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Circulation: Arrhythmia and Electrophysiology On the Beat


Dec 19, 2017

 

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

                                In our first study, Boris Schmidt and associates studied 134 patients with persistent atrial fibrillation, randomized to laser balloon or wide area circumferential pulmonary vein isolation using irrigated radiofrequency current ablation and 3D mapping.

                                They found that 71% of patients in the laser balloon group had freedom from atrial fibrillation between 90 and 365 days after a single ablation, similar to 69% of patients in the radiofrequency group, p=0.40. In the laser balloon group, one patient developed stroke, one had false aneurysm and one had phrenic nerve palsy. In the radiofrequency group, two patients developed a false aneurysm and one patient needed surgical repair. Procedure and fluoroscopy times were similar between the two groups. The authors concluded that the two methods were associated with similar efficacy in patients with persistent atrial fibrillation.

                                In the next study, Kairav Vakil and associates examined the success of VT ablation in elderly patients who were part of the International VT Center Collaborative Study Group Registry. Of the 2,049 patients in the registry, 33% or 681 were greater than or equal to 70 years of age with a mean age of 75 years.

                                Compared to patients less than 70 years, patients 70 years or greater had higher in-hospital, 4.4% versus 2.3%, p=0.1 mortality, and also a higher one year mortality, 15% versus 11%, p=0.002. But they had a similar instance of VT recurrence, 26% versus 25% and a similar time to recurrence, 280 versus 289 days.

                                The authors concluded that VT ablation in elderly is feasible with reasonable safety and modestly higher in-hospital and one year mortality with similar rates of VT recurrence at a one year compared to younger patients.

                                In the next study, Angel Ferrero-de Loma-Osorio and associates studied the optimal dosage of cryotherapy using cryoballoon ablation of pulmonary veins. The study the prospective, randomized, multicenter, non-inferiority study including 140 patients with paroxysmal atrial fibrillation which was refractory to antirrhythmic drugs.

                                Patients were randomly assigned to a conventional strategy group of 180 seconds cryoablation applications per vein with a bonus freeze 70 patients or a shorter time application protocol with one application that lasted the time required for a electrical time to effect plus 60 seconds and a 120 second freeze bonus, 70 patients.

                                At one year followup there was no difference in freedom from atrial fibrillation 79.4% of the control group versus 78.3% in the study group, p=0.87. The time to effect was detected in 72% of the veins. The study and control group had similar mean number of applications per patient, 9.6 versus 9.9. compared to controls the study group had a significantly shorter cryotherapy time, 28.3 versus 19.4 minutes, p<0.001. In shorter left atrial time, 104 versus 92 minutes, p<0.01, and shorter total procedure time 135 versus 119 minutes, p<0.01 there were no differences observed in complications or reconnections.

                                The authors concluded that the new to effect base cryotherapy dosage protocol led to shorter cryoablation procedure times with similar safety and similar acute and one year followup results compared to the conventional approach.

                                In the next study, Shinsuke Miyazaki, examined which procedural steps during balloon cryoablation of atrial fibrillation created the greatest number of micro-embolic signals as detected by transcranial doppler. They examined this because catheter ablation has been associated with silent cerebral infarction and the number of micro-embolic signals has been associated in previous studies with the silent cerebral infarctions.

                                The author studies 40 patients with paroxysmal atrial fibrillation undergoing pulmonary vein isolation using the second generation cryoballon with single 28 millimeter balloon, 3 minute freeze. A mean of 5.0 cryoablation applications were applied with a left atrial dwell time of 76.7 minutes. The total micro-embolic signal count per procedure was 522 with a range of 426 to 626. During cryoapplications, micro-embolic signal counts were greatest during the first cryoapplication, 117, especially after the balloon stretch of deflation, 43 micro-embolic signal counts.

                                Reinsertion of once withdrawn cryoablation balloon and subsequent applications produced a high number of micro-embolic signals, a mean of 205. Other steps produced a mean of less that 65 micro-embolic signals per procedure including pre and post potential mapping with lasso catheters, left atrial access, flex cath feed insertion and touch up ablation. Using radiofrequency ablation for transeptal access, increased the micro-embolic signal count during transeptal punctures.

                                Interestingly electro-cardio version did not generate any micro-embolic signal counts. Silent cerebral events were detected in 11 or 32% of patients and silent cerebral lesions were detected in four or 11.7% of patients. Patients with silent cerebral events were older than those without, however, there were no significant factors associated with silent cerebral events, including the occurrence of micro-embolic signals in this series.

                                In the next study, David Haines and associates studies the ability of a novel ultrasound imaging catheter to provide information about catheter contact, wall thickness and ablation lesion formation during radiofrequency ablation. The authors tested an open irrigated radiofrequency ablation catheter with four ultrasound transducers for near field ultrasound imaging in 19 dogs in all four heart chambers.

                                While previous in vitro studies showed that the measured wall thickness exceeded actual tissue or phantom thickness by 13 to 20%, in vivo the chamber wall thickness measured by near field ultrasound imaging, correlated well with intracardiac echocardiograpy, r=0.86, p value less than 0.0001. Near field ultrasound imaging visualize electrotissue contact and the sensitivity of lesion identification by this technique was 94% for atrial and 95% for ventricular ablations. Lesion transmurality was correctly identified for 87% of atrial lesions.

                                The authors concluded that this technique may aid in optimizing power delivery to create transmural lesion formation.

                                In the next study, William Stephenson and associate examined the significance of inducible nonsustained ventricular tachycardia after catheter ablation of ventricular tachycardia in ischemic cardiomyopathy. In 165 consecutive patients who underwent catheter ablation for sustained monomorphic ventricular tachycardia due to ischemic cardiomyopathy, they examined inducibility of ventricular tachycardia.

                                After ablation, 44 patients did not have induction testing or only had ventricular fibrillation induced. They labeled this group C. In the remaining 121 patients, 38 patients or 23% had inducible sustained monomorphic ventricular tachycardia. Of the 83 patients without inducible sustained monomorphic ventricular tachycardia after ablation, nonsustained ventricular tachycardia defined as five or more beats lasting less than 30 seconds was induced in 34 patients or 21%, representing group B. The remaining 49 patients had no ventricular tachycardia induced, this was 30% and designated as group A.

                                After a median followup of 18.7 months, freedom from ventricular tachycardia at 24 months was 60% in group A, those who had no inducible ventricular tachycardia. 45% in group B who had nonsustained ventricular tachycardia. This is a p value of 0.017 versus the noninducible group and 38% in group C, those who had no testing or had ventricular fibrillation only. In patients without inducible sustained monomorphic ventricular tachycardia, inducible nonsustained ventricular tachycardia and left ventricular ejection fraction were independently associated with VT recurrence with a hazard ratio of 3.66 and 1.07.

                                The authors concluded that inducible nonsustained ventricular tachycardia post ablation suggests that functional arrhythmia substrate is still present. Future trials are needed to assess whether additional ablation would improve outcome in this group.

                                In the next study Derek Dosdall and associates examined the mechanisms driving ventricular fibrillation. The authors used a 64 electrode basket catheter on the left ventricular endocardium and 54 six electrode plunge needles inserted into the left ventricles of six dogs to map electrical activity. Following short duration ventricular fibrillation 10 seconds or long duration ventricular fibrillation, seven minutes, shocks of increasing strengths were delivered every 10 seconds until ventricular fibrillation terminated.

                                The results showed that the chaotic pattern was predominantly present in early ventricular fibrillation but the regular pattern emerged as ventricular fibrillation progressed. The synchronized pattern only emerged occasionally during late ventricular fibrillation. Failed defibrillation shocks changed chaotic and regular activation patterns synchronized in late duration ventricular fibrillation but not in short duration ventricular fibrillation. The regular and synchronized patterns of activation were driven by rapid activations on the endocardial surface but blocked and broke up transmurally leading to an endocardial to epicardial activation rate gradient as the long duration ventricular fibrillation progressed.

                                In the next study, in order to examine if atrial fibrillation incidence is affected by the use of ACE inhibitor as antihypertensive therapy, Greg Marcus and associate performed a secondary analysis of the antihypertensive and lipid lower treatment to prevent heart attack trial ALLHAT which was a randomized, double blind, active controlled clinical trial in which hypertensive individuals, 55 years of age or greater, were assigned to receive amlodipine, lisinopril or chlorthalidone. Participants had at least one other cardiovascular risk factor and those with elevated fasting LDLC levels were also randomized to pravastatin versus usual care.

                                Using either atrial fibrillation or atrial flutter diagnosed from serial study ECGs or Medicare claims data as the primary outcome, the authors found that 2,514 of the 14,837 participants developed atrial fibrillation or atrial flutter during the mean followup of 7.5 years. Compared to chlorthalidone, randomization to either lisinopril, hazard ratio of 1.04 or amlodipine, hazard ratio of 0.93, was not associated with a significant reduction in incident atrial fibrillation or atrial flutter.

                                In the next study, David Calvo and associates studied the mechanism of rotor ablation in 13 patients with long standing persistent atrial fibrillation with a duration ranging from 12 to 72 months. The authors used phase frequency mapping with Hilbert Fourier transforms and Cartofinder in the left and right atria. Ablation was performed by circumferential pulmonary vein isolation plus linear ablation of extra pulmonary rotor domain. A rotor domain was defined as an area displaying at least three consecutive rotations. The authors identified 19 rotor domains in 10 patients, 1.8 per patient, seven being in the right atrium and 12 in the left atrium and 15 of those extra pulmonary vein.

                                Overall, rotor domains having 9.2 rotations, displayed higher frequency activation, 6.41 hertz compared to non-rotor domains, 6.17 hertz with a p value of 0.02. Ablation of rotor domains and ablation line with a mean of 3.5 centimeters effectively decreased the frequency of activation in both ipsilateral and contralateral atria, p<0.5 while ablation on non-rotor domains did not. Acute conversion to sinus rhythm was observed in two patients after ablation rotor domains. At a one year followup, 70% of patients remained in sinus rhythm.

                                In the next paper, Sophia Klehs and associates examined the success of radiofrequency catheter ablation of atrial tachyrhythmias in patients with congenital heart disease. The authors reported acute success of 81% of catheter ablation performed in 144 patients with congenital heart disease and atrial arrhythmias, acute success was lower for tachycardias involving the left atrium compared to right atrial tachycardias. Complexity of congenital heart disease was associated with longer procedural times. Major complications occurred in four patients and were related to vascular access. Tachycardia recurrence was observed in 54% of patients after a total followup of 7.4 years. 75% of these recurrences occurred within the first year.

                                The authors found that recurrence of tachycardia was more likely in patients with complex surgical atrial anatomy such as Fontan palliation or atrial switch procedures.

                                In our final paper, Bernard Belhassen and associates conducted a survey of 678 regatta syndrome patients at 23 centers examining the age at first arrhythmic event. These arrhythmic events were either aborted cardiac arrest in 426 patients, group A or occurred after prophylactic ICD implantation in 252 patients, group B.

                                91% of all patients were males. Only 4.3% patients in either group were less than 16 years of age and 1.5% greater than 70 years of age. The peak arrhythmic event rate occurred between 38 and 48 years with a mean of 41.9 years. Group A patients, those with cardiac arrest were younger than those in group B, those that had events after prophylactic ICD implantation by a mean 6.7 years, p value 0.001. In adult patients, females experienced arrhythmic events 6.5 years later than males, p=.003. In addition, the authors found that Caucasians and Asians exhibited their first arrhythmic event at the same median age, 43 years.

                                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. And welcome back everybody to On the Beat where today I'm going to summarizing articles from across the electrophysiology literature published in the month of November 2017. Today we'll be focusing on 19 particularly hard hitting articles that have the potential to alter the science in our field.

                                The first article we will review is by Landry et al., published in the New England Journal of Medicine last month, entitled Sudden Cardiac Arrest during Participation in Competitive Sports.

                                We often worry about young people and even middle aged people engaging in competitive athletics. The fear of possible sudden death, in particular, is one thing that affects not only players but teams as well. While their recommendations as far as pre-athletic screening and advising on how to manage patients who might be at risk of sudden death or cardiovascular events in the setting of competitive athletics. The actual incidence of sudden cardiac arrest during participation in competitive sports is less well understood. Thus in this study, Landry et al., sought to evaluate what the overall incidence of sudden cardiac arrest during participation in competitive sports actually is.

                                They used the Rescu Epistry cardiac arrest database which contains records of every cardiac arrest that was attended to by paramedics within the network region in Canada and they sought all out-of-hospital cardiac arrests that occurred from 2009 to 2014 in those age 12 to 45 years of age during sport participation. All cases were adjudicated.

                                What they demonstrated was that over the course of 18.5 million person-years of observation, a total of 74 sudden cardiac arrests occurred during participation in a sport. Specifically, 16 occurred during competitive sports and another 58 occurred during noncompetitive sports. Thus the estimated and overall incidence of sudden cardiac arrest during competitive sports of .76 cases per 100,000 athlete-years. Interestingly, less than half of the athletes survived until discharge from the hospital. Furthermore only two of the deaths were attributed to hypertrophic cardiomyopathy and they didn't identify any deaths attributable to arrhythmogenic right ventricular cardiomyopathy. They did not however that three cases of sudden cardiac arrest could have been avoided had they undergone preparticipation screening.

                                The importance of these data lies in advising patients whose children or who themselves want to engage in competitive sports as well as what the actual incidence is. While this particular study focuses on a specific region in Canada, and thus might not be generalizable to all populations, it is important to understand that the overall incidence does in fact tend to be quite low. Furthermore the fact that three cases of sudden cardiac arrest, could have been avoided by preparticipation screening highlights the importance of focusing on this.

                                Changing gears but staying within the realm of ventricular arrhythmias, we next review the article by Yu et al., published in the Journal of American College of Cardiology entitled Optogenetic Modulation of Cardiac Sympathetic Nerve Activity to Prevent Ventricular Arrhythmias.

                                It is well recognized that sympathetic modulation might improve cardiac arrhythmias. In specific terms, in ventricular arrhythmias, people have demonstrated at various points that either sympathectomy or left stellate ganglion blockade or even spinal cord stimulation can improve ventricular arrhythmogenesis. However, most of these approaches require either permanent sympathectomy such as done when a stellate gangliectomy is performed or something that is very transient and invasive such as performing lidocaine injection into the stellate ganglion. Newer techniques involving viral vectors have allowed investigators to be able to better control the body by introducing novel genes into cells locally that can allow them to be stimulated or inhibited by other feedback mechanisms such as the use of light of specific frequencies. The term for this is optogenetics.

                                Thus in this study, Yu et al., used a viral vector to deliver an inhibitory light-sensitive opsin to the left stellate ganglion neurons. They reviewed 20 male beagles and used a control group as well as an optogenetics group. They then induced myocardial ischemia in order to evaluate ventricular arrhythmias. They used a transient light-emitting diode to illuminate the left stellate ganglion in those who were optogenetically modified versus those who were not.

                                They demonstrated in those that were optogenetically modified there was suppression of left stellate ganglion function, neural activity and  sympathetic nerve indices of heart rate variability as well as prolongation of the left ventricular effective refractory periods after stimulation. Furthermore, ischemia induced ventricular arrhythmias were significantly suppressed by illumination in the optogenetics group only.

                                Thus they concluded that optogenetic modulation can potentially reversibly inhibit the neural activity of the left stellate ganglion, thereby offering electrophysiologic benefit. Optogenetics have been evaluated in other forms in the animal including as possibility for pacing and even resynchronization or defibrillation that would be painless. These findings are in support of optogenetics as a potential future modality for treatment of arrhythmias by various mechanisms.

                                Next, changing gears a little bit, we'll review an article on the realm of atrial fibrillation by Halcox et al., published in Circulation this past month entitled Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation.

                                The importance of recognizing asymptomatic atrial fibrillation is increasingly seen amongst all providers irrespective of their roles in primarily treating these patients. Early identification of even asymptomatic atrial fibrillation can allow for a more appropriate anticoagulation to prevent stroke morbidity and mortality.

                                Thus in this study, Halcox et al., performed a large, randomized controlled trial of atrial fibrillation screening using smartphone enabled AliveCor Kardia monitor in ambulatory patients. They looked specifically at patients greater than 65 years of age with a CHADS-VASc score at least 2 who as far as was understood at the time of inclusion, were free from a diagnosis of atrial fibrillation. They were randomized to either routine care or what was termed the iECG arm wherein they recorded ECGs twice weekly over 12 months using the AliveCor monitor. The time to diagnosis of atrial fibrillation was the primary outcome measure. But they also sought to evaluate the overall cost of the device, ECG interpretations and patient management. They also looked at patient attitudes and experience over the course of time.

                                Amongst the 1,000 patients, the mean CHADS-VASc score was three with a mean age of 73. 19 patients in the iECG group of the overall cohort of 500, were ultimately diagnosed with atrial fibrillation over the 12 month study period versus only five in the routine care arm. Thus, they estimated a cost per AF diagnosis using the AliveCor monitor of $10,780. They noticed similar number of stroke or transient ischemic attack between the iECG group versus the routine care group. The also found the majority of patients were satisfied with the monitor, finding it easy to use and not causing significant anxiety or restricting their daily activities.

                                Thus, they concluded that screening with twice weekly single lead iECG is, with remote interpretation could potentially identify more patients with an incident of atrial fibrillation than routine care over a 12 month period. They also noted that this seemed to be highly acceptable to patients in this trial. The limitations in this trial include the fact that we don't necessarily know how much atrial fibrillation would have been missed with routine care in the other population. Another limitation is when we review the cost effectiveness, noting that the overall outcomes of systemic embolisms, TIA or stroke were no different, what is the actual benefit that is being attained when we think about the cost of identifying an additional episode of atrial fibrillation. While it's well recognized that identifying asymptomatic atrial fibrillation in high risk populations that would benefit from stroke prevention is important, it is also important to weigh costs as well as to understand when we create more actionable evidence how that evidence is going to be be employed and have an effect of overall patient outcomes.

                                Speaking about outcomes, we next review a paper by Elming et al., published in Circulation this past month as well, entitled Age and Outcomes of Primary Prevention Implantable Cardioverter Defibrillators in Patients With Nonischemic Systolic Heart Failure.

                                The recently published DANISH study was very important in that contrary to prior studies, it did not demonstrate an overall effect on all-cause mortality with ICD implantation. However, there was some subgroup analyses that might suggest age-dependent associations between ICD implantation mortality. Namely that younger patients might benefit more than older patients.

                                Thus these investigators sought to evaluate amongst patients from the DANISH study, whether or not IC implantation outcomes varied based on age. They also sought to evaluate on optimal age cutoff nonparametrically with selection impact curves. Then did also define death into sudden cardiac death and nonsudden death, comparing these between patients younger and older than the age cutoff that was defined.

                                The median age of the study population of over 1,000 patients was 63 years. They noted that there was a linear decreased relationship between ICD and mortality with age. The optimal age cutoff they defined was actually ≤70 years of age. They noted there was an association between reduced all-cause mortality and ICD use in patients ≤70 years of age with a hazard ratio of .7 but not in patients above 70 years of age. They noted that the sudden death rate in patients ≤70 years of age was 1.8 while a nonsudden death rate was 2.7. But for patients >70 years, the sudden cardiac death rate was 1.6 but the nonsudden death rate was twice as high at 5.4 events per 100 patient-years.

                                Thus they felt that in patients with systolic heart failure due to nonischemic causes, the benefit of an ICD might actually be highly dependent on age. As a result patient at younger ages, mainly ≤70 years, likely should be treated as a different cohort in terms of risk benefit than those >70 years of age. These findings are critical when thinking about how we stratify patients and make clinical decisions into who should get an ICD and who shouldn't, especially at a population level. The findings here that an age cutoff as low 70 might define those who might benefit versus those who might not is important to consider. Most of the guideline criteria consider patients >80 or >90, especially when one refers to the appropriate use criteria where appropriateness was reclassified based on what the age range was and what the indication was from a primary prevention defibrillator. Further study is need to understand whether we really should apply an age cutoff to the benefit of ICDs but it is an important thing to consider when counseling patients, especially in light of evolving evidence in this area.

                                Still staying in the realm of heart failure but now going to more basic electrophysiology, we review a paper published in Circulation this past month by Cho et al., entitled Delayed Repolarization Underlies Ventricular Arrhythmias in Rats With Heart Failure and Preserved Ejection Fraction.

                                Increasingly, heart failure with preserved ejection fraction is being diagnosed to the point where it is now approximately half of all diagnosed heart failure with incidences that continue to increase nevertheless. One of the leading causes of mortality in heart failure with preserved ejection fraction is sudden death but the underlying mechanisms for this is less clear.

                                Thus in a rat model, Cho et al., sought to evaluate why heart failure with preserved ejection fraction might result in an increase risk of sudden death. They exposed salt sensitive rats to a high salt diet and evaluated the effect on systolic and diastolic function. After verifying, some rats that suffered from HFpEF at this point versus control rats, they underwent programmed electrical stimulation and they measured corrected QT interval from surface ECG as well. Furthermore they did optical mapping, whole-cell patch clamping and quantitative polymerase chain reaction and Western blotting to evaluate ion channel expression.

                                They noted that 31 of 38 rats exposed to a high salt diet demonstrated diastolic dysfunction and preserved ejection fraction along with signs of heart failure. There was an increased susceptibility to ventricular arrhythmias amongst these particular rats when compared to controls. They also noted that the corrected QT interval was significantly longer. Interestingly optical mapping showed that these rats had prolonged action potentials and multiple reentry circuits during induced ventricular arrhythmias. Furthermore there was confirmed a delay of repolarization based on patch clamping with a downregulation of transient outward potassium currents or ITO. Finally they noted that there was a downregulation of IK1 as well as IKR.

                                Thus they felt that the susceptibility to ventricular arrhythmias was indeed markedly increased, at least in a rat model of HFpEF. These could be caused by QT prolongation, which is associated with delayed repolarization from downregulation of potassium currents and also associated multiple reentry circuits which can mediate ventricular arrhythmia. These findings are significant in that they highlight both potential targets for sudden death risk in the setting of HFpEF as well as potential targets for treatments that might prevent ventricular arrhythmias in the long term.

                                Staying within the realm of ventricular arrhythmias, we next review an article by Do et al., published in the Journal of the American Heart Association this past month, entitled Thoracic Epidural Anesthesia Can Be Effective for the Short‐Term Management of Ventricular Tachycardia Storm.

                                Similar to the earlier discussed article, of optogenetic stimulation of left stellate ganglion, even short term management options for VT storm are important. Some inject lidocaine or bupivacaine into the left stellate ganglion or into both stellate ganglia in order to get control. However, depending on comfort level, the utility of this may be variable at different institutions.

                                Thus, novel therapies aimed at modulating the autonomic nervous system that might be available at other institutions such as thoracic epidural anesthesia are important to consider. The group sought to evaluate via multicenter experience what the effect on VT storm was with thoracic epidural anesthesia.

                                They noted amongst 11 patients reviewed between July 2005 and March 2016 that the majority who underwent thoracic epidural anesthesia had incessant VT with a minority of them being polymorphic VT. Furthermore almost half of them had nonischemic cardiomyopathies. Almost half of the patients had a complete response to thoracic epidural anesthesia where the VT became quiescent. And one patient had a partial response.

                                Thus, they suggested that thoracic epidural anesthesia may be effective and should be considered as a therapeutic option in patients with VT storm, especially those with incessant VT, who are refractory to initial management. They also noted clinically that improvement in VT burden associated with deep sedation may suggest a higher likelihood of responding to thoracic epidural anesthesia. For a clinical electrophysiologist especially in community hospitals where rapid utilization of ablation may not be possible or other advanced methods of autonomic modulation might not be feasible, options such as thoracic epidural anesthesia are important to be considered. They exist in an armament that includes intravenous drugs, left stellate ganglion injections, general anesthesia and use of IV beta blockers. These findings are highly suggestive and the fact that certain clinical characteristics might suggest those that are more likely to benefit might just to clinicians exposed to a patient of VT storm what the next step should be.

                                Changing gears a little bit we will now review an article by Rafaat in the Journal of the American Heart Association entitled Swine Atrioventricular Node Ablation Using Stereotactic Radiosurgery: Methods and In Vivo Feasibility Investigation for Catheter‐Free Ablation of Cardiac Arrhythmias.

                                The group sought to demonstrate using a linear accelerator based stereotactic radiosurgery system whether or not atrioventricular node ablation could be safely performed with minimal damage to surrounding structures. They used the linear accelerator to apply energy in a pig model after implantation of a pacemaker using a CT scan to guide therapy. They also performed pathologic evaluation of the region of the AV node and the surrounding tissues. They found that all animals included had disturbances of AV conduction with progressive transition into complete heart block. There was no damage to the surrounding myocardium and all pigs had preserved systolic function echocardiography.

                                Thus they suggested that catheter free radioablation using this approach might be feasible in an intact swine. These findings are important because they build on other studies done by groups at other centers suggesting that noninvasive linear accelerator based therapies either using stereotactic radiosurgery with existing technologies, proton beams, carbon beams or other approaches, might offer feasible methodologies for noninvasive treatment for cardiac arrhythmias. Further study is indeed needed to validate what the effect on surrounding tissues actually is.

                                Next we will review an article published by Williamson et al., in JACC Clinical Electrophysiology this past month entitled Real-World Evaluation of Magnetic Resonance Imaging in Patients With a Magnetic Resonance Imaging Conditional Pacemaker System.

                                Results of four year prospective followup in over 2,600 patients, while MRI conditional pacemakers are more increasingly used, long term longevity as well as effects of multiple MRI scans in terms of MRI functioning the devices is unclear. Thus, the study was sought to be a large scale, real world evaluation of MRI in patients with MRI conditional pacemakers. They included over 2,600 patients in multiple centers and all these patients had a SureScan pacing system. They noted that there were no MRI related complications occurring during or after the MRI, meeting the primary objective. In fact, almost a third of the patients underwent two or more scans and even then there was no cumulative increase in problems in these patients. The pacing capture thresholds stayed stable throughout all patients.

                                Thus this report constituted the largest longitudinal MRI experience in patients implanted with an MRI conditional device. The importance of this is to be able to highlight to patients that in fact even multiple MRIs despite having a device in place is safe. There is an increasing body of data that suggests that however, MRIs might be safe in a controlled setting, even in patients with legacy pacemakers. Whether MR conditional pacemakers actually offer incremental safety over legacy pacemakers however, is less clear and will likely require randomized trials of a large scale given the low number of events to really come to a conclusion. However, in most centers where it's not possible to do MRIs in legacy pacemakers, this offers some level of certainty that patients will likely be safe even undergoing multiple MRIs in a setting of having chronic pacemakers that are MRI conditionally safe.

                                Staying within the realm of looking at large multicenter experiences, we review an article by Hosseini et al., entitled Catheter Ablation for Cardiac Arrhythmias, Utilization and In-Hospital Complications, 2000 to 2013, published in JACC Clinical Electrophysiology this past month.

                                In this study, Hosseini et al., sought to investigate the overall utilization and in-hospital complications associated with catheter ablation in of all types in the United States between 2000 and 2013 using the National Inpatient Sample and Nationwide Inpatient Samples. They included all patients 18 years of age and older who underwent inpatient catheter ablation over this time period.

                                They estimated total a total of almost 520,000 inpatient ablations performed in this time period with a median age of 62 years amongst patients. Interestingly the annual volume of ablations and the number of hospitals performing ablations increased year over year but the rate of complications and length of stay also increased. A large number, almost more than a quarter of inpatient ablation procedures were actually performed in low volume hospitals and in turn were associated with an increased risk for complications with an odds ratio 1.26. Independent predictors of in-hospital complications and in-hospital mortality included complex ablations for atrial fibrillation and ventricular tachycardia, older age and a greater number of comorbidities. In addition to this, lower hospital volumes was an independent predictor of complications.

                                Thus the authors note that there has been a steady progressive in the number of in-hospital catheter ablation procedures. However, despite the increasing number, the number of periprocedural complications is increasing which may be partly mediated by taking in sicker patients from a complex procedures but also to performing these at lower volume centers. These findings are critical when considering the future of ablation strategies and ablation performance when we consider multicenter experiences or when we consider where certain procedures might be performed based on the experience of the operator or the institution. Why exactly it is that lower volume centers of higher complication rates still needs to be evaluated. However, it should be understood that ablations are  complex procedures and thus require a certain amount of experience in order to allow for procedural efficacy and safety similar to any cardiac surgery or other procedure. It remains to be understood what the number of procedures to be able to be felt to be competent and safe should be. But, these findings should be considered by all providers based on their own personal experience and based their own personal numbers.

                                Staying with the realm of catheter ablation, we will next review an article by Haldar et al., published regarding Catheter ablation vs electrophysiologically guided thoracoscopic surgical ablation in longstanding persistent atrial fibrillation: The CASA-AF Study in last month's edition of Heart Rhythm.

                                In this article, they sought to evaluate catheter ablation outcomes for longstanding persistent atrial fibrillation as compared with those of thoracoscopic surgical ablation. There's a limited amount of data comparing these two methodologies for ablation. They included 51 patients with de novo symptomatic atrial fibrillation. 26 underwent thoracoscopic surgical ablation and the remainder underwent stepwise left atrial ablation with a primary end point being single-procedure freedom from atrial fibrillation and atrial tachycardia lasting >30 seconds without antiarrhythmic drugs at 12 months. They noted that single- and multi procedure freedom from atrial fibrillation was higher in the surgical ablation group than in the catheter ablation group. Namely the overall success rate from the surgical ablation group was 73% versus 32% in the catheter ablation group. It should be noted that there was testing of the surgical ablation lesion set by electrophysiologists that was felt increased success rate in achieving acute conduction block by 19%. It also should be noted that the complication rate in the surgical ablation group, was significantly higher than the catheter ablation group, namely 27% versus 8%. This did not reach statistical significance however, possibly due to the low numbers considered.

                                The conclusion from the authors was that meticulous electrophysiologically guided thoracoscopic surgical ablation as a first line strategy in long standing persistent atrial fibrillation, may provide excellent single procedure success rates as compared with traditional catheter ablation. However again, there is an increased upfront risk of nonfatal complications. These considerations are important when thinking about what strategy to use in specific patients. Whether at a large level, thoracoscopic surgical ablation should be routinely used is still unclear and larger studies are likely needed to compare different modalities of ablation to better evaluate which is the right one for which patients.

                                Again staying in Heart Rhythm in 2017, we next review an article by Sheldon et al., published regarding Catheter ablation in patients with pleomorphic, idiopathic, premature ventricular complexes.

                                When a patient presents with idiopathic PVCs that are a single monomorphic focus, it is often considered reasonable to ablate them. However when patients have pleomorphic PVCs or polymorphic PVCs, the role of ablation is less clear and often considered more complex. Thus in this study, Sheldon et al., sought to evaluate patients who underwent ablation with pleomorphic PVCs. They reviewed about 100 consecutive patients 31% of whom had pleomorphic versus 69% who had monomorphic PVCs, however all of who were considered idiopathic. They noted the overall success rate was lower in patients with pleomorphic PVCs, namely 71% versus 90%. In fact, the presence of pleomorphic PVCs was independently associated with unsuccessful ablation. Also, pleomorphic PVCs more often had an epicardial origin than did monomorphic PVCs. And repeat ablation procedures were required in almost 20% of the cohort. Interestingly, three of the patients who came back for another procedure, had an increase of a nonpredominant PVC and one patient had a newly emerged PVC focus.

                                The conclusion by Sheldon et al. Was the presence of pleomorphic PVCs can affect ablation outcomes but it's still possible to achieve successful elimination of the predominant PVC even if not all PVCs are targeted. Furthermore, they suggested that most recurrences are due to reemergence of the originally targeted predominant PVC morphology though sometimes other PVC morphologies may arise. Larger scale evaluation is still necessary to understand when a patient should be taken to ablation and when not. We recognize that sometimes the presumption of idiopathic might be due to a lack of consideration of other ideologies such as subclinical inflammation that can be related to myocarditis or sarcoidosis or other finding. Thus it should always be considered what the actual underlying substrate is with rigorous imaging such as MRI or PET scanning. However, the findings by Sheldon et al. suggest that just because there are multiple PVC morphologies present, does not necessarily mean that they cannot be ablated.

                                Switching gears away from PVCs, we next review an article by Romero et al. published in Heart Rhythm this past month entitled Emergence of atrioventricular nodal reentry tachycardia after surgical or catheter ablation for atrial fibrillation: Are we creating the arrhythmia substrate?

                                They reviewed patients who had AVNRT ablation performed and sought to evaluate how many of them had prior surgical or catheter ablation for atrial fibrillation. They reviewed cases of ablation for specifically persistent atrial fibrillation who eventually required a repeat ablation procedure and had a diagnosis of AVNRT at that time. A total of nine patients were identified meeting these characteristics. All of these patients were noted to have evidence of atrial fibrosis in the septum or proximal CS, and in fact six had undergone ablation either at the septum or the coronary sinus ostium or body and the other three had inferior mitral lines at a surgical MAZE approach. All had typical AVNRT inducible that was abolished with slow pathway ablation, though five required ablation in the roof of the coronary sinus or on the mitral valve annulus.

                                Thus Romero et al. concluded that ablation involving the septum or proximal CS may create a substrate that can induce AVNRT. These findings are important when we consider ablation. Oftentimes when we do ablation, we think of a targeting substrate without thinking about the substrate we might create. Thus, rigorous evaluation for other mechanisms of tachycardia that one might not think of because of the absence of it during the index ablation should always be considered such as the creation of substrate for AVNRT. While most of us will consider atrial flutters or focal atrial tachycardias or macro reentry atrial tachycardias as the principle mechanisms of tachycardia in patients returning after prior atrial fibrillation ablation should also be considered that we might be creating substrate for other types of arrhythmias such as AVNRT.

                                The next article we will review is published in the American Journal of Physiology, Heart and Circulatory Physiology by Yang et al., entitled Effect of ovariectomy on intracellular calcium regulation in guinea pig cardiomyocytes.

                                It is believed that long-term deficiency of ovarian hormones after ovariectomy can alter cellular calcium handling mechanisms in the heart that can in turn result in the formation of a proarrhythmic substrates. This is important when considering possible arrhythmogenic mechanisms in women who might be undergoing ovariectomy or who might be in a post menopausal state. Thus in a series of animals, they evaluated the effective of ovariectomy as well as estrogen supplementation to ovariectomized animals on calcium handling at the level of the heart. They demonstrated that the ovariectomized guinea pig cardiac myocytes had higher frequencies of calcium waves and isoprenaline challenged cells displayed more early after depolarizations after ovariectomy. In addition to this, they noted the observations of calcium regulation alternations were not observed in myocytes from ovariectomized guinea pigs who were supplemented with 17β-Estradiol suggesting that in fact, these changes in the arrhythmogenic substrate were due to ovarian hormone deficiency resulting in dysregulation of cardiac calcium.

                                While this was all performed at the level of guinea pigs, it is an important consideration again, as a potential mechanisms of cardiac arrhythmogenesis in women who might be undergoing ovariectomy or who might be post menopausal. In some cases ovarian hormones might be beneficial in regulating the arrhythmogenic substrate.

                                The next article we review is published in Heart this past month by Stewart et al., entitled Nitric oxide synthase inhibition restores orthostatic tolerance in young vasovagal syncope patients.

                                Syncope is probably one of the most difficult things that we treat in electrophysiology. In particular, vasovagal syncope. People have looked at different pacing maneuvers and specialized pacemakers for treatments. However, there's improving body of knowledge regarding other mechanisms, specific physiologic mechanisms that might underlie vasovagal syncope. This group in question had previously demonstrated that impaired post synaptic adrenergic responsiveness in those who have vasovagal syncope may be reversed by blocking nitric oxide synthase. Thus, they sought to evaluate volunteers who either had vasovagal syncope or were otherwise healthy, what the effect of a nitric oxide synthase inhibitor would be.

                                They demonstrated that arterial vasoconstriction is impaired in young vasovagal syncope patients but inhibiting nitric oxide synthase could correct this problem. Namely, that this might provide a potential mechanism of avoiding the changes in blood pressure associated with orthostatic intolerance resulting in vasovagal syncope. Whether or not this proves to be an ambulatory therapy still remains to be seen but at least in the acute study state within which these patients were evaluated, it suggests to be a potential promising target.

                                The next paper we review is also published in Heart this past month by Lazzerini et al., entitled Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes.

                                There is increasing evidence of the role systemic inflammation can play in arrhythmogenesis and particularly in acquired long QT syndrome in patients with sarcoid or myocarditis and other disease states is well recognized that ventricular arrhythmias that are potentially life threatening can happen. What the role of correcting this inflammatory state is, is less clear. However, this group decided to evaluate whether systemic inflammation may represent a currently overlooked risk factor contributing to torsades de pointes in the general population. They looked at 40 consecutive patients who experienced torsades and enrolled them to evaluate circulating levels of different inflammatory biomarkers and compared them with patients with active rheumatoid arthritis, comorbidity or healthy controls. They demonstrated that in the torsades group, 80% of patients showed an elevated inflammatory markers and in fact a definite inflammatory disease was identifiable in 18 of the 40 patients with 12 having acute infections, five having immune mediated diseases and one described as other.

                                Thus they proposed that systemic inflammation via elevated IL-6 levels could represent a novel QT-prolonging risk factor that can contribute to torsades. In their group they showed that CRP reduction was associated with IL-6 level decrease and resulted in QTC shortening. It remains to be seen whether this increased inflammatory pathway might be due to the torsades event itself or the cause. However, it does bring up the interesting question of whether or not systemic inflammation may in fact be causing untoward effects on normal arrhythmic profiles resulting in a greater risk of ventricular arrhythmias.

                                The next article we review is published by Kottkamp et al., entitled Global multielectrode contact mapping plus ablation with a single catheter: Preclinical and preliminary experience in humans with atrial fibrillation in this past month's issue of the Journal of Cardiovascular Electrophysiology.

                                Within the realm of catheter ablation for atrial fibrillation, There's a constant search for new approaches to achieve either more durable or quicker or safer pulmonary vein isolation. It is well recognized that pulmonary vein isolation is the cornerstone of atrial fibrillation ablation. In this particular paper, they sought to evaluate the utility of a catheter, namely a basket catheter that could allow for both diagnostic mapping as well as targeted ablation. This novel catheter has a distal multielectrode array with 16 ribs with 122 gold-plated electrodes. With each electrode being able to ablate, pace and able to measure tissue contact, temperature, current, and intracardiac electrograms. They noted in three patients that complete pulmonary vein isolation was achieved in all 12 and in most veins, PVI was achieved with a single placement in front of that respective vein though in one case there was a single gap requiring reapplication.

                                This suggests a new technique for quote unquote, single shot pulmonary vein isolation. Furthermore, the fact that multiple electrodes could be used to map at the same time as performing ablation, suggest that there might be opportunities for mapping more than just the veins themselves. What the safety and utility of this approach would be over other quote unquote, single shot approaches, such as laser and cryo based balloon systems, is unclear. Furthermore, whether or not they actually reflect a paradigm that offer additional utility due to the ability for more mapping, also remains to be seen. However, the critical portion of understanding these different tools is being able to differentiate them in practice and understanding what their relative values and opportunities are will be critical as one makes selections of which technologies to use.

                                The next article we review is published in Europace this past month by Hellenthal et al., entitled Molecular autopsy of sudden unexplained deaths reveals genetic predispositions for cardiac diseases among young forensic cases.

                                While we recognize that coronary artery disease causes the majority of sudden cardiac deaths in the older population. When we have a young patient who experiences sudden cardiac death, we always have to be concerned about the role of a genetic component. This is not just important for the patient themselves but also for family members who might still be alive. In this study they sought to determine the portion of underlying genetic heart disease among unexplained putative sudden cardiac death cases from a large German forensic departments.

                                The number included were only 10 patients who had sudden unexplained death aged 19 to 40 years. DNA was analyzed for 174 candidate genes and also genetic testing was offered to affected families. Amongst 172 forensic cases again, 10 cases of sudden unexplained death were identified and a genetic disposition was found in eight of 10 cases, with pathogenic mutations in three and variants of uncertain significance in five. Furthermore, subsequent selective screening of the family members revealed two additional mutation carriers in family members who had not suffered from a sudden death event yet.

                                The role of molecular autopsy in patients is evolving. However, the amount of molecular autopsies that are sent are still too low. All patients who are young and die unexpectedly, might benefit from molecular autopsy beyond just traditional forensic pathology to understand whether or not there's a genetic predisposition that led to their event. This might help the family members of that affected individual, especially in understanding whether or not they may also be at risk.

                                The next article we review is by Constantino et al., entitled Neural networks as a tool to predict syncope risk in the Emergency Department in Europace this past month.

                                Many patients when they pass out immediately come into the emergency department. However, it can be very difficult to understand what the risk of that syncope patient is and thus many are automatically admitted to the hospital despite the fact that history might provide a lot of data. In this study, Constantino et al., sought to evaluate the utility for artificial neural networks in stratifying risk in patients presenting with syncope to the hospital. They analyzed individual level data from three prior prospective studies and included a a cumulative sample of 1,844 patients. They included ten variables from patient history, ECG, and the circumstances of syncope to train and test the neural network. They actually had two different approaches used for training and validating neural network given the exploratory nature of the study. They found that they could identify adverse events after syncope with a sensitivity if 95% if they used one approach versus 100% if they used an approach that considers more factors.

                                Thus the study suggested that artificial neural networks could effectively predict the short-term risk of patients with syncope after presenting to the emergency departments. They did not seek to address what the predictive capability of the artificial neural network would be when compared with traditional clinical judgment and existing rule sets that might exist in various emergency departments. The reason this study's important is that as artificial neural networks become more robust we might find that their role in complementing physician decision making might become more and more important. This is especially true on the front lines amongst emergency department physicians or in other groups and consideration of employment of novel technologies or rule sets or methodologies to augment decision making on risk of patients who are being evaluated might need to be considered. It also might help individual stratify patients into those that require sooner evaluation.

                                The final article we review is published in the Journal of Interventional Cardiac Electrophysiology this past month by Schmier et al., entitled Effect of battery longevity on costs and health outcomes associated with cardiac implantable electronic devices: a Markov model-based Monte Carlo simulation.

                                Economic effects of increasing utilization of cardiac implantable electronic devices is of increasing concern. We also note that a lot of focus goes on what the battery life of a device is. However, how that battery longevity might affect overall cost and health outcomes is less clear. Thus in this study, Schmier et al., sought to develop a Monte Carlo Markov model simulation model to evaluate what happens to patients based on the battery longevity. They sought evaluations such as infection and non-infectious complication rates as well as overall costs over the lifetime of that individual patient. These outcomes were largely derived from Medicare data. They noted that an increase in battery longevity was an associated reduction in the number of revisions needed by 23%, the number of battery changes needed by 44%, the number of infections by 23%, the number of non-infectious complications by 10% and total costs per patient by 9%.

                                Thus, they demonstrated that using batteries that have longer longevity could be associated with fewer adverse outcomes and reduced healthcare costs. The understanding of the magnitude of the cost benefits of extended battery life is critical and how to optimize the battery life is also critical. It might be that as we move forward, when encountering a situation or a patient in which the battery life is far less than expected, consideration of the reasons why that battery life was limited will be critical in order to optimize the ongoing chronic care of that patient. Both to reduce the burden on the healthcare system and to improve that individual patient's long term outcomes in terms of infectious risk or other issues.

                                This is primarily simulation model and was not necessarily tested in a prospective fashion though this would be quite difficult given the long duration over which would be required to see a lot of these beneficial costs and complication rate effects. However, it is provocative in the fact that it allows us to understand that there might be benefits from taking further care in selecting not just the right device based on indication but the right device based on patient age, the number of general changes one expects a patient to have and what the longevity of that patient is expected to be.

                                I appreciate everyone's attention in these key and hard hitting articles that we have just focused on from this past months 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 not an easier way to stay in touch with the latest advances. These summaries and a list of all major articles in our field each month can be downloaded from the Circulation, Arrhythmia and 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.