Circulation: Arrhythmia and Electrophysiology On the Beat January 2018

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Dr. Paul Wong: Welcome to the monthly podcast, On The Beat, for Circulation: Arrhythmia and Electrophysiology. I'm Dr. Paul Wong, 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 article, Ratika Parkash and associates examined whether the outcomes following escalated antiarrhythmic drug therapy, or catheter ablation, depended on whether ventricular tachycardia with amiodarone refractory or sotalol refractory in patients with prior myocardial infarction in the VANISH study.

At baseline, 169, or 65%, were amiodarone refractory, while the remaining were sotalol refractory. Amiodarone refractory patients had more renal insufficiency; 23.7% versus 10%. Worse, new ARC Heart Association class, 82.3% versus 65.5% class II or III; and lower ejection fraction, 29% versus 35%. Within the amiodarone refractory group, ablation resulted in a reduction of any ventricular arrhythmias compared to escalated drug therapy, with a hazard ratio of 0.53, P = 0.02.

Sotalol refractory patients had trends towards higher mortality in VT storm with ablation, with no effect on ICD shocks. Within the escalated drug arm, amiodarone refractory patients had a higher rate of composite endpoint, with a hazard ratio of 1.94 and a P value of 0.01. In a trend toward higher mortality, hazard ratio 2.4, P = 0.07. While mortality was not different between amiodarone and sotalol refractory patients within the ablation treatment group.

In our next study, Junaid Zaman and associates examined 57 cases in which local ablation of persistent atrial fibrillation terminated to sinus rhythm or organized tachycardia. The authors analyze unipolar electrograms collected during atrial fibrillation from multi-polar basket catheters to reconstruct isochronal activation maps for multiple cycles, and computational modeling and phase analysis were used to study mechanisms of map variability.

At all signs of atrial fibrillation termination, localized, repetitive activation patterns were observed, 21% with complete rotational activity, 46% with partial rotational circuits, and 33% with focal patterns. In computer simulations incomplete segments of partial rotations coincided with areas of slow conduction, characterized by complex, multi-component electrograms.

In our next article, Matthew Kalscheur and associates sought to use a novel machine-learning approach to predict outcomes following resynchronization therapy in the companion trial. The random forest algorithm resulted in the best performing model. In 595 CRTD patients in the companion trial, 105 deaths occurred, with a median follow-up of 15.7 months. The survival difference across subgroups differentiated by bundle branch block morphology and cure restoration did not reach significance, P = 0.08. The random forest model, however, produced quartiles of patients with an eight-fold difference in survival between those with the highest and lowest predictive probability for events, hazard ratio 7.96 with a P value of less than 0.0001.

The model also discriminated the risk of composite endpoint of all cause mortality, or heart failure hospitalization, better than subgroups based on bundle branch block morphology and cure restoration. Future studies are needed to validate this model in other populations.

In our next paper, Amr Barakat and associates examined the clinical outcomes of trans-venous lead extraction for CIED infection based on renal function. The authors examined 1,420 consecutive patients undergoing trans-venous lead extraction of infected CIEDs over a 14 year period. Groups with normal renal function, Group 1, consisting of 1,159 patients, Group 2, 163 patients with renal dysfunction not requiring dialysis, and Group 3, 98 patients on dialysis. Complete procedural success rates were comparable in the three groups: 94%, 96%, and 94% in Groups 1, 2 and 3, respectively. This was not statistically significant.

The mortality rates were significantly higher in dialysis patients at one month. The procedure-related complication was 12.2% in dialysis patients versus 6.5% in Group 1 and 6.1% in Group 2. Other factors associated with mortality were lead material retention, functional New York Heart Association Class, and occurrence of procedural complications.

In our next paper, Eric Johnson and associates studied the contribution of the current ITO, two left ventricular re-polarization in the human heart, since the current has been shown to have an important role in animal models. The authors found that using whole-cell voltage clamp recordings from myocytes, isolated from the left ventricle, non-failing human hearts, that there were two, distinct transient currents, ITO fast and ITO slow.

The two currents have significantly different rates of recovery from inactivation and pharmacological sensitivities. ITO fast recovers in about 10 milliseconds, 100 times faster than ITO slow, and it's selectively blocked by KV4 channel toxin SNX 482. Using current clamp experiments, they found that regional differences in action potential wave forms, with a notch in phase one in the left ventricular subepicardial myocytes.

In failing, left ventricular subepicardial myocytes, ITO fast was reduced, while ITO slow was increased. In addition, the notch and plateau potentials were depolarized, and action potential durations were prolonged, both statistically significantly.

Slowing ITO fast inactivation results in a dramatic action potential shortening. The authors concluded that remodeling of ITO fast in failing, human left ventricular subepicardial myocytes, attenuates transmural differences in action potential wave forms.

In our next paper, Ravi Vaidyanathan and associates examine the interaction between Caveolin 3 domain in the inward rectifier potassium channels. Although the IK1 current is mainly composed of Kir2.1, there are Kir2.2 and Kir2.3 heterotetromerisoforms that occur and modulate the IK1 current, but these have not been studied. Kir2.x isoforms have unique, subcellular co-localization in human cardiomyoctyes and co-immunoprecipitate with Cav3. Using induced pluripotential stem-cell-derived cardiomyocytes, the LQT9 Cav3 mutation, F97CCav3 resulted in actual potential prolongation. Based on the technique FRET, which is Fluorescent Resonance Energy Transfer, the authors calculated the distance between KR2.2 and cath ray proteins to be 6.61 nanometers. LQT9 is caused by Cav3 mutations. Prior work has shown that F97CCav3 mutation increases the late sodium current, and decreases KR2.1 current density by distinctive mechanisms. This study extends the authors' previous observations on the impact of LQT9 Cav3 mutation on Kir2.1 current, by demonstrating that mutation affects the Kir2.2 current. LQT9 causing Cav3 mutation differentially regulates current density and cell surface expression of Kir2.x homomeric and heteromeric channels. The authors show that the mutation does not affect Kir2.3 current, but the heterotetromer Kir2.2-2.3 demonstrated loss of function.

Using the Li-Rudy [inaudible 00:09:45] model and myocyte mathematical model, the authors' data suggest that both loss of IK1 and increased sodium L are required for arrhythmia generation in LQT9.

In our next study, Christophe Teuwen and associates use high resolution epicardial mapping electrodes, 128 or 192, with an inter-electrode distance of 2.0mm of the entire atrial surface in 164 patients. These patients were undergoing open-chest cardiac surgery. This study was designed to examine the conduction of atrial extrasystoles. The authors found that a higher degree of aberrancy was associated with a higher instance of conduction disorders. Most conduction disorders were provoked by atrial systoles emerging as epicardial breakthroughs. Atrial extrasystoles cause most conduction disorders in patients with left atrial dilatation or diabetes mellitus.

In our next paper, Yuki Komatsu and associates examine 31 patients with idiopathic ventricular arryhthmias, using a two french microcatheter placed in a communicating vein between the great cardiac vein and small cardiac venous system, which passes between the aortic and pulmonary annulae, and is located in close associated with the left ventricular summit. They found that 14 patients had summit ventricular arryhthmias. The remaining 17 patients control group had ventricular arryhthmias originate from the right ventricular outflow track in the aortic cusps.

In patients with summit ventricular arryhthmias, the earliest activation during ventricular arryhthmias in the summit, preceded to cure as onset by 34 milliseconds. The summit ventricular arryhthmias exhibited inferior axes, negative polarity in lead one, deeper Q wave in AVL than AVR, nonspecific bundle branch morphology with an RS ratio in lead V1 of 0.67, distinguishing them from arryhthmias originating from the right ventricular outflow track or right ventricular cusp. Overall, ablation success was achieved in 10, or 71% of patients with summit ventricular arryhthmias, and 88% in the control group, P = 0.24.

In our final paper, Deepak Padmanabhan and associates examine differences in mortality in patients with non-MRI conditional CID undergoing brain MRI compared to controls. Patients with CIDs undergoing brain MRI were compared with three control groups matched for age, sex, imaging year, and type of CID. These groups included 1) no CID and brain MRI, 2) CID in brain-computed CT, and 3) no CID in brain CT.

They estimated all cause mortality at five years for CID MRI group, was not significantly different from patients who underwent CT, with or without a device. There was a significant increase in the mortality between CIED versus no CID MRI groups, hazard ratio 1.46 with a P value of 0.04.

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

Saraj Kapa: Thank you Paul, and welcome back to On the Beats where this month we'll be focusing on articles that are particularly hard-hitting, published across the literature in December of 2017. It's my pleasure to introduce 20 different articles that seem to have either particular interest or might change the field in the future.

First, within the area of atrial fibrillation, we'll focus within the area of anticoagulation and stroke prevention. In the Journal of the American College of Cardiology, Vivek Reddy et al published on the five-year outcomes after left atrial appendage closure, from the Prevail and Protect AF trials. They included a total of 1,114 patients, with a total of 4,343 patient years of follow-up, randomized two to one to closure versus Warfarin.

While ischemic stroke and systemic embolism of [inaudible 00:14:32] were numerically higher with closure, this did not reach statistical significance in terms of hemorrhagic stroke, unexplained death, and post-procedure bleeding favor left atrial appendage closure. These findings further support a role for left atrial appendage closure in the specific groups of patients enrolled in the Protect and Prevail Studies.

Of course, we always need to understand, that extrapolation to patients who may not have met inclusion criteria will be difficult. In particular, given both trials had their own fundamental limitations in the Prevail study. There was a relatively low rate of [inaudible 00:15:09] in the Warfarin arm. And in turn, there was a relatively high complication rate in Protect AF with left atrial appendage closure. Part of the differences might be due to the fact that, with more experience, complication rates might decrease. Furthermore, a comparison with more novel agents, such as the new oral anticoagulants, remains to be seen.

Next, within the realm of cardiac mapping and ablation for atrial fibrillation, we review an article by Vlachos et al published in the Journal of Cardiovascular Electrophysiology entitled Low-Voltage Areas Detected by High-Density Electroanatomical Mapping for Recurrence of Ablation after a Paroxysmal Atrial Fibrillation.

They presented the results from a series of 80 patients undergoing ablation for paroxysmal atrial fibrillation, performing high-density voltage mapping to characterize the total area involved by low voltage. They demonstrated, when low voltage areas, defined as less than 0.4 millivolts, were seen in greater than 10% of the left atrial surface area, this served as an independent predictor of atrial fibrillation recurrence. These data support prior research, including that of MRIs, suggesting the characterization of the atrial substrate may correlate with likelihood of ablation success.

Identifying methods however, to accurately and reproduce will identify these patients with more atrial substrate prior to ablation, remains to be seen. The importance of this, however, is our ability to better counsel patients on the likelihood of treatment success.

Next within the realm of atrial fibrillation, we review elements of risk stratification managements. First, in the December issue of the Journal of American College of Cardiology, Takimoto et al published on how Eplerenone may reduce atrial fibrillation burden without preventing atrial electrical remodeling. In a randomized controlled ovine atrial tachy pacing model of atrial fibrillation. The authors provided daily, oral Eplerenone and compared this with a placebo. They showed that Eplerenone significantly reduced the rate of left atrial dilatation, with less smooth muscle actin protein, atrial fibril [inaudible 00:17:17]. Furthermore, Eplerenone further prolonged the time to persist in atrial fibrillation in 26% of animals. However, interestingly, Eplerenone did not prevent AF-induced electrical remodeling. These data suggest that Eplerenone, or other medications that can be used to prevent or reverse structural remodeling, may offer an upstream therapy to reduce atrial fibrillation burden, and decrease likely the persistent atrial fibrillation.

Giving the ever-growing population of patients suffering from atrial fibrillation, identifying upstream approaches to prevent it will be critical. Of course, these need to be taken with due consideration, however. Specifically, the model used here, namely that of an atrial tachy pacing model, might not be applicable to all human atrial fibrillation. Thus, whether or not such therapies actually offer benefit in clinical models, is as of yet unclear.

Finally, from the realm of atrial fibrillation, we review the article by Rowin et al published in circulation entitled Clinical Profile of Consequences of Atrial Fibrillation Hypertrophic Cardiomyopathy. In patients presenting with hypertrophic cardiomyopathy, atrial fibrillation is known to be a significant co-morbidity. However, the implications of atrial fibrillation in terms of worsening of heart failure status, or long-term morbidity mortality are less clear.

Rowin et al reviewed the natural history of atrial fibrillation amongst 1,558 patients, prospectively followed at a single center. Nearly 20% of the population developed atrial fibrillation with the majority having symptomatic paroxysmal atrial fibrillation. However, atrial fibrillation was not associated with any increase in cardiovascular mortality or worsening of heart failure status. Furthermore, mortality that was directly related to atrial fibrillation was nearly exclusively related to thrombolic stroke. Anticoagulation [inaudible 00:19:13] reduced this risk. The traditional scoring systems fared poorly in assessing the stroke risk of this population.

About 121 patients underwent invasive rhythm control approaches, including 72 patients undergoing maze and 49 catheter ablation. The success rate of maze was significantly greater at around 75%. These data are important when counseling hypertrophic cardiomyopathy patients presenting with new-onset atrial fibrillation. While it is clear that paroxysmal atrial fibrillation has a significant impact on symptoms and quality of life, it does not cause worsened, overall, long-term outcomes. However, it does highlight the importance of anticoagulation in this population, nearly irrespective of the underlying risk score.

In terms of rhythm control options, it appears that rhythm control options can be successful in these patients. Finding that catheter ablation is associated with a 40 to 50% success rate is in keeping with prior published data. Thus, consideration of when a patient needs to be referred to maze, needs to be considered in the clinical inpatient context.

Changing gears, we will next review articles within the realm of ICDs, pacemakers, and CRT. In the New England Journal of Medicine this past month, Nazarian et al published on their experience regarding the safety of magnetic resonance imaging in patients with cardiac devices. They performed a prospective non-randomized study of the safety of, specifically, 1.5 tesla-strength MRI scans on legacy. In other words, not MRI conditionally-safe pacemakers and defibrillators. A total of 2,103 scans were done among 1,580 patients. They demonstrated no long term clinically significant adverse events. Nine patients did experience a reset to a backup mode, though eight of which were transients.

The most common change seen acutely was a decrease in PVA amplitude in one percent of patients, and in a long term follow-up, 4% of patients experiencing a decrease in PVA amplitude, increase in atrial catheter sheer threshold, or increase in right or left ventricular capture threshold. However, none of these events were considered clinically significant. Furthermore, there was not a good [inaudible 00:21:23] group to know if this long term change in amplitudes or thresholds might have been seen in patients who had devices that were not exposed to MRI.

These findings are complimentary to multiple, prior, published reports, indicating the safety of performing MRIs under clinical protocol in legacy pacemakers and defibrillators. It calls into question whether MRI conditional devices truly offer an additional safety factor furthermore, over legacy devices.

Next we review an article by Lakkireddy et al published in Heart Rhythm entitled A Worldwide Experience, the Management of Battery Failures and Chronic Device Retrieval of the Nanostim Leadless Pacemaker. Lakkireddy et al reported their large multi-center experience on the overall risk of battery failure. Amongst 1,423 implanted devices there were 34 battery failures occurring, on the average, three years after implants. Furthermore, about 73 patients underwent attempted device retrieval, and this was successful in 90%, with the seven failures of retrieval being due to either inaccessibility of the docking button, or dislodgement of the docking button in one patient, in whom it embolized to the pulmonary artery.

An additional 115 patients interestingly received an additional pacemaker after release of the device advisory. These data suggest that there may be as high as an overall 2% risk of battery failure with the Nanostim device, even late after implants. This highlights the need for close follow-up, even if the battery appears relatively stable up to two year after implants. Furthermore, almost 10% of devices cannot be successfully retrieved. However, in those patients, even with re-implantation of a separate device, there was no device-device interaction seen.

Further innovation will be needed to optimize device longevity, and close follow-up of all patients undergoing implantation will be critical to understand the overall long term efficacy and safety when compared to other traditional devices.

Finally, within the realm of device care, we focus on an article by Kiehl et al, again published in Heart Rhythm this past month entitled Incidence and Predictors of Late Atrial Ventricular Conduction Recovery Among Patients Requiring Permanent Pacemaker for complete heart block after cardiac surgery. They reviewed the likelihood of recovery of conduction in their retrospective cohort of 301 patients. Interestingly, 12% of patients had recovery of AV conduction on average six months after surgery. Those who did not recover tended to more likely have preoperative conduction abnormalities.

Saraj Kapa: Findings that suggested a higher likelihood of long term conduction recovery included female sex and the existence of transient periods of AV conduction postoperatively. These data highlight that recovery of AV conduction is possible in a significant number of patients undergoing cardiac surgery. However, being able to predict long term recovery may assist in device selection, to avoid more costly device implantations that may not be needed over chronic follow-up.

Prospective studies amongst larger numbers of patients are needed to better understand mechanisms of block, mechanisms of recovery, an optimal device in patient selection.

Changing focus, we will next review two articles within the realm of supraventricular tachycardias. First we read an article by Han et al published in JACC Clinical Electrophysiology, entitled Clinical Features in Sites of Ablation for Patients With Incessant Supraventricular Tachycardia From Concealed Nodofascicular and Nodoventricular Tachycardias.

Han and group describe three cases of concealed nodovascicular, nodoventricular re-entrant tachycardias, and focus on the different mechanisms of proving their participation in tachycardia. In all cases, atrial ventricular re-entering tachycardia was excluded. Successful ablation for these tachycardias occurred either at the slow pathway region, the right bundle branch, or the proximal coronary sinus.

This is the first described case of incessant, concealed tachycardias related to these pathways. The importance of this article highlights an understanding the mechanisms proving the contribution to tachycardia, and the importance of recognition when performing electrophysiology studies, and being unable to reveal traditional mechanisms, which exist in most patients, such as atrial tachycardia, AVNRT or AVRT.

Next we review an article by Guo et al published in Europace entitled Mapping and Ablation of Anteroseptal Atrial Tachycardia in Patients With Congenitally Corrected Transposition of the Great Arteries: Implications of Pulmonary Sinus Cusps.

They reviewed three separate cases of anteroseptal atrial tachycardias in the setting of congenitally corrected transposition. They demonstrated that in these cases, there was successful ablation performed with the pulmonary sinus cusps. The result is successful and durable suppression.

The reason this article is important lies in the fact that it's critical to understand both cardiac anatomy and cardiac nomenclature. The pulmonary valve in CCTJ is affectively the systemic ventricular arterial valve, given that the right ventricle is the systemic ventricle. Thus, mapping in this region of CCTJ abides the same principles as mapping the aortic valve in structurally normal hearts for similar tachycardias. However, understanding the nomenclature and that despite the variant anatomy, the utility of similar approaches to mapping of the systemic outflow are important when matching these complex, congenital anatomy or arrhythmia patients.

Changing gears yet again, we review an article within the realm of sudden death and cardiac arrest. Baudhuin et al published in Circulation and Genetics entitled Technical Advances for the Clinical Genomic Evaluation of Sudden Cardiac Death.

Baudhuin et al reviewed the utility of formal and fixed paraffin-embedded tissue, which is routinely obtained in an autopsy, to perform post-mortem, genetic testing. One of the main limitations to advising family members who have had prior family history of sudden death in closely related relatives, is that blood is often not available to perform DNA screening late after death. DNA however is often degraded in the tissues that are commonly available at autopsy, namely the formal and fixed paraffin-embedded tissues.

The authors sought to evaluate if your next generation techniques could make these types of tissue adequate for diagnosis. They demonstrated amongst 19 samples, that performance characteristics were similar between whole blood and these tissue samples, which could be as old as 15 years.

It can be critical to identify disease-causing mutations in family members, as individuals who might not yet be affected, but at risk, need to know about that overall risk. Given that decision to sequence might also not be universally applied at all centers, or in all situations, oftentimes these paraffin-embedded tissues might be the only available option, sometimes over a decade after death.

This represents the first report of using next-generation sequencing approaches to successfully and accurately sequence for specific mutations using paraffin-embedded tissue. This may offer additional options to help family members achieve diagnoses for sudden death-inducing conditions.

Within the realm of cellular electrophysiology, we review an article by Lang et al published in Circulation Research entitled Calcium-Dependent Arrhythmogenic Foci Created by Weakly Coupled Myocytes in the Failing Heart.

Lang et al reviewed the effect of cell-cell coupling on the likelihood of triggered arryhthmias. In a [inaudible 00:28:45] model, they demonstrated the myocytes that are poorly synchronized with adjacent myocytes were more prone to triggered activity due to abnormal calcium handling when compared to myocytes with normal connection to adjacent cells. Thus, adequate coupling leads to voltage clamping during calcium waves, thus preventing triggering arrhythmias. While poorly coupled myocytes aren't able to to this due to a weakened currency, making them more prone arrhythmogenesis.

These data highlight another critical cellular basis for arrhythmogenesis. In heart failure, while the focus for clinical management is typically areas of scar, there's clearly a role at the cellular level where cell-cell coupling abnormalities can lead to dynamic changes that can increase tendencies to arrhythmogenesis.

The role in understanding the varying, arrhythmogenic risk based on varying factors, is important, and might have importance in the future advances in mapping technologies.

Changing gears, we review an article published in the Journal of the American College of Cardiology by Mazzanti et al within the realm of genetic channelopathies entitled Hydroxyquinoline Prevents Life-Threatening Arrhythmic Events in Patients With Short QT Syndrome.

They reviewed a cohort of 17 patients and demonstrated that hydroxyquinoline resulted in a reduction of arrhythmic events from 40% to 0% of patients. QTc prolongation was seen in all patients. These data clearly demonstrate that hydroxyquinoline plays a role in lowering the incidence of arrhythmic events in patients suffering from short QT syndrome. However, it's important to note that in many markets, quinoline has been difficult to access.

In the specific case of QT syndrome thus, there's clearly a role for hydroxyquinoline. However, it also must be noted, the comparative efficacy with more commonly available drugs still needs to be evaluated.

This past month has been of particular interest in the realm of ventricular arrhythmias, with multiple, potentially ground-breaking articles. One of the well-recited articles published this past month already is by Cuculich et al entitled Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia published in the New England Journal of Medicine.

Cuculich et al reported the first in-human data on the use of stereotactic body radiation therapy to perform noninvasive ablation of ventricular arryhthmias. Using a combination of noninvasive electrocardiographic imaging curing ventricular tachycardia, and stereotactic radiation, patients were treated with a single fraction of 25 [inaudible 00:31:15] while awake.

A total of five patients were included with a mean ablation time of only 14 minutes. During the three months prior to treatment, there was a total of 6,577 VT episodes seen, and during a six week post-ablation period, considered a blanking period, there were 680 episodes. After this blanking episodes, there were only four episodes of VT seen over the ensuing 46 patient months. This study is important because it reflects the first in-human proof of concept that noninvasive ablation using radiation therapy traditionally as for treatment of solid tumors, may be affective in targeting cardiac tissue.

Furthermore, modern techniques such as noninvasive electrocardiographic imaging might allow for a fully noninvasive experience for the patients. This is a vast advance seen within the realm of cardiac electrophysiology. In the early days, all we could do was map invasively and then have to go to much more invasive, open-heart surgery to treat arryhthmogenic substrates. Since the advent of catheter and radiofrequency ablation, surgical ablation is relatively fallen by the wayside, to a less invasive approaches.

A completely noninvasive approach to successfully targeting tissue is potentially ground-breaking. However, there are several limitations in this study that can only be ascertained by reading the actual article. When we actually review the patients included, the long term follow-up was limited to only four patients, as one patient actually died within the blanking period, and in fact, this patient suffered from the largest burden overall of VT. Furthermore, amongst the remaining four patients, one required a redo ablation within the blanking period, and one had to be restarted on amioderone after the blanking period was over. Thus further data is really needed to clarify efficacy, given the overall success rate appears to be less than 50% on a per patient basis. Though on an overall episode basis, there was significant reduction.

The exact type of radiation to be used also needs to be considered, within the realm of solid oncology. Stereotactic radiation is considered an older modality, with proton beam, and more recently, carbon beams offer more directed therapy. Thus, a lot more data is required to identify the promise of radiation therapy. Though again, this is a significant advance.

Next, within the realm of invasive electrophysiology, we review an article by Turagam et al published in the JACC Clinical Electrophysiology entitled Hemodynamic Support in Ventricular Tachycardia Ablation: An International VT Ablation Center Collaborative Group Study.

The utility of hemodynamic support during VT ablation is relatively unclear. Studies have been variable and limited. This group included 1,655 patients who underwent 105 VT ablations using hemodynamic support with a percutaneous ventricular assist device. Those undergoing support overall tend to be sicker, including lower ejection fractions and [inaudible 00:34:07] classes, and more VT events, including ICD shocks and VT storm. Hemodynamic support use interestingly, was an independent predictor of mortality with a hazard ratio of 5, though there was no significant difference in VT recurrence rates irrespective of the subgroup considered.

These data indicate that, while patients are receiving hemodynamic support were overall sicker, there was no clear incremental benefit in use of hemodynamic support in terms of long term outcomes.

In the area of substrate ablation, whether use of hemodynamic support to facilitate mapping during VT, actually alters outcomes remains to be seen. This study highlights the potential importance of randomized clinical approaches to better evaluate whether hemodynamic support truly alters the long term outcomes of the VT ablation.

Next, we review an article by Munoz et al that focuses more on prediction of those patients who might be at risk for ventricular arrhythmias, again published in the last edition of JACC Clinical Electrophysiology and entitled Prolonged Ventricular Conduction and Repolarization During Right Ventricular Stimulation Predicts Ventricular Arrhythmias and Death in Patients With Cardiomyopathy.

Munoz et al reviewed the relationship between paced QRS and pace Qtc and long term risk. A total of 501 patients with mean ejection fractions of 33% were included. Longer paced ventricular QRS and Qtc was associated with a higher risk of ventricular arrhythmia, and all caused death or arrhythmia, irrespective or ejection fraction. A paced QRS duration of 190 milliseconds was associated with 3.6 fault higher risk of arrhythmia, and a 2.1 fault higher risk of death or arrhythmia.

These data suggest that findings during [inaudible 00:35:47] pacing and otherwise normal rhythm, including paced QRS and QTc may independently result in elevation of overall risk of ventricular arrhythmia and death. Physiologically these data make sense. In light of the fact that longer cure restorations are probably related to a greater degree of myopathy. While these data offer a prognostic indication, whether they alter outcomes or decision making regarding ICM implantation, remains to be seen.

Next, also published in JACC Clinical Electrophysiology, Vandersickel et al reviewed a more cellular basis for toursades in an article entitled Short-Lasting Episodes of Toursades de Pointes in the Chronic Atrial Ventricular Model Have Focal Mechanism While Longer-Lasting Episodes are Maintained by Reentry.

Vandersickel et al reviewed the mechanisms underlying toursades, and demonstrated that both focal and reentry mechanisms may exist. In five canines they used broadly distributed neuro electrodes to simultaneously map across the heart. They demonstrated that initiation and termination was always focal, but longer and non-terminal episodes always had reentry mechanisms.

These data suggest that the mechanisms underlying toursades actually reflect a spectrum of potentially dynamic, electrophysiologic phenomenon the heart, including both focal and reentry activity. Understanding these mechanisms, and the fact that focal mechanisms almost universally underlie initiation may bring into consideration the optimal treatments whether in the form of pacing and defibrillation techniques or medication techniques for toursades.

Finally, in the realm of ventricular arrhythmia, we review an article published in the last month's edition of Heart Rhythm by Penela et al entitled Clinical Recognition of Pure Premature Ventricular Complex-Induced Cardiomyopathy at Presentation.

As we know, it's sometimes difficult to recognize patients when they present with frequent PVCs and a depressed injection fraction in terms of, whose injection fractions are purely caused by the presence of PVCs, and whose PVCs are only exacerbated by the presence of an underlying myopathy.

The group included 155 patients and excluded all patients who did not normalize their elevated ejection fraction, or who had previously diagnosed structural heart disease, leaving a total cohort under consideration, of 81 patients.

About 50% were diagnosed as having a PVC-induced cardiomyopathy on the basis of normalization of elevated function after PVC suppression. While the remainder was considered to have PVC exacerbated cardiomyopathy on the basis that things did not entirely resolve, and thus had an independent mechanism for nonischemic myopathy. Characteristics that suggested patients with a lower likelihood of EF normalization included those with longer intrinsic QRSs, above 130 milliseconds, a lower PVC burden of baseline, considered less than 17%, and larger [inaudible 00:38:33] greater than 6.3 cm. PVCs as a cause of [inaudible 00:38:35] are obviously a well-recognized treatable cause of myopathy, however again, it might be difficult to differentiate. Those patients whose PVCs are a result of the underlying myopathy versus those whose PVCs are the cause, and for whom ablation or suppression may reverse the myopathic process.

The work of Penela et at offers an initial attempt at helping differentiate these processes, however validation of larger cohort is necessary.

Next we review an article within the realm of syncopy entitled Prohormones in the Early Diagnosis of Cardiac Syncopy by Badertscher et al published in the Journal of the American Heart Association this month. They review the utility of circulating prohormones [inaudible 00:39:14] autonomic dysfunction or neurohormonal abnormalities, to differentiate cardiac from non-cardiac causes of syncopy in the emergency departments.

They measured four novel prohormones in a multi-center study. In the emergency departments there is a specific protocol used to determine the perceived likelihood of the cause of syncopy to be cardiac versus non-cardiac. In addition to this, the prohormones are drawn. After this, everyone's final diagnosis was reached. Two independent cardiologists reviewed the cases to determine if it was a truly cardiac or non-cardiac cause of syncopy. Among 689 patients included, 125 overall were adjudicated as cardiac syncopy. Measure of the specific marker MR-proANP in combination with emergency department suspicion of syncopy, performed better than suspicion alone, to differentiate cardiac causes of syncopy.

A combination of a circulating MR-proANP, less than 77, picomoles per liter, an [inaudible 00:40:17] probability of cardiac syncopy could be less than 20%, had a very high sensitivity negative predictive value of 99%. The significant resources are often used to manage patients with syncopy presenting to the emergency departments, and it's often extremely difficult at this stage to differentiate cardiac from non-cardiac causes of syncopy. And the amount of evaluation that can be done in the emergency department is often limited.

Cardiac caused of syncopy are not good to miss, however, since these can include ventricular arrhythmias, and transient AV block, that might result in death as well. As is well-recognized, emergency department evaluation in clinical [inaudible 00:40:49] are limited in terms of their utility. This raises the utility of objective measures to help differentiates.

These data suggest that circulating prohormones [inaudible 00:40:59] your hormonal function drawn during your emergency department evaluation, may be a useful adjunct to differentiate cardiac from non-cardiac syncopy. Whether they can be used to prospectively differentiate those patients requiring inpatient admission or now, however, remains to be seen.

The last two articles we'll choose to focus on will fall under the realm of broader, other EP concepts. The first article we will review is by Varghese et al published in Cardiovascular Research entitled Low-Energy Defibrillation With Nanosecond Electric Shocks.

Varghese et al reviewed the potential of low-energy nanosecond duration shocks for defibrillation in rapid hearts. In induced fibrillation examples, the repeated defibrillated nanosecond impulses as low as three kilovolts demonstrated effective defibrillation. The energy required is significantly lower than from monophasic shocks and longer pulse durations. Furthermore, there was no detectable evidence of electroporation, namely cardiac or so injury after defibrillation. Using nanosecond impulses, it may be feasible to defibrillate the heart with significantly lower energies.

The implications for patients experiencing defibrillation, for example pain, is unclear without in-human studies. However, the ability to use lower energies could have implications in battery life. Further [inaudible 00:42:11] studies will be critical to study ambulatory efficacy as this research is performed in [inaudible 00:42:19] hearts.

Finally, we review an article published in Circulation entitled Mortality in Supravascular Events After Heart Rhythm Disorder Management Procedures by Lee et al. Amongst three centers, a retrospective cohort study regarding the mortality and risk of supravascular events, was performed. They included a variety of heart rhythm [inaudible 00:42:40] procedures, including defibrillation threshold testing, lead extraction, device implant, and invasive electrophysiology studies and ablation procedures.

Amongst 48,913 patients, 62,065 procedures were performed and an overall mortality of .36% was seen. Supravascular [inaudible 00:42:58] was lower at .12%. Interestingly, and expectedly, the highest risk was seen with lead extraction patients, with an overall mortality risk of 1.9%. Less than half of the deaths seen, however, were directly attributable to the procedure itself. The most common cause of procedural death was cardiac tamponade, largely seen amongst device implant patients. This is critical, as the number of ablation and other invasive electrophysiology procedures performed, is increasing.

These data provide a large, contemporary experience regarding the overall risk attributable to a variety of heart rhythm disorder procedures. Interestingly, half of the procedure related deaths were associated with device implantation procedures. With the predominant cause being tamponade, highlighting the importance of early recognition of this treatable complication. Tamponade may not always be considered as a major issue after device implantation, however these data clearly suggest that it is.

In addition, extraction, as expected, carried the highest incident of both supravascular events and mortality. Though, this is likely related to the higher rate of core morbidity in this population, including active infection.

In summary, this month, we have reviewed 20 articles in various areas of electrophysiology published across the literature. Particularly high impact articles range from those reviewing experience regarding left atrial appendage closure and the efficacy of this, to the utility of using atrial fibrillation to predict risk and long term morbidity and mortality in hypertrophic cardiomyopathy, to further evidence regarding the safety of magnetic resonance imaging in legacy pacemakers and defibrillators, and novel considerations regarding supraventricular tachycardias and there diagnosis and management, especially invasively.

Other potential groundbreaking articles included evidence that we can successfully use formal and fixed paraffin-embedded tissue that can be as old as 15 years, to successfully identify genetic mutations that might be responsible for sudden death. And evidence that using novel techniques, we might be able to perform completely noninvasive therapies for arrhythmias by using radiation therapies.

However questions were also raised such as regarding the role of hemodynamic support for VT ablation. How to better differentiate those patients who will have recovery of AV conduction from those who won't, as they meet class I indications post cardiac surgery? And whether other factors such as right ventricular pacing during [inaudible 00:45:28] study might further differentiate patients at risk for ventricular arrhythmias in spite of a low ejection fractions.

Many of the papers had to deal with tranlational work that still remains to be proven in terms of value at a clinical level, such as demonstrating mechanisms underlying trousades de pointes. Or the potential value of low-energy defibrillation with nanosecond electric shocks. Clinical protocols involving the use of prohormones in the early diagnosis of cardiac syncopy. How to differentiate PVC induced from other causes of myopathy, and how to manage, in the long term, these devices. Also, likely requires further study.

Finally, covering all areas of electrophysiology, we reviewed one large article focusing on mortality in supravascular events after heart rhythm management disorder procedures at large. This article highlights the importance of considering institutional experience and reporting it to use as a benchmark to help better optimize our counseling of patients, as well as our procedures and protocols.

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

Dr. Paul Wong: Thanks Seraj. 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 advance. 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.

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