Organized Sources Are Spatially Conserved in Recurrent Compared to Pre-Ablation Atrial Fibrillation: Further Evidence for Non-Random Electrical Substrates.

INTRODUCTION: Recurrent atrial fibrillation (AF) after ablation is associated with reconnection of initially isolated pulmonary vein (PV) trigger sites. Substrates are often targeted in addition to PVI, but it is unclear how substrates progress over time. We studied if substrates in recurrent AF are conserved or have developed de novo from pre-ablation AF. METHODS AND RESULTS: Of 137 patients undergoing Focal Impulse and Rotor Mapping (FIRM) at their index procedure for AF, 29 consecutive patients (60 ± 8 years, 79% persistent) recurred and were also mapped at repeat procedure (21 ± 20 months later) using carefully placed 64-pole baskets and RhythmView(TM) (Topera, Menlo Park, CA, USA) to identify AF sources and disorganized zones. Compared to index AF, recurrent AF had a longer cycle length (177 ± 21 vs. 167 ± 19 milliseconds, P = 0.01). All patients (100%) had 1 or more conserved AF rotors between procedures with surrounding disorganization. The number of sources was similar for recurrent AF post-PVI versus index AF (3.2 ± 1.4 vs. 3.1 ± 1.0, P = 0.79), but was lower for recurrent AF after FIRM+PVI versus index AF (4.4 ± 1.4 vs. 2.9 ± 1.7, P = 0.03). Overall, 81% (61/75) of AF sources lay in conserved regions, while 19% (14/75) were detected de novo. CONCLUSION: Electrical propagation patterns for recurrent AF after unsuccessful ablation are similar in individual patients to their index AF. These data support temporospatial stability of AF substrates over 1-2 years. Trials should determine the relative benefit of adding substrate mapping and ablation to PVI for recurrent AF.

Cardiac Device Implant Skin Closure with a Novel Adjustable, Coaptive Tape-Based Device.

BACKGROUND: The purpose of this study was to compare a unique zip-type adjustable coaptive tape-based skin closure device to traditional subcuticular sutures in three domains: time, cosmesis, and wound closure-related outcomes in cardiac implantable electronic device (CIED) procedures. METHODS: A total of 40 patients were enrolled in a prospective randomized controlled trial to assess time to wound closure, as well as cosmesis and wound closure-related outcomes. RESULTS: The adjustable coaptive tape-based skin closure device had shorter overall closure time (78 ± 6.6 seconds vs 216 ± 21.5 seconds; P < 0.001) and mean closure time per centimeter (18.0 ± 2.0 s/cm vs 50.1 ± 6.7 s/cm; P < 0.001) versus sutures, with less intersurgeon and interpatient variability with the use of adjustable coaptive device versus sutures (P < 0.001). There was no difference between groups in postoperative pain or scar cosmesis during the follow-up period. Neither group had any closure-related adverse events. CONCLUSIONS: The adjustable coaptive tape-based skin closure device demonstrated shorter closure times with less variability when compared to sutures. It is a safe and acceptable alternative to sutures for skin closure following CIED implantation.

Compatibility of Radiofrequency Surgical Sponge Detection Technology with Cardiac Implantable Electronic Devices and Temporary Pacemakers.

BACKGROUND: Radiofrequency (RF) technology has improved detection of retained surgical sponges with a reported 100% sensitivity and specificity. However, the potential for interactions of the RF signals emitted by the detection system with cardiac implantable electronic devices (CIEDs) or temporary pacemakers may limit its use in those patients with these devices. This study investigated whether RF detection technology causes interference or clinically significant changes in the programmed settings of implanted pacemakers and defibrillators or temporary epicardial pacemakers. METHODS: Fifty patients who were scheduled either for CIED removal or placement of a temporary epicardial pacemaker (at the time of open heart surgery) were recruited for this study. Device settings and measurements from separate interrogations before and after scanning with the RF detection system were compared. For the temporary pacemakers, we observed for any changes in hemodynamics or signs of pacing interference. RESULTS: Twenty (40%) pacemakers, 20 (40%) implantable cardioverter defibrillators, and 10 (20%) temporary pacemakers were analyzed in this study. During scanning, no signal interference was detected in any permanent device, and there were no significant changes in programmed settings after scanning with the RF detection system. However, pacing inhibition was detected with temporary pacing systems when programmed to a synchronous mode (DDD). CONCLUSIONS: RF detection technology can be safely used to scan for retained surgical sponges in patients with permanent CIEDs and temporary pacemakers set to asynchronous mode.

Modifying Ventricular Fibrillation by Targeted Rotor Substrate Ablation: Proof-of-Concept from Experimental Studies to Clinical VF.

INTRODUCTION: Recent work has suggested a role for organized sources in sustaining ventricular fibrillation (VF). We assessed whether ablation of rotor substrate could modulate VF inducibility in canines, and used this proof-of-concept as a foundation to suppress antiarrhythmic drug-refractory clinical VF in a patient with structural heart disease. METHODS AND RESULTS: In 9 dogs, we introduced 64-electrode basket catheters into one or both ventricles, used rapid pacing at a recorded induction threshold to initiate VF, and then defibrillated after 18±8 seconds. Endocardial rotor sites were identified from basket recordings using phase mapping, and ablation was performed at nonrotor (sham) locations (7 ± 2 minutes) and then at rotor sites (8 ± 2 minutes, P = 0.10 vs. sham); the induction threshold was remeasured after each. Sham ablation did not alter canine VF induction threshold (preablation 150 ± 16 milliseconds, postablation 144 ± 16 milliseconds, P = 0.54). However, rotor site ablation rendered VF noninducible in 6/9 animals (P = 0.041), and increased VF induction threshold in the remaining 3. Clinical proof-of-concept was performed in a patient with repetitive ICD shocks due to VF refractory to antiarrhythmic drugs. Following biventricular basket insertion, VF was induced and then defibrillated. Mapping identified 4 rotors localized at borderzone tissue, and rotor site ablation (6.3 ± 1.5 minutes/site) rendered VF noninducible. The VF burden fell from 7 ICD shocks in 8 months preablation to zero ICD therapies at 1 year, without antiarrhythmic medications. CONCLUSIONS: Targeted rotor substrate ablation suppressed VF in an experimental model and a patient with refractory VF. Further studies are warranted on the efficacy of VF source modulation.

Rotors and focal sources for human atrial fibrillation: mechanistic paradigm with direct clinical relevance.

Outcomes for patients with atrial fibrillation (AF) have changed little despite many advances in technology. In large part, this reflects fundamental uncertainty about the mechanisms for AF in humans, which must reconcile diverse observations. Despite the complexity of AF, many electrophysiologists have witnessed modulation of 'chaotic' AF after the first few ablation lesions, or before lines are complete or trigger sites are isolated, and numerous analyses demonstrate temporospatial stability in AF. These common observations challenge the concept that AF is driven by spatially disorganized, widespread mechanisms. Using mathematical techniques applied to other complex systems, evidence is rapidly accumulating that human AF is largely sustained by localized rotors and focal sources. Elimination of sources by Focal Impulse and Rotor Modulation (FIRM)-guided ablation has been shown by independent laboratories to substantially improve success compared with pulmonary vein isolation alone. These data advance our mechanistic understanding of AF. Randomized trials are underway to verify the relative efficacy of ablation at AF sources (substrate) vs. conventional trigger ablation. The renewed focus on AF substrates is a paradigm shift, but also a re-alignment of concepts for AF towards those for other cardiac arrhythmias that are generally defined by sustaining mechanisms (substrates).

Rotors as drivers of atrial fibrillation and targets for ablation.

Atrial fibrillation (AF) is the most common arrhythmia targeted by catheter ablation. Despite significant advances in our understanding of AF, ablation outcomes remain suboptimal, and this is due in large part to an incomplete understanding of the underlying sustaining mechanisms of AF. Recent developments of patient-tailored and physiology-based computational mapping systems have identified localized electrical spiral waves, or rotors, and focal sources as mechanisms that may represent novel targets for therapy. This report provides an overview of Focal Impulse and Rotor Modulation (FIRM) mapping, which reveals that human AF is often not actually driven by disorganized activity but instead that disorganization is secondary to organized rotors or focal sources. Targeted ablation of such sources alone can eliminate AF and, when added to pulmonary vein isolation, improves long-term outcome compared with conventional ablation alone. Translating mechanistic insights from such patient-tailored mapping is likely to be crucial in achieving the next major advances in personalized medicine for AF.

Cardiac resynchronisation therapy in patients with chronic heart failure.

Cardiac resynchronisation therapy (CRT) is common treatment for congestive heart failure (HF) with decreased LV function and wide QRS complex. Its foundations are set in the understanding of the pathophysiology of ventricular dyssynchrony. Over the last several decades, CRT has evolved through changes in implantation techniques, device and lead design, imaging modalities and our growing clinical experience. This review article will discuss the vast clinical experience that has led to current guidelines recommendations for CRT in patients with mild-to-severe HF. In addition, the article will also discuss recent evidence of benefits of CRT in patients beyond the guidelines. The article will also address the issue of non-responders, optimisation of CRT, postimplant evaluation and remote monitoring.

Mechanisms Underlying AF: Triggers, Rotors, Other?

OPINION STATEMENT: There is ongoing debate regarding the precise mechanisms underlying atrial fibrillation (AF). An improved understanding of these mechanisms is urgently needed to improve interventional strategies to suppress and eliminate AF, since the success of current strategies is suboptimal. At present, guidelines for AF ablation focus on pulmonary vein (PV) isolation for the prevention of arrhythmia. Additional targets are presently unclear, and include additional linear ablation and electrogram-guided substrate modification, without clear mechanistic relevance. PV and non-PV triggers are likely central in the first few seconds of AF initiation. Rapid activation from such triggers interacts with transitional mechanisms including conduction velocity slowing, action potential duration (APD) alternans, and steep APD restitution to cause conduction block and initiate functional reentry. However, complete suppression of potential triggers has proven elusive, and the intra-procedural mapping and targeting of transitional mechanisms has not been reported. A growing body of research implicates electrical rotors and focal sources as central mechanisms for the maintenance of AF. In several recent series, they were observed in nearly all patients with sustained arrhythmia. Ablation of rotor and focal source sites, prior to pulmonary vein isolation, substantially modulated atrial fibrillation in a high proportion of patients, and improved ablation outcomes versus pulmonary vein isolation alone. These results have subsequently been confirmed in multicenter series, and the improved outcomes have been found to persist to a mean follow-up of 3 years. Recently, rotors have been observed by multiple groups using diverse technologies. These findings represent a paradigm shift in AF, focusing on sustaining mechanisms, as is currently done with other arrhythmias such as atrioventricular node reentrant tachycardia. Studies are currently underway to assess the optimal strategy for the application of rotor-based ablation in AF management, including clinical trials on the relative efficacy of rotor-only ablation versus PVI-only ablation, which will inform future practice guidelines.

Human atrial fibrillation initiates via organized rather than disorganized mechanisms.

BACKGROUND: It is unknown how atrial fibrillation (AF) is actually initiated by triggers. Based on consistencies in atrial structure and function in individual patients between episodes of AF, we hypothesized that human AF initiates when triggers interact with deterministic properties of the atria and may engage organized mechanisms. METHODS AND RESULTS: In 31 patients with AF, we mapped AF initiation after spontaneous triggers or programmed stimulation. We used 64-pole basket catheters to measure regional dynamic conduction slowing and to create biatrial activation maps during transitions to AF. Sixty-two AF initiations were recorded (spontaneous, n=28; induced, n=34). Notably, AF did not initiate by disorganized mechanisms, but by either a dominant reentrant spiral wave (76%) or a repetitive focal driver. Both mechanisms were located 21±17 mm from their triggers. AF-initiating spirals formed at the site showing the greatest rate-dependent slowing in each patient. Accordingly, in 10 of 12 patients with multiple observed AF episodes, AF initiated using spatially conserved mechanisms despite diverse triggers. CONCLUSIONS: Human AF initiates from triggers by organized rather than disorganized mechanisms, either via spiral wave re-entry at sites of dynamic conduction slowing or via repetitive focal drivers. The finding that diverse triggers initiate AF at predictable, spatially conserved functional sites in each individual provides a novel deterministic paradigm for AF with therapeutic implications.

Mapping and ablating stable sources for atrial fibrillation: summary of the literature on Focal Impulse and Rotor Modulation (FIRM).

Atrial fibrillation (AF) is the most common sustained arrhythmia and the most common indication for catheter ablation. However, despite substantial technical advances in mapping and energy delivery, ablation outcomes remain suboptimal. A major limitation to AF ablation is that the areas targeted for ablation are rarely of proven mechanistic importance, in sharp contrast to other arrhythmias in which ablation targets demonstrated mechanisms in each patient. Focal impulse and rotor modulation (FIRM) is a new approach to demonstrate the mechanisms that sustain AF ("substrates") in each patient that can be used to guide ablation then confirm elimination of each mechanism. FIRM mapping reveals that AF is sustained by 2-3 rotors and focal sources, with a greater number in patients with persistent than paroxysmal AF, lying within spatially reproducible 2.2 ± 1.4-cm(2) areas in diverse locations. This temporospatial reproducibility, now confirmed by several groups using various methods, changes the concepts regarding AF-sustaining mechanisms, enabling localized rather than widespread ablation. Mechanistically, the role of rotors and focal sources in sustaining AF has been demonstrated by the acute and chronic success of source (FIRM) ablation alone. Clinically, adding FIRM to conventional ablation substantially improves arrhythmia freedom compared with conventional ablation alone, and ongoing randomized trials are comparing FIRM-ablation with and without conventional ablation to conventional ablation alone. In conclusion, ablation of patient-specific AF-sustaining mechanisms (substrates), as exemplified by FIRM, may be central to substantially improving AF ablation outcomes.

Ablation of rotor and focal sources reduces late recurrence of atrial fibrillation compared with trigger ablation alone: extended follow-up of the CONFIRM trial (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation).

OBJECTIVES: The aim of this study was to determine if ablation that targets patient-specific atrial fibrillation (AF)-sustaining substrates (rotors or focal sources) is more durable than trigger ablation alone at preventing late AF recurrence. BACKGROUND: Late recurrence substantially limits the efficacy of pulmonary vein isolation for AF and is associated with pulmonary vein reconnection and the emergence of new triggers. METHODS: Three-year follow-up was performed of the CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial, in which 92 consecutive patients with AF (70.7% persistent) underwent novel computational mapping. Ablation comprised source (focal impulse and rotor modulation [FIRM]) and then conventional ablation in 27 patients (FIRM guided) and conventional ablation alone in 65 patients (FIRM blinded). Patients were followed with implanted electrocardiographic monitors when possible (85.2% of FIRM-guided patients, 23.1% of FIRM-blinded patients). RESULTS: FIRM mapping revealed a median of 2 (interquartile range: 1 to 2) rotors or focal sources in 97.7% of patients during AF. During a median follow-up period of 890 days (interquartile range: 224 to 1,563 days), compared to FIRM-blinded therapy, patients receiving FIRM-guided ablation maintained higher freedom from AF after 1.2 ± 0.4 procedures (median 1; interquartile range: 1 to 1) (77.8% vs. 38.5%, p = 0.001) and a single procedure (p < 0.001) and higher freedom from all atrial arrhythmias (p = 0.003). Freedom from AF was higher when ablation directly or coincidentally passed through sources than when it missed sources (p < 0.001). CONCLUSIONS: FIRM-guided ablation is more durable than conventional trigger-based ablation in preventing 3-year AF recurrence. Future studies should investigate how ablation of patient-specific AF-sustaining rotors and focal sources alters the natural history of arrhythmia recurrence. (The Dynamics of Human Atrial Fibrillation; NCT01008722).

Frequency analysis of atrial action potential alternans: a sensitive clinical index of individual propensity to atrial fibrillation.

BACKGROUND: Few clinical indices identify the propensity of patients to atrial fibrillation (AF) when not in AF. Repolarization alternans has been shown to indicate AF vulnerability, but is limited in its sensitivity to detect changes in action potential (AP) duration (APD), which may be subtle. We hypothesized that spectral analysis would be a more sensitive and robust marker of AP alternans and thus a better clinical index of individual propensity to AF than APD alternans. METHODS AND RESULTS: In 31 patients (12 persistent AF, 15 paroxysmal AF, 4 controls with no AF), we recorded left (n=27) and right (n=6) atrial monophasic APs during incremental pacing from cycle length 500 ms (120 beats per minute) to AF onset. Alternans was measured by APD and spectral analysis. At baseline pacing (median cycle length [1st, 3rd quartiles], 500 ms [500, 500]), APD alternans was detected in only 7 of 27 AF patients (no controls), whereas spectral AP alternans was detected in 18 of 27 AF patients (no controls; P=0.003); AP alternans was more prevalent in persistent than paroxysmal AF, and absent in controls (P=0.018 APD; P=0.042 spectral). Spectral AP alternans magnitude at baseline was highest in persistent AF, with modest rate-dependent amplification, followed by paroxysmal AF, with marked rate dependence, and undetectable in controls until just before induced AF. CONCLUSIONS: Spectral AP alternans near baseline rates can identify patients with, versus those without, clinical histories and pathophysiological substrates for AF. Future studies should examine whether the presence of spectral AP alternans during sinus rhythm may obviate the need to actually demonstrate AF, such as on ambulatory ECG monitoring.

Targeted ablation at stable atrial fibrillation sources improves success over conventional ablation in high-risk patients: a substudy of the CONFIRM Trial.

BACKGROUND: Pulmonary vein (PV) isolation has disappointing results in patients with obesity, heart failure, obstructive sleep apnea (OSA) and enlarged left atria (LA), for unclear reasons. We hypothesized that these comorbidities may cause higher numbers or non-PV locations of atrial fibrillation (AF) sources, where targeted source ablation (focal impulse and rotor modulation [FIRM]) should improve the single-procedure success of ablation. METHODS: The Conventional Ablation of AF With or Without Focal Impulse and Rotor Modulation (CONFIRM) trial prospectively enrolled 92 patients at 107 AF ablation procedures, in whom computational mapping identified AF rotors or focal sources. Patients underwent FIRM plus conventional ablation (FIRM-guided), or conventional ablation only, and were evaluated for recurrent AF quarterly with rigourous, often implanted, monitoring. We report the n = 73 patients undergoing first ablation in whom demographic information was available (n = 52 conventional, n = 21 FIRM-guided). RESULTS: Stable sources for AF were found in 97.1% of patients. The numbers of concurrent sources per patient (2.1 ± 1.1) rose with LA diameter (P = 0.021), lower left ventricular ejection fraction (P = 0.039), and the presence of OSA (P = 0.002) or hypomagnesemia (P = 0.017). Right atrial sources were associated with obesity (body mass index ≥ 30; P = 0.015). In patients with obesity, hypertension, OSA, and LA diameter > 40 mm, single-procedure freedom from AF was > 80% when FIRM-guided was used vs. < 50% when conventional ablation was used (all; P < 0.05). CONCLUSIONS: Patients with "difficult to treat" AF exhibit more concurrent AF sources in more widespread biatrial distributions than other patients. These mechanisms explain the disappointing results of PV isolation, and how FIRM can identify patient-specific AF sources to enable successful ablation in this population.

Atrial conduction slows immediately before the onset of human atrial fibrillation: a bi-atrial contact mapping study of transitions to atrial fibrillation.

OBJECTIVES: The aim of this study was to determine whether onset sites of human atrial fibrillation (AF) exhibit conduction slowing, reduced amplitude, and/or prolonged duration of signals (i.e., fractionation) immediately before AF onset. BACKGROUND: Few studies have identified functional determinants of AF initiation. Because conduction slowing is required for reentry, we hypothesized that AF from pulmonary vein triggers might initiate at sites exhibiting rate-dependent slowing in conduction velocity (CV restitution) or local slowing evidenced by signal fractionation. METHODS: In 28 patients with AF (left atrial size 43 ± 5 mm; n = 13 persistent) and 3 control subjects (no AF) at electrophysiological study, we measured bi-atrial conduction time (CT) electrogram fractionation at 64 or 128 electrodes with baskets in left (n = 17) or both (n = 14) atria during superior pulmonary vein pacing at cycle lengths (CL) accelerating from 500 ms (120 beats/min) to AF onset. RESULTS: Atrial fibrillation initiated in 19 of 28 AF patients and no control subjects. During rate acceleration, conduction slowed in 23 of 28 AF patients (vs. no control subjects, p = 0.01) at the site of AF initiation (15 of 19) or latest activated site (20 of 28). The CT lengthened from 79 ± 23 ms to 107 ± 39 ms (p < 0.001) on acceleration, in a spectrum from persistent AF (greatest slowing) to control subjects (least slowing; p < 0.05). Three patterns of CV restitution were observed: 1) broad (gradual CT prolongation, 37% patients); 2) steep (abrupt prolongation, at CL 266 ± 62 ms, 42%); and 3) flat (no prolongation, 21% AF patients, all control subjects). The AF initiation was more prevalent in patients with CV restitution (17 of 23 vs. 2 of 8; p = 0.03) and immediately followed abrupt re-orientation of the activation vector in patients with broad but not steep CV restitution (p < 0.01). Patients with broad CV restitution had larger atria (p = 0.03) and were more likely to have persistent AF (p = 0.04). Notably, neither amplitude nor duration (fractionation) of the atrial signal at the AF initiation site were rate-dependent (both p = NS). CONCLUSIONS: Acceleration-dependent slowing of atrial conduction (CV restitution) precedes AF initiation, whereas absence of CV restitution identifies inability to induce AF. Conduction restitution, but not fractionated electrograms, may thus track the functional milieu enabling AF initiation and has implications for guiding AF ablation and pharmacological therapy.

Rate-dependent action potential alternans in human heart failure implicates abnormal intracellular calcium handling.

BACKGROUND: Alternans in action potential voltage (APV-ALT) at heart rates <110 bpm is a novel index to predict ventricular arrhythmias. However, the rate dependency of APV-ALT and its mechanisms in failing versus nonfailing human myocardium are poorly understood. It is hypothesized that APV-ALT in human heart failure (HF) reflects abnormal calcium handling. OBJECTIVE: Using a modeling and clinical approach, our objectives were to (1) determine how APV-ALT varies with pacing rate and (2) ascertain whether abnormalities in calcium handling explain the rate dependence of APV-ALT in HF. METHODS: APV-ALT was analyzed at several cycle lengths (CLs) using a dynamic pacing protocol applied to a human left ventricle wedge model with various alterations in calcium handling. Modeled APV-ALT was used to predict APV-ALT in left ventricle monophasic action potentials recorded from HF (n = 3) and control (n = 2) patients with the same pacing protocol. RESULTS: Reducing the sarcoplasmic reticulum calcium uptake current < or =25%, the release current < or =11%, or the sarcolemmal L-type calcium channel current < or =43% of control predicted APV-ALT to arise at CL > or =600 ms and then increase in magnitude by >400% for CL <400 ms. In HF patients, APV-ALT arose at CL = 600 ms and then increased in magnitude by >500% at CL <350 ms. For all other model alterations and for control patients, APV-ALT occurred only at CL <500 ms. CONCLUSIONS: APV-ALT shows differing rate dependence in HF versus control patients, arising at slower rates in HF and predicted by models with abnormal calcium handling. Future studies should investigate whether APV-ALT at slow rates identifies patients with deranged calcium handing, including HF patients before decompensation or at risk for arrhythmias.