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Circulation: Arrhythmia and Electrophysiology On the Beat


Jan 12, 2021

Paul J. 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.

In our first paper, Zak Loring and associates examined 3,139 patients undergoing atrial fibrillation (AF) ablation, between 2016 and 2018 in the Get With The Guidelines-Atrial Fibrillation Registry from 24 US centers. Patients undergoing AF ablation were predominantly male (63.9%) and Caucasian (93.2%) with a median age of 65. Hypertension was the most common comorbidity (67.6%), and persistent atrial fibrillation patients had more comorbidities than paroxysmal AF patients. Drug refractory, paroxysmal AF was most common ablation indication (class I, 53.6%) followed by drug refractory, persistent AF (class I, 41.8%). Radio-frequency, RF ablation, with contact force sensing was the most common ablation modality (70.5%) and 23.7% of patients underwent cryoballoon ablation. Pulmonary vein isolation was performed in 94.6% of de novo ablations. The most common adjunctive lesion included left atrial roof or posterior/inferior lines and cavotricuspid isthmus ablation. Complications were uncommon (5.1%) and were life-threatening in 0.7% of cases.

In our next paper, Brian Howard and associates hypothesize that pulse field ablation (PFA) would reduce pulmonary vein stenosis risk and collateral injury compared to irrigated radiofrequency ablation (IRF). IRF and PFA deliveries were randomized in eight dogs with two superior pulmonary veins (PVs), ablated with using one technology and two inferior PVs ablated with the other technology. IRF energy (25-30 watts) or PFA with delivered (16 pulse trains) at each PV in a proximal and in a distal site. Contrast computed tomography (CT scans) were collected at 0, 2, 4 and 8, and 12 week, including termination time points to monitor PV cross-sectional area at each PV ablation site. Maximum average change in normalized cross-sectional area at 4 weeks was 46.1%±45.1% post IRF compared to -5.5±20.5% for PFA (P≤ to 0.001). Necropsy showed expansive PFA lesions without stenosis in the proximal PV sites compared to more confined and often incomplete lesions after IRF. At the distal PV sites only IRF ablations were grossly identified based on focal fibrosis. Mild pulmonary chronic parenchymal hemorrhage was noted in three left superior pulmonary vein lobes after IRF. Damage to vagus nerves, as well as evidence of esophagus dilation, occurred at sites associated with IRF. In contrast, no lung, vagal nerve, or esophageal injury was observed at PFA sites.

In our next paper, Mohamed Diab and associates aimed to assess the safety of ablation for atrial fibrillation (AF) with trans-esophageal (TEE) screening on intracardiac echocardiography (ICE) imaging of the appendage in direct oral anticoagulant (DOAC) compliant patients. They studied 900 patients with a medium CHA2DS2-VASc score of two. Interquartile range one to three. All consecutive patients presenting with AF or atrial flutter on DOAC were included. All were on DOACs (333 Rivaroxaban, 285 Dabigatran, 281 Apixaban and one Edoxaban). Thromboembolic complications occurred in four patients (0.3%), two ischemic strokes, one transient ischemic attack without residual deficit and one splenic infarct, all with no further complications. Bleeding complications incurred in 5 patients (0.4%), including 2 pericardial effusions (1 intraoperative, 1 after 30 days, both drained), and 3 groin hematomas (1 due to needing heparin for venous thrombosis, none requiring intervention). No patients required emergent surgeries.

In our next paper, Alexios Hadjis and associates aim to explore the role of complete diastolic pathway activation mapping on ventricular tachycardia (VT) recurrence. They studied 85 consecutive patients who underwent VT ablation using and guided by high-density mapping. During activation mapping, the presence of electrical activity in all segments of diastole defined the evidence of having had recorded the whole diastolic interval. Patients were categorized as having recorded the full diastolic pathway, partial diastolic pathway or no diastolic pathway map performed. Recurrences of VT were defined as appropriate IC therapies or on the basis of EC documented arrhythmia. Complete recording of the diastolic pathway was achieved in 36 of 85 (42.4%). Partial recording of the diastolic pathway of clinical VT was achieved in 24 of 85 (28.2%). No recording of the diastolic pathway of clinical VT was feasible in 25 of 85 patients (29.4%). At a mean of 12.8 months, freedom from VT recurrences was 67% in the overall cohort. At a mean of 12.8 months, freedom from VT recurrence was 88% in patients who had full diastolic activity recorded, 50% of partial diastolic activity recorded and 55% in those who underwent substrate modification (P=0.02). The authors concluded that mapping of the entire diastolic pathway was associated with a higher freedom from VT occurrence compared to partial diastolic pathway recording and substrate modification. The use of multielectrode mapping catheters in recording diastolic activity may help predict those VTs employing intramural circuits and further optimize ablation strategies.

In our next paper, Hui-Nam Pak and associates investigated whether electrical posterior box isolation (POBI) may improve rhythm outcome of catheter ablation in patients in whom persistent atrial fibrillation changes to paroxysmal atrial fibrillation after antiarrythmic drug medication and cardioversion. They prospectively randomized 114 patients, 75% male, 59.8 years old to circumferential pulmonary vein ablation (CPVI) alone (n=57) and an additional POBI group (n=57). Primary endpoint was AF recurrence after a single procedure, and secondary endpoints were recurrence pattern, cardioversion rate and response to antiarrhythmic drugs (AAD). After a mean follow-up of 23.8 months, the clinical recurrence rate did not significantly differ between the CPVI alone and additional POBI group (31.6% versus 28.1%; P=0.682). The recurrence rate as atrial tachycardias, 5.3% versus 12.3% (P=0.14) and cardioversion rates, 5.3% versus 10.5% (P=0.25) were not significantly different between the CPVI and POBI group. At the final follow-up, sinus rhythm was maintained without antiarryhthmic drug in 52.6% of CPVI group and 59.6% of the POBI group (P=0.45). No significant difference was found in major complications between the two groups, 5.3% versus 1.8% (P=0.618). But the total ablation time was significantly longer in the POBI group (4187 seconds versus 5337 seconds; P<0.001).

In our next paper, Dan Musat and associates assess the incidents and predictors of very late occurrence (VLR) when atrial fibrillation occurs 12 months or more after ablation in patients who underwent cryoballoon pulmonary vein isolation alone (PVI), had an ILR and were confirmed AF free (atrial fibrillation free) for at least one year. They included 188 patients, mean 66 years, 62% male and 54% paroxysmal atrial fibrillation with CHA2DS2-VASc 2.6. After one year post PVI, 49% of patients remained AF free. During subsequent follow-up, 32% had very late recurrence of atrial fibrillation. The only independent risk factor for very late recurrence was an elevated CHA2DS2-VASc score (hazard ratio 1.317; P=0.06). Patients with CHA2DS2-VASc score greater than four represented a quarter of the population and were at highest risk.

In our next paper, Daniele Pastori, Danilo Menichelli, Gregory Yip and associates in the ATHERO-AF Study Group investigate the association between family history of atrial fibrillation (AF) in cardiovascular events (CVEs), major adverse events (MACE), and cardiovascular mortality. They conducted a multicenter prospective observational cohort study, including 1,722 nonvalvular AF patients from February 2008 to August 2019 in Italy. Family history of AF was defined as the presence of AF in a first-degree relative: mother, father, sibling, or children. Primary outcome was a composite of CVEs, including fatal/non-fatal ischemic stroke and myocardial infarction and cardiovascular death. Second, they analyze the association with MACE. Mean age 74.6 years, 44% women. Family history of AF was detected in 368 or 21.4% of patients, and 3.5% had two or more relatives affected by AF. Age of AF onset progressively decreased from patients without family history of AF compared to those with single and multiple first-degree affected relatives (P<0.001). During a mean follow-up of 23.7 months or 4,606 patient years, 145 CVEs, that's 3.15% per year, 98 MACE (2.13% per year) and 57 cardiovascular deaths (0.9% per year) occurred. After adjustment for cardiovascular risk factors, family history of AF was associated with a higher risk of CVEs (hazard ratio. 1.524: P=0.039), MACE (hazard ratio 1.917; P=0.006) and cardiovascular mortality (hazard ratio 2.008; P=0.036). Subgroup analysis showed that this association was modified by age, sex, and prior ischemic heart disease. The authors concluded that in a cohort of elderly patients with high atherosclerotic burden, family history of AF was evident in more than 20% of patients and was associated with an increased risk of CVEs and mortality.

In our next paper, Louise Reilly and associates created the first patient-inspired KCNJ2 transgenic mouse and studied the effects of this mutation on cardiac function, IK1 and calcium handling to determine the underlying cellular arrhythmic pathogenesis. A cardiac specific KCNJ2-R67Q mouse was generated and bred for heterozygosity. That's R67Q+/-. Echocardiography was performed at rest and under anesthesia. In vivo electrocardiogram, ECG recording, and whole heart optical mapping of intact hearts was performed before and after adrenergic stimulation in wild-type littermates and R67Q+/- mice. In IK1 measurements and action potential AP characterization, intracellular calcium imaging from isolated ventricular myocytes at baseline and after adrenergic stimulations were performed in wild-type and R67Q+/- mice. R67Q+/- mice (n=17) showed normal cardiac function structure baseline electrical activity compared to wild-type (n=10). Following epinephrine and caffeine, only the R67Q+/- mice had bidirectional ventricular tachycardia, frequent ventricular ectopy and/or bigeminy and optical mapping demonstrated high prevalence of spontaneous and sustained ventricular arrhythmia. Both R67Q+/- (n=8) and wild-type myocytes (n=9) demonstrated typical n-shaped IK1 IV relationship. However, following isoproterenol, max outward IK1 increased by about 20% in wild-type, but decreased by 24% in R67Q+/- (P<0.01). R67Q+/- myocytes (n=5) demonstrated prolonged action potential at 90% repolarization and after 10 nmol/L isoproterenol compared to wild-type (n=7; P<0.05). Calcium transient amplitude, 50% decay and SR calcium content were not different between wild-type (n=17) and R67Q+/- (n=16) myocytes. R67Q+/- myocytes (n=10) under adrenergic stimulation showed frequent spontaneous development early after depolarization that occurred at phase 3 of action potential repolarization. The authors concluded that KCNJ2 mutation R67Q+/- causes adrenergic-dependent loss of IK1 during terminal repolarization and vulnerability to phase 3 early after depolarization.

In our next paper, Michael Liu and associates use computational modeling to simulate 1D, 2D and 3D tissue under a variety of conditions to test the ability of genetically engineered non-arrhythmogenic stabilizer cells to suppress triggered activity due to delayed or early afterdepolarization. Due to source-sink relationships in cardiac tissue, a minority (20 to 50%) of randomly distributed stabilizer cells engineered to be non-arrhythmogenic can suppress the ability of arrhythmogenic cells to generate delayed or early afterdepolarization related arrhythmias. Stabilizer cell gene therapy strategy can be designed to correct a specific arrhythmogenic mutation such as in CPVT mice studies, or more generally to suppress delayed or early afterdepolarization from any cause by overexpressing the inward rectifier potassium, Kir2.1 in stabilizer cells. The authors propose this as a promising antiarrhythmic strategy.

In our next paper Wei Hu, Dongchen Zhou, and associates used high resolution mapping to study the determinants of flutter wave morphology on surface ECG in patients with peri-mitral atrial flutters (PMAFLs) that develops post atrial fibrillation (AF) ablation or post-cardiac surgery. The mean tachycardia cycle length (TCL) was 264 milliseconds with right atrial RA activation time, 155 milliseconds, 60.8% of the tachycardia cycle length, and the flutter wave duration, 107 milliseconds or 41.6% of the tachycardia cycle length. The overlap between the RA activation time and the flutter wave duration was 102 milliseconds, which takes 68.5% of the RA activation time and 95.7% of the flutter wave duration respectively. The authors found that the ECG flutter wave morphology of PMAFLs is mainly dependent on RA activation pattern. Quantitative analysis also showed that during the flutter wave duration, more percentage of the endocardial area was activated in the RA than in the LA (70.0% versus 45.2%: P<0.001). The RA anterior wall rightward activation corresponded to the positive component in V1 in both flutter patterns, and the RA downward activation corresponded to the positive component in the counterclockwise group or the upward activation corresponded to the negative component in the clockwise group in the inferior leads. The passive RA activation patterns varied with spontaneous atrial scarring or previous linear ablation.

In our next paper, Peter van Dam, Emanuela Locati and associates sought to localize electric activity in Brugada syndrome using novel CINeECG method, which creates an inverse electrocardiogram (IECG) from standard 12-lead electrocardiogram (ECG). They studied 15 spontaneous Brugada syndrome patients and 18 ajmaline-induced Brugada syndrome patients at baseline and after ajmaline in whom epicardial potential duration maps (PDM) were available. 17 type-3 Brugada syndrome patients not showing type-1 Brugada syndrome after ajmaline, that is ajmaline-negative, in 47 normal subjects. In 18 right bundle branch block (RBBB) patients in spontaneous or ajmaline-induced Brugada syndrome patients CineECG localized the terminal forces in the RVOT congruent with arrhythmogenic substrate location detected by epicardial potential duration maps (PDM). The RVOT location was never observed in normal right bundle branch block or ajmaline-negative patients. In most ajmaline-induced Brugada syndrome patients (78%), the RVOT location with already evident at baseline. The CineECG classified all normal subjects and ajmaline-negative patients at baseline as normal or undetermined and all right bundle branch block patients as RBBB while all spontaneous ajmaline-induced Brugada syndrome patients as Brugada. Compared to a standard 12-lead ECG, CineECG at baseline had 100% positive predictive value and an 81% negative predictive value in predicting ajmaline test results.

In our next paper Zhen Wang and associates examined the circadian cardiac electrophysiology properties in relationship to age. The authors examined adult male mice hearts, 12 to 18 weeks, that were isolated during light, ZT4 and ZT9 and dark, ZT14 and ZT21 from adult male mice and aged (18 - 20 months) male hearts. They were isolated at ZT4 and ZT14. All hearts were Langendorff-perfused for optical mapping with voltage and calcium channel sensitive dyes (n=4-7 per group). Cardiac gene and protein expression was assessed using real time PCR (four to six per group) and Western blot, three to four per group. Adult hearts showed circadian differences in actual potential duration (APD) and calcium transient duration with the shortest values at ZT14. The pacing frequency at which calcium T alternans emerge was faster, and average calcium T alternans magnitude was significantly reduced at ZT14 compared to other time points. There was a trend for decreased spontaneous PVCs, premature ventricular contractions, and pacing-induced ventricular arrhythmias at ZT14, and the hearts at ZT14 had diminished responses to isoproterenol compared to ZT4 (ZT4: 49.5% versus ZT14: 22.7% decrease in action potential duration, P<0.01). In contrast, aged hearts exhibited no difference between ZT14 and ZT4 in nearly every parameter assessed except for action potential duration 80 (ZT4: 39.7 ms versus ZT14: 33.8 ms, P<0.01). Gene expression of KCNA5, including Kv1.5, was increased, whereas gene expression of ADRB1 adrenergic receptors was decreased at ZT14 versus ZT4 in adult hearts. No time-of-day changes in expression or phosphorylation of calcium handling proteins, SERCA2, ryanodine 2 and PLB, were found in ex vivo perfused adult isolated hearts.

In our next paper, Christopher Cheung and associates reported on the patients who underwent repeat ablation procedures for symptomatic atrial tachyarrhythmia with the objective of evaluating pulmonary vein (PV) reconnections in this CIRCA-DOSE study. This study was a multi-center randomized trial that demonstrated that pulmonary vein isolation (PVI) performed by second generation or contact force (CF-RF) resulted in comparable freedom from atrial tachyarrhythmia as measured by continuous cardiac monitoring using an implantable loop. Among the 346 patients randomized in the CIRCA-DOSE trial, 52 patients, or 15%, underwent a repeat ablation procedure. There were no significant differences in baseline characteristics between patients undergoing repeat ablation and the remaining cohort, apart from higher baseline atrial fibrillation (AF) burden, percent time in AF, and those who underwent a repeat procedure (10.1% versus 1.6%; P=0.002). At the repeat procedure, PV reconnection was noted in 4,752 or 90.4% of patients with no significant difference between the two groups (14 out of 16 or 97.5% after CF-RF and 17 out of 18 or 94.4% after CRYO 4, and 16 out of 18 or 88.9% after CRYO 2, P=0.64). The median number of reconnected PVs per patient was two after CF-RF and two after CRYO 2 and one after CRYO 4 (P=0.46). A total of 89 out of 201 PVs, that's 44.3%, were reconnected. This included 23 out of 52 or 44.2% right superior, 27 out of 52 (51.9%) right inferior, 17 out of 42 (40.5%) left superior and 15 out of 42 (35.7%) left inferior. One out of three or 33% right middle and six out of 10 or 60% of left common. There was no difference in the pattern of reconnection between the CF-RF and cryoballoon groups.

In our next paper, a research letter, Joshua Payne and associates examine how well low energy shock impedance is correlated with high energy shock impedance with subcutaneous implantable cardioverter defibrillator, S-ICD implantation. Consecutive patients received pair 10 and 65 joule shocks were studied. The 65 joule shock was delivered either during induced VF or synchronously during sinus rhythm. All 10 joule shocks were delivered synchronously in sinus rhythm. There were 28 patients in this study, including 24 who underwent new device implantation. Defibrillation threshold testing was performed in 21 or 75% of patients. All but one, 96%, were successfully defibrillated at 65 joules. There was a significantly higher impedance for 10 joule shocks compared to 65 joule shocks, 73.1 ohms versus 70.3 ohms respectively (P=0.023) with a mean difference of 2.8 ohms. The impedances for the two shock energies were highly correlated (R-squared=0.97; P<0.01). There were three outliers with very different impedances for the low and high energy shocks with no obvious distinguishing characteristic of this subset. The differences between impedance at 10 joules and 65 joules were similar in patients who underwent defibrillation threshold testing and those who only had shocks during sinus rhythm. Multivariate analysis, using covariates of age, gender, ethnicity, BMI (body mass index) and indication showed no significant predictors of the difference between low and high energy shock differences. Using a cutoff of 90 ohms to predict successful defibrillation threshold testing, only one patient (3.6%) exceeded this threshold at 10 joules or 92 ohms and was then less than 90 ohms at 65 joules, 88 ohms. There were no patients with an impedance less than 90 ohms at 10 joules or greater than 90 ohms at 65 joules.

In our next research letter, Paolo Compagnucci and associates conducted a single center retrospective observational study by enrolling patients in electrophysiologic (EP) procedures at a tertiary level referral center in Italy during the COVID-19 pandemic. They examined all consecutive patients who underwent EP procedures since March 9, 2020 when the novel health care measures were taken in the cardiology department due to the COVID-19 outbreak until April 26, 2020. These patients were compared to those undergoing EP procedures in the preceding six months. During the COVID emergency, only non deferrable procedures were performed giving priority to electrical storm, refractory device infections requiring lead or device extraction, pacemaker or defibrillator implantations and generator changes. During the COVID-19 emergency 79 EP procedures were performed. The most common interventions included generator changes, pacemaker implantation to (2 with leadless devices), defibrillator implantations, catheter ablations and device extractions. In the six months before the lockdown 592 EP procedures were performed, most commonly pacemaker implementations (three with leadless devices), generator change and catheter ablations for atrial fibrillation. Their findings suggest three key messages. One, overall there's a drastic reduction in the numbers of EP procedures due to postponement of non-urgent interventions. Two, EP laboratory model and extensively adopting personal protective equipment (PPE) and other preventative measures proved safe for healthcare professionals. And three, weekly rates of electrical storm catheter ablation significantly increased.

In our next research letter, Seigo Yamashita and associates examine the risk of coronary sinus ablation during mitral isthmus ablation. Out of 712 patients who underwent mitral isthmus (MI) linear ablation in their institution, epicardial ablation within the coronary sinus (CS) was performed in 446 or 62.6% because of incomplete block by endocardial ablation only. 126 of 446 (28.3%) patients had redo procedures due to AF/AT recurrence, and they were retrospectively included in this study. Age 55 years, persistent AFib in 117. The coronary sinus post procedure (CS post) diameter was 5.6 millimeters with a mean reduction in 11.1% compared to coronary sinus pre diameter (CS pre) 6.0 millimeters. Among 126 patients, 15 or 12% demonstrated coronary sinus (CS) stenosis located at three to four or four o'clock in the LAO view in 33%, 20% and 40% of patients respectively with a mean reduction of 61.0%, but all were asymptomatic. These three cases demonstrated severe stenosis with a 5 Fr CS mapping catheter impossible to cross. The severe stenosis was located at the level of three o'clock on the LAO in all. On multi-variable analysis adjusted for age, atrial fibrillation type, minimum CS diameter, and TactiCath use, narrower coronary sinus diameter was the only independent predictor of coronary sinus stenosis (odds ratio 0.07 or P<0.001). The CS pre diameter of less than 4.6 millimeters could predict the occurrence of CF stenosis when a sensitivity of 86.7% and a specificity of 91.8%.

In our next research letter, Min-Young Kim, Belinda Sandler and associates compare the anatomical distribution of ectopic-triggering ganglionated plexus (GP) to that of atrial ventricular dissociating GP in patients with atrial fibrillation. The highest probability of ectopic-triggering ganglionated plexus greater than 30% were in the roof mid anterior wall around all pulmonary vein ostia except for the right inferior pulmonary vein in the posterior wall, suggesting that they inadvertently ablated during conventional pulmonary vein isolation procedures for atrial fibrillation, possibly explaining why some patients remain symptom-free with reconnected pulmonary veins. On the other hand, the majority of atrial ventricular dissociating GP lie outside the pulmonary vein isolation target regions.

In our next special report, Arwa Younis, May Goldenberg and associates aim to evaluate the yield of MADIT-CRT response score to predict the long-term risks of clinical events and life-threatening ventricular arrhythmias by QRS morphology. Among patients with left bundle branch block, the rate of life-threatening ventricular tachyarrhythmias or death at three years was lowest (8%) among CRTD patients with a high response score and highest among ICD patients with a low response score (22%). Log rank P-value for the difference during follow-up, P<0.001. In contrast, among non left bundle branch block patients, there is a risk reversal wherein corresponding event rates were highest among CRTD patients with a high response score.

In our next special report, Alexandra Benz and associates prospectively collected data from asymptomatic atrial fibrillation, stroke evaluation, and pacemaker patients in the Atrial Fibrillation Reduction Atrial Pacing Trial, or ASSERT Trial found that implementation of inactive fixation atrial lead was not associated with a higher incidence of atrial fibrillation compared to implantation of a passive fixation atrial lead both early post implantation and over long-term followup.

In our next special report, Siddharth Trivadi and associates conducted a longitudinal follow-up study of speckle tracking strain echocardiography and assessment of myocardium mechanics in patients with idiopathic ventricular arrhythmia. They were able to demonstrate subtle abnormalities in myocardial mechanics and dispersion that persist for prolonged periods of time, despite successful abolishment of the inciting arrhythmia or the absence of overt cardiomyopathy or established arrhythmia-related cardiomyopathy. The study suggests that patients with idiopathic ventricular arrhythmias are not truly idiopathic and that subtle subclinical myocardial changes exist.

In a perspective piece, Pietro Enea Lazzerini and associates provide recommendations about electrocardiographic QTC monitoring along with this decisional guide for optimizing risk-benefit ratio when exploratory drugs are administered. The document also highlights that severely ill COVID-19 patients are frequently burdened by comorbidities, especially electrolyte imbalances, concomitant QT prolonging drugs in the high grade systemic inflammatory state, further increasing torsades de pointes susceptibility. They comment that specifically dampening inflammation-driven arrhythmic risk via IL-6 blockade could reduce the need for withholding or withdrawing potentially useful COVID-19 repurposed pharmacotherapies.

That's it for this month. We hope that you'll find the journal to be the go-to place for everyone interested in the field. See you next time. This program is copyright American Heart Association 2020.