Sanjiv M. Narayan

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).

Microvolt T-wave alternans physiological basis, methods of measurement, and clinical utility--consensus guideline by International Society for Holter and Noninvasive Electrocardiology.

This consensus guideline was prepared on behalf of the International Society for Holter and Noninvasive Electrocardiology and is cosponsored by the Japanese Circulation Society, the Computers in Cardiology Working Group on e-Cardiology of the European Society of Cardiology, and the European Cardiac Arrhythmia Society. It discusses the electrocardiographic phenomenon of T-wave alternans (TWA) (i.e., a beat-to-beat alternation in the morphology and amplitude of the ST-segment or T-wave). This statement focuses on its physiological basis and measurement technologies and its clinical utility in stratifying risk for life-threatening ventricular arrhythmias. Signal processing techniques including the frequency-domain Spectral Method and the time-domain Modified Moving Average method have demonstrated the utility of TWA in arrhythmia risk stratification in prospective studies in >12,000 patients. The majority of exercise-based studies using both methods have reported high relative risks for cardiovascular mortality and for sudden cardiac death in patients with preserved as well as depressed left ventricular ejection fraction. Studies with ambulatory electrocardiogram-based TWA analysis with Modified Moving Average method have yielded significant predictive capacity. However, negative studies with the Spectral Method have also appeared, including 2 interventional studies in patients with implantable defibrillators. Meta-analyses have been performed to gain insights into this issue. Frontiers of TWA research include use in arrhythmia risk stratification of individuals with preserved ejection fraction, improvements in predictivity with quantitative analysis, and utility in guiding medical as well as device-based therapy. Overall, although TWA appears to be a useful marker of risk for arrhythmic and cardiovascular death, there is as yet no definitive evidence that it can guide therapy.

Optimizing Hemodynamics in Heart Failure Patients by Systematic Screening of Left Ventricular Pacing Sites : The Lateral Left Ventricular Wall and the Coronary Sinus Are Rarely the Best Sites

OBJECTIVES We sought to evaluate the impact of the left ventricular (LV) pacing site on hemodynamic response to cardiac resynchronization therapy (CRT). BACKGROUND CRT reduces morbidity and mortality in heart failure patients. However, 20% to 40% of eligible patients may not fully benefit from CRT device implantation. We hypothesized that selecting the optimal LV pacing site could be critical in this issue. METHODS Thirty-five patients with nonischemic dilated cardiomyopathy referred for CRT device implantation were studied. Intraventricular dyssynchrony and latest activated LV wall were defined by tissue Doppler imaging analysis before the study. Eleven predetermined LV pacing sites were systematically assessed in random order: basal and mid-cavity (septal, anterior, lateral, inferior), apex, coronary sinus (CS), and the endocardial site facing the CS pacing site. For each patient, +dP/dT(max), -dP/dT(min), pulse pressure, and end-systolic pressure during baseline (AAI) and DDD LV pacing were compared. Two atrioventricular delays were tested. RESULTS Major interindividual and intraindividual variations of hemodynamic response depending on the LV pacing site were observed. Compared with baseline, LV DDD pacing at the best LV position significantly improved +dP/dT(max) (+31 +/- 26%, p < 0.001) and was superior to pacing the CS (+15 +/- 23%, p < 0.001), the lateral LV wall (+18 +/- 22%, p < 0.001), or the latest activated LV wall (+11 +/- 17%, p < 0.001). CONCLUSIONS The pacing site is a primary determinant of the hemodynamic response to LV pacing in patients with nonischemic dilated cardiomyopathy. Pacing at the best LV site is associated acutely with fewer nonresponders and twice the improvement in +dP/dT(max) observed with CS pacing.

Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation.

Computational Mapping of Rotors and Focal Impulses in Human AF. Introduction: The perpetuating mechanisms for human atrial fibrillation (AF) remain undefined. Localized rotors and focal beat sources may sustain AF in elegant animal models, but there has been no direct evidence for localized sources in human AF using traditional methods. We developed a clinical computational mapping approach, guided by human atrial tissue physiology, to reveal sources of human AF.

Long-term follow-up of idiopathic ventricular fibrillation ablation: a multicenter study.

OBJECTIVES This multicenter study sought to evaluate the long-term follow-up of patients ablated for idiopathic ventricular fibrillation (VF). BACKGROUND Catheter ablation of idiopathic VF that targets ventricular premature beat (VPB) triggers has been shown to prevent VF recurrences on short-term follow-up. METHODS From January 2000, 38 consecutive patients from 6 different centers underwent ablation of primary idiopathic VF initiated by short coupled VPB. All patients had experienced at least 1 documented VF, with 87% having experienced > or =2 VF episodes in the preceding year. Catheter ablation was guided by activation mapping of VPBs or pace mapping during sinus rhythm. RESULTS There were 38 patients (21 men) age 42 +/- 13 years, refractory to a median of 2 antiarrhythmic drugs. Triggering VPBs originated from the right (n = 16), the left (n = 14), or both (n = 3) Purkinje systems and from the myocardium (n = 5). During a median post-procedural follow-up of 63 months, 7 (18%) of 38 patients experienced VF recurrence at a median of 4 months. Five of these 7 patients underwent repeat ablation without VF recurrence. Survival free of VF was predicted only by transient bundle-branch block in the originating ventricle during the electrophysiological study (p < 0.0001). The number of significant events (confirmed VF or aborted sudden death) was reduced from 4 (interquartile range 3 to 9) before to 0 (interquartile range 0 to 4) after ablation (p = 0.01). CONCLUSIONS Ablation for idiopathic VF that targets short coupled VPB triggers is associated with a long-term freedom from VF recurrence.

Classifying fractionated electrograms in human atrial fibrillation using monophasic action potentials and activation mapping: Evidence for localized drivers, rate acceleration, and nonlocal signal etiologies

BACKGROUND Complex fractionated electrograms (CFAEs) detected during substrate mapping for atrial fibrillation (AF) reflect etiologies that are difficult to separate. Without knowledge of local refractoriness and activation sequence, CFAEs may represent rapid localized activity, disorganized wave collisions, or far-field electrograms. OBJECTIVE The purpose of this study was to separate CFAE types in human AF, using monophasic action potentials (MAPs) to map local refractoriness in AF and multipolar catheters to map activation sequence. METHODS MAP and adjacent activation sequences at 124 biatrial sites were studied in 18 patients prior to AF ablation (age 57 ± 13 years, left atrial diameter 45 ± 8 mm). AF cycle length, bipolar voltage, and spectral dominant frequency were measured to characterize types of CFAE. RESULTS CFAE were observed at 91 sites, most of which showed discrete MAPs and (1) pansystolic local activity (8%); (2) CFAE after AF acceleration, often with MAP alternans (8%); or (3) nonlocal (far-field) signals (67%). A fourth CFAE pattern lacked discrete MAPs (17%), consistent with spatial disorganization. CFAE with discrete MAPs and pansystolic activation (consistent with rapid localized AF sites) had shorter cycle length (P <.05) and lower voltage (P <.05) and trended to have higher dominant frequency than other CFAE sites. Many CFAEs, particularly at the septa and coronary sinus, represented far-field signals. CONCLUSION CFAEs in human AF represent distinct functional types that may be separated using MAPs and activation sequence. In a minority of cases, CFAEs indicate localized rapid AF sites. The majority of CFAEs reflect far-field signals, AF acceleration, or disorganization. These results may help to interpret CFAE during AF substrate mapping.

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.

Repolarization Alternans Reveals Vulnerability to Human Atrial Fibrillation

Background— The substrates for human atrial fibrillation (AF) are poorly understood, but involve abnormal repolarization (action potential duration [APD]). We hypothesized that beat-to-beat oscillations in APD may explain AF substrates, and why vulnerability to AF forms a spectrum from control subjects without AF to patients with paroxysmal then persistent AF. Methods and Results— In 33 subjects (12 with persistent AF, 13 with paroxysmal AF, and 8 controls without AF), we recorded left (n=33) and right (n=6) atrial APD on pacing from cycle lengths 600 to 500 ms (100 to 120 bpm) up to the point where AF initiated. Action potential duration alternans required progressively faster rates for patients with persistent AF, patients with paroxysmal AF, and controls (cycle length 411±94 versus 372±72 versus 218±33 ms; P<0.01). In AF patients, APD alternans occurred at rates as slow as 100 to 120 bpm, unrelated to APD restitution (P>0.10). In this milieu, spontaneous ectopy initiated AF. At fast rates, APD alternans disorganized to complex oscillations en route to AF. Complex oscillations also arose at progressively faster rates for persistent AF, paroxysmal AF, and controls (cycle length: 316±99 versus 266±19 versus 177±16 ms; P=0.02). In paroxysmal AF, APD oscillations amplified before AF (P<0.001). In controls, APD alternans arose only at very fast rates (cycle length <250 ms; P<0.001 versus AF groups) just preceding AF. In 4 AF patients in whom rapid pacing did not initiate AF, APD alternans arose transiently then extinguished. Conclusions— Atrial APD alternans reveals dynamic substrates for AF, arising most readily (at lower rates and higher magnitudes) in persistent AF then paroxysmal AF, and least readily in controls. APD alternans preceded all AF episodes and was absent when AF did not initiate. The cellular mechanisms for APD alternans near resting heart rates require definition.