Circulation: Arrhythmia and Electrophysiology On the Beat September 2017

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Dr. Paul Wang : Welcome to the monthly podcast On the Beat for circulation, arrhythmia and electrophysiology. I’m Dr. Paul Wang editor in chief with some of the key highlights from this month’s issue. We’ll also hear from Dr. Suraj Kapa reporting on new research for the latest journal articles in the field.

The first article in this month's issue is by Yoav Michowitz and Associates who examine the morphological ECG characteristics of left posterior fascicular ventricular tachycardia and differentiated from right bundle branch block and left anterior hemiblock aberrancy. 183 ECGs with left posterior fascicular ventricular tachycardia in patients who underwent ablation were identified using a systematic Medline search were examined and compared to 61 ECGs with right bundle branch block in left anterior hemiblock aberrancy with no obvious cardiac pathology by echocardiography.

Using four variables including atypical right bundle branch block like V1 morphology, positive QRS in aVR, V6R greater than S ratio of less than one and QRS less than or equal to 140 ms, a prediction model was developed that predicted posterior fascicular ventricular tachycardia with a sensitivity of 82% and a specificity of 78%. Patients with three out of four positive variables had a high probability of having left posterior fascicular ventricular tachycardia whereas patients with less than or equal to one positive variable always had right bundle branch block plus left anterior hemiblock.

In the next article, Anna Thøgersen and associates describe a case series of 10 patients in whom implantable cardioverter defibrillators failed to treat ventricular tachyarrhythmias. The authors examine whether consensus derive generic rate threshold cutoffs between 185 and 200 beats per minute were employed in this case series. In nine patients, ventricular fibrillation did not satisfy program detection criteria. Five patients died with untreated ventricular fibrillation, four had cardiac arrest requiring external shocks and one was rescued by a delayed ICD shock. Seven of these patients had slowest detection rates that were consistent with generic recommendations but not tested in a peer review trial for their manufacturer’s ICDs.

In the reported cases, manufacturer specific factors interacted with fast detection rates to withhold therapy including strict ventricular fibrillation episode termination rules, enhancements to minimize T-wave over sensing and features that restrict therapy to regularly rhythms in VT zones. Untreated ventricular fibrillation despite recommended programming accounted for 56% of the deaths and 11% of all of deaths. The authors concluded that complex and unanticipated interactions between manufacturer specific features and generic programming can prevent therapy for ventricular fibrillation.

In the next article, Miguel Rodrigo and associates describe from 17 simulations of atrial fibrillation, atrial flutter and focal atrial tachycardia the ability to understand signal processing that can affect identification of reentrant activity using electrograms, body surface potential mapping and electrocardiographic imaging ECGI phase maps. Reentrant activity was identified by singularity point recognition and raw signals and in signals after narrow band pass filtering at the highest dominant frequency.

Reentrant activity was identified without filtering in 60% of unipolar records but filtering was required to increase reentrant activity detection from 1% to 62% in bipolar recordings. The filtering resulted in residual false reentrant activity in about 30% of bipolar recordings. The authors concluded that rotor identification is accurate and sensitive and does not require additional signal processing in measured or noninvasively computed unipolar electrograms while bipolar electrograms and body surface potential mapping do require highest dominant frequency filtering in order to detect rotors at the expense of a decrease specificity.

In the next article, Raymond Yee and associates examine the ability of a new automated antitachycardia pacing algorithm to reduce ICD shocks. The new automated ATP algorithm was based on electrophysiologic first principles and prescribed the ATP sequences in real time using the same settings for all patients. In 144 patients who had dual chamber or CRT ICDs as well as a history of one or more ICD treated VT or VF episodes or a recorded sustained monomorphic ventricular tachycardia episode. Detection was sent to ventricular fibrillation interval detection of 24 out of 32 ventricular tachycardia interval detection of 16 or greater in a fast VT zone of 242 to 320 ms.

There were 1,626 treated episodes in 49 patients over 14.5 month’s follow up. Data logs permitted adjudication of 702 episodes including 669 sustained monomorphic ventricular tachycardia episodes, 20 polymorphic ventricular tachycardia episodes, 10 SVT episodes and three mal sensing episodes. The novel automated antitachycardia pacing algorithm terminated 39 out of 69 episodes or adjusted 59% of the sustained monomorphic ventricular tachycardia events in the fast VT zone, but 509 out of 590 or 85% adjusted in the VT zone and 6 out of 10 in the VF zone. No SVTs were converted to VT or VF and no anomalous ATP behavior was observed. The authors concluded that this new automated ATP algorithm could be used safely in all zones without need for individualized programming.

In the next study Pablo Ávila and associates studied the incidence and clinical predictors of atrial tachycardias in adults in a cohort of 3,311 patients with congenital heart disease. Prospectively followed in a tertiary center for 37,607 person years. The study patients were divided into three categories; 49% simple, 39% moderate and 12% complex congenital heart disease. In this cohort, 153 or 4.6% of patients presented with atrial tachycardia. The atrial tachycardia burden was highest in complex congenital heart disease such as single ventricle 22.8% or D-TGA 22.1%.

The authors found that univentricular physiology, previous intracardiac repair, systemic right ventricle, pulmonary hypertension, pulmonary regurgitation, pulmonary AV valve regurgitation and pulmonary and systemic ventricular dysfunction were independent risk factors for developing atrial tachycardia. At the age of 40 years, atrial tachycardia free survival in patients with zero risk factors was 100%. With one risk factor, it was 94%. With two risk factors was 76% and three or more risk factors was 50%. These authors confirm these findings in a validation cohort.

In the next article, Khidir Dalouk and associates compare clinical outcomes between ICD patients followed up in a telemedicine videoconferencing clinic and a conventional in person clinic. In this retrospective study, the authors compared time to first appropriate ICD therapy, time to first inappropriate ICD therapy, time to first shock and overall survival. The authors studied 287 patients in the telemedicine videoconferencing clinic group and 236 patients in the conventional in person clinic over mean follow-up duration of 4.8 years. The authors found that telemedicine videoconferencing clinic was not inferior to in person follow-up for the pre-specified outcomes.

In the next article, Elisabeth Mouws and associates studied the epicardial breakthrough waves in sinus rhythm possibly giving insight to the arrhythmogenic substrate in atrial fibrillation. In 381 patients with ischemic or valvular heart disease, intraoperative epicardial mapping with intro electro distance of 2 mm was performed of the right atrium, Bachmann’s bundle, the left atrioventricular groove and the pulmonary vein area. Epicardial breakthrough waves were referred to as sinus node breakthrough waves if they were the earliest right atrial activated site. A total of 218 epicardial breakthrough waves and 57 sinus node breakthrough waves were observed in 168 patients or 44%.

Epicardial breakthrough waves mostly occurred at the right atrium and 48% at the left atrioventricular groove and 31% followed by Bachmann’s bundle and 12% and the pulmonary vein area and 9%. Epicardial breakthrough waves occurred most often in ischemic heart disease patients 49% to valvular patient's 17%. Epicardial breakthrough wave electrograms most often consisted of double or fractionated electrograms seen in 63%. Fractionated epicardial breakthrough wave potentials were more often observed at the right atrium or Bachmann's bundle. The authors concluded that epicardial breakthrough waves are present in over a third of patients possibly indicating muscular connections between the endocardium and epicardium that may enhance the occurrence of epicardial breakthrough waves during atrial fibrillation promoting AF persistence.

In the next article, Shouvik Haldar and associates compare horizontal and vertical orientation bipolar electrograms with novel omnipolar peak to peak voltages in sinus rhythm and atrial fibrillation using a high density fixed multi-electrode plaque placed on the epicardial surface of the left atrium in dogs. Bipolar orientation had significant impact on bipolar electrogram voltages obtained either in sinus rhythm or atrial fibrillation. Omnipole Vmax values were 99.9% larger than both horizontal or vertical electrograms in sinus rhythm in larger than horizontal or vertical electrograms in atrial fibrillation.

Further vector analysis of omnipole electrograms showed that omnipolar electrograms can record electronic voltage unaffected by collision and fractionation. The authors concluded that omnipolar electrograms can attract maximal voltages from AF signals which are not influenced by directional factors, collision or fractionation compared to contemporary bipolar techniques.

In our final article for the month, Pauline Quenin and associates examine the efficacy of screening in relatives of subjects who died suddenly. The authors provided clinical screening to 64 families who experienced unexplained sudden cardiac death before age 45 in a prospective multicenter registry. The diagnosis was established in 16 families, 25% including Brugada syndrome, long QT syndromes, dilated cardiomyopathy and hypertrophic cardiomyopathy. The diagnostic yield was mainly dependent on a number of screen relatives with 3.8 screen relatives in the diagnosed family versus 2.0 in the non-diagnosed families rising to 40% with at least three relatives.

It additionally increased from 9% to 41% when both parents were screened. Diagnostic performance was also dependent on the exhaustiveness of the screening. 70% of complete screening versus 25% with incomplete screening with 17 Brugada syndrome and 15 long QT syndrome diagnoses based on pharmacologic tests. The authors concluded that even without autopsy, familial screening after sudden death in young patients is effective greatly increasing the likelihood of diagnosis in families.

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

Suraj Kapa: Thank you Paul. It is my pleasure to welcome everybody back to our continued series of On the Beat articles from across the electrophysiology literature especially selected to highlight their potential importance in terms of either current or future practice within the realm of cardiac electrophysiology. Again, my name is Suraj Kapa and it is my pleasure to walk us through a variety of hard-hitting articles.

Today we’ll be starting within the realm of atrial fibrillation specifically as it relates to cardiac mapping and ablation. The first article was by Iwasawa et al entitled Temperature Controlled Radiofrequency Ablation for Pulmonary Vein Isolation in Patients with Atrial Fibrillation published in volume 70 of the Journal of the American College of Cardiology. In this article, Iwasawa and colleagues discuss the role of novel temperature controlled irrigated ablation catheter to attempt to obtain deeper transmural lesions in cardiac tissue, specifically they tested the utility of a diamond embedded tip for rapid cooling accompanying six surface thermocouples to better reflect tissue temperature.

They demonstrated in this first in human series that a temperature controlled irrigated ablation could produce rapid, efficient and durable PV isolation. The importance of this particular article lies in the continued development of novel tools that can achieve pulmonary vein isolation either more safely or more quickly. This was highlighted in the article by Iwasawa et al when they demonstrated that the mean radiofrequency application duration was significantly less by almost a factor of three and those using the novel radiofrequency ablation catheter versus those with older models.

They also noted that there was lower acute dormant pulmonary vein re-conduction rates and patients tend to have more frequent durable isolation when remapped after ablation. While the study group only consisted of 35 patients within the treatment group and 35 patients within the control group, the potential of these novel catheters to achieve aims of both shortening procedure duration as well as improving procedure and success need to be taken in consideration.

The next article is by Dr. Gopinathannair entitled Atrial Tachycardia after Surgical Atrial Fibrillation Ablation Clinical Characteristics, Electrophysiological Mechanisms and Ablation Outcomes from a large multicenter study published in the August 2017 issue of JACC Clinical Electrophysiology. In this article, Dr. Gopinathannair reviews the outcomes of cardiac mapping and ablation targeted atrial tachycardias occurring after surgical atrial fibrillation ablation. They reviewed a large number of patients nearly 137 undergoing catheter ablation for symptomatic postsurgical atrial fibrillation ablation atrial tachyarrhythmias across three high volume institutions in the United States.

They demonstrated that the vast majority had a left atrial origin though up to a third also had a right atrial origin further atrial tachyarrhythmias. The predominant circuits noted were cavotricuspid isthmus but also frequently perimitral roof and left or right pulmonary veins. In addition, most of the patients namely 93% had at least one pulmonary vein reconnection requiring re-isolation. The key point with the article however were the outcomes. They demonstrated that acute termination inducibility could be achieved in as many as 97% of right atrial and 93% of left atrial tachyarrhythmias in the setting of prior surgical ablation.

Furthermore, 12 month followup demonstrated an 80% success rate. Traditionally, surgical atrial fibrillation ablation is seen as a complex procedure with the remapping of arrhythmias requiring a lot more complexity. However, these findings cross a large group of patients suggesting that we can have a high rate of success should propose to individuals that perhaps targeted ablation at these postsurgical atrial tachyarrhythmias should be amenable towards ablation especially at high volume complex ablation centers.

Next will discuss the article by Pathik et al entitled Epicardial-Endocardial Breakthroughs through Stable Macroreentry: Evidence from ultra-high-resolution three-dimensional mapping published in Heart Rhythm in August 2017. In this article, the group of Pathik et al decided to review whether epicardial-endocardial breakthrough could be discerned during stable right atrial macroreentry using high density and high spatial resolution three-dimensional mapping. Twenty-six patients were studied and they noted that up to 14 patients had evidence of epicardial-endocardial breakthrough. Using systematic entrainment confirmation, stable atrial macroreentry with epicardial-endocardial breakthrough was consistently demonstrated.

The principle of epicardial-endocardial breakthrough or dissociation is critically important during cardiac mapping. While widely accepted for ventricular mapping, the tradition because of lack of available tools and atrial mapping has suggested that endocardial only mapping should reveal the entire cardiac circuits. Advances in signal processing as well as cardiac mapping techniques and technologies has allowed for better discernment of potentially deeper manifestations of cardiac tissue involvement in cardiac arrhythmias. As been well recognized that there can be significant epicardial and endocardial dissociation in cases of persistent atrial fibrillation.

The article by Pathik et al is important in that it highlights that such events can manifest themselves even in the setting of relatively organized or stable atrial macroreentry. Part of the reason this becomes so critical is that when we consider endocardial only remapping and rely on these signals alone, we may run into situations where we miss a significant chamber of atrial tissue namely the epicardium, thus the focus of this article and the consideration of it in the clinician's repertoire of cardiac mapping and ablation should lie in an understanding of the fact that the entire story of an electrical circuits may not be told by traditional endocardial mapping alone without consideration for epicardial-endocardial breakthrough.

The next article we will focus on is by Dr. Chun et al regarding the impact of cryoballoon versus radiofrequency ablation for paroxysmal atrial fibrillation on healthcare utilization and costs and economic analysis. This was from the FIRE and ICE Trial published in the Journal of the American Heart Association this past month. In this study they sought to assess payer cost following cryoballoon or radiofrequency catheter ablation for paroxysmal atrial fibrillation. They demonstrated that there are cost savings of as much as $355,000 related to the use of cryoballoon over traditional radiofrequency catheter ablation. This reduction in resource use and payer costs was consistent across three different national healthcare systems.

Furthermore, the reason for the reduced cost was primarily attributable to fewer repeat ablations and a reduction in cardiovascular rehospitalizations with cryoballoon ablation. In this era of cost reduction, it is important to consider the potential implications of use of novel technologies in terms of procedural costs. The ability to identify novel techniques that can actually both reduce costs and either achieve equal or improved outcomes needs to be strongly considered. While the three national healthcare systems reviewed here might not reflect all healthcare systems or all insurance needs, it still brings up an important economic consideration that all novel technology may not necessarily result in increased costs, and utilization must be considered both in the context of the particular system as well as the particular provider.

Changing pace, we’ll move on with an atrial fibrillation to the role of anticoagulation. The first major article recently published is by Pollack et al regarding the use of Idarucizumab for dabigatran Reversal, the full cohort analysis published the New England Journal of Medicine. Idarucizumab is a monoclonal antibody fragments developed to reverse the anticoagulant effect with dabigatran and represents the first reversal agent available for reversal of any of the novel oral anticoagulant drugs. In this study which is both multicenter, prospective and open label, patients were enrolled to undergo treatment with this reversal agents.

A total 503 patients were included and the median maximum percentage reversal dabigatran was 100% which was measured using the diluted thrombin time or the ecarin clotting time. In those with active bleeding, the median time to cessation of bleeding was around 2.5 hours. Furthermore, in a surgical cohorts who underwent reversal in order to accommodate them going to surgery, the time to initiation of an intended procedures was 1.6 hours with periprocedural hemostasis assessed as normal in 93%, mildly abnormal in 5% and moderately abnormal in 1.5%. Thrombotic events occurred in about 6.3% of patients undergoing reversal because of active bleeding and then 7.4% undergoing reversal for surgical accommodation.

Mortality rates were around 18% to 19%. Thus it was demonstrated that in emergency situations Idarucizumab can rapidly, durably and safely reverse the anticoagulant effect of dabigatran. However, it is important to note that there was a signal for thrombotic events and consideration of the risk of rapid reversal of anticoagulation regardless of the type of anticoagulation in combination with the actual need for reversal should be considered in the patient context.

The next article we will review is by Jackevicius et al entitled Early Non-persistence with Dabigatran and Rivaroxaban in Patients with Atrial Fibrillation, published in Heart this past month. In this article, the group reviewed how patients manage being on their novel oral anticoagulants over the course of time after initial diagnosis and prescription. One of the concerns regarding novel oral anticoagulants is given the fact that there is no actual tracking or no actual measurements needed to ensure continued adherence to the drug, whether or not there will be higher rates of nonpersistence with use of these novel oral anticoagulants.

Amongst 15,857 dabigatran users and 10,119 rivaroxaban users, they noted that at six months about a third of patients were nonpersistent with either drug. In those patients who were nonpersistent with use of the drug, the combined endpoint of stroke, TIA and death was significantly higher with hazard ratios of 1.76 in the dabigatran cohort and 1.89 in the rivaroxaban cohort. Furthermore, the risk of stroke or TIA was markedly higher in nonpersistent patients with about a hazard ratio of 3.75 in dabigatran nonpersistence and 6.25 in rivaroxaban nonpersistence.

Given these relatively high rates of nonpersistence in clinical practice and the negative outcomes associated with nonpersistence, this highlights the importance of continued validation of the need for persistence with use of oral anticoagulation in patients prescribed these perceived to be at high risk of stroke associate with atrial fibrillation. In an era of improving drug use or improving drugs that can be used without the need for blood testing, it must also be considered that these drugs may be more easily stopped on the patient's own discretion without any knowledge from a provider as there is no active blood test associated. Thus this further highlights the importance of continued discussion between patients and physicians over the course of therapy and care regarding the need for continuation.

Changing paces. We review the article by Godier et al entitled Predictors of Pre-procedural Concentrations of Direct Oral Anticoagulants a prospective multicenter study published at the European Heart Journal. We all know that one of the major issue with a direct oral anticoagulants is that these patients frequently undergo elective invasive procedures and in this setting the management can be very challenging specifically as it relates to when the direct oral anticoagulants should and can be safely stopped.

In clinical practice, there is wide variability in the timing by which providers inform patients to stop these new oral anticoagulants prior to invasive procedure. In this prospective multicenter study, 422 patients were evaluated with preprocedural DOAC concentrations and routine hemostasis assays performed to determine those patients who achieved a minimal preprocedural concentration based on the timing of their discontinuation of the drug. They ranged the duration of discontinuation of the oral anticoagulant from 1 to 218 hours. They noted after a 49 to 72 hour discontinuation period, 95% of the concentration of the direct oral anticoagulants in patients had levels that were significantly low suggesting safety and proceeding with any sort of invasive procedure.

Thus a 72 hour discontinuation period predicted sufficiently low concentrations of DOACs with 91% specificity. In multivariable analyses, duration of the DOAC discontinuation with creatinine clearances and antiarrhythmics were independent predictors of a minimal preprocedural DOAC concentration, namely better renal function, longer duration of DOAC discontinuation and interestingly the use of antiarrhythmic drugs were all associated with lower DOAC concentrations. The conclusion from this article was a last DOAC intake of three days before a procedure resulted in a minimal preprocedural anticoagulant effect for almost all patients considered.

The exception would be in moderate renal impairment especially in dabigatran treated patients and antiarrhythmics in anti-Xa-treated patients could result in the need for longer DOAC interruption. Thus, the key things here to note are that antiarrhythmics can result in the need for longer DOAC interruption to achieve minimal blood concentrations and that similarly moderate renal impairment especially in dabigatran treated patients may result in the same. Another outcome other studies suggested a lack of association between routine assays such as routine hemostasis assays and DOAC concentrations suggesting that in situations where testing is believed to be needed routine assays should not replace DOAC concentration measurement in decision-making regarding whether or not the DOAC has sufficiently gone down in concentration to safely proceed.

Along these lines, the final article we will review within the realm of anticoagulation is by Brendel et al entitled the Anticoagulant Effect of Heparin during Radiofrequency Ablation in Patients Taking Apixaban or Rivaroxaban published in the Journal of Interventional Cardiac Electrophysiology this past month. One concern regarding the use of the direct oral anticoagulants is the fact that during procedures where heparin is needed, knowledge of how much heparin to give is unclear. This is both in the setting of understanding what the synergistic effect of the simultaneous and continued use of apixaban or rivaroxaban or other direct oral anticoagulants in combination with heparin might be and also what the effect on actual activated coagulation time might be.

As it is felt that be ACT may not necessarily reflect the true anticoagulant activity of drugs. Thus in a prospective study, Brendel et al studied about 90 patients with atrial fibrillation undergoing radiofrequency ablation procedures. During radiofrequency ablation, unfractionated heparin was given to maintain ACT of 250 to 300 ms with blood samples taken before and up 360 minutes after heparin administration. They demonstrated that heparin displayed a lower anti-Xa activity in rivaroxaban treated patients compared to apixaban treated patients.

In contrast, D-dimer and prothrombin fragment F1+2 plasma levels indicated a higher activation of the coagulation cascade in apixaban/heparin combinations than in rivaroxaban/heparin combinations. While there was clear differences in the level of anticoagulant effect, depending on which DOAC was combined with heparin, they had no clinical impact in terms of bleeding or thromboembolic complications from the procedure. This article is significant in that it highlights that there are clear and different biochemical responses based on which DOAC is used in combination with heparin during radiofrequency ablation.

While in the small study, there was no clear effect on clinical impact, precautions should still be considered when monitoring periprocedural hemostasis in DOAC patients to avoid mismanagement especially considering the variability that might occur between DOACs themselves and not just between DOACs and warfarin.

Changing paces to risk stratification and management within atrial fibrillation. We’ll review the article by Labombarda et al entitled Increasing Prevalence of Atrial Fibrillation and Permanent Atrial Arrhythmias in Congenital Heart Disease published in this past month's issue of the Journal the American College of Cardiology. In this article, they sought to assess the types and patterns of atrial arrhythmias, associate factors and age-related trends in a multicenter cohort of patients with adult congenital heart disease. What they demonstrated is that by far the most common presenting arrhythmia was intraatrial reentrant tachycardia in almost two-thirds of patients with the remaining including atrial fibrillation in up to 30% of patients and focal atrial tachycardias in up to 10% of patients.

The association of intraatrial reentrant tachycardia with congenital heart disease was stronger with higher complexities of congenital heart disease. With those with more complex defects having a higher frequency of IART than those with simple effects. Furthermore, as is commonly seen in the general population, the frequency of atrial fibrillation increased with age to eventually suppress IART as the most common arrhythmia in those greater than equal to 50 years of age. The predominant arrhythmia pattern was paroxysmal in almost two-thirds of patients though almost 30% were persistent.

Furthermore, the frequency of permanent atrial arrhythmias increased with age. While it is commonly seen that patients with congenital heart disease were living longer and as a result it is expected that the frequency of arrhythmias in this population will likely increase. The interesting outcome from the study is the high frequency of intraatrial reentrant tachycardia as the presenting atrial arrhythmia in patients with congenital heart disease and also with the predominantly paroxysmal pattern. The finding also that atrial fibrillation increases in prevalence highlights the importance of closely monitoring these patients in order to assess for anticoagulation needs and options for treatment.

Changing gears to cellular electrophysiology. We focus on an article by Qiao et al entitled transient Notch activation induces long-term gene expression changes leading to sick sinus syndrome in mice published in this past month's issue of Circulation Research. Notch signaling programs cardiac conduction during development and in the adult ventricle. It is noted that injury can induce notch reactivation resulting in global transcriptional and epigenetic changes. Thus, the group sought to determine whether notch reactivation may alter atrial ion channel gene expression arrhythmia inducibility.

They demonstrated that notch signaling regulates transcription factor in ion channel gene expression in adult atrial myocardium. With reactivation inducing electrical changes resulting in sinus bradycardia, sinus pauses and a susceptibility atrial arrhythmias, altogether contributing to a phenotype resembling sick sinus syndrome. The importance of these findings lies in the mechanism underlying sick sinus syndrome.

While we search for genetic clues for why patients might develop atrial fibrillation or sick sinus syndrome or sinus bradycardia as they age, the importance of activation of typically quiet signaling patterns in the adult myocardium and their role in arrhythmogenesis is important because it might highlight novel targets for treatment. Understanding how the arrhythmogenic substrate develops and the mechanisms underlying it, may allow for a better understanding of why in certain patients certain drugs may be effective or not or certain invasive therapies may be effective or not.

Next with the realm of electrocardiography, we’ll review the article by Christophersen et al entitled 15 Genetic Loci Associated with Electrocardiographic P-wave published in Circulation Genetics this past month. Similar to the previous article by Dr. Qiao et al, the importance of the article by Christophersen et al lies in the identification of a number of genetic underpinnings for what forms the final electrocardiographic P-wave that is seen.

Six novel genetic loci associated with P-wave duration and six novel loci associated with P-wave terminal force were identified by the group. Both in the case of the transient Notch activation findings as well as in the findings related to a specific genetic loci associated with electrocardiographic P-wave abnormalities might highlight potential genetic targets either with existing drugs not traditionally used for atrial electrophysiology or potentially future drug targets.

Changing gears yet again, we’ll move on to their own sudden death cardiac arrest and specifically to an article published by Fallavollita et al entitled the denervated myocardium is preferentially associate with sudden cardiac arrest in ischemic cardiomyopathy a pilot competing risks analysis of cost specific mortality. Previous studies identify multiple factors associated with total cardiac mortality but we all recognize the ejection fraction has limited value. Thus within this article published in Circulation: Cardiovascular Imaging, the group decided to do a competing risks analysis the National Institutes of Health sponsored prediction of arrhythmic events with positron emission tomography trial.

They demonstrated that sudden cardiac arrest was correlated with greater volumes of denervate myocardium based on defects on positron emission tomography using a norepinephrine analog carbon 11 hydroxy ephedrine. However, they also demonstrated that other factors such as lack of angiotensin inhibition therapy, elevated BNP and large left particular end-diastolic volume were further associated with sudden cardiac arrest.

The importance of potential modifying factors to better attribute cardiac arrest risk and thus the need for defibrillator or other therapies in patients with myopathy needs to continue to be highlighted especially in light of recently published Danish and other studies suggesting that the mortality benefit conferred by ICD is an ischemic and nonischemic populations may not be equivalent in newer studies. The fact that further risk stratification opportunities can exist underlying the pathophysiologic basis for why these patients develop ventricular arrhythmias is critical. While recognized for a few decades now that myocardial denervation may be associated with sudden cardiac arrest risk, this study highlights the continued need for further study to help further clarify these populations.

Moving onto the realm of genetic channelopathies, we review the article by Anderson et al entitled Lidocaine Attenuation Testing: An in vivo Investigation of Putative LQT3-Associated Variants in the SCN5A-encoded sodium channel published in this past month's issue of Heart Rhythm. Long QT syndrome type 3 represents one of the more difficult types of long QT syndrome to adequately diagnose both by genetic testing as well as through traditional means. Approximate 2% of healthy individuals can have rare variance of uncertain significance in the SCN5A channel and thus distinguishing true LQT3 causative mutations for background genetic noise can be quite difficult in this population.

Anderson et al decided to assess the utility of lidocaine attenuation testing in evaluating patients with possible LQT3. They gave a loading dose of 1 mg per kg of intravenous lidocaine followed by continuous infusions of 50 micrograms for 20 minutes. If the corrected QT interval shortened by at least 30 ms, the LAT was defined as positive. They demonstrated that use of this test can help distinguish true LQT3 causative mutations from otherwise noncontributory variance of uncertain significance. Thus in this era of increasing genetic testing where one might identify a variant of uncertain significance in either a family member affected with sudden cardiac arrest or in a patient being evaluated for any sort of uncertain significant variant, the use of lidocaine testing in those variance as they apply to LQT type 3 may offer significant clinical use.

Next we will review the article by Ishibashi et al published in this past month's edition of Heart entitled Arrhythmia Risk and Beta Blocker Therapy in Pregnant Woman with Long QT Syndrome. One of the biggest concerns of patients with long QT syndrome especially woman is pregnancy. The fact is because of the different hormonal states, it is possible that pregnancy may alter arrhythmic risk and the safety of beta blocker therapy given both the potential fetal effects as well as the continued efficacy at the level those seen previously.

Thus Ishibashi et al reviewed 136 pregnancies across 76 long QT pregnant patients. They retrospectively analyzed clinical and electrophysiological characteristics in pregnancy outcomes in both the presence and absence of beta blocker therapy. All of the beta blocker group had prior events while the majority of the nonbeta blocker group had not been diagnosed with pregnancy. Pregnancy was noted to increase heart rate in those not treated with beta blockers, but interestingly, between the two groups there was no significant difference over the course of pregnancy in QT intervals.

In the beta blocker group, only two events occurred and these were relegated to the postpartum period. However, 12 events occurred in the nonbeta blocker group either during pregnancy and half or in the postpartum period and the remaining half. There was no difference in this frequency of spontaneous abortion between the two groups, and furthermore, fetal growth rates and proportion of infants with congenital malformation were similar between the two groups. However, premature delivery and low birth weight infants were more common in those taking beta blockers.

Given the high risk of events and the relative safety of beta blocker therapy in this population of patients with long QT who become pregnant, it was felt that the use of early diagnosis and beta blocker therapy could be critical both the during pregnancy and during the postpartum period. It was also felt the beta blocker therapy may be tolerated for babies in long QT pregnant patients. This highlights that the continued use of beta blockers throughout the pregnancy and consideration of the introduction of beta blockers in those not already on them during pregnancy may be an important consideration.

Finally within the realm of genetic channelopathies, we focus on the article by Roberts et al entitled Loss of Function in KCNE2 Variants: True Monogenic Culprits of Long QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation published in this past month's issue of Circulation: Arrhythmia Electrophysiology. As we identify more and more genes the baby is associated with long QT syndrome, the understanding of the clinical phenotype associated with that syndrome requires better study. In this particular study, Roberts et al reviewed the role of long QT syndrome type 6 stemming from mutations in the KCNE2 encoded voltage gated channel beta subunits.

They reviewed mutations identified during arrhythmia evaluation from either inherited arrhythmia clinics or the Rochester long QT syndrome registry. They demonstrated that the high allelic frequencies of LQT6 mutations in the Exome aggregation consortium database and the absence of previous documentation of genotype phenotype segregation suggest many KCNE2 variants and potentially all were actually erroneously designated as LQT as causative mutations. Instead, it was felt the KCNE2 variants may actually confer proarrhythmic susceptibility when provoked by additional environmental and/or acquired or genetic factors.

What they are saying is that identifying the KCNE2 variants as the principal culprits may be over calling the role of the KCNE2 variants and instead it might be a combination of effects such as two hit affect the requires further provocation by either outside or additional genetic factors. Furthermore, complex genetic studies were likely needed to better understand how variants and genes that may not have been previously designated as disease causing play a role in the actual disease process, whether as potentiating other factors that might exist that might also otherwise be relatively benign or as unique singular hits that might by themselves result in the clinical phenotype.

Next moving onto the realm of ventricular arrhythmias, we first focus on an article published in this past month's issue of the American Journal of Physiology, Heart and Circulatory Physiology by Howard Quijano et al entitled Spinal Cord Stimulation Reduces Ventricular Arrhythmias during Acute Ischemia by Attenuation of Regional Myocardial Excitability. In this article, they demonstrated in a porcine model ventricular ischemia that spinal cord stimulation decrease sympathetic nerve activation regionally in ischemic myocardium while having no effect on normal myocardium. They demonstrated that the antiarrhythmic effects conferred by spinal cord stimulation were likely secondary to attenuation of some sympathoexcitation locally in ischemic myocardium rather than changes in the global myocardial electrophysiology.

This is important because it highlights the mechanisms by which spinal cord stimulation may confer in antiarrhythmic benefits in both animal and human models. As we search for novel interventions that can be used for the treatment of ventricular arrhythmias, understanding the underlying pathophysiologic mechanisms by which they work is critical. The understanding that the use of spinal cord stimulation is primarily conferred in a regional way primarily in terms of its effect on an ischemic myocardium, further study is also needed in terms of how the effect is seen in nonischemic myopathies where there may be more patchy scar in the same role of denervation, nerve sprouting and hyper innervation may play different roles.

In the next article we choose to focus on is by Berte et al entitled a New Cryo-energy for Ventricular Tachycardia Ablation a Proof of Concept Study published in this past month's edition of Europace. One of the key problems in ventricular tachycardia ablation is the lack of transmural lesion formation. This is an important determinant of arrhythmia recurrence. Thus the group decided to do a proof of concept study to evaluate the safety and efficacy of a new and more powerful cryoablation system for ventricular ablation. They demonstrated that a novel cryoablation system to create large transmural ventricular lesions, whether it delivered by endocardial or epicardial approach. It was felt that this technology can hold potential for both surgical and catheter-based VT ablation in humans.

While primarily studied in sheep models, it nevertheless highlights the importance of novel therapies that might better achieve through and through lesions. There are many different novel products being developed for the hope of achieving transmural lesions partly to target the myocardial circuits and partly to ensure achievement of through and through lesions without leaving residual potential substrate, because of only partial thickness lesions. These include things like needle ablation catheters, the safety of which still has to be fully evaluated, bipolar ablation or the use of technology such as novel cryo-energy approaches. Comparative efficacy of these different approaches however will be critical to determining which one is safest and best in any given clinical situation.

Next we’ll review the article by Venlet et al published this past month's issue of Circulation Arrhythmia and Electrophysiology entitled Unipolar Endocardial Voltage Mapping in the Right Ventricle: Optimal Cutoff Values Correcting for Computed Tomography-derived Epicardial Fat Thickness and their clinical value for substrate delineation. The work by [inaudible 00:53:37] and others highlighted the importance of using unipolar and bipolar voltage cutoffs and helping delineate areas of both endocardial as well as potentially more distal such as epicardial scar during endocardial mapping. It is felt the low endocardial unipolar voltage during bipolar voltage mapping endocardially may indicate epicardial scar.

However, the primary issues, the additional presence of epicardial fat both in the right ventricle and left ventricle and how this epicardial fat may effect normal unipolar voltage cutoffs. Thus, Venlet et al decided to review using computed tomography data the effective epicardial fat on unipolar voltage cutoffs. They demonstrated that endocardial unipolar voltage cutoff of 3.9 millivolts was more accurate than previously reported cutoff values for right ventricular epicardial scar during endocardial mapping.

It was further demonstrated that while epicardial abnormal electrograms may be associated with transmural scar when associated with low endocardial bipolar voltage, the additional use of endocardial unipolar voltage and normal bipolar voltage sites can improve the diagnostic accuracy resulting in identification of all epicardial abnormal electrograms at sites with less than 1 mm of fat. Thus, the unipolar voltage not only assisted in evaluating whether epicardial scar was present, but also in further clarifying epicardial abnormal electrograms in terms of whether or not they truly represented potential transmural scar.

Finally, within the realm of electrogram mapping of ventricular arrhythmias, we focus on the article by Magtibay et al entitled Physiological Assessment of Ventricular Myocardial Voltage using Omnipolar Electrograms published in the Journal of the American Heart Association this past month. Bipolar electrograms are traditionally used to characterize myocardial health. However, dependence on these electrograms may reduce the reliability of voltage assessment along different planes of arrhythmic myocardial substrates.

Thus, newer catheters rely on evolving tools that might allow for different approaches to bipolar mapping. Using omnipolar electrograms, Magtibay et al studied in healthy rabbits, pigs and diseased humans under paced conditions the role of two bipolar electrode orientations both horizontal and vertical. Voltage maps were created for both bipoles and omnipoles, and they noted that electric orientation affected the bipolar voltage map with an average absolute difference between horizontal and vertical of up to 0.25 millivolts in humans. Thus, they demonstrated omnipoles can provide physiologically relevant and consistent voltages along the maximal bipolar direction and provide an advantage over traditionally obtained bipolar electrograms.

When we consider the use of evolving techniques to get an understanding of myocardial health whether for the purpose of cardiac mapping and ablation or even for the purpose of other intervention such as cardiac biopsy, understanding what the voltage abnormalities perceived actually are is critical to understanding what substrate is actually being targeted. However, given directionality issues in terms of assessment of voltage as well as relative orientation of the catheter in understanding the relevance of received voltage, use of novel signal processing and electro designs are important to consider in the light of their effects on substrate mapping compared to traditional techniques.

Changing gears yet again, but nevertheless related to cardiac mapping and ventricular arrhythmias, we focus on article by Yalagudri et al published in this past month's issue of the Journal of Cardiovascular Electrophysiology entitled A Tailored Approach for Management of Ventricular Tachycardia in Cardiac Sarcoidosis. While in a small number of patients, nearly 14 patients, they attempt to develop a methodology for approaching patients with cardiac sarcoidosis for management of their ventricular arrhythmias. Patients with either cardiac myocarditis or cardiac sarcoidosis represent a particularly difficult cohort to treat.

Prior work by Dr. Roderick Tung and others has demonstrated the high-frequency of perceived inflammatory abnormalities based on cardiac FDG PET scanning amongst patients with ventricular arrhythmias. Whether this reflects cardiac sarcoidosis or other hypermetabolic activity is unclear. However, how to take into account the FDG PET abnormalities when deciding whether or not to take a patient for ablation or how to best treat them in light of their primary disease process is critical.

In this study, the group tried to tailor therapy for ventricular tachycardia and cardiac sarcoidosis according to the phase of disease results. Namely based on the degree of inflammation noted on the FDG PET scan. They noted that via their named clinical protocol, that this tailored therapy could result in good clinical outcome and avoid unnecessary immunosuppression in some patients. Whether or not the use of this tailored therapy approach may apply in larger populations remains to be seen.

Finally within the realm of other EP concepts that might apply broadly across the electrophysiology landscape, we focus on two articles. The first is by Kudryashova et al entitled Virtual Cardiac Monolayers for Electrical Wave Propagation in Nature Scientific Reports this past month. It is the complex structure of cardiac tissue that is considered to be one the main determinants of whether a substrate becomes arrhythmogenic or not. Multiple mathematical and computational models have been developed in order to recapitulate this complex cardiac structure. However, there been varying degrees of limitations in these approaches.

Using a joint in silico-in vitro approach, the group carefully characterized the morphology of cardiac tissue and cultures of neonatal rat ventricular cells and then proposed mathematical models to result in tissue morphology that could be recapitulated for virtual studies of cardiac electrophysiology mainly in order to study wave propagation. They demonstrated in their virtual cardiac monolayers, that the simulated waves had the same anisotropy ratios and wave form complexity as those in in vitro experimental models.

Thus, they demonstrated that they could reproduce both the morphological and physiological properties of cardiac tissue in a virtual landscape. These findings are critical to improving the ability to better study the effects of different antiarrhythmic drugs or interventional techniques on overall cardiac electrophysiology. The difficulty in existing techniques using traditional in vitro cultures is the fact that they’re costly and requires sacrifice of animals that adds to the additional cost of routine studies. The ability to recapitulate actual hearts within a virtual landscape to mimic the cardiac electrophysiology and then study it in a more controlled setting that can be reproducible based on the availability of appropriate computing power is important in terms of future studies within the realm of our field.

The final article we will review is by Das and Dutta published in Physical Review E this past month entitled Controlling Three-Dimensional Vortices using Multiple and Moving External Fields. One of the key studies over the course of the last several years has been that of the role of the spiral and scroll waves in not just atrial fibrillation but ventricular fibrillation and other arrhythmias. It is well recognized that the spiral or scroll waves depending on whether one thinks in a two dimensional or three dimensional substrate may have significant contribution to arrhythmogenesis. Whether targeting the spiral or scroll waves actually eliminates arrhythmias remains to be fully elucidated. However, it also remains to be elucidated exactly how one should control the spiral or scroll waves.

The review by Das and Dutta demonstrated that in fact the spiral or scroll waves could actually be physically moved around and controlled using moving external electric fields and thermal gradients. They show that the scroll rings can be made to trace cyclic trajectories on a rotating electric field or that application of thermal gradients in addition to electric field could deflect the motion and change the nature of a trajectory of a spiral or scroll wave. These findings are important in that they might represent non-ablative techniques that can eventually be used to control spiral or scroll waves in cardiac media, and thus result in either their alteration or termination without the need for additional cardiac injury.

One the biggest problems with additional cardiac ablation in cases such as atrial fibrillation is the fact that they often lead to additional regions of scarring that might lead towards further organized atrial arrhythmias. However, the ability to potentially terminate critical sites responsible for arrhythmogenesis in real time without the need for ablation may represent novel interventions or devices in the future.

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

Dr. Paul Wang : Thanks Suraj. You did a terrific job surveying all journals for the latest articles on topics of interest in our field. There is 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 could be downloaded from the Circulation: Arrhythmia and Electrophysiology website. We hope that 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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