Arvindh Kanagasundram

Common Genetic Variants and Response to Atrial Fibrillation Ablation

Background—Common single nucleotide polymorphisms (SNPs) at chromosomes 4q25 (rs2200733, rs10033464 near PITX2), 1q21 (rs13376333 in KCNN3), and 16q22 (rs7193343 in ZFHX3) have consistently been associated with the risk of atrial fibrillation (AF). Single-center studies have shown that 4q25 risk alleles predict recurrence of AF after catheter ablation of AF. Here, we performed a meta-analysis to test the hypothesis that these 4 AF susceptibility SNPs modulate response to AF ablation. Methods and Results—Patients underwent de novo AF ablation between 2008 and 2012 at Vanderbilt University, the Heart Center Leipzig, and Massachusetts General Hospital. The primary outcome was 12-month recurrence, defined as an episode of AF, atrial flutter, or atrial tachycardia lasting >30 seconds after a 3-month blanking period. Multivariable analysis of the individual cohorts using a Cox proportional hazards model was performed. Summary statistics from the 3 centers were analyzed using fixed effects meta-analysis. A total of 991 patients were included (Vanderbilt University, 245; Heart Center Leipzig, 659; and Massachusetts General Hospital, 87). The overall single procedure 12-month recurrence rate was 42%. The overall risk allele frequency for these SNPs ranged from 12% to 35%. Using a dominant genetic model, the 4q25 SNP, rs2200733, predicted a 1.4-fold increased risk of recurrence (adjusted hazard ratio,1.3 [95% confidence intervals, 1.1–1.6]; P=0.011). The remaining SNPs, rs10033464 (4q25), rs13376333 (1q21), and rs7193343 (16q22) were not significantly associated with recurrence. Conclusions—Among the 3 genetic loci most strongly associated with AF, the chromosome 4q25 SNP rs2200733 is significantly associated with recurrence of atrial arrhythmias after catheter ablation for AF.

A Novel Criterion for Conduction Block After Catheter Ablation of Right Atrial Tachycardia After Mitral Valve Surgery

Background—One operative approach to the mitral valve, the superior transseptal incision, is proarrhythmic because of extensive atriotomies. The objective of this study is to describe complex atrial tachycardias (ATs) that occur after this approach and propose methods to verify lines of block as an end point for catheter ablation. Methods and Results—Of the 69 patients who had electrophysiological studies for AT after mitral valve surgery, 20 patients had prior superior transseptal incisions. Of these, 14 had complex ATs involving the lateral right atrium (RA). There were 9 dual-loop, 4 single-loop, and 1 focal tachycardias. Lateral wall ablation was performed either by creating a linear lesion from the lateral atriotomy to the inferior vena cava, superior vena cava, or tricuspid annulus or by ablating focally in the lateral RA. After a single ablation procedure, conduction block in the lateral wall was verified in 10 of 14 patients using 1 of 2 distinct patterns of block. One pattern consisted of late activation in an anterolateral corridor of the RA, and a second pattern consisted of wide-spaced double potentials. Recurrent conduction through the lateral wall lesions was associated with intraprocedural and late recurrences of ATs. Conclusions—The optimal end point for ablating ATs after mitral valve surgery with the superior transseptal approach is to establish lines of block that can be recognized by characteristic patterns of activation in the lateral RA. A novel criterion for lateral conduction block after catheter ablation is identification of a late-activated corridor in the anterolateral RA.

Cardiac sympathectomy for the management of ventricular arrhythmias refractory to catheter ablation

BACKGROUND Catheter ablation is now a mainstay of therapy for ventricular arrhythmias (VAs). However, there are scenarios where either physiological or anatomical factors make ablation less likely to be successful. OBJECTIVE The purpose of this study was to demonstrate that cardiac sympathetic denervation (CSD) may be an alternate therapy for patients with difficult-to-ablate VAs. METHODS We identified all patients referred for CSD at a single center for indications other than long QT syndrome and catecholaminergic polymorphic ventricular tachycardia who had failed catheter ablation. Medical records were reviewed for medical history, procedural details, and follow-up. RESULTS Seven cases of CSD were identified in patients who had failed prior catheter ablation or had disease not amenable to ablation. All patients had VAs refractory to antiarrhythmic drugs, with a median arrhythmia burden of 1 episode of sustained VA per month. There were no acute complications of sympathectomy. One of 7 patients (14%) underwent heart transplant. No patient had sustained VA after sympathectomy at a median follow-up of 7 months. CONCLUSION Because of anatomical and physiological constraints, many VAs remain refractory to catheter ablation and remain a significant challenge for the electrophysiologist. While CSD has been described as a therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia, data regarding its use in other cardiac conditions are sparse. This series illustrates that CSD may be a viable treatment option for patients with a variety of etiologies of VAs.

Measurement of diffuse ventricular fibrosis with myocardial T1 in patients with atrial fibrillation

Atrial fibrillation (AF) is associated with cardiac fibrosis, which can now be measured noninvasively using T1‐mapping with cardiac magnetic resonance imaging (CMRI). This study aimed to assess the impact of AF on ventricular T1 at the time of CMRI.

Non-pulmonary vein mediated atrial fibrillation: A novel sub-phenotype

Background Atrial fibrillation (AF) is a mechanistically heterogeneous disorder, and the ability to identify sub-phenotypes (“endophenotypes”) of AF would assist in the delivery of personalized medicine. We used the clinical response to pulmonary vein isolation (PVI) to identify a sub-group of patients with non-PV mediated AF and sought to define the clinical associations. Methods Subjects enrolled in the Vanderbilt AF Ablation Registry who underwent a repeat AF ablation due to arrhythmia recurrence were analyzed on the basis of PV reconnection. Subjects who had no PV reconnection were defined as “non-PV mediated AF”. A comparison group of subjects were identified who had AF that was treated with PVI-only and experienced no arrhythmia recurrence >12 months. They were considered a group enriched for “PV-mediated AF”. Univariate and multivariable binary logistic regression analysis was performed to investigate clinical associations between the PV and non-PV mediated AF groups. Results Two hundred and twenty nine subjects underwent repeat AF ablation and thirty three (14%) had no PV reconnection. They were compared with 91 subjects identified as having PV-mediated AF. Subjects with non-PV mediated AF were older (64 years [IQR 60,71] vs. 60 [52,67], P = 0.01), more likely to have non-paroxysmal AF (82% [N = 27] vs. 35% [N = 32], P<0.001), and had a larger left atrium (LA) (4.2cm [3.6,4.8] vs. 4.0 [3.3,4.4], P = 0.04). In univariate analysis, age (per decade: OR 1.56 [95% CI: 1.04 to 2.33], P = 0.03), LA size (per cm: OR 1.8 [1.06 to 3.21], P = 0.03) and non-paroxysmal AF (OR 8.3 [3.10 to 22.19], P<0.001) were all significantly associated with non-PV mediated AF. However, in multivariable analysis only non-paroxysmal AF was independently associated with non-PV mediated AF (OR 7.47 [95% CI 2.62 to 21.29], P<0.001), when adjusted for age (per decade: OR 1.25 [0.81 to 1.94], P = 0.31), male gender (OR 0.48 [0.18 to 1.28], P = 0.14), and LA size (per 1cm: 1.24 [0.65 to 2.33], P = 0.52). Conclusions Non-paroxysmal AF was the only clinical variable found to be independently associated with non-PV mediated AF. We demonstrated that analysis of AF ablation outcomes data can serve as a tool to successfully identify a sub-phenotype of subjects who have non-PV mediated AF. Clinical trial registration ClinicalTrials.gov ID # NCT02404415.

Pulmonary Vein Sleeve Length and Association With Body Mass Index and Sex in Atrial Fibrillation

The pulmonary vein (PV) sleeves are extensions of left atrial tissue that cover the proximal surface of the PV adventitia. Despite the importance of the PV sleeves for atrial fibrillation (AF) pathogenesis and as a target of therapy, surprisingly little is known about the variability in their size

Inducibility Conundrum for Ablation of Ventricular Tachycardia: Are We Done Yet?

See Article by Oloriz et al The application of programmed electrical stimulation (PES) by Wellens et al1 to the evaluation of ventricular tachycardia (VT) in humans was a landmark achievement establishing a method that has led to pathophysiologic insights and improved VT diagnosis and therapy for >4 decades. The ability to initiate VT, ablate, and then demonstrate that VT is no longer inducible has been fundamental to assessing the acute effects of catheter ablation. Although there has been substantial progress with ablation in patients with heart disease and scar-related reentry and it is superior to escalating antiarrhythmic drug therapy in many situations, multicenter trials continue to report arrhythmia recurrences in 20% to 50% of patients.2,3 Recurrences are more frequent for nonischemic dilated cardiomyopathies and are associated with increased mortality and hospitalizations.2,4,5 Can PES shed light on the reasons for ablation failure? Or is its use to assess the acute procedural endpoint part of the problem? When one ablates an accessory pathway, the arrhythmia is no longer inducible, but we also confirm that the pathway is gone. Does use of noninducibility as an endpoint obfuscate the goal of abolishing the substrate? There are many limitations and caveats in the use of PES for assessing procedure outcome. VT inducibility is probabilistic and influenced by drugs, autonomic state, and the nuances of the stimulation protocol. The pacing sites, number of extrastimuli, and manner in which the extrastimuli are applied vary among laboratories. Some patients do not have inducible VT at baseline. Initiation of reentrant VT demonstrates that the substrate for reentry is present but is not informative about the existence of initiating triggers. Programmed stimulation is generally performed from sites remote from the reentry circuit, whereas recordings of spontaneous VT initiation often show that …

USE OF DABIGATRAN ETEXILATE TO PREVENT STROKE AND THROMBOEMBOLISM IN PATIENTS UNDERGOING LEFT ATRIAL CATHETER ABLATION PROCEDURES FOR PAROXYSMAL OR PERSISTENT (NON-PERMANENT) ATRIAL FIBRILLATION AND LEFT ATRIAL FLUTTER

Background: Optimal dosing of dabigatran in patients undergoing left atrial (LA) ablation procedures for atrial fibrillation (AF) or LA flutter is unknown. Retrospective data suggest increased bleeding risk with continuous dabigatran, and increased embolic risk when interrupted. We sought to confirm

Ventricular Tachycardia Ablation: Are We in a New Age?

See Article by Vakil et al Since the first electrocardiographic recordings, ventricular tachycardia (VT) has been associated with both significant morbidity and mortality.1 VT most commonly occurs in the presence of structural heart disease that produces myocardial fibrosis, such as myocardial infarction, nonischemic cardiomyopathy, sarcoidosis, and many other diseases. As such, the prognosis of a patient with VT mainly mirrors the extent of underlying heart disease. The prevalence of coronary artery disease in the US population has been shown to increase with age, reaching 20% in subjects >75 years of age.2 Prior to implantable cardioverter defibrillators, the overall downward trajectory of patients with VT proved insurmountable (and at times accelerated) by antiarrhythmic pharmacological therapies in those with structural heart disease.3 The era of revascularization and neurohormonal blockade has seen significant improvement in long-term morbidity and mortality for patients with heart failure.4 With modern medical therapy, patients are living longer and competing risks begin to emerge. VT remains a shadow in the dark—an ever-present threat that often presents itself during significant clinical deterioration but can …

Partial Duplication and Poly(A) Insertion in KCNQ1 Not Detected by Next-Generation Sequencing in Jervell and Lange–Nielsen Syndrome

Jervell and Lange–Nielsen syndrome is caused by absence of the voltage-gated potassium current I Ks through either homozygous recessive or compound heterozygous mutations in KCNQ1 or KCNE1 . We report here a case of Jervell and Lange–Nielsen syndrome with typical clinical features in which clinical genetic testing using next-generation sequencing (NGS) revealed only a known single heterozygous KCNQ1 mutation (R518X), but failed to recognize an unusual and complex 52-bp duplication-insertion. This type of variant has not been previously reported in Long QT syndrome (LQTS) and may therefore account for a portion of genetic variant negative cases. A 47-year-old woman with congenital deafness, severe QT prolongation (≥800 ms on Holter monitoring; Figure 1A and 1B), and striking exercise-induced QT lability and torsades de pointes was seen in referral. She had her first episode of syncope at 6 years of age, was reported to have marked QT prolongation, started β-blocker therapy, and was then lost to follow-up. At age 40, she had an episode of syncope while working outdoors in the heat, and β-blocker (propranolol at that time) was continued although she admitted to incomplete compliance because of fatigue. At age 46, she had another syncopal episode and was switched to metoprolol 100 mg daily. An implantable cardioverter-defibrillator was recommended but she declined. During an exercise test to assess the adequacy of β-blockade, she developed marked T wave lability followed by a 40-second, self-terminating episode of torsades de pointes, during which she lost consciousness (Figure 1C). Notably, this T wave instability occurred in an unusual (nonalternans) pattern,1 compatible with temporal variability in repolarization with …