Circulation: Arrhythmia and Electrophysiology On the Beat February 2018

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

In our first article, Mathew Daly and associates examine whether a high-resolution, 9 French, infrared thermography catheter can continuously image esophageal temperatures during atrial fibrillation catheter ablation. The infrared temperature catheter was inserted nasally or orally into the esophagus, adjacent to the left atrium. Endoscopy was performed within 24 hours to document esophageal injury. Thermal imaging showed that 10 out of 16 patients experienced one or more events where the peak esophageal temperature was greater than 40 degrees centigrade. Three patients experienced temperatures greater than 50 degrees centigrade and one experienced greater than 60 degrees centigrade. Analysis of temperature data from each subject's maximal thermal event revealed high radius, 2.3 degrees centigrade per millimeter and rates of change 1.5 degrees centigrade per second, with an average length of esophageal involvement of 11.0 millimeters.

Endoscopy identified three distinct thermal lesions, all in patients with temperatures greater than 50 degrees centigrade, all resolving within two weeks. The authors concluded that infrared thermography, high-resolution mapping of esophageal temperatures during catheter ablation may be performed. Esophageal thermal injury occurs with temperatures greater than 50 degrees centigrade, and was associated with large spacial-temporal gradients.

In our next article, Nitesh Sood and associates reported on the real-world incidence and predictors of perioperative complications in transvenous lead extractions involving ICD leads in the NCDR ICD registry. Lead extraction was defined as removal of leads implanted for greater than one year. Predictors of major perioperative complication for all extraction procedures, 11,304, and for high voltage leads, 8,362, or 74% across 762 centers were analyzed, using univariate and multivariate logistic regression. Major complications occurred in 258, or 2.3% of the extraction procedures. Of these, 258 procedures with a complication, 41 or 16% required urgent cardiac surgery. Of these, 14 or 34% died during surgery. Among the total 98, or 0.9% deaths reported, 18 or 0.16% of the total occurred during extraction.

In multivariate, logistic regression analysis of all extractions, female sex, admission other than electively for the procedure, three or more leads extracted, longer implant duration, dislodgement of other leads, patients' clinical status, requiring lead extraction, such as infection or perforation, were associated with increased risk of complications. For high voltage leads, smaller lead diameter, a flat versus round coil shape, in greater proximal surface coil area, were multivariate predictors of major perioperative complications.

The rate of major complications and mortality with transvenous lead extraction is similar in the real world compared to single center studies from high volume centers. There remains a significant risk of urgent cardiac surgery with a very high mortality, and planning for appropriate cardiothoracic surgical backup is imperative.

In our next paper, Bence Hegyi and associates, have reported on the repolarization reserve in failing rabbit ventricular myocytes, and the role of calcium and beta-adrenergic effects on delayed and inward rectifier potassium currents. The authors measured the major potassium currents, IKr, IKs, IK1, and their calcium and beta-adrenergic dependence in rabbit ventricular myocytes, in chronic pressure, in volume overload, induced heart failure, and compared them to age-matched controls.

The authors made a number of observations. One, action potential duration was significantly prolonged only at lower pacing rates, 0.2 to 1 Hertz, in heart failure under physiological ionic conditions and temperature. Two, beat to beat variability of action potential duration was also significantly increased in heart failure. Three, both IKr and IKs were significantly regulated in heart failure under action potential clamp but only when cytosolic calcium was not buffered. Four, CaMKII inhibition abolished IKs upregulation in heart failure, but did not affect IKr. Five, IKs response to beta-adrenergic stimulation was also significantly diminished in heart failure, and, six, IK1 was also decreased in heart failure regardless of calcium buffering, CaMKII inhibition or beta-adrenergic stimulation.

These observations changed when cytosolic calcium was buffered. The action potential prolongation in heart failure was also significant in higher pacing rates. The authors concluded that in heart failure, calcium dependent up regulation of IKr and IKs counter-balances the reduced IK1, maintaining the repolarization reserve, especially at higher heart rates. In physiologic conditions, unlike conditions of strong cytosolic calcium buffering. Under beta-adrenergic stimulation, reduced IKs responsiveness, severely limits the integrated repolarizing potassium current in repolarization reserve in heart failure, increasing the arrhythmia propensity.

In the next paper, Christopher Piorkowski and associates report on the feasibility of a combined endo-epicardial catheter approach for mapping the ablation of atrial fibrillation. The authors studied 59 patients with permanents pulmonary veins isolation and had further symptomatic recurrences of paroxysmal atrial fibrillation, persistent atrial fibrillation, or atrial tachycardia. These patients underwent repeat ablation using bi-atrial endo- and epicardial mapping and ablation. Identification of arrhythmia substrates and selection of ablation strategy were based on sinus rhythm voltage mapping. In all patients, endo-epicardial mapping ablation were feasible using standard technologies of catheter access, three dimensional mapping, and radiofrequency ablation.

Epicardial mapping and ablation did not add procedural risk. Exclusively, epicardial low voltage substrate were found in 14% of patients. For the first time, novel epicardial conduction abnormalities located in the epicardial fiber network were described in human patients, 19% of the cohort. Epicardial ablation was needed in 80% of the patients. Over 23 months of follow up, freedom from arrhythmia recurrence was 73%. The authors used continuous monitoring and three months blanking period. Freedom from ATR of greater than two minutes was defined as the primary end-point.

The authors concluded that endo-epicardial mapping ablation was feasible and safe. Epicardial ablation increases transient mortality of ablation lesions. Further studies will be needed to demonstrate reproducibility and long-term outcomes, and how the technique compares to other methods.

In the next article, Michael Wolf and associates examined the long-term results of substrate modification for ablation of ventricular tachycardia using substrate elimination, targeting local, abnormal ventricular activities, or LAVA, post-myocardial infarction. They reported on 159 consecutive patients undergoing first ablation, age 65, 92% with ICDs, 54% with storms, and 73% with appropriate shocks. LAVA were identified in 92% and VT was inducible in 73%. Complete LAVA elimination after ablation was achieved in 64% and non-inducibility was achieved in 85%. During a median follow-up of 47 months, single procedure, ventricular free survival was 55%, 10% storms, and 19% shocks. The ventricular arrhythmia free survival was 73% after one year and 49% after five years.

Complete LAVA elimination was associated with improved outcomes, ventricular arrhythmia free survival of 82% at one year and 61% at five years. The subgroup treated with multi-electrode mapping and real-time image integration had improved ventricular arrhythmia free survival, 86% at one year and 65% at four years. Repeat procedures were also performed in 18% of patients. The outcomes improved, 69% ventricular arrhythmia free survival during a median follow-up of 46 months.

In a single center study, substrate modification, targeting LAVA for post myocardial infarction ventricular tachycardia resulted in a substantial reduction in ventricular tachycardia storm and ICDs shocks with up to 49% of patients free of arrhythmias at five years after a single procedure. Complete LAVA elimination, multi-electrode mapping, and real-time integration were associated with improved ventricular arrhythmia free survival.

In the next paper, Jean-Baptiste Gourraud and associates examined the safety and feasibility of transvenous lead extraction in adults with congenital heart disease over a 20 year period at a single center. The authors reported on 71 transvenous lead extraction procedures in 49 patients with adult congenital heart disease, mean age 38 years in which a total of 121 leads were extracted. The primary indication for extraction were infection in 48%, lead failure in 31%. A laser sheath was required in 46% and a femoral approach in 8%. Complete transvenous lead extraction was achieved in 92% of the leads. 49% of the patients had transposition of the great arteries. In multivariate analysis, lead duration was predictive of transvenous lead extraction failure. No perioperative death or pericardial effusion was observed. Subpulmonary, atrioventricular valve regurgitation increased in eight patients, five of whom had TGA and were independently associated with ICD leak or valvular vegetation.

After a median of 54 months of follow up after the first lead extraction, three deaths occurred independently from lead management. The authors concluded that despite complex anatomical issues, transvenous lead extraction can be achieved successfully in most adult congenital heart disease patients using advanced extraction techniques. Subpulmonary AV valve regurgitation is a prevalent complication, particularly in patients with transposition of the great arteries.

In the next paper, Gabriela Orgeron and associates examined the incidence of ventricular arrhythmias and follow-up in ARVC patients grouped by the level of indication for ICD placement, based on the 2015 International Task Force Consensus Statement Risk Stratification Algorithms for ICD Placement in arrhythmogenic right ventricular dysplasia/cardiomyopathy. In 365 of arrhythmogenic right ventricular dysplasia/cardiomyopathy patients, the authors found that the algorithm accurately differentiates survival from any sustained VT/VF among the four risk groups, p < 0.001. Patients with a Class I indication had significantly worst survival from VT/VF than patients with a Class IIa indication or a Class IIb. However, the algorithm did not differentiate survival free from VF or V flutter between patients with Class I and Class II indications. Adding Colter results, less than 100 PVCs per 24 hours to the classification, helps differentiate the risk.

Patients with a high PVCs burden, greater than 1000 PCVs per 24 hours had a poor survival from both VT/VF and VF and V flutter.

In the next paper, Takeshi Kitamura and associates studied eight patients that had bi-atrial tachycardia, a rare form of atrial macroreentrant tachycardia, in which both atria form a critical part of the circuit and were mapped using an automatic, high resolution, mapping system. 708 patients had a history of persistent atrial fibrillation, including septal or anterior left atrial ablation before developing bi-atrial tachycardia. One of the patients had a history of atrial septal path closure with a massively enlarged right atrium. The authors found that 9 atrial tachycardias, with a median cycle length of 334 milliseconds had three different types. Three were peri-mitral and peri-tricuspid reentrant circuit, three utilized the right atrial septum in a peri-mitral circuit, and three utilized only the left atrium and the left right atrial septum.

Catheter ablation successfully terminated eight of the nine bi-atrial tachycardias. The authors found that all patients who developed bi-atrial tachycardia had an electrical obstacle on the intraseptal left atrium, primarily from prior ablation lesions.

In our next paper, Kwang-No Lee and associates randomized 500 patients with paroxysmal atrial fibrillation to one of two strategies after pulmonary vein isolation. One, elimination of non-PV triggers in 250 patients, group A, or, two, step-wise substrate modification using complex fractionated atrial electrogram or linear ablation until non-inducibility of atrial tachyarrhythmias was achieved, 250 patients in group B. Recurrence of atrial tachyarrhythmias was higher in group B compared to group A. 32% of patients in group A experienced at least one episode of recurrent atrial tachyarrhythmia after the single procedure, compared to 43.8% in group B. P-value of 0.012 after a median follow-up of 26 months. Competing risk analysis showed that the cumulative incidence of atrial tachycardia was significantly higher in group B compared to group A (p= 0.007).

The authors concluded that elimination triggers as the end-point of ablation in paroxysmal atrial fibrillation patients decreased long-term recurrence of atrial tachyarrhythmias compare to non-inducibility approach achieved by additional empiric ablation.

In our final paper of the month, Roland Tilz and associates reported on 10 year outcome after circumferential pulmonary vein isolation using a double lasso and three dimensional electro anatomic mapping technique. From 2003 to 2004, 161 patients with symptomatic drug refractory paroxysmal atrial fibrillation underwent electro-anatomical mapping guided circumferential pulmonary vein isolation. The procedure end-point was absence of pulmonary vein spikes thirty minutes after isolation, after a single procedure and a median follow up of 129 months, stable sinus rhythm was present in 32.9% of patients based on Holter-ECGs and telephonic interviews. After multiple procedures, mean 1.73 and median follow up of 123.4 months, stable sinus rhythm was seen in 62.7% of patients. Progression towards persistent atrial fibrillation was observed in 6.2%.

The authors concluded that although the 10-year single procedure outcome in patients with paroxysmal atrial fibrillation was low, 32.9%, it increased to 62.7% after multiple procedures and the progression rate to persistent atrial fibrillation was remarkably low.

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.

Dr Kapa: Thank you Paul, and welcome back everybody to Circulation’s “On the Beat”, where we'll be discussing hard hitting articles across the electrophysiology literature.

Today, we'll be reviewing 22 separate articles of particular interest, published in January 2018. The new year saw plenty of articles that are of particular interest either for the future of our field of for present management of our patients. First, within the realm of atrial fibrillation, we'll review several articles within the realm of anticoagulation and left atrial appendage occlusion.

The first article we'll review is by Yong et al in the American Heart Journal, volume 195, entitled "Association of insurance type with receipt of oral anticoagulation in insured patients with atrial fibrillation: A report from the American College of Cardiology NCDR PINNACLE registry." In this publication, the author sought to evaluate the effect of insurance type on the appropriate receipt of anticoagulant therapy, specifically looking at warfarin versus NOACs. They reviewed retrospectively over 360,000 patients and found significant differences in appropriate prescription of anticoagulants, irrespective of which anticoagulant was considered. Medicaid patients received less appropriate anticoagulant prescription than those who were privately insured on Medicare or military insured. Furthermore, those on military or private insurances had a higher rate of NOAC prescription than those with Medicare.

Furthermore, there was an even wider disparity in NOAC use than warfarin use amongst differently insured patients. These data are important in that they highlight potential variability in appropriate management of patients based on insurance type. Of course, there are many issues that might impact this, such as health care access or available pharmacy coverage of specific medications. Furthermore, the authors do not dive into the impact on outcomes based on the therapy availability.

The next article we'll review is by Jazayeri et al, entitled "Safety profiles of percutaneous left atrial appendage closure and lysis: An analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 2009 to 2016" published in the Journal of Cardiovascular Electrophysiology in volume 29 issue 1. Here, the authors sought to evaluate the overall safety profiles of procedures performed with different percutaneous left atrial appendage occlusion devices, including LARIAT and WATCHMAN. They review 356 unique reports and compared outcomes pre- and post- approval of the WATCHMAN device. The look at the specific composite outcome of stroke, TIA, pericardiocentesis, cardiac surgery, and death. They noted that this composite outcome occurred more frequently with WATCHMAN than with LARIATs, and this is irrespective of pre- or post- approval status.

These findings highlight the importance of postoperative monitoring in evaluation of overall outcomes. The reason by which there was more frequent negative outcomes in the WATCHMAN than LARIATs need to be considered. Obviously there's several limitations in the MAUDE database, similar with all large databases. However, it does highlight the importance of considering the mechanisms or sure decision making necessary, not just amongst patients and their providers but amongst operators of the staff or amongst physicians and industry executives. To determine how to optimize devices going forward.

Speak of left atrial appendage occlusion devices and the potential future of these, we next review an article by Robinson et al, entitled "Patient-specific design of a soft occluder for the left atrial appendage" published in nature biomedical engineering, in volume two in the year 2018. Robinson et al used 3D printing to create a soft, immunocompatible, biocompatible, endocardial implant to occlude the left atrial appendage. They use the individual CT of an in vivo pig to three D print using a specialized material, a left atrial appendage occlusion device, and demonstrated feasibility of achieving adequate occlusion. This paper is important and is one of the initial [inaudible 00:22:03] to how three D printing may be used to optimize patient care. In fact, three D printing has the potential to overturn medical manufacturing and device development.

Anatomy tends to be more often patient-specific than not. That's one size fits all implant designs may not be optimal, and resulting exclusion or inadequate occlusion amongst many patients. Decide of three D printable patient specific rapidly prototype soft devices that are biocompatible and hemocompatible, holds the potential to revolutionize the occlusion.

Staying in the field of left atrial appendage occlusion, we next review an article by Lakkireddy et al entitled "left atrial appendage closure and systemic homeostasis: The LAA homeostasis study" published in JACC. The authors sought to evaluate the effect of epicardial-versus endocardial left atrial appendage occlusion on systemic homeostasis, including effects on neuro-hormonal profiles of patients. They performed a prospective, single center, observational study, including 77 patients, about half of whom received endocardial versus epicardial device. Interestingly, they noted that the epicardial left atrial appendage occlusion cohort exhibited significant decrease in blood adrenaline, noradrenaline and aldosterone levels. Those are not seen with endocardial devices. Internal epicardial devices are associated with increases in adiponectin and insulin levels as well as a decrease in free fatty acids and consistently lower systemic blood pressure.

These data suggest a significant difference in the effect of epicardial versus endocardial closure left atrial appendage on neurohormonal profile. The authors propose several mechanisms for these findings but not the exact mechanisms as yet unclear. Several factors potentially could lead to these findings. One is that epicardial ligation may result in more total ischemia of the left atrial appendage than endocardial closure. Another potential mechanism maybe that the presence for material in the pericardial space versus in the bloodstream may have different effects on neuro-hormonal profile. However, these significant differences in outcomes highlight the importance of considering whether all approaches of left atrial appendage occlusion are considered equal. Many flaws of this study is that it's observational and not randomized. Does it possible those receiving epicardial closure may have been perceived to be lower risk for epicardial puncture, in this, as result, had better long-term outcomes.

Changing gears now but staying within the realm of atrial fibrillation, we next review elements for cardiac mapping and ablation. The first article we review is one that has received significant press, published by Marrouche et al entitled "Catheter ablation for atrial fibrillation with heart failure" in the New England Journal of Medicine, volume 378. It is well recognized that morbidity and mortality are higher in heart failure patients who also have atrial fibrillation. Marrouche et al published the results of the CASTLE-AF trial, which attempted to determine if catheter ablation [inaudible 00:24:46] better outcomes among patients with heart failure and atrial fibrillation. They randomized 179 patients to ablation and 184 to medical therapy, which consisted of either rate or rhythm control. Inclusion criteria were those with NYHA class II to IV heart failure, LVEF of 35% or less, and an ICD.

The primary endpoint was a composite where the death from many causes or hospitalizations for worsening heart failure. They noted over a median of three as a follow up, the end-point was reached in 28.5% of the ablation group and 44.6% of the medical therapy group, accounting for a significant hazard ratio of 0.62. Furthermore, fewer patients that in the ablation group died from any cause, were hospitalized for worsening heart failure, or died from cardiac causes. These data made a big splash because they're highly supportive of the premise that catheter ablation may be beneficial in some patients with atrial fibrillation and heart failure, often beyond that of medical therapy alone.

One major strength of this paper is that the actual AF burden was tracked by the ICD, so we know for sure whether or not the procedure was successful and how controlled the atrial fibrillation was. One thing to note however, is that subgroup analysis suggest that those with more symptomatic heart failure, namely NYHA class III to IV, not benefit as much from ablation. Furthermore, it's also important to note that the five years expected mortality in patients was higher than predicted in the CASTLE-AF trial, however overall these trials highly suggest that the potential benefit that ablation may hold over conventional medical therapy. Extrapolation to comparison with the utility of interventions such as biventricular pace with AV node ablation, however, remains to be considered.

Next, we review an article by Chugh et al entitled "Spectrum of atrial arrhythmias using ligament of Marshall in patients with atrial fibrillation" published in Heart Rhythm volume 15, issue 1. They reviewed the spectrum of presentations associated with arrhythmogenesis attributed to the ligament of Marshall, amongst patients with atrial fibrillation. They demonstrate that nearly a third of those patients, ligament of Marshall associated arrhythmias had a pulmonary vein ligament connection, that variously required ablation, the left lateral ridge, the mitral annulus, or alcohol ablation. In addition, they noted about a quarter of patients had atrial tachycardia attributable to the ligament, and the remaining had periatrial reentry requiring either ablation or alcohol injection of the ligament to attain a conduction block.

The relevance of this publication, albeit it is of a small number of patients and a small center, lies in highlighting on the right mechanisms by which the ligament of Marshall may contribute to arrhythmogenesis. Namely, can include direct venous connections, inhibition to inaudibility to attain mitral block, and directly attributed atrial arrhythmias. Recognition of the various ways and situations under which the ligament of Marshall may play a role in arrhythmogenesis in atrial fibrillation patients, may optimize physician decisions to look for identify and target the ligaments. What is not as well understood however is the frequency with which ligament of Marshall plays a significant role in arrhythmogenesis in atrial fibrillation.

Moving gears, we next review an article by Pathik et al entitled "Transient rotor activity during prolonged three-dimensional phase mapping in human persistent atrial fibrillation" published in a special issue of JACC Clinical Electrophysiology, that focus on atrial fibrillation specifically, in volume 4 issue 1. Pathik et al sought to validate three-dimensional phase mapping system for persistent atrial fibrillation. Commercially available rotor mapping systems project the heart into two dimensions based on a three-dimensional catheter. Instead, Pathik et al used a combination of basket catheters along with the non-left atrial surface geometry to construct three D representations of phase progression. Amongst 9 out of 14 patients, they identified 34 rotors, with all these rotors being transients. Of particular interest, the rotors were only seen in areas of high electric density, where internal electric distances were shorter. They also noted the single wave front is also the most common propagation pattern. The importance of this publication lies in considering two things. First is the three dimensional representation of rotor position and the feasibility of this, and the second is really the high electro-density necessary to observe for others.

This has been one of the main problems in rotor analysis, namely what the spacial and temporal density is, that is required to identify rotors, especially given how transient they often are. The presence of rotors does not necessarily mean they're ablation targets in all patients. However, the question still remains regarding the optimal approach to mapping rotors, it needs to be remembered that rotors actually are meant to represent three dimensional scrollway phenomena, that cannot necessarily always be reflected in traditional two D mapping schema. Furthermore, to be remembered that when we claim three-dimensional mapping, this just reflects a two-dimensional surface being wrapped in three dimensions to reflect overall internal surface geometry but it does not take into account transmural activation.

Thus, taking into account all these elements it should be remembered as sometimes, it is possible that a rotor might exist but it's just not evident based on the two-dimensional representation or a two-dimensional representation that looks like a rotor may in fact not be a rotor when you consider it in a three-dimensional media.

Our last article within the realm of cardiac mapping and ablation we will consider is by Zghaib et al, entitled "Multimodal examination of atrial fibrillation substrate: Correlation of left atrial bipolar voltage using multielectrode fast automated mapping, point by point mapping, and magnetic resonance imaging intensity ratio", published in JACC Clinical Electrophysiology, in the same volume as the previous article. The authors sought to compare fast automated mapping with multiple electrodes versus point by point mapping and correlate with weighed gadolinium enhancement as seen by MRI, termed the image intensity ratio.

We all recognize that bipolar voltage is critical to recognizing and evaluating substrate. It's traditionally used in decay regions of substrate in both the atrium and ventricles. However, whether a newer automated approach used to characterize substrate perform equally well in comparison with traditional point to point mapping is still unknown. Thus, the authors in 26 patients perform cardiac MRI and mapping endocardial using both voltage mapping techniques. They noted that for each unit increase in image intensity ratio on MRI, in other words, increasing late enhancement, there was 57% reduction of bipolar voltage. They also noted that the bipolar voltage using other fast elevating mapping or point by point was significantly related with actual differences in calculated voltage, becoming more dissimilar in the extreme of high and low voltage areas.

The relevance of this publication is highlight in the potential utility of fast automated mapping in creating accurate voltage maps. The correlation of voltage values with image-intensity ratios suggest the utility of either approach. In turn, correlation with MRI suggest a pathologic correlate for all of these findings. However, whether substrate characterization guide ablation carries incremental benefit remains to be seen.

Changing gears but staying in the realm of atrial fibrillation, we next review elements of risk stratification and management. The first article we review is by Friedman et al, entitled "Association of left atrial appendage occlusion and readmission for thromboembolism amongst patients with atrial fibrillation undergoing concomitant cardiac surgery", published in JAMA, volume 319, issue four. Friedman et al sought to evaluate whether surgical left atrial appendage occlusion let to a reduction in long-term thromboembolic risk in a large database of Medicare recipients. They included the primary outcome as readmission for thromboembolism, including stroke, TIA, or systemic embolism, in up to three years of follow-up. With secondary end-points including hemorrhagic stroke, all-cause mortality, and a composite end-point of all outcomes.

Amongst more than 10,000 patients, there were almost 4,000 patients receiving surgical occlusion of left atrial appendage. Surgical occlusion was associated with a reduction in thromboembolic risk, OR of 6%, all cause mortality, 17 versus 24%, and the composite end-point, 21 versus 29%. However, interestingly, surgical occlusion was only associated with reduction in thromboembolic risk compared with no occlusion amongst those discharged without anticoagulation and those discharge with it. Namely, the thromboembolic risk reduction was primarily seen in those where the surgical occlusion, those who were sent home without any sort of anticoagulation. These data suggest that surgical occlusion leads to reduction of thromboembolic risk overall. As any large database based study, there are massive flaws in the database itself. Namely, we're relying on the coding of hospitals and operators. To know exactly what was done and what happens latter.

However, these data are hypothesis generating. One key element is the fact that surgical left atrial appendage occlusion was only superior in reducing thromboembolic risk amongst those discharged without anticoagulation. This raises the question as why. Was left atrial appendage completely closed in these patients? In which case, they may be at further increased risk or that the operators felt that there is a high risk for other reasons that cannot be cleaned from an administrative datasets? While the data support consideration of the benefit of left atrial appendage occlusion in a surgical manner, a kin to what has been seen in papers on WATCHMEN and other approaches, and how is the critical nature of randomized trials in this regard.

We next review an article published in JAMA Cardiology, volume three issue one by Inohara et al, entitled "Association of atrial fibrillation clinical phenotypes with treatment patterns and outcomes: A multicenter registry study." Traditionally classification of AF has depended largely on factors such as the nature of AF, paroxysmal versus persistent, LA size, and other factors such as extend of the late enhancement. Inohara et al sought to evaluate whether cluster analysis could better define heterogeneity of AF in the population. They included an observational cohort of almost 10,000 patients admitted to 124 sites in the United States in the ORBIT-AF registry.

Outcome was a composite major address cardiovascular and neurological events or major bleeding. Amongst these patients, they identified four clusters, including one those with lower rates of risk factors and comorbidities than other clusters, two, those with AF at younger ages and with comorbid behavior disorders. Three, those with AF with tachycardia-bradycardia type syndromes and had devices for sinus node dysfunction, and four, those with AF with other risk factors such as a coronary disease. Those in the first cluster had significantly lower risks of major events. All clusters were noted to have symptom dissociation to specific clinical outcomes.

These data are interesting and highlight the highly heterogeneous nature of classifying risk attributable to atrial fibrillation. When broad datasets associated atrial fibrillation with specific outcomes. Maybe suggest an attribution to all patients with atrial fibrillation. However, this single relationship was specific to the outcomes suggest the limitation of applying outcome as approach to understand atrial fibrillation impacts and outcomes, namely depending on clusters that may take into account patient age or comorbidities, it may be irrelevant in discriminating patient outcomes than the traditional paradigm in the same paroxysmal versus persistent or depending on the left atrial size.

These data also highlight the importance of considering the inclusion criteria in randomized trials of atrial fibrillation before stripling real world outcomes to patients who don't fit within that trial.

Next, we will be reviewing an article by Chou et al entitled "Relationship of aging and incident comorbidities to stroke risk in patients with atrial fibrillation," published in JACC, volume 71 issue two. Chou et al sought to evaluate the effect of aging and evolving instant comorbidities to stroke risk in patients with atrial fibrillation. Many large database studies or trials where added baseline CHADSVASC score and the then ensuing follow up period to define risk over time of ischemic stroke.

The authors hypothesized that as patients age, develop new comorbidities that would change the score, may be more predictable of long-term outcomes than the score itself. They included over 31,000 patients who do not have comorbidities to CHADSVASC aside from age and sex but had atrial fibrillation. They didn't calculate a delta score defined as the difference between the baseline and follow up scores. The mean baseline score was 1.29 with an increase in 2.3 during follow up, with an average delta of one. The score may not change over follow up in 41% of patients. Interestingly, significantly more patients had a delta CHADSVASC of one or more and develop ischemic stroke than non-ischemic stroke. The delta CHADSVASC was shown to better predictor of ischemic stroke than either baseline or follow up CHADSVASC score. This data suggest that additive shifts in the CHADSVASC score over time may be more predictive of stroke risk than the actual score itself.

These findings are thoughtful and logical. They indicate the potential impact of continued aging or acquisition identification of new comorbidities. In some patients, potential discovery or new comorbidities or follow-up; for example, hypertension and coronary artery disease may lead to reclassification of stroke risk. That is important to maintain close follow up of atrial fibrillation patients, and not to show a continued need or lack of need of anticoagulation on the basis of a baseline evaluation. This also holds relevance single center long-term outcomes in patients specific scores. Whether is acquisition of new comorbidities or presence of baseline comorbidities or predict a long-term score, should we consider when assessing the need for anticoagulation, particularly in perceived initially low risk cohorts who go on to develop ischemic stroke.

Lastly, within the realm of atrial fibrillation, we review an article by Hussain et al, entitled "Impact of cardiorespiratory fitness on frequency of atrial fibrillation, stroke, and all-cause mortality" published in the American Journal of Cardiology, volume 121 issue one. Hussain et al review the effect of cardiorespiratory fitness on overall outcomes and incidence of atrial fibrillation and outcomes amongst patients with atrial fibrillation. Amongst over 12,000 individuals prospectively followed up after treadmill exercise test, they noted 1,222 had a incidence of AF, 1,128 developed stroke, and 1,580 died. For every 10% increase in functional layover capacity, there was a 7% decrease in risk of incident AF, stroke, or death.

Similarly, in those who developed AF, stroke was lower in those with higher functional aerobic capacity. These findings support the notion known to other areas of cardiovascular disease that better cardiorespiratory fitness is associated with better outcomes, in this case to stroke, incident AF, or mortality. Furthermore, even on the presence of AF, those with better functional capacity had a lower risk of stroke. These data highlight the continued importance of counseling patients on the benefits of physical fitness even in the setting of already present AF.

Moving on to a different area of electrophysiology, we review the realm of ICD pacemakers and the CRT.

The first article review is by Sze et al entitled "Impaired recovery of left ventricular function in patients with cardiomyopathy and left bundle branch block" published in JACC volume 71 issue 3. Patients with left bundle branch block and cardiomyopathy are known to respond to CRT therapy. Thus the investigators sought to evaluate whether guideline medical therapy in patients with reduced LVEF and left bundle branch block, afford a beneficial first line approach therapy. The reason for this currently guidelines suggest waiting at least three months before consideration of CRT has had as some patients may recover on guideline directed medical therapy without the need for device implantation.

They review patients with a LVEF of less or equal than 35% and baseline ECG showing left bundle branch block. In evaluating left ventricular ejection fraction at follow up of three to six months. They excluded patients with severe valvular disease, and already present cardiac device, an LVAD, or heart transplant. Among 659 patients meeting criteria, they notice 74% had a narrow QRS duration of less than 120 whereas 17% had QRS duration greater than 120, and the remainder had a QRS duration greater 120 but was not left bundle branch block. The mean increase in the left ventricular ejection fraction on guideline directed medical therapy was in those with a narrow QRS duration and least in those with left bundle branch block, 8.2%.

Furthermore, when comparing mean LVEF improvement, those with on versus non-on guideline directed medical therapy, there was virtually no difference in rates of recovery. Furthermore, composite end-point of heart failure hospitalization mortality was highest in those with left bundle branch block. These data suggest that those with bundle branch block and cardiomyopathy received less overall benefit from guideline directed medical therapy over the three to six months follow up period. Whether this is due to already more severe myopathic process to start with or due to the CRT is unclear. However, it may suggest that in some patients, left bundle branch block may benefit from inclusion of CRT early in their disease course as known the significant number of patients up to three to six months guideline directed medical therapy with insufficient DF recovery may then benefit from CRT. As well as intervening earlier may result in better outcomes, especially knowing the high and term raise mortality in heart failure hospitalization remains to be seen.

A trial studying early implantation of CRT on these patients may be relevant.

The next article review is by Gierula et al entitle "Rate-response programming tailored to the force-frequency relationship improves exercise tolerance in chronic heart failure" published in JACC Heart Failure, in volume six, issue two. The authors sought to evaluate whether tailored rate-response programming improved exercise tolerance in chronic heart failure. The double blinded, randomized, control, crossover study, they compared the effects of tailored programming on the basis of calculated force-frequency relationship, defined as including critical heart rate, peak contractility, and the slope, multidimensional programming and exercise time and maximal oxygen consumption. They demonstrate amongst 98 enrolled patients that rate-response settings limiting heart rate raise to below the critical heart rate led to create exercise timing and higher peak oxygen consumption.

These data suggest that personalizing rate-response therapies may improve exercise time and oxygen consumption values in patients with heart failure and pacing devices. The main limitation of the study is that the number of patients was small, 90, and then the number of patients crossing over was even smaller, 52. However, highlights the potential of working closely between device programmers and consideration of individual's characteristics and their exercise needs in determining optimal programming strategy.

Finally, within the realm of devices, we review an article by Hawkins et al, entitled "Long-term complications, reoperations, and survival following cardioverter defibrillator implant" published in Heart, volume 104 issue three. Hawkins et al sought to evaluate the long-term complications and risk of reoperation associated with defibrillator implantations in a large [inaudible 00:41:56] population of 300,410 patients, they noted over a 30-month follow up period there was a 12% reoperation rate within the year of implant. This is most prominent for CRT devices, with a risk of 18% in one year post-implant. Furthermore, CRT had the highest rate of early complications, with device complexity, age, or the presence of atrial fibrillation being significantly associated with complication risk.

Mortality also increased over time from 5% within the first year to nearly a third after five years. However, younger patients exhibited five years survival similar to the general population with a progressive decline of this as older patients were considered. These findings highlight several critical issues. First, they report a high one year reoperation rate for a variety of reasons. This finding highlights the importance of considering protocols to minimize the need for reoperation. Furthermore, they note the higher rate amongst CRT patients, with seems logical given the likely longer associated procedural risk and need for more leads. Finally, the impact of age on expectant survival are to be taken into consideration with the device and the life-saving potential of the defibrillator.

Moving on to cellular electrophysiology, review one article by Zhang et al, entitled "Reduced N-type calcium channels in atrioventricular ganglion neuron are involved in ventricular arrhythmogenesis" published at the journal of the American Heart Association, in volume seven issue two. Zhang et al reported a rat model of ventricular arrhythmogenesis and characterized the role of atrioventricular ganglion neurons in risk of arrhythmogenesis as well as the mechanism for this risk this model relates in humans to the attenuated cardiac vagal activity in heart failure patients, which is known to relate to their arrhythmic risk. The demonstrated reduced N-type calcium channel in these AV ganglion neurons, which project innervating systems to the myocardium, resulting in increased risk of PVCs, and increased susceptibility to induction of ventricular arrhythmias with programmed stimulation.

The relevance of the intrinsic cardiac nervous system arrhythmogenesis has become increasingly prominent as methods to study it have improved. Understanding the direct and most relevant inputs may facilitate better understanding of risk of arrhythmias in patients. In the case of this study by Zhang et al, the critical finding is that disorder of the atrioventricular ganglion neurons may lead to increased susceptibility for ventricular arrhythmogenesis. Clinical relevance includes consideration of effects on this specific ganglion when performing ablation on for other conditions, and potential long-term effect on arrhythmogenic risk, as well as potentially relevant functional explanations for arrhythmogenesis.

Moving on to the genetic channelop, these are considered two separate articles. The first one by Bilmayer et al, entitled "ExomeChip-Wide analysis of 95,626 individuals identified ten novel loci associated QT and JT intervals" published in Circulation: Genomic and Precision Medicine, in volume 11 issue 1. This whole exome study reviewed several novel loci that modified the QT and JT intervals. They include over 100,000 individuals and identified ten novel loci not previously reported in the literature. This increases the number of known loci that impact from ventricular portal adjacent by nearly one third. These loci appear to be responsible for myocyte and channel structure and interconnections that internally impact the ventricular repolarization.

While long QT syndrome be characterized amongst the known genes in 75% of affected individuals, that also means one fourth long QT syndrome cannot be characterized based on known genes impacting ventricular repolarization. The identification of novel loci or novel that may be affect repolarization kinetics to unique means are critical to define novel therapies as well as in genetic counseling the patients in potential effects on family members when screening them for potential disease risk. These findings should assess an opportunity for further studying the mechanisms by which these loci modulate QT and JT intervals and the potential contribution to phenotypic risk.

The second paper within this realm we review is by Zumhagen et al, entitled "Impact of presynaptic sympathetic imbalance on long QT syndrome by positron emission tomography" published in Heart, volume 104. The authors sought to evaluate by a PET scan the impact of sympathetic heterogeneity on long-QT syndrome risk. Amongst 25 patients with long-QT syndrome, including long-QT type I and II, and 20 ostensibly healthy controls, they noted that regional retention in disease were similar between affected patients and controls. However, regional washout rates were higher in the lateral left ventricles in patients with long-QT syndrome. Internal global washout rates were associated with greater frequency of clinical symptoms. That's there seem to be some relationship between regional and global sympathetic heterogeneity, particularly during washout, with overall risk in long-QT syndrome patients.

These findings report the notion for sympathetic imbalance, partly mediating the risk attributable to long-QT syndrome. The findings on PET suggest regional imbalance of presynaptic cathecholamine and reuptake and release, being one mechanisms. This was most prominent in long-QT I patients who also often drive most benefit from left sided sympathectomy. The novelty of these findings is in the potential role of imaging to determine basic contributors to congenital long-QT syndrome in given patients. The larger prospect of size would really need to be evaluated this further.

Moving on to the realm of ventricular arrhythmias, we review three different articles. The first one, by Hamon et al, entitled "Circadian variability patterns predict and guide premature ventricular contraction ablation, procedural disability, and outcomes" published in Heart Rhythm, volume 15 issue one. Hamon et al sought to evaluate whether circadian variability of PVC frequency can predict optimal drug response intraprocedurally during PVC ablation. One of the main problems of PVC ablation is when PVC are infrequent and tend to disappear during the procedure, achieving procedural success or attaining sufficient frequencies of PVCs to map becomes very difficult. Next, they use Holter monitoring in the ambulatory stripe to define three groups. Those of higher PVC burden during faster heart rates, those with higher PVC burden during slower heart rates, and those with no correlation between their PVCs burden and their heart rate.

More than half the one hundred and one patients included a high burden of PVCs at fast rate while 40% had no correlation between the two and 10% had higher burden in slower heart rates. Almost one third of patients taken for ablation have infrequent PVCs during a procedure, while the best predictor of this being a low ambulatory PVC burden of less than 120 per hour. Isoproterenol infusion was only useful in lessening PVCs in those with PVCs associated with fast heart rates. The isoproterenol washout or phenylephrine where used with those associated with slower heart rates.

Interestingly, not a single drug was effective in inducing PVCs in those with infrequent PVCs that have not heart rate correlation in the ambulatory stages. They noted that outcomes ablates were similar amongst those with higher heart rate associated PVCs and non-heart rate correlated PVCs previously responded to a drug. But, [inaudible 00:48:08] noted only a 15% success rate from ablation in infrequent PVCs in patients who lacked correlation between PVC burden and heart rate and who were unresponsive to drug previously. These data are important highlighting the potential for further defining idiopathic PVC ablation needs and likelihood of success based on ambulatory data, by correlating PVC burden with heart rate and their circadian variability, it's possible to predict likelihood specific intraoperative drugs working when dealing with infrequent intraprocedural PVCs.

Furthermore, the finding of lack of correlation with slower or fast heart rate in terms of PVC burden is associated with the poor success rate unless those PVCs are drug responsive. Highlights the potential benefit of performing preoperative antiarrhythmic drug testing to get likelihood of ablation success in this patients.

The next article we review is by Lee et al, entitled "Incidence and significance of the lesions encountered during epicardial mapping and ablation of ventricular tachycardia in patients with no history of prior cardiac surgery or pericarditis" published in Heart Rhythm, volume 15 issue one. Lee et al sought to determine the frequency of pericardial lesions, impeding mapping in patients without prior surgery, operative procedure, or pericarditis, in other words virgin hearts. Amongst 155 first time attempts of access, 8% had pericardial lesions. The only clinical predictor was the presence of severe renal impairment.

In addition, no patients with supposedly normal hearts had a lesions. Notably, those with a lesion had more frequent impairment in mapping and lower overall success rates; there were similar complication rates as those without the lesions. These data are relevant in highlighting the ease of mapping of pericardial access may not always be present, even when dealing with inversion of pericardial space. A lesion may be present in patients, particularly with severe renal disease. Advising patients of this possibility prior to the procedure and considering that epicardial access may be impaired in a fair number of patients, even the absence of prior history of surgery, epicardial access or pericarditis isn't important.

The final article we'll review within the realm of ventricular arrhythmias is by Kumar et al, published in Journal of Cardiovascular Electrophysiology, volume 29 issue one, entitled "Right ventricular scar-related ventricular tachycardia in nonischemic cardiomyopathy: Electrophysiological characteristics, mapping, and ablation underlying heart disease." Kumar et al sought to evaluate the substrate and outcomes associated with right ventricle scar related ventricular tachycardia ablation in nonischemic patients at large, but particularly in those with neither stroke or coronary artery disease as potential explanations for this scar. They reviewed 100 patients consecutively over half of whom had ARVC and the remainder was sarcoid or RV scar of unclear origin. Those with RV scar of unknown origin tend to be older compared to the ARVC patients, and had more severe LV dysfunction compared with saroid patients.

However, the scar distribution extend was similar within all these groups. Furthermore VT/VF survival was higher in those with RV scar of unknown origin. The velocity of survival free or death or cardiac transplant and VT/VF survival seen in sarcoid patients. These data suggest that close to one third of patients, RV scar related VT may have VT of unknown cause. Total outcome was superior overall to those with defined myopathic processes. What's most interesting is, over follow up, none of those with RV scar of unknown origin develop any further findings to reclassify them as sarcoid or ARVC. It is possible this group reflects some mild form of either disease however. Again, the exact pathophysiologic process remains unclear. These findings may help in counseling patients who are in long-term expected outcomes from ablation intervention.

The final article we'll review this month is within the realm of other EP concepts that may be broadly applicable, published by van Es et al, entitled "Novel methods for electrotissue contact measurement with multielectrode catheters", published in Europace, volume 20 issue one. In this publication, the authors sought to evaluate the potential utility of a novel measure on evaluating electro tissue contact. With multielectrode catheters it is known that one of the problems with assessing contact is a contact force that cannot be used. Electro with coupling index is often used but even this has fragile problems, especially when you get into high impedance areas, that can be affected by surrounding ion impedance structures. Due to the fact that measuring contacts forces challenging in such multielectrode catheters, the authors measure electric interface resistance by applying a low level electrical field, pushing neighboring electrodes. They compared the effectiveness of assessing contact by this approach without using contact force in a poor side model.

They know that this measure was directly correlated with contact force in measuring tissue contacts. These findings support a role for aversion of an active electrode location and determining tissue proximity and contact-based on the coupling between the electrodes on multipolar catheters in the tissue. These findings may be highly useful when there is a variety of catheters where contact force cannot be implemented. Further studies on the methods and cutoff to establish tissue proximity on the end of contact will be also needed.

To summarize, however, as a term was brilliant here that was not well explained, active electrical location is actually a phenomenon that occurs in nature. This is seen in deep sea fish, which actually have multiple electrodes oriented around its body. They emit a small electrical field that results in a general impedance field surrounding the fish. This essentially is the way of visualizing the world around them. Perturbations based on proximity to different structures, whether they are live or death, and based on whether they are live or death, results in changes in the perturbations of this resistive fields, resulting in proximity determination by the fish. Several individuals are looking into potential applications of this to understanding tissue proximity when using catheters in the body. This consideration of impedance is fundamentally different than the traditional measure impedance were used by traditional generator.

I appreciate everyone's attention to this key and hardening articles that we've just focus on or this past month of cardiac electrophysiology across literature. Thanks for listening. Now back to Paul.

Dr Wong: Thanks Suraj, you did a terrific job surveying all journals for the latest articles on topics of interesting in our field. There's not an easier way of staying in touch with the latest advances. These summaries and the list of all major articles in our field for month can be downloaded from the Circulation: Arrhythmia and Electrophysiology website. We hope that you find the journal to be the go to place for everyone interested in the field.

See you next month.

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