Kalyanam Shivkumar

Treatment of Atrial Fibrillation by the Ablation of Localized Sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) Trial

OBJECTIVES We hypothesized that human atrial fibrillation (AF) may be sustained by localized sources (electrical rotors and focal impulses), whose elimination (focal impulse and rotor modulation [FIRM]) may improve outcome from AF ablation. BACKGROUND Catheter ablation for AF is a promising therapy, whose success is limited in part by uncertainty in the mechanisms that sustain AF. We developed a computational approach to map whether AF is sustained by several meandering waves (the prevailing hypothesis) or localized sources, then prospectively tested whether targeting patient-specific mechanisms revealed by mapping would improve AF ablation outcome. METHODS We recruited 92 subjects during 107 consecutive ablation procedures for paroxysmal or persistent (72%) AF. Cases were prospectively treated, in a 2-arm 1:2 design, by ablation at sources (FIRM-guided) followed by conventional ablation (n = 36), or conventional ablation alone (n = 71; FIRM-blinded). RESULTS Localized rotors or focal impulses were detected in 98 (97%) of 101 cases with sustained AF, each exhibiting 2.1 ± 1.0 sources. The acute endpoint (AF termination or consistent slowing) was achieved in 86% of FIRM-guided cases versus 20% of FIRM-blinded cases (p < 0.001). FIRM ablation alone at the primary source terminated AF in a median 2.5 min (interquartile range: 1.0 to 3.1 min). Total ablation time did not differ between groups (57.8 ± 22.8 min vs. 52.1 ± 17.8 min, p = 0.16). During a median 273 days (interquartile range: 132 to 681 days) after a single procedure, FIRM-guided cases had higher freedom from AF (82.4% vs. 44.9%; p < 0.001) after a single procedure than FIRM-blinded cases with rigorous, often implanted, electrocardiography monitoring. Adverse events did not differ between groups. CONCLUSIONS Localized electrical rotors and focal impulse sources are prevalent sustaining mechanisms for human AF. FIRM ablation at patient-specific sources acutely terminated or slowed AF, and improved outcome. These results offer a novel mechanistic framework and treatment paradigm for AF. (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation [CONFIRM]; NCT01008722).

Expedited PublicationTreatment of Atrial Fibrillation by the Ablation of Localized Sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) Trial

OBJECTIVES We hypothesized that human atrial fibrillation (AF) may be sustained by localized sources (electrical rotors and focal impulses), whose elimination (focal impulse and rotor modulation [FIRM]) may improve outcome from AF ablation. BACKGROUND Catheter ablation for AF is a promising therapy, whose success is limited in part by uncertainty in the mechanisms that sustain AF. We developed a computational approach to map whether AF is sustained by several meandering waves (the prevailing hypothesis) or localized sources, then prospectively tested whether targeting patient-specific mechanisms revealed by mapping would improve AF ablation outcome. METHODS We recruited 92 subjects during 107 consecutive ablation procedures for paroxysmal or persistent (72%) AF. Cases were prospectively treated, in a 2-arm 1:2 design, by ablation at sources (FIRM-guided) followed by conventional ablation (n = 36), or conventional ablation alone (n = 71; FIRM-blinded). RESULTS Localized rotors or focal impulses were detected in 98 (97%) of 101 cases with sustained AF, each exhibiting 2.1 ± 1.0 sources. The acute endpoint (AF termination or consistent slowing) was achieved in 86% of FIRM-guided cases versus 20% of FIRM-blinded cases (p < 0.001). FIRM ablation alone at the primary source terminated AF in a median 2.5 min (interquartile range: 1.0 to 3.1 min). Total ablation time did not differ between groups (57.8 ± 22.8 min vs. 52.1 ± 17.8 min, p = 0.16). During a median 273 days (interquartile range: 132 to 681 days) after a single procedure, FIRM-guided cases had higher freedom from AF (82.4% vs. 44.9%; p < 0.001) after a single procedure than FIRM-blinded cases with rigorous, often implanted, electrocardiography monitoring. Adverse events did not differ between groups. CONCLUSIONS Localized electrical rotors and focal impulse sources are prevalent sustaining mechanisms for human AF. FIRM ablation at patient-specific sources acutely terminated or slowed AF, and improved outcome. These results offer a novel mechanistic framework and treatment paradigm for AF. (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation [CONFIRM]; NCT01008722).

The role of the autonomic nervous system in sudden cardiac death.

T he cardiac autonomic nervous system consists of 2 branches—the sympathetic and the parasympathetic systems—that work in a delicately tuned, yet opposing fashion in the heart. This extrinsic control mechanism can dominate intrinsic regulatory mechanisms that modulate heart rate and cardiac output. These branches differ in their neurotransmitters (norepinephrine and acetylcholine) and exert stimulatory or inhibitory effects on target tissue via adrenergic and muscarinic receptors. Stimulation of the sympathetic branch exerts facilitatory effects on function, increasing heart rate and myocardial contractility, whereas the stimulation of the parasympathetic branch exerts inhibitory effects that decrease heart rate and contractility. The interplay between these two branches is complex and susceptible to control at several levels, from centrally mediated baroreceptors and chemoreceptors to local interneuronal interactions. Alterations in autonomic function occur in several interrelated cardiac conditions including sudden cardiac death, congestive heart failure, diabetic neuropathy, and myocardial ischemia. Although the full extent of these changes has not been elucidated, multiple autonomic remodeling mechanisms have been observed at both the neuronal fiber and myocardial cellular level that contribute to an arrhythmogenic substrate. We describe the anatomy of both systems in this review. However, the review will premdominantly

EHRA/HRS/APHRS expert consensus on ventricular arrhythmias.

Christian Torp Pedersen (EHRA Chairperson, Denmark), G. Neal Kay (HRS Chairperson, USA), Jonathan Kalman (APHRS Chairperson, Australia), Martin Borggrefe (Germany), Paolo Della-Bella (Italy), Timm Dickfeld (USA), Paul Dorian (Canada), Heikki Huikuri (Finland), Youg-Hoon Kim (Korea), Bradley Knight (USA), Francis Marchlinski (USA), David Ross (Australia), Frédéric Sacher (France), John Sapp (Canada), Kalyanam Shivkumar (USA), Kyoko Soejima (Japan), Hiroshi Tada (Japan), Mark E. Alexander (USA), John K. Triedman (USA), Takumi Yamada (USA), and Paulus Kirchhof (Germany)

Neuraxial modulation for refractory ventricular arrhythmias: value of thoracic epidural anesthesia and surgical left cardiac sympathetic denervation.

Background— Reducing sympathetic output to the heart from the neuraxis can protect against ventricular arrhythmias. The purpose of this study was to assess the value of thoracic epidural anesthesia (TEA) and left cardiac sympathetic denervation (LCSD) in the management of ventricular arrhythmias in patients with structural heart disease. Methods and Results— Clinical data of 14 patients (25 to 75 years old, mean±SD of 54.2±16.6 years; 13 men) who underwent TEA, LCSD, or both to control ventricular tachycardia (VT) refractory to medical therapy and catheter ablation were reviewed. Twelve patients were in VT storm, and 2 experienced recurrent VT despite maximal medical therapy and catheter ablation procedures. The total number of therapies per patient before either procedure ranged from 5 to 202 (median of 24; 25th and 75th percentile, 5 and 56). Eight patients underwent TEA, and 9 underwent LCSD (3 patients had both procedures). No major procedural complications occurred. After initiation of TEA, 6 patients had a large (≥80%) decrease in VT burden. After LCSD, 3 patients had no further VT, 2 had recurrent VT that either resolved within 24 hours or responded to catheter ablation, and 4 continued to have recurrent VT. Nine of 14 patients survived to hospital discharge (2 TEA alone, 3 TEA/LCSD combined, and 4 LCSD alone), 1 of the TEA alone patients underwent an urgent cardiac transplantation. Conclusions— Initiation of TEA and LCSD in patients with refractory VT was associated with a subsequent decrease in arrhythmia burden in 6 (75%) of 8 patients (68% confidence interval 51% to 91%) and 5 (56%) of 9 patients (68% confidence interval 34% to 75%), respectively. These data suggest that TEA and LCSD may be effective additions to the management of refractory ventricular arrhythmias in structural heart disease when other treatment modalities have failed or may serve as a bridge to more definitive therapy.

Characterization of the Arrhythmogenic Substrate in Ischemic and Nonischemic Cardiomyopathy: Implications for Catheter Ablation of Hemodynamically Unstable Ventricular Tachycardia

OBJECTIVES The purpose of this study was to compare the characteristics and prevalence of late potentials (LP) in patients with nonischemic cardiomyopathy (NICM) and ischemic cardiomyopathy (ICM) etiologies and evaluate their value as targets for catheter ablation. BACKGROUND LP are frequently found in post-myocardial infarction scars and are useful ablation targets. The relative prevalence and characteristics of LP in patients with NICM is not well understood. METHODS Thirty-three patients with structural heart disease (NICM, n = 16; ICM, n = 17) referred for catheter ablation of ventricular tachycardia were studied. Electroanatomic mapping was performed endocardially (n = 33) and epicardially (n = 19). The LP were defined as low voltage electrograms (<1.5 mV) with onset after the QRS interval. Very late potentials (vLP) were defined as electrograms with onset >100 ms after the QRS. RESULTS We sampled an average of 564 +/- 449 points and 726 +/- 483 points in the left ventricle endocardium and epicardium, respectively. Mean total low voltage area in patients with ICM was 101 +/- 55 cm(2) and 56 +/- 33 cm(2), endocardial and epicardial, respectively, compared with NICM of 55 +/- 41 cm(2) and 53 +/- 28 cm(2), respectively. Within the total low voltage area, vLP were observed more frequently in ICM than in NICM in endocardium (4.1% vs. 1.3%; p = 0.0003) and epicardium (4.3% vs. 2.1%, p = 0.035). An LP-targeted ablation strategy was effective in ICM patients (82% nonrecurrence at 12 +/- 10 months of follow-up), whereas NICM patients had less favorable outcomes (50% at 15 +/- 13 months of follow-up). CONCLUSIONS The contribution of scar to the electrophysiological abnormalities targeted for ablation of unstable ventricular tachycardia differs between ICM and NICM. An approach incorporating LP ablation and pace-mapping had limited success in patients with NICM compared with ICM, and alternative ablation strategies should be considered.

Cardiac sympathetic denervation in patients with refractory ventricular arrhythmias or electrical storm: Intermediate and long-term follow-up

BACKGROUND Left and bilateral cardiac sympathetic denervation (CSD) have been shown to reduce burden of ventricular arrhythmias acutely in a small number of patients with ventricular tachyarrhythmia (VT) storm. The effects of this procedure beyond the acute setting are unknown. OBJECTIVE The purpose of this study was to evaluate the intermediate and long-term effects of left and bilateral CSD in patients with cardiomyopathy and refractory VT or VT storm. METHODS Retrospective analysis of medical records for patients who underwent either left or bilateral CSD for VT storm or refractory VT between April 2009 and December 2012 was performed. RESULTS Forty-one patients underwent CSD (14 left CSD, 27 bilateral CSD). There was a significant reduction in the burden of implantable cardioverter-defibrillator (ICD) shocks during follow-up compared to the 12 months before the procedure. The number of ICD shocks was reduced from a mean of 19.6 ± 19 preprocedure to 2.3 ± 2.9 postprocedure (P < .001), with 90% of patients experiencing a reduction in ICD shocks. At mean follow-up of 367 ± 251 days postprocedure, survival free of ICD shock was 30% in the left CSD group and 48% in the bilateral CSD group. Shock-free survival was greater in the bilateral group than in the left CSD group (P = .04). CONCLUSION In patients with VT storm, bilateral CSD is more beneficial than left CSD. The beneficial effects of bilateral CSD extend beyond the acute postsympathectomy period, with continued freedom from ICD shocks in 48% of patients and a significant reduction in ICD shocks in 90% of patients.

The Cardiac Atlas Project—an imaging database for computational modeling and statistical atlases of the heart

Motivation: Integrative mathematical and statistical models of cardiac anatomy and physiology can play a vital role in understanding cardiac disease phenotype and planning therapeutic strategies. However, the accuracy and predictive power of such models is dependent upon the breadth and depth of noninvasive imaging datasets. The Cardiac Atlas Project (CAP) has established a large-scale database of cardiac imaging examinations and associated clinical data in order to develop a shareable, web-accessible, structural and functional atlas of the normal and pathological heart for clinical, research and educational purposes. A goal of CAP is to facilitate collaborative statistical analysis of regional heart shape and wall motion and characterize cardiac function among and within population groups. Results: Three main open-source software components were developed: (i) a database with web-interface; (ii) a modeling client for 3D + time visualization and parametric description of shape and motion; and (iii) open data formats for semantic characterization of models and annotations. The database was implemented using a three-tier architecture utilizing MySQL, JBoss and Dcm4chee, in compliance with the DICOM standard to provide compatibility with existing clinical networks and devices. Parts of Dcm4chee were extended to access image specific attributes as search parameters. To date, approximately 3000 de-identified cardiac imaging examinations are available in the database. All software components developed by the CAP are open source and are freely available under the Mozilla Public License Version 1.1 (http://www.mozilla.org/MPL/MPL-1.1.txt). Availability: http://www.cardiacatlas.org Contact: a.young@auckland.ac.nz Supplementary information: Supplementary data are available at Bioinformatics online.

Direct or Coincidental Elimination of Stable Rotors or Focal Sources May Explain Successful Atrial Fibrillation Ablation: On-Treatment Analysis of the CONFIRM Trial (Conventional Ablation for AF With or Without Focal Impulse and Rotor Modulation)

OBJECTIVES This study sought to determine whether ablation of recently described stable atrial fibrillation (AF) sources, either directly by Focal Impulse and Rotor Modulation (FIRM) or coincidentally when anatomic ablation passes through AF sources, may explain long-term freedom from AF. BACKGROUND It is unclear why conventional anatomic AF ablation can be effective in some patients yet ineffective in others with similar profiles. METHODS The CONFIRM (Conventional Ablation for AF With or Without Focal Impulse and Rotor Modulation) trial prospectively revealed stable AF rotors or focal sources in 98 of 101 subjects with AF at 107 consecutive ablation cases. In 1:2 fashion, subjects received targeted source ablation (FIRM) followed by conventional ablation, or conventional ablation alone. We determined whether ablation lesions on electroanatomic maps passed through AF sources on FIRM maps. RESULTS Subjects who completed follow-up (n = 94; 71.2% with persistent AF) showed 2.3 ± 1.1 concurrent AF rotors or focal sources that lay near pulmonary veins (22.8%), left atrial roof (16.0%), and elsewhere in the left (28.2%) and right (33.0%) atria. AF sources were ablated directly in 100% of FIRM cases and coincidentally (e.g., left atrial roof) in 45% of conventional cases (p < 0.05). During a median (interquartile range) of 273 days (138 to 636 days) after one procedure, AF was absent in 80.3% of patients if sources were ablated but in only 18.2% of patients if sources were missed (p < 0.001). Freedom from AF was highest if all sources were ablated, intermediate if some sources were ablated, and lowest if no sources were ablated (p < 0.001). CONCLUSIONS Elimination of stable AF rotors and focal sources may explain freedom from AF after diverse approaches to ablation. Patient-specific AF source distributions are consistent with the reported success of specific anatomic lesion sets and of widespread ablation. These results support targeting AF sources to reduce unnecessary ablation, and motivate studies on FIRM-only ablation.

Initial independent outcomes from focal impulse and rotor modulation ablation for atrial fibrillation: multicenter FIRM registry.

The success of pulmonary vein isolation (PVI) for atrial fibrillation (AF) may be improved if stable AF sources identified by Focal Impulse and Rotor Mapping (FIRM) are also eliminated. The long‐term results of this approach are unclear outside the centers where FIRM was developed; thus, we assessed outcomes of FIRM‐guided AF ablation in the first cases at 10 experienced centers.