group 140 milliseconds. The QRS duration in the ratio R to S in leads V6 and lead-1 could predict a proximal or distal origin of left posterior fascicular ventricular tachycardia with high sensitivity and specificity.

In our next article, Niv Ad and associates examined the safety and success of on-pump minimally invasive stand-alone Cox-Maze 3/4 procedure via right mini-thoracotomy in 133 patients with nonparoxysmal atrial fibrillation five years after surgery. The mean follow-up was 65 months in a patient population with a mean age of 57.3 years, mean left atrial size of 4.9 centimeters, mean AF duration of 51 months and 78% with longstanding persistent atrial fibrillation. All procedures were performed with no conversion to mid-sternotomy. No renal failure, strokes or operative mortality in less than 30 days. They reported a TIA in one patient, re-operation for bleeding in two patients, and median length of stay in four days. At five years, 73% of patients were in sinus rhythm off anti-arrhythmic drugs following a single intervention.

In the next article, Richard Soto-Becerra and associates reported that unipolar endocardial electro-anatomic mapping may be used to identify scar epicardially in chagasic cardiomyopathy. In 19 sick patients, a total of 8,494 epicardial and 6,331 endocardial voltage signals in 314 epicardial and endocardial match pairs of points were analyzed. Basolateral left ventricular scar involvement was observed in 18 out of 19 patients. Bipolar epicardial and endocardial voltages within scar were low, 0.4 and 0.54 millivolts, respectively in confluent indicating a dense transmural scarring process. The endocardial unipolar voltage value with the newly proposed less than of equal to four-millivolt cutoff predicted the presence and extent of epicardial bipolar scar, p less than 0.001.

In our next article, Bing Yang and associates reported the results of the stable SR study, which is a multicenter clinical trial of 229 symptomatic nonparoxysmal atrial fibrillation patients random-eyed one-to-one to two ablation strategies. In the stable SR group following pulmonary vein isolation, cavotricuspid isthmus ablation in conversion to sinus rhythm left atrial high density mapping was performed. Areas of low voltage and complex electrogram were further homogenized and eliminated, respectively. Dechanneling was done if necessary. In the step-wise group, additional linear lesions and defragmentation were performed. The primary endpoint was freedom of documented atrial tachyarrhythmias lasting 30 seconds or more after a single ablation procedure without anti-arrhythmic medications at 18 months. At 18 months, success according to intention-to-treat analysis was similar in the two arms with 74.0 success in the stable SR group and 71.5% success in the step-wise group; p=0.3. However, shorter procedure time reduced fluoroscopic time after pulmonary vein isolation and shorter energy delivery time were observed in the stable SR group compared to the step-wise group.

In the final paper, Alan Sugrue and associates studied the performance of a morphological T-wave analysis program in defining breakthrough long QT syndrome arrhythmic risk beyond the QTc value. The author studied 246 genetically confirmed LQT1 patients and 161 LQT2 patients with a mean follow-up of 6.4 years. A total of 23 patients experienced more than one breakthrough cardiac arrhythmic event with 5 and 10-year event rates of 4% and 7%. Two independent predictors of future long Qt syndrome-associated cardiac events were identified from the surface ECG using a proprietary novel T-wave analysis program. The authors found that the most predictive features included the left slope of T-wave in V6, hazard ratio of 0.40, and T-wave center of gravity X-axis in lead-1, hazard ratio 1.9, C statistic of 0.77. When added to QTc, discrimination improved from 0.68 for QTc alone to 0.78. Genotype analysis showed weaker association between these T-wave variables in LQT1 triggered events while these features were stronger in patients with LQT2 and significantly outperformed the QTc interval.

That's it for this month, but keep listening. Suraj Kapa will be surveying all journals for the latest topics of interest in our field. Remember to download the podcast On the Beat. Take it away, Suraj.

Suraj Kapa: Thank you, Paul. This month, we will again focus on hard-hitting articles from across the electrophysiological literature. I am Suraj Kapa and we're particularly focusing on articles published in October 2017.

The first article we will focus on is within the realm of atrial fibrillation specifically related to anticoagulation. In Journal of the American Heart Association in Volume 6, Issue 10, Lin, et al. sought to develop a prediction model for time in therapeutic range in older adults taking vitamin K antagonists. As we know, time in therapeutic range is critical for management of patients on vitamin K antagonists. As poor time in therapeutic range either due to subtherapeutic or supratherapeutic INRs, can lead to increased bleeding or thromboembolic risk. While novel oral anticoagulants have improved care of patients requiring anticoagulation, many patients either due to cost or due to other factors are unable to take the novel oral anticoagulants and thus must be maintained on vitamin K antagonists. In this study, Lin, et al. Used well-over 2,500 patients to create training and validation sets and thereby create two models for estimating time in therapeutic range. Through this, they created a simple model term PROSPER consisting of seven variables including pneumonia, renal dysfunction, prior bleeding, hospital stay more than seven days, pain medication use, lack of access to structured anticoagulation services, and treatment with antibiotics.

Using this, they showed that they can predict time in therapeutic range greater than 70% as well as thromboembolic and bleeding outcomes better than other existing time in therapeutic range scoring systems, such as the same TT2R2 score. The reason these scores are important are both to help patients understand when they may be at risk for not maintaining a time in therapeutic range and to assist them in identification of the right anticoagulant methodology or strategy. Also, perhaps to prospectively consider if we can identify patients who may require more intensive monitoring or structured therapy strategies. However, one must also consider that for scores like this, utilization is always critical. In other words, continuous validation of the scoring system must be done in order to make sure it's applicable across populations and across different groups of people in different communities.

Next, within the realm of anticoagulation and atrial fibrillation, we'll review the article by Chang, et al. published in JAMA in Volume 318, Issue 13 entitled Association Between Use of Non-Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding Non-Valvular Atrial Fibrillation. With any new drug that comes out, there's always the possibility of various medication interactions. The source of these medication interactions might be variable. They might include direct effects of other medications on systems by which the primary drug is metabolized. Also, might be due to synergistic effects of medications that might be unpredictable or effects on different aspects of systems the drugs are trying to treat. Thus oftentimes, larger population studies are required before one can appreciate drug interactions that might exist. This is particularly true with novel oral anticoagulant drugs. Part of the promise of the novel oral anticoagulants was that because of the extensive medication interactions associating vitamin K antagonists, the availability of the drug perhaps with fewer medication interactions resulting in alteration and bleeding or thromboembolic tendency will be very important.

In this important paper, Chang, et al. reviewed the effect of other medications on major bleeding events in patients on non-vitamin K oral anticoagulants such as dabigatran, apixaban, and rivaroxaban. Amongst over 91,000 patients, they noted that the concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with the novel oral anticoagulant alone was associated with a significant increase many times by odds ratio of 100 in risk of major bleeding. Several drugs including atorvastatin, digoxin, erythromycin or clarithromycin when used concurrently with NOACs interestingly were associated with the reduced risk of bleeding without elevating thromboembolic risk. The recent advent of NOACs in clinical use especially in patients who might be taking other medications always need to be considered in the context of how the other medications might affect the bleeding or thromboembolic risk. One of the key findings in this publication is the potential interaction with amiodarone and how concurrent use of amiodarone may increase the risk of major bleeding. Because of the general lack of tools to monitor the effects of NOACs on bleeding risk in patients, one needs to consider these population studies and whether or not there might be synergistic effects between medications going forward.

Unfortunately, we cannot adopt guidelines purely based on this data as to whether or not a dose adjustment should occur or whether or not the medication can be used at all. However, it does highlight the care that should be taken when using many of these drugs in conjunction with NOACs.

Finally within the realm of anticoagulation and atrial fibrillation, we'll review the article by Cannon, et al. in The New England Journal of Medicine entitled Dual Antithrombotic Therapy with the Dabigatran After PCI in Atrial Fibrillation. In this study, Cannon, et al. sought to systematically review the role of a warfarin strategy post-PCI versus dabigatran strategy post-PCI. They randomized patients to use of a combination of warfarin, aspirin, and a P2Y12 inhibitors such as clopidogrel post-PCI versus using dabigatran plus a P2Y12 inhibitor. They demonstrated that dual therapy approach with dabigatran resulted in significantly lower bleeding events than the triple antithrombotic/antiplatelet therapy group. There was no difference in adverse events including thromboembolism, unplanned revascularization or death between the groups. These findings were irrespective of whether patients were on 110 mg of dabigatran or 150 mg of dabigatran. These findings suggest that a dual therapy approach in the post-PCI setting with the NOACs as the dabigatran and the P2Y12 inhibitors such as clopidogrel lowers bleeding risk without increasing risk of major adverse events including thromboembolism or stent thrombosis after PCI.

However, it should be noted that one major criticisms of this trial is that the incremental bleeding risk conferred by aspirin could not be accounted for in the triple therapy cohort as aspirin was not used in the dual therapy cohorts. Thus, one cannot necessarily say whether the same finding would have been noted in a warfarin plus P2Y12 inhibitor versus dabigatran plus P2Y12 inhibitor especially given recent evidence suggesting no incremental benefit of aspirin particularly for thromboembolic risk associated with atrial fibrillation. However, the critical element of these findings is that a strategy excluding aspirin where dabigatran plus the P2Y12 inhibitor are used post-PCI might be actually safe.

Changing gears, we will next focus on an article within the realm of cardiac mapping and ablation in atrial fibrillation. This was published in the Journal of the American College of Cardiology in Volume 70, Issue 16 by Prabhu, et al. entitled Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study. In this study, Prabhu, et al. studied in the multicenter randomized clinical trial the effect of catheter ablation for atrial fibrillation in the setting of left ventricular systolic dysfunction versus medical rate control. They looked at the change in ejection fraction over a follow-up of six months. A total of 68 patients were randomized in the study. They demonstrated an absolute improvement in EF by 18% in the ablation group versus 4% in the rate control group, with also a greater rate of EF normalization with ablation. In fact, over 50% of patients had EF normalization after ablation whereas only about 9% had a good medical rate control.

Furthermore, the improvements in EF correlated with the absence of late gadolinium enhancement on MRI and in the medical rate control group an average heart rate less than 90 beats per minute was achieved across the population randomized this approach. These findings are somewhat contrary to other studies that suggested that a rate versus a rhythm control approach were not really much different in patients with reduced left ventricular systolic function. These challenges are paradigm by suggesting that in fact successful restoration of normal rhythm in patients postablation can actually confer improvement in ejection fraction in some patients even when rate controlled. The success rates that should be noted in this study were similar to those published in most existing literature with about 56% of patients without further atrial fibrillation after a single ablation off medications and a success rate of 75% after a single ablation on medications. While the number of patients included are small and thus may be difficult to challenge the paradigm that was created, the rate versus rhythm control are equivalent in patients with reduced systolic function.

This finding should raise awareness that it is quite possible that there might actually be benefits in restoring normal rhythm by modern approaches in patients with reduced systolic function.

Moving on, still within the realm of atrial fibrillation, however, we'll next review the article by Aronsson, et al. in Europace Volume 19, Issue 10 entitled Designing an Optimal Screening Program for Unknown Atrial Fibrillation: A Cost-Effectiveness Analysis. More and more with an understanding that atrial fibrillation is essentially of epidemic proportions, but many patients tend to be asymptomatic and yet having an elevated stroke risk. People are focusing on how do we screen these populations in a manner that is both cost-effective as well as strategic. Aronsson, et al. tried to use computer simulation modeling to determine what the optimal age was to initiate screening for atrial fibrillation. They ran more than two billion different design screening programs that could be implemented at different age ranges and using data from published scientific literature. They tested these various screening programs. They demonstrated that the screening starting at the age of 75 was associated with the relatively low cost per gained quality adjusted life year. The overall cost at this level was 4,800 euros across the population for quality adjusted life year gained across that population.

The relevance of this publication while simulation model lies in highlighting the importance of considering what programs can we actually achieve in the modern day to better identify patients with atrial fibrillation who are not yet identified. Across the literature and in recent clinical meetings, there's a number of articles that are being published regarding the role of different strategies in identifying the asymptomatic, not yet diagnosed atrial fibrillation patients. This study presents an initial foray into systematizing programs that might be applied to recognition of these patients.

Along a similar course, we'll also review an article by Reiffel, et al. in JAMA Cardiology Volume 2, Issue 10 entitled Incidence of Previously Undiagnosed Atrial Fibrillation using Insertable Cardiac Monitors in a High-Risk Population: The REVEAL AF Study. In this study, Reiffel, et al. Reviewed the incidence of atrial fibrillation identified using implantable loop recorders in those with a high risk of stroke nearly a CHADS2 score of 3 or greater, but had not been previously diagnosed. It should be noted that while these patients have never been diagnosed with atrial fibrillation, 90% had nonspecific symptoms such as fatigue, dyspnea or palpitations, then theory could be attributed to atrial fibrillation. A total of 385 patients received monitors. They noted that by 30 months of monitoring, about 40% of patients have been identified as having atrial fibrillation that had not been diagnosed. If patients were only monitored for the first 30 days, however, the incident rate of atrial fibrillation in terms of new diagnosis was only 6%. In fact, the median time from device insertion to first episode of atrial fibrillation was almost four months at about 123 days.

In line with the previous discussed study by Arosson, et al., this study notes the importance of consideration of how we monitor patients at risk for stroke. The issue at hand is when we do screening, what is enough. The strategies used to identify atrial fibrillation of patients raised from advising on twice daily poll checks, which when done by the patient regularly might allow for identification of atrial fibrillation if they do it well to doing a single ECG, to doing a 24-hour Holter, to doing a 30-day monitor, to doing things like implantable loop recorders. However, this study by Reiffel, et al. suggests the a 30-day continuous monitor is truly insufficient if there is a high concern for atrial fibrillation. Thus with the goals to identify atrial fibrillation on high-risk patients or whether a significant clinical suspicion, one should always consider longer term monitoring by this study.

Finally, within the realm of atrial fibrillation, we'll review the article by Tilz, et al. published in Europace Volume 19, Issue 10 on left atrial appendage occluder implantation in Europe, indications anticoagulation post-implantation, results of the European Heart Rhythm Association survey. Currently, there's a high level of utilization of left atrial appendage occlusion for patients with atrial fibrillation who cannot otherwise be on a novel oral anticoagulants in Europe. Tilz, et al. performed a survey of providers performing these procedures. They found that about 52% of those centers performing left atrial appendage occlusion had electrophysiologist performing it as opposed to the remainder using interventional cardiologists. The most common indication for implantation was in those with high risk for stroke and with absolute contraindication to oral anticoagulation or history of bleeding. However, was most interesting from their study was that there was a very wide ranging practice in management after implantation in terms of use of antiplatelets for anticoagulants with 41% prescribing no therapy after implantation. There is even greater variability in therapies for patients who are found to have a thrombus after left atrial appendage occlusion ranging from no therapy to surgery.

These findings highlight the difficulty in managing practice patterns with novel technologist and in particular with left atrial appendage occlusion. The highly heterogeneous practice pattern found here suggests that large-scale population outcomes will be difficult to understand unless we understand the individual practice variation that is occurring such as considering what medications patients were prescribed on in the post-implant period or how patients were included in terms of whether or not they met the standard criteria. Furthermore, when a complication occurs such a thrombus septal left atrial appendage occlusion one might suspect that the implications of different strategies such as not doing any therapy all the way to routinely doing surgery tumor to clot should be considered.

Next, we will move on to the realm of ICDs, pacemakers, and CRT. First, reviewing the article by Pokorney, et al. published in Circulation in Volume 136, Issue 15 entitled Outcomes Associated With Extraction Versus Capping and Abandoning Pacing and Defibrillator Leads. In this study, Pokorney, et al. reviewed these two different approaches in abandoned leads amongst 6,859 patients. They found that extraction was associated with the lower risk of device infection, but there was no association between difference in mortality, need for future lead revision, or need for future extraction. This involved patients in the Medicare age group, but extraction patients of note, tended to be younger with fewer comorbidities, more often female and had a shorter lead dwell time. While they're statistically different, however, the actual number of years by which patients tended to be younger or to have a shorter lead dwell time was only a year.

The fact is that it is always hard to know what to do with an abandoned lead. Having more leads in the vascular system might lead to venous stenosis or might lead to patients having future problems when they need an extraction because of infection, or might make it harder to manipulate this in the vascular space. Thus whether extracting abandoned leads as opposed to just capping them and leaving there needs to be considered when taking any patient in for a lead revision or a lead addition for other reasons. These findings suggest that extraction confer similar mortality risk but lower long-term infection risk than capping them. However, it should be noted this is retrospective data set and given the extraction patients already were younger and had their leads for relatively shorter durations with your comorbidities, they might have reflected to healthier population anyway. However, these data are suggestive and highly the need for further study into whether a more aggressive approach with abandoned lead should be considered. Without randomized data, it will not be for certain.

Next, also within the realm of lead extraction, we'll review the article by Bongiorni, et al. published in the European Heart Journal in Volume 38, Issue 40 entitled The European Lead Extraction Controlled Study: A European Heart Rhythm Association Registry of Transvenous Lead Extraction Outcomes. This prospect of registry on lead extraction the largest to dates, Bongiorni, et al. reviewed safety and complications in addition to relationship to the type of center. They noted that the overall hospital major complication rate was 1.7% with mortality rate of 0.5% associated with lead extraction. The most common complication was actually pericardial synthesis, need for a chest tube or need for surgical repair. Overall, success rates for lead extraction in terms of complete removal of all lead components was 97%. However, it should be noted the overall complication rate and success rates were better in high-volume centers than low-volume centers. These findings are consistent with prior data published by [Desmott 35:22] and others, suggesting that more experience associates with better outcomes in lead extraction. However, these data represent the largest prospective registry on lead extraction and confirm the safety and efficacy of overall current practices.

These better data on modern lead extraction may help facilitate discussions with patients regarding actual outcomes and also decisions on whether or not extraction should be engaged in individual practices.

Next, we'll review the article by Aro, et al. in the realm of sudden death cardiac arrest entitled Electrical Risk Score Beyond Left Ventricular Ejection Fraction: Prediction of Sudden Cardiac Death in the Oregon Sudden Unexpected Death Study in the Atherosclerosis Risk and Communities Study, published in the European Heart Journal in Volume 38, Issue 40. In this study, Aro, et al. reviewed what features beyond ejection fraction could predict sudden death in community cohorts. They specifically focus on the electrocardiogram and demonstrated an electrocardiogram risk score based on the presence or absence of a number of features related to heart rate, left ventricular hypertrophy, QRS transition zone, QTc, and others. They found that amongst those patients with a left ventricular ejection fraction greater than 35%, the presence of four more of these ECG abnormalities confer an odd ratio of sudden death of 26.1. The importance of this article is highlighting how more complex considerations of clinical risk might help in further adjudication of sudden death in poorly characterized cohorts.

While most studies have concluded that addition of a variety of additional features such a T-wave alternans do not really confer incremental benefit beyond the ejection fraction in adjudicating sudden death risk and in helping decision making regarding ICD implantation. The fact is that more complex analyses that might exist in more nonlinear approaches or consider more advanced features, the ECG and combination, might confer some benefit in poorly characterized populations such as those with moderately reduced ejection fraction between 35 and 50. We know that while those with an ejection fraction less than 35% is a population have a higher risk within that population, the majority of patients who suddenly die do not have an EF less than 35%. Thus, identifying patients without an EF less than 35% who might be at risk is important. This study by Aro, et al. indicates one potential option to help discriminate patients who might not fit within normal categories for sudden death adjudication and did not fit neatly within the trials. However, prospect of evaluation of application of scoring systems either this one or others that may come in the future will be critical.

Changing realms yet again, we'll focus on cellular electrophysiology on an article by Kofron, et al. entitled Gq-Activated Fibroblasts Induce Cardiomyocyte Action Potential Prolongation and Automaticity in a Three-Dimensional Microtissue Environment, published in The American Journal of Physiology, Heart and Circulatory Physiology in Volume 313, Issue 4. In this publication, Kofron, et al. demonstrated that in this three-dimensional microtissue model, fibroblasts cause effects on the normal action potential in the surrounding environment leading to proarrhythmogenic automaticity. This model effectively demonstrated the activation of this fibroblast alone taken out of context by other triggers such as abnormalities of innervation, et cetera, could probably contribute to arrhythmogenicity into these hearts. It is well recognized in other studies that fibroblasts don't just cause proarrhythmic effects because of myocardial disarray. In fact, they can have paracrine effects on surrounding cells. This study by Kofron, et al. further highlights those potential effects. The presence of fibroblast amidst cardiomyocytes do not cause proarrhythmic tendency purely by shift in myocardial conduction direction, but also results from the effects of fibroblast once activated on these running cardiomyocytes action potentials of cells.

This study is suggesting specifically proarrhythmogenic arrhythmogenicity related to automaticity in those cardiomyocytes that are adjacent to fibroblast, highlights potential future targets for therapies and also highlights potential mechanisms by which arrhythmias might occurrence population.

Changing gears, we next look at genetic channelopathies in one article within the realm of Brugada syndrome and the second article within the realm of predicting QT interval. First, Hernandez-Ojeda, et al. published an article in The Journal of the American College of Cardiology Volume 70, Issue 16 entitled Patients With Brugada Syndrome and Implanted Cardioverter-Defibrillators: Long-Term Follow-Up. Amongst the 104 patients with long-term follow-up nearly greater than nine years on average, they noted a rate of appropriate therapy was very common especially in secondary prevention patients, however, was as much as 9% in otherwise asymptomatic patients. Appropriate ICD therapies, however, especially amongst asymptomatic patients were exclusively in those spontaneous type I Brugada ECG patterns and inducible ventricular arrhythmias, or those obviously the secondary prevention devices who have prior spontaneous ventricular arrhythmias. However, what is more interesting is that more than 20% of patients had some ICD-related complication. Furthermore, the overall incidence of inappropriate shocks was 8.7%, nearly the same rate as appropriate ICD therapies in the primary prevention population. These findings highlight that there is in fact a reasonable incidence of ventricular arrhythmic events needing ICD therapy even in asymptomatic Brugada patients.

However, I think the most striking finding is the high incidence of device-related complications of a follow-up, which highlights the need for considered selection and adequate device programming to avoid inappropriate ICD shocks and finally the need for regular follow-up of these relatively young patients receiving ICDs who might be more prone to complication with the long-term.

Changing gears, we'll next review an article by Rosenberg, et al. published in Circulation Genetics in Volume 10, Issue 5 entitled Validation of Polygenic Scores for QT Interval in Clinical Populations. Using more extensive genomic analyses, Rosenberg, et al. used populations and real-world cohorts including 2,915 individuals of European ancestry and 366 individuals of African ancestry. They demonstrated that clinical variables could account for about 9 to 10% of variation in QTc in Europeans and 12 to 18% in African ancestry individuals. However, interestingly, polygenic scores provided incremental explanation of a QTc variation but only in individuals of European ancestry. The reason we find this article interesting is the importance of understanding how much genetics can actually tell us and how what it can tell us might vary between difference, individuals of different backgrounds thus how we apply findings from one study to any other study. In the area of genetic testing, the Holy Grail is fully identifying overall risk scores to tell the patient what they may have without having to rely on clinical studies or other clinical variables. However, we do know that there is both an environmental component as well as the genetic components.

This study by Rosenberg highlights the importance of potentially considering both. The issue with the article, however, is the fact that while there was clear benefit of the polygenic score in patients of European ancestry, the African ancestry patients reflect the much smaller population almost one-eighth that of the patients included of European ancestry. Also, European versus African ancestry tend to be very broad-based terms. Whether or not there is greater polygenic variation within those of African ancestry as compared to those Europeans ancestry is relatively unclear. Thus while this study should be taken with grain of salt, it should also be considered in the context of providing a foray into seeing how polygenic scores could augment or understanding of how question intervals might vary in a population of people and might be identified immigrant patients.

Moving to the realm of ventricular arrhythmias, we'll first review the article by Siontis, et al. published in Heart Rhythm Volume 14, Issue 10 entitled Association of Preprocedural Cardiac Magnetic Resonance Imaging with Outcomes of Ventricular Tachycardia Ablation in Patients with Idiopathic Dilated Cardiomyopathy. In this study, Siontis, et al. tried to identify whether or not use of preprocedural MRI had any impact on overall procedural outcomes. They compared in a more modern practice where they are routinely obtaining cardiac MRI versus prior practice where they do not routinely obtain preprocedural MRI for ablation in patients with idiopathic dilated cardiomyopathy. They demonstrated that moderate use of preprocedural MRIs was associated with significantly greater procedural success mainly 63% in the modern approach versus 24% previously. The importance of the study why is in trying to understand what the actual value of preprocedural cardiac MRI is when patients are undergoing VT ablation particularly with non-ischemic cardiomyopathy. VT ablation outcomes are notoriously even harder to predict in non-ischemic cardiomyopathy cohorts than ischemic cardiomyopathy cohorts. Improved procedural experience, however, or different technologies may also alter long-term outcomes.

Thus, because the populations were not randomized and rather retrospective with a discrete change in practice that occurred temporally and just did not vary in terms of utilization over the course of periods of time when success rates might not have been affected just by incremental procedural success is difficult. However, these data suggest that future studies into the incremental role of MRI for VT ablation are needed to determine its utility.

Next, we'll review an article by Ho, et al. published in The Journal of Cardiovascular Electrophysiology in Volume 28, Issue 10 entitled ECG Variation During Ventricular Fibrillation Than Focal Sources Due to Wavebreak, Secondary Rotors, and Meander. Ho, et al. in this publication reviewed the role of rotors and focal sources in ventricular fibrillation. They attempted VF induction of 31 patients and use the combination of surface ECG and biventricular basket catheters to create face mask. They showed there's three differences between those with ventricular fibrillation that was mediate by rotors and those with ventricular fibrillation mediated by focal sources. Specifically those with rotor-based VF had greater voltage variation, which they demonstrated zero wavebreak, secondary rotor formation and rotor meander. One of the most critical findings of this study is the fact that a one-size-fits-all approach to consideration of the mechanism of fibrillation is likely unreasonable in most patients. They discriminate between rotor-based ventricular fibrillation and focal source-based ventricular fibrillation and highlighted there are discrete features that differentiate the two populations.

While this should be considered an initial foray into understanding these patients, clinical and computational size will be important into understand how we can discriminate mechanisms of complex arrhythmias between patients to help understand, which patients might most benefit from a specific ablation approach or therapeutic decision. This might also apply to atrial fibrillation where multiple mechanisms may coexist in the same patient for the pathogenesis of the arrhythmia.

Finally, we'll review an animal model by Patterson, et al. published in The Journal of Cardiovascular Electrophysiology in Volume 28, Issue 10 entitled Slow Conduction Through an Arc of Block: A Basis for Arrhythmia Formation Postmyocardial Infarction. In this study performed in the University of Oklahoma, Patterson, et al. reviewed a novel basis for arrhythmia formation after MI in an animal model. Amongst 108 anesthetized dogs, they demonstrated the delay potentials may decrement over shorter pacing cycle lengths leading to potential premature ventricular beat initiation after sufficient delay of the second potential. Thus, they demonstrated that there is a Wenckebach-like patterns of delayed activation specifically within this arc of conduction block associated with the region infarcted. These findings suggest that even across line of apparent conduction block there may be a potential for premature beat formation due to very slow conduction and thus a novel mechanism of PVC formation following myocardial infarction. Furthermore, it might highlight the mechanism by which to induce PVCs in this patient population

Just because there is conduction block the region of baseline mapping further provocative maneuvers to initiate or to discriminate where there might be very slow conduction might be critical to elicit arrhythmia in some patients.

Next, within the realm of syncope. We focus on article by Baron-Esquivias, et al. published in The Journal of American College of Cardiology Volume 70, Issue 14 entitled Dual-Chamber Pacing With Closed Loop Stimulation in Recurrent Reflex Vasovagal Syncope: The SPAIN Study. In this randomized double blind control study, Baron-Esquivias, et al. study the value of closed loop stimulation in the specific cohort of patients with cardio-inhibitory vasovagal syncope above 40 years of age. They demonstrated amongst 46 patients the closed loops stimulation was associated with the more than 50% reduction in syncopal spells in nearly three quarters of patients. However, it should be noted that up to 9% of patients continue to have syncope in your consistent frequency to prior. However, it should also be noted that sham cohort 46% of patients continue to have syncope while only a quarter were relieved. Syncope is one of the most challenging diagnosis to manage in electrophysiologic practice. This is both due to the heterogeneity of manifestation of syncope in terms of cause as well as the lack of many therapies that affect some of the autonomic features that mediate syncope. Largely, vasovagal syncope can be strategized into cardio-inhibitory and vasodilatory groups.

Generally, pacing will be more effective in theory for those more of a cardio-inhibitory than a vasodilatory component thus certainly patients can have both and thus that might be only partial attenuation of syncopal events by fixing the cardio-inhibitory by pacing but not the vasodilatory, which often requires medications. In this study, the use of closed loops stimulation seems to offer significant benefit in the specific population with cardio-inhibitory vasovagal syncope in age greater than 40 years. However, care should be taken not to necessarily apply these findings to patients not within this age group or within this diagnosis group.

Next within the realm of electrocardiography, we'll review an article by Yasin, et al. published in The Journal of Electrocardiology Volume 50, Issue 5 entitled Noninvasive Blood Potassium Measurement Using Signal-Processed, Single-Lead ECG Acquired from a Handheld Smartphone. Yasin, et al. reviewed the ability to determine changes in potassium level using the ECG. They demonstrated amongst 22 patients undergoing hemodialysis in whom estimation models could then be trained. The mean absolute error of ambulatory follow-up between the potassium estimated off of a single lead handheld smartphone-enabled ECG in the actual blood potassium was 0.38 milliequivalents per liter or a difference of 9% of the average potassium level. These findings suggest that in terms of clinical robustness a single lead smartphone-enabled handheld base ECG might be sufficient to estimate ambulatory potassium levels in patients who might be at high risk especially of hyperkalemia. The fact is that electrolytes and other abnormalities of a body homeostasis may be reflected in the ECG. However, whether the ECG may in turn be used to finally determine changes in characteristics such as electrolytes levels has not been very well described.

Previous work by the same group has suggested that the 12-lead ECG may be utilized to determine find potassium changes in patients undergoing hemodialysis. These findings while in small number of patients in this particular article highlights that ambulatory technologies such as the one they used here might in fact be utilized to discriminate potassium levels in patients who might be at risk of variations of potassium levels that can sometimes be life-threatening. Further validation will be required in larger populations, but this initial foray might create a paradigm for use of the ECG in ways beyond just looking for arrhythmias.

The final article we'll review is by Calzolari, et al. published in The Journal of American College of Cardiology, Clinical Electrophysiology in Volume 3, Issue 10 entitled In Vitro Validation of the Lesion Size Index to Predict Lesion Width and Depth After Irrigated Radiofrequency Ablation in a Porcine Model. In this paper published in the special of JACCEP focused on biophysics of ablation, Calzolari, et al. reviewed in vitro validation of lesion size indexing using radiofrequency ablation. Specifically, they reviewed the novel measure that incorporates not just contact force, power and time, but also impedance into predicting lesion quality. They noted that while lesion with in depth did not correlate with power or contact force alone, it did with either the lesion size indexing tool that they created and also with the force-time integral. However, the lesion size indexing where impedance was included was incrementally better than force-time integral. The truth is that improved prediction model lesion size inadequacy are critical during radiofrequency ablation.

Predicting lesion formation might help physicians know whether or not they have done adequate intervention at the time of application. They demonstrated incorporating impedance along with contact force, power, and time. The predictive value of their lesion indexing approach was quite good. However, further validation in association with an outcome is necessary to look at the incremental value. It also should be noted that this lesion size indexing tool did not necessarily predict steam pop formation, which is more often associated with power.

I appreciate everyone's attention to this key and hard-hitting articles that we have just focused on from this past month of cardiac electrophysiology across the literature. Thanks for listening. Now back to Paul.

Paul Wang: Thanks Suraj. You did a terrific job surveying all journals for the latest articles on topics of interest in our field. There's none an easier way to stay in touch with the latest advances. These summaries and a list of major articles in our field each month could be downloaded from Circulation, Arrhythmia, Electrophysiology website. We hope you'll find the journal to be the go-to place for everyone interested in the field. See you next month.

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