When Is Cardiac Resynchronization Therapy with a Defibrillator Indicated in Patients with Heart Failure, Especially Elderly Patients?

One benefit of an implantable cardioverter-defibrillator is the prevention of sudden cardiac death (SCD). It is recommended for patients with a low left ventricular ejection fraction (LVEF). However, the choice of cardiac resynchronization therapy (CRT) with or without a defibrillator (CRT-D and CRT-P) in elderly patients is controversial. To understand the current situation for proper device selection, we investigated the impact of defibrillators on mortality in elderly patients with heart failure.Consecutive patients who underwent CRT implantation were retrospectively recruited. Baseline characteristics, all-cause mortality, cardiac death, and defibrillator implantation rates were investigated in patients aged > 75 or ≤ 75 years.A total of 285 patients (79 patients aged > 75 years) were analyzed. Elderly patients had more comorbidities, but a lower proportion had ventricular arrhythmia. During the mean follow-up of 47 months, 109 patients died (67 due to cardiac death). Kaplan-Meier analysis showed higher mortality in elderly patients (P = 0.0428) but no significant difference in cardiac death by age group (P = 0.7472). There were no significant differences in mortality between patients with CRT-D versus CRT-P (P = 0.3386).SCD was rare. A defibrillator had no significant impact on mortality. In elderly patients, comorbidities are common and related to mortality. The selection of CRT-D versus CRT-P should take those factors into account.

Calcium-mediated rapid movements defend against herbivorous insects in Mimosa pudica.

Animals possess specialized systems, e.g., neuromuscular systems, to sense the environment and then move their bodies quickly in response. Mimosa pudica, the sensitive plant, moves its leaves within seconds in response to external stimuli; e.g., touch or wounding. However, neither the plant-wide signaling network that triggers these rapid movements nor the physiological roles of the movements themselves have been determined. Here by simultaneous recording of cytosolic Ca2+ and electrical signals, we show that rapid changes in Ca2+ coupled with action and variation potentials trigger rapid movements in wounded M. pudica. Furthermore, pharmacological manipulation of cytosolic Ca2+ dynamics and CRISPR-Cas9 genome editing technology revealed that an immotile M. pudica is more vulnerable to attacks by herbivorous insects. Our findings provide evidence that rapid movements based on propagating Ca2+ and electrical signals protect this plant from insect attacks.

A multi-site, multi-disorder resting-state magnetic resonance image database.

Machine learning classifiers for psychiatric disorders using resting-state functional magnetic resonance imaging (rs-fMRI) have recently attracted attention as a method for directly examining relationships between neural circuits and psychiatric disorders. To develop accurate and generalizable classifiers, we compiled a large-scale, multi-site, multi-disorder neuroimaging database. The database comprises resting-state fMRI and structural images of the brain from 993 patients and 1,421 healthy individuals, as well as demographic information such as age, sex, and clinical rating scales. To harmonize the multi-site data, nine healthy participants ("traveling subjects") visited the sites from which the above datasets were obtained and underwent neuroimaging with 12 scanners. All participants consented to having their data shared and analyzed at multiple medical and research institutions participating in the project, and 706 patients and 1,122 healthy individuals consented to having their data disclosed. Finally, we have published four datasets: 1) the SRPBS Multi-disorder Connectivity Dataset 2), the SRPBS Multi-disorder MRI Dataset (restricted), 3) the SRPBS Multi-disorder MRI Dataset (unrestricted), and 4) the SRPBS Traveling Subject MRI Dataset.

Rapid movements in plants.

Plant movements are generally slow, but some plant species have evolved the ability to move very rapidly at speeds comparable to those of animals. Whereas movement in animals relies on the contraction machinery of muscles, many plant movements use turgor pressure as the primary driving force together with secondarily generated elastic forces. The movement of stomata is the best-characterized model system for studying turgor-driven movement, and many gene products responsible for this movement, especially those related to ion transport, have been identified. Similar gene products were recently shown to function in the daily sleep movements of pulvini, the motor organs for macroscopic leaf movements. However, it is difficult to explain the mechanisms behind rapid multicellular movements as a simple extension of the mechanisms used for unicellular or slow movements. For example, water transport through plant tissues imposes a limit on the speed of plant movements, which becomes more severe as the size of the moving part increases. Rapidly moving traps in carnivorous plants overcome this limitation with the aid of the mechanical behaviors of their three-dimensional structures. In addition to a mechanism for rapid deformation, rapid multicellular movements also require a molecular system for rapid cell-cell communication, along with a mechanosensing system that initiates the response. Electrical activities similar to animal action potentials are found in many plant species, representing promising candidates for the rapid cell-cell signaling behind rapid movements, but the molecular entities of these electrical signals remain obscure. Here we review the current understanding of rapid plant movements with the aim of encouraging further biological studies into this fascinating, challenging topic.

Calcium dynamics during trap closure visualized in transgenic Venus flytrap.

The leaves of the carnivorous plant Venus flytrap, Dionaea muscipula (Dionaea) close rapidly to capture insect prey. The closure response usually requires two successive mechanical stimuli to sensory hairs on the leaf blade within approximately 30 s (refs. 1-4). An unknown biological system in Dionaea is thought to memorize the first stimulus and transduce the signal from the sensory hair to the leaf blade2. Here, we link signal memory to calcium dynamics using transgenic Dionaea expressing a Ca2+ sensor. Stimulation of a sensory hair caused an increase in cytosolic Ca2+ concentration ([Ca2+]cyt) starting in the sensory hair and spreading to the leaf blade. A second stimulus increased [Ca2+]cyt to an even higher level, meeting a threshold that is correlated to the leaf blade closure. Because [Ca2+]cyt gradually decreased after the first stimulus, the [Ca2+]cyt increase induced by the second stimulus was insufficient to meet the putative threshold for movement after about 30 s. The Ca2+ wave triggered by mechanical stimulation moved an order of magnitude faster than that induced by wounding in petioles of Arabidopsis thaliana5 and Dionaea. The capacity for rapid movement has evolved repeatedly in flowering plants. This study opens a path to investigate the role of Ca2+ in plant movement mechanisms and their evolution.

Pain Control by Co-adaptive Learning in a Brain-Machine Interface.

Innovation in the field of brain-machine interfacing offers a new approach to managing human pain. In principle, it should be possible to use brain activity to directly control a therapeutic intervention in an interactive, closed-loop manner. But this raises the question as to whether the brain activity changes as a function of this interaction. Here, we used real-time decoded functional MRI responses from the insula cortex as input into a closed-loop control system aimed at reducing pain and looked for co-adaptive neural and behavioral changes. As subjects engaged in active cognitive strategies orientated toward the control system, such as trying to enhance their brain activity, pain encoding in the insula was paradoxically degraded. From a mechanistic perspective, we found that cognitive engagement was accompanied by activation of the endogenous pain modulation system, manifested by the attentional modulation of pain ratings and enhanced pain responses in pregenual anterior cingulate cortex and periaqueductal gray. Further behavioral evidence of endogenous modulation was confirmed in a second experiment using an EEG-based closed-loop system. Overall, the results show that implementing brain-machine control systems for pain induces a parallel set of co-adaptive changes in the brain, and this can interfere with the brain signals and behavior under control. More generally, this illustrates a fundamental challenge of brain decoding applications-that the brain inherently adapts to being decoded, especially as a result of cognitive processes related to learning and cooperation. Understanding the nature of these co-adaptive processes informs strategies to mitigate or exploit them.

Benefit of Rate Response with Closed-Loop Stimulation in Patients with Difficult Hemodialysis.

Rate-responsive pacing is known to improve quality of life (QOL) in patients with sick sinus syndrome and chronotropic incompetence. However, the sensors for rate response include accelerometers, closed-loop stimulation (CLS), and minute ventilation sensors (MV sensors), each of which has a different mode of action. For this reason, it is important to select appropriate sensors that match the daily habits and behavioral patterns of the patient. For example, young and active patients are expected to have a rate increase when an accelerometer is used, while elderly patients and patients with a physical disability who are only able to move slowly often have a poor response to the accelerometer. MV sensors are therefore better suited to these patients. Furthermore, CLS is considered effective for patients who require an increase in heart rate when at rest, for example, patients undergoing maintenance dialysis.We describe a representative case, demonstrating the effectiveness of closed-loop stimulation in a patient with hypotension during dialysis.

Narrower QRS may be enough to respond to cardiac resynchronization therapy in lightweight patients.

A prolonged QRS duration (QRSd) is promising for a response to cardiac resynchronization therapy (CRT). The variation in human body sizes may affect the QRSd. We hypothesized that conduction disturbances may exist in Japanese even with a narrow (< 130 ms)-QRS complex; such patients could be CRT candidates. We investigated the relationships between QRSd and sex and body size in Japanese. We retrospectively analyzed the values of 338 patients without heart failure (HF) (controls) and 199 CRT patients: 12-lead electrocardiographically determined QRSd, left ventricular diastolic and systolic diameters (LVDd and LVDs), body surface area (BSA), body mass index (BMI), and LVEF. We investigated the relationships between the QRSd and BSA, BMI, and LVD. The men's and women's BSA values were 1.74 m2 and 1.48 m2 in the controls (p < 0.0001), and 1.70 m2 and 1.41 m2 in the CRT patients (p < 0.0001). The men's and women's QRSd values were 96.1 ms and 87.4 ms in the controls (p < 0.0001), and 147.8 ms and 143.9 ms in the CRT group (p = 0.4633). In the controls, all body size and LVD variables were positively associated with QRSd. The CRT response rate did not differ significantly among narrow-, mid-, and wide-QRS groups (83.6%, 91.3%, 92.4%). An analysis of the ROC curve provided a QRS cutoff value of 114 ms for CRT responder. The QRSd appears to depend somewhat on body size in patients without HF. The CRT response rate was better than reported values even in patients with a narrow QRSd (< 130 ms). When patients are considered for CRT, a QRSd > 130 ms may not be necessary, and the current JCS guidelines appear to be appropriate.

Brain-specific homeobox Bsx specifies identity of pineal gland between serially homologous photoreceptive organs in zebrafish.

The pineal gland functioning as a photoreceptive organ in non-mammalian species is a serial homolog of the retina. Here we found that Brain-specific homeobox (Bsx) is a key regulator conferring individuality on the pineal gland between the two serially homologous photoreceptive organs in zebrafish. Bsx knock-down impaired the pineal development with reduced expression of exorh, the pineal-specific gene responsible for the photoreception, whereas it induced ectopic expression of rho, a retina-specific gene, in the pineal gland. Bsx remarkably transactivated the exorh promoter in combination with Otx5, but not with Crx, through its binding to distinct subtypes of PIRE, a DNA cis-element driving Crx/Otx-dependent pineal-specific gene expression. These results demonstrate that the identity of pineal photoreceptive neurons is determined by the combinatorial code of Bsx and Otx5, the former confers the pineal specificity at the tissue level and the latter determines the photoreceptor specificity at the cellular level.

Classification and characterisation of brain network changes in chronic back pain: A multicenter study.

Background. Chronic pain is a common, often disabling condition thought to involve a combination of peripheral and central neurobiological factors. However, the extent and nature of changes in the brain is poorly understood. Methods. We investigated brain network architecture using resting-state fMRI data in chronic back pain patients in the UK and Japan (41 patients, 56 controls), as well as open data from USA. We applied machine learning and deep learning (conditional variational autoencoder architecture) methods to explore classification of patients/controls based on network connectivity. We then studied the network topology of the data, and developed a multislice modularity method to look for consensus evidence of modular reorganisation in chronic back pain. Results. Machine learning and deep learning allowed reliable classification of patients in a third, independent open data set with an accuracy of 63%, with 68% in cross validation of all data. We identified robust evidence of network hub disruption in chronic pain, most consistently with respect to clustering coefficient and betweenness centrality. We found a consensus pattern of modular reorganisation involving extensive, bilateral regions of sensorimotor cortex, and characterised primarily by negative reorganisation - a tendency for sensorimotor cortex nodes to be less inclined to form pairwise modular links with other brain nodes. Furthermore, these regions were found to display increased connectivity with the pregenual anterior cingulate cortex, a region known to be involved in endogenous pain control. In contrast, intraparietal sulcus displayed a propensity towards positive modular reorganisation, suggesting that it might have a role in forming modules associated with the chronic pain state. Conclusion. The results provide evidence of consistent and characteristic brain network changes in chronic pain, characterised primarily by extensive reorganisation of the network architecture of the sensorimotor cortex.

Anterior cingulate cortex connectivity is associated with suppression of behaviour in a rat model of chronic pain.

A cardinal feature of persistent pain that follows injury is a general suppression of behaviour, in which motivation is inhibited in a way that promotes energy conservation and recuperation. Across species, the anterior cingulate cortex is associated with the motivational aspects of phasic pain, but whether it mediates motivational functions in persistent pain is less clear. Using burrowing behaviour as an marker of non-specific motivated behaviour in rodents, we studied the suppression of burrowing following painful confirmatory factor analysis or control injection into the right knee joint of 30 rats (14 with pain) and examined associated neural connectivity with ultra-high-field resting state functional magnetic resonance imaging. We found that connectivity between anterior cingulate cortex and subcortical structures including hypothalamic/preoptic nuclei and the bed nucleus of the stria terminalis correlated with the reduction in burrowing behaviour observed following the pain manipulation. In summary, the findings implicate anterior cingulate cortex connectivity as a correlate of the motivational aspect of persistent pain in rodents.

Impact of Sinus Node Recovery Time after Long-Standing Atrial Fibrillation Termination on the Long-Term Outcome of Catheter Ablation.

Atrial electrical and structural remodeling is related to the perpetuation of atrial fibrillation (AF) subsequent to sinus node dysfunction. We investigated the relationship between AF recurrence after catheter ablation and sinus node dysfunction in long-standing persistent AF patients using the sinus node recovery time (SNRT) after defibrillation.Fifty-one consecutive patients who underwent a first ablation for long-standing persistent AF were enrolled. Intracardiac cardioversion was applied before ablation in the absence of any antiarrhythmic drugs, and the power required to defibrillate, number, and SNRT after defibrillation were measured. All patients underwent the same designed radiofrequency catheter ablation procedure.No patient required permanent pacemaker implantation due to sinus dysfunction after the ablation. During the follow-up period of 28.4 months (3.6-43.7), 35 out of 51 patients (69%) experienced an AF recurrence. The AF recurrence was significantly associated with an older age (60 ± 11 versus 52 ± 12 years in the non-recurrence group, P = 0.0196), longer SNRT after defibrillation (1722 [1410-2656] versus 1295 [676-1651] msec, P = 0.0125), and larger left atrial (LA) volume (59 ± 25 versus 41 ± 15 mL, P = 0.0119). There were no significant differences in the AF duration, AF cycle length, and right and total atrial conduction times between the 2 groups. A longer SNRT after defibrillation (adjusted HR 2.13, 95%CI 1.16-3.71, P = 0.0152) and larger LA volume (adjusted HR 1.03, 95%CI 1.01-1.04, P = 0.0054) were independent predictors of AF recurrence after ablation.Assessment of the SNRT after defibrillation may help to predict a successful ablation in patients with long-standing persistent AF.

Hot Balloon Versus Cryoballoon Ablation for Atrial Fibrillation: Lesion Characteristics and Middle-Term Outcomes.

BACKGROUND: Hot balloon ablation (HBA) and cryoballoon ablation (CBA) were developed to simplify ablation for atrial fibrillation. Because the lesion characteristics and efficacy of these balloon modalities have not been clarified, we compared lesion characteristics and outcomes of HBA and CBA. METHODS: Of 165 consecutive patients who underwent initial catheter ablation for atrial fibrillation, 74 propensity scorematched (37 HBA and 37 CBA) patients were included in our study. RESULTS: Patients' clinical characteristics, including age, sex, body mass index, atrial fibrillation subtype, CHA2DS2-VASc score, and left atrial dimension, were similar between the 2 groups. Touch-up radiofrequency ablation was required for residual/dormant pulmonary vein conduction in 52% of the patients with HBA versus 24% of the patients with CBA (P=0.02) and often in the anterior aspect of the left superior pulmonary vein after HBA (41%) versus the inferior aspect of the inferior pulmonary veins after CBA (22%). HBA lesions were smaller than CBA lesions (23.8±7.9 versus 33.5±14.5 cm2; P=0.0007). Similar results were observed when lesions in each pulmonary vein were compared between groups. Twentyfour hours after the procedure, serum levels of the cardiac biomarkers, including troponin-T, creatine kinase, and creatine kinase-MB, were higher in the HBA group than in the CBA group. Atrial fibrillation recurrence did not differ between the groups within 6 (3% versus 11%; P=0.36) or 12 months (16% versus 16%; P=1.00). CONCLUSIONS: Although HBA lesions appear to be smaller than CBA lesions, middle-term outcomes are not statistically different between these balloon modalities.

The control of tonic pain by active relief learning.

Tonic pain after injury characterises a behavioural state that prioritises recovery. Although generally suppressing cognition and attention, tonic pain needs to allow effective relief learning to reduce the cause of the pain. Here, we describe a central learning circuit that supports learning of relief and concurrently suppresses the level of ongoing pain. We used computational modelling of behavioural, physiological and neuroimaging data in two experiments in which subjects learned to terminate tonic pain in static and dynamic escape-learning paradigms. In both studies, we show that active relief-seeking involves a reinforcement learning process manifest by error signals observed in the dorsal putamen. Critically, this system uses an uncertainty ('associability') signal detected in pregenual anterior cingulate cortex that both controls the relief learning rate, and endogenously and parametrically modulates the level of tonic pain. The results define a self-organising learning circuit that reduces ongoing pain when learning about potential relief.

Mechanistic Insights Into Durable Pulmonary Vein Isolation Achieved by Second-Generation Cryoballoon Ablation.

BACKGROUND: The mechanism explaining the efficacy of cryoballoon ablation (CBA) for atrial fibrillation has not been clarified. METHODS AND RESULTS: We compared lesion characteristics between patients in whom pulmonary vein isolation (PVI) was performed by CBA (n=56) and those by contact force (CF)-based RF ablation (n=56). We evaluated the 3-dimensional PV morphology before and after cryoballoon inflation. After PVI, a 3D left atrial voltage map was created. Pacing (10 mA and 2 ms) was performed within the low voltage area from the ablation line, and electrically unexcitable ablated tissue was identified. ATP-provoked dormant conduction after PVI occurred in 9 of the 224 (4%) PVs in the CBA group and in 13 of the 224 (6%) PVs in the CF group (P=0.3935). The inflated balloon stretched the PV from the original PV ostial surface by 7.1±3.5 mm, but at sites with (vs, sites without) residual PV potential/dormant conduction, the extent of the PV distension was reduced (4.0±4.0 mm vs. 7.2±3.4 mm, P<0.0001). The unexcitable ablated tissue around the PVs was significantly wider in CB patients than in CF patients (16.7±5.1 mm vs. 5.3±2.3 mm, P<0.0001). CONCLUSIONS: Use of the cryoballoon significantly distends the PV. Without this extensive distention, PVI may not be successful. CBA seems to yield wide unexcitable ablation zones. These factors seem to explain the durability of CBA lesions.

Scar characteristics derived from two- and three-dimensional reconstructions of cardiac contrast-enhanced magnetic resonance images: Relationship to ventricular tachycardia inducibility and ablation success.

BACKGROUND: The relationship between cardiac contrast-enhanced magnetic resonance imaging (CE-MRI)-derived scar characteristics and substrate for ventricular tachycardia (VT) in patients with structural heart disease (SHD) has not been fully investigated. METHODS: This study included 51 patients (mean age, 63.3±15.1 years) who underwent CE-MRI with SHD and VT induction testing before ablation. Late gadolinium-enhanced (LGE) regions on MRI slices were quantified by thresholding techniques. Signal intensities (SIs) 2-6 SDs above the mean SI of the remote left ventricular (LV) myocardium were considered as scar border zones, and SI>6 SDs, as scar zone, and the scar characteristics related to VT inducibility and successful ablation via endocardial approaches were evaluated. RESULTS: The proportion of the total CE-MRI-derived scar border zone in the inducible VT group was significantly greater than that in the non-inducible VT group (26.3±9.9% vs. 19.2±7.8%, respectively, P=0.0323). The LV endocardial scar zone to total LV myocardial scar zone ratio in patients whose ablation was successful was significantly greater than that in those whose ablation was unsuccessful (0.61±0.11 vs. 0.48±0.12, respectively, P=0.0042). Most successful ablation sites were located adjacent to CE-MRI-derived scar border zones. CONCLUSIONS: By CE-MRI, we were able to characterize not only the scar, but also its location and heterogeneity, and those features seemed to be related to VT inducibility and successful ablation from an endocardial site.

Thermosensory Perceptual Learning Is Associated with Structural Brain Changes in Parietal-Opercular (SII) Cortex.

The location of a sensory cortex for temperature perception remains a topic of substantial debate. Both the parietal-opercular (SII) and posterior insula have been consistently implicated in thermosensory processing, but neither region has yet been identified as the locus of fine temperature discrimination. Using a perceptual learning paradigm in male and female humans, we show improvement in discrimination accuracy for subdegree changes in both warmth and cool detection over 5 d of repetitive training. We found that increases in discriminative accuracy were specific to the temperature (cold or warm) being trained. Using structural imaging to look for plastic changes associated with perceptual learning, we identified symmetrical increases in gray matter volume in the SII cortex. Furthermore, we observed distinct, adjacent regions for cold and warm discrimination, with cold discrimination having a more anterior locus than warm. The results suggest that thermosensory discrimination is supported by functionally and anatomically distinct temperature-specific modules in the SII cortex.SIGNIFICANCE STATEMENT We provide behavioral and neuroanatomical evidence that perceptual learning is possible within the temperature system. We show that structural plasticity localizes to parietal-opercular (SII), and not posterior insula, providing the best evidence to date resolving a longstanding debate about the location of putative "temperature cortex." Furthermore, we show that cold and warm pathways are behaviorally and anatomically dissociable, suggesting that the temperature system has distinct temperature-dependent processing modules.

Usefulness of filtered unipolar electrogram morphology for evaluating transmurality of ablated lesions during pulmonary vein isolation.

BACKGROUND: Although alteration of the amplitude and morphology of bipolar electrograms is used widely as a guide of the ablation effect, there is little information concerning unipolar electrograms. The amplitude and morphology of filtered bipolar (BP) and filtered unipolar (UP) electrograms were compared during pulmonary vein isolation in patients with atrial fibrillation. METHODS: BP (30-250 Hz) and UP (30-100 Hz) signals from the ablation catheter were recorded before and after each ablation point at the pulmonary vein antrum in 6 patients with atrial fibrillation. RESULTS: In the electrogram group with low-voltage amplitude in BP electrograms before ablation (<0.5 mV), the reduction in amplitude after ablation was significantly greater in the UP than in the BP electrograms, whereas the reduction was similar between the two recording methods in the electrogram group with high-voltage amplitude in BP electrograms (≥0.5 mV). Furthermore, the S wave in the UP electrograms disappeared at the sites of no pace capture after ablation, whereas no characteristic morphologic changes were observed in the BP electrograms. CONCLUSION: Filtered UP electrograms may be useful in assessing the effectiveness of lesion formation.

Dissociable Learning Processes Underlie Human Pain Conditioning.

Pavlovian conditioning underlies many aspects of pain behavior, including fear and threat detection [1], escape and avoidance learning [2], and endogenous analgesia [3]. Although a central role for the amygdala is well established [4], both human and animal studies implicate other brain regions in learning, notably ventral striatum and cerebellum [5]. It remains unclear whether these regions make different contributions to a single aversive learning process or represent independent learning mechanisms that interact to generate the expression of pain-related behavior. We designed a human parallel aversive conditioning paradigm in which different Pavlovian visual cues probabilistically predicted thermal pain primarily to either the left or right arm and studied the acquisition of conditioned Pavlovian responses using combined physiological recordings and fMRI. Using computational modeling based on reinforcement learning theory, we found that conditioning involves two distinct types of learning process. First, a non-specific "preparatory" system learns aversive facial expressions and autonomic responses such as skin conductance. The associated learning signals-the learned associability and prediction error-were correlated with fMRI brain responses in amygdala-striatal regions, corresponding to the classic aversive (fear) learning circuit. Second, a specific lateralized system learns "consummatory" limb-withdrawal responses, detectable with electromyography of the arm to which pain is predicted. Its related learned associability was correlated with responses in ipsilateral cerebellar cortex, suggesting a novel computational role for the cerebellum in pain. In conclusion, our results show that the overall phenotype of conditioned pain behavior depends on two dissociable reinforcement learning circuits.

Effect of adenosine triphosphate on left atrial electrogram interval and dominant frequency in human atrial fibrillation.

BACKGROUND: Complex fractionated atrial electrograms (CFAEs) and high dominant frequency (DF) are targets for atrial fibrillation (AF) ablation. Although adenosine triphosphate (ATP) is known to promote AF by shortening the atrial refractory period, its role in the pathogenesis of CFAEs and DF during AF is not fully understood. METHODS: We recorded electrical activity from a 64-electrode basket catheter placed in the left atrium (LA) of patients with paroxysmal AF (PAF, n=18) or persistent AF (PerAF, n=19) before ablation. Atrial electrogram fractionation intervals (FIs) and DFs were measured from bipolar electrograms of each adjacent electrode pair. Offline mean atrial FIs and DFs were obtained before bolus injection of 30 mg ATP. Peak effect was defined as an R-R interval >3 s. RESULTS: With ATP, the mean FI decreased (from 110.4±29.1 ms to 90.5±24.7 ms, P<0.0001) and DF increased (from 6.4±0.6 Hz to 7.1±0.8 Hz, P<0.0001) in all patients. There was no difference in the FI decrease between the two groups (-20.3±20.5 ms vs. -19.6±14.5 ms, P=0.6032), but the increase in DF was significantly greater in PAF patients (1.1±0.8 Hz vs. 0.3±0.6 Hz, P=0.0051). CONCLUSIONS: ATP shortens atrial FIs and increases DFs in both PAF and PerAF patients. The significant increase in DF in PAF patients suggests that pathophysiologic characteristics related to the frequency of atrial fractionation change as atrial remodeling progresses.