Continuous daily assessment of multiple sclerosis disability using remote step count monitoring.

Disability measures in multiple sclerosis (MS) rely heavily on ambulatory function, and current metrics fail to capture potentially important variability in walking behavior. We sought to determine whether remote step count monitoring using a consumer-friendly accelerometer (Fitbit Flex) can enhance MS disability assessment. 99 adults with relapsing or progressive MS able to walk ≥2-min were prospectively recruited. At 4 weeks, study retention was 97% and median Fitbit use was 97% of days. Substudy validation resulted in high interclass correlations between Fitbit, ActiGraph and manual step count tally during a 2-minute walk test, and between Fitbit and ActiGraph (ICC = 0.76) during 7-day home monitoring. Over 4 weeks of continuous monitoring, daily steps were lower in progressive versus relapsing MS (mean difference 2546 steps, p < 0.01). Lower average daily step count was associated with greater disability on the Expanded Disability Status Scale (EDSS) (p < 0.001). Within each EDSS category, substantial variability in step count was apparent (i.e., EDSS = 6.0 range 1097-7152). Step count demonstrated moderate-strong correlations with other walking measures. Lower average daily step count is associated with greater MS disability and captures important variability in real-world walking activity otherwise masked by standard disability scales, including the EDSS. These results support remote step count monitoring as an exploratory outcome in MS trials.

Role of the Na(+)/H(+) exchanger in short-term atrial electrophysiological remodeling.

BACKGROUND: The pathophysiology underlying electrophysiological remodeling (ER) from rapid atrial rates is unknown. We tested the hypothesis that activation of the Na(+)/H(+) exchanger (NHE) by ischemia contributes to ER. METHODS AND RESULTS: Twenty-eight dogs were studied under autonomic blockade. In 15 closed-chest dogs, atrial fibrillation was simulated by right atrial pacing at 600 bpm over 5 hours. Of these, 9 (pace/NHEI) received HOE642, a selective inhibitor of the NHE, and 6 (pace/control) received saline. In pace/controls, atrial effective refractory period (AERP) at a drive cycle length (DCL) of 400 ms shortened from 143+/-7 to 118+/-5 ms (1 hour) and to 122+/-17 ms (5 hours). Shortening of AERP was prevented in the pace/NHEI group (P=0.02 compared with pace/controls). At baseline in all 15 dogs, pacing at shorter DCL resulted in shortening of AERP (physiological rate adaptation), which was lost at 5 hours in pace/controls. In pace/NHEI animals, rate adaptation was maintained despite 5 hours of pacing (P=0.02). In 13 other open-chest dogs, right atrial ERP was determined before and after occlusion of the right coronary artery. Five received HOE642 (ischemia/NHEI), 5 saline (ischemia/control), and 3 intravenous glibenclamide. In ischemia/controls, AERP(400) decreased (156+/-30 to 130+/-32 ms). Shortening of AERP was not prevented by glibenclamide (180+/-20 to 153+/-33 ms) but was prevented in ischemia/NHEI dogs (169+/-12 to 184+/-19 ms, P=0.001 compared with ischemia/controls and ischemia/glibenclamide). Rate adaptation was lost in ischemia/controls and preserved in ischemia/NHEI dogs (P=0. 02). CONCLUSIONS: Activation of the NHE is one mechanism underlying short-term ER.

Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation.

BACKGROUND: Structural and electrophysiological changes of the atria occur with prolonged rapid rates; however, the effects of sustained atrial fibrillation (AF) on autonomic innervation of the atria are unknown. We hypothesized that electrophysiological remodeling from rapid atrial rates is accompanied by altered atrial autonomic innervation. METHODS AND RESULTS: Six dogs (paced group) underwent atrial pacing at 600 bpm; 9 dogs (control animals) were not paced. All paced dogs developed sustained AF by week 4 of pacing. All 15 animals underwent positron emission tomography imaging of the atria with [C-11] hydroxyephedrine (HED) to label sympathetic nerve terminals. HED retention in the atria was significantly greater in paced dogs compared with control animals (P=0.03). Tissue samples from the atrial appendages had a greater concentration of norepinephrine in paced animals than in control animals (P=0.01). The coefficient of variation of HED retention was also greater in paced animals (P=0.05) and was greater in the right atrium than in the left atrium (P=0.004). Epicardial activation maps of AF were obtained in the paced animals at baseline and with autonomic manipulation. Mean AF cycle length was longer in the right atrium (109.2+/-5 ms) than in the left atrium (85.8+/-5.5 ms) at baseline (P=0.005). AF cycle length did not vary significantly from baseline (97.6+/-13.4 ms) with stellate stimulation (100.5+/-6 ms) but lengthened with propranolol (107.5+/-6.1 ms, P=0.03). CONCLUSIONS: Rapid rates of AF produce a heterogeneous increase in atrial sympathetic innervation. These changes parallel disparate effects of rapid pacing-induced AF on atrial electrophysiology.

Inhibition of the Na(+)/H(+) exchanger delays the development of rapid pacing-induced atrial contractile dysfunction.

BACKGROUND: Atrial mechanical stunning due to atrial fibrillation may persist after restoration of sinus rhythm. Although the mechanism of rapid rate-related contractile dysfunction remains unknown, ischemia, pH changes, and calcium overload have been postulated as potential mechanisms. We hypothesized that blockade of the Na(+)/H(+) exchanger (NHE) would alter atrial contractile dysfunction from rapid rates. METHODS AND RESULTS: Twenty-three anesthetized dogs were studied and subjected to 5 hours of rapid right atrial pacing. Ten received an inhibitor of the NHE, 10 received saline, and 3 received nifedipine. All animals underwent placement of 2 sonomicrometers on the left atrium, transesophageal echocardiography, and invasive hemodynamic monitoring. All measurements were made in sinus rhythm. Except for baseline and postdrug measurements, reduction in left atrial fractional shortening was significantly less at all time points in the NHEI group than in the control and nifedipine groups (P:=0.05). The percent change from baseline of left atrial function at all time intervals as assessed by left atrial appendage contraction velocity (LAACV) was significantly less in the NHEI group than in the control (P:=0.05) group. LAACV was significantly preserved at all time intervals (except 300 minutes) in the NHEI group compared with the nifedipine group (P:=0.05). The only significant difference in hemodynamics among the groups was between the control and the nifedipine groups at 30 minutes after drug (P:=0.05). CONCLUSIONS: Treatment with HOE642 significantly blunts the decline in left atrial mechanical function from rapid atrial rates compared with both control and nifedipine-treated groups.

Comparison of high energy direct current and radiofrequency catheter ablation of the atrioventricular junction.

OBJECTIVES: The goal of the study was to determine short- and long-term success and complications of radiofrequency atrioventricular (AV) junction catheter ablation and to compare these with those of high energy direct current catheter ablation. BACKGROUND: Catheter ablation of the AV junction with radiofrequency or direct current energy is an accepted treatment for drug-refractory supraventricular tachycardias. Few data are available on the long-term success and effects of radiofrequency ablation or its comparison with direct current ablation. METHODS: Fifty-four patients who underwent attempted AV junction ablation with radiofrequency energy were followed up for a mean of 24 +/- 8.4 months. These patients were retrospectively compared with 49 patients who underwent attempted AV junction ablation with direct current energy and were followed up for a mean of 41 +/- 23 months. RESULTS: The early success rate at the time of discharge for radiofrequency ablation was 81.5%, which was not statistically different from that for direct current ablation (85.7%). Fewer sessions were required to achieve complete AV block in the radiofrequency group (1.05 +/- 0.23) (mean +/- SD) compared with the direct current group (1.21 +/- 0.41) (p = 0.02). Although overall complication rates were similar for both groups (9.3% in the radiofrequency group and 8.2% in the direct current group), there was a trend toward more life-threatening early complications in those patients who received direct-current shocks (6.8%) than in those who underwent radiofrequency ablation alone (2.3%) (p = 0.1). Early sudden death (one patient), early ventricular tachycardia (two patients) and cardiac tamponade (one patient) were seen only in those patients who underwent ablation with direct current energy, whereas pulmonary embolism (one patient) was the only early life-threatening complication in the radiofrequency group. During follow-up, the rate of recurrence of AV conduction was the same (5%) for both the direct current and radiofrequency groups. In the direct current group, one patient died suddenly 2 weeks after the procedure and another had a cardiac arrest due to ventricular tachycardia 6 h after the procedure. In the radiofrequency group, two patients died suddenly at 11 and 7 months, respectively. Two patients, one who had unsuccessful radiofrequency ablation and required direct current ablation, were resuscitated from ventricular tachycardia. CONCLUSIONS: Radiofrequency energy appears to be as efficacious as and perhaps safer than direct current energy for AV junction ablation.

Differences in organization between acute and chronic atrial fibrillation in dogs.

OBJECTIVES: The purpose of this study was to determine differences in acute and chronic atrial fibrillation (AF) "organization" in canine models. BACKGROUND: Electrophysiologic changes occur during atrial remodeling, but little is known about how remodeling affects AF organization. We hypothesized that atrial remodeling induced by long-term rapid atrial rates heterogeneously decreases AF organization. METHODS: In seven dogs, acute AF was induced by atrial burst pacing, and in eight dogs chronic AF was created by six weeks of continuous rapid atrial pacing. Atrial fibrillation was epicardially mapped from the right atria (RA) and left atria (LA). Atrial cycle length (CL), spatial organization and activation maps were compared. Spatial organization was quantified by an objective signal processing measure between multiple electrograms. RESULTS In acute AF, mean CL was slightly shorter in the LA (124 +/- 16 ms) than it was in the RA (131 +/- 14 ms) (p < 0.0001). In chronic AF, LA CL (96 +/- 14 ms) averaged 24 ms shorter than RA CL (121 +/- 18 ms) (p < 0.0001). Right atria and LA in acute AF had similar levels of organization. In chronic AF, the LA became approximately 25% more disorganized (p < 0.0001) while the RA did not change. In acute AF, a single broad wave front originating from the posterior and medial atrium dominated LA activation. In chronic AF, LA activation was more complex, sustaining multiple reentrant wavelets in the free wall and lateral appendage. CONCLUSIONS: Acute and chronic AF exhibit heterogeneous differences in CL, organization and activation patterns. The LA in chronic AF is faster and more disorganized than it is in acute AF. Differences in the models may be due to heterogeneous electrophysiologic remodeling and anatomic constraints. The design of future AF therapies may benefit by addressing the patient specific degree of atrial remodeling.

Mechanism of initiation of atrial flutter in humans: site of unidirectional block and direction of rotation.

OBJECTIVES: Using a standardized induction protocol, we investigated the mechanism of initiation of atrial flutter, before ablation, to determine the site of initiating unidirectional block and to test the hypothesis that the direction of rotation of atrial flutter depends on the pacing site from which it initiates. BACKGROUND: The high recurrence rate of atrial flutter after presumed successful ablation may be due to difficulty in reinduction after termination. In addition, induction of clockwise flutter is currently of unknown clinical importance. METHODS: Ten patients with documented typical flutter were studied before ablation. A standard protocol consisting of single and double extrastimuli followed by burst pacing was performed from four sites in the right atrium (high and low trabeculated and smooth right atrium) to assess efficacy at inducing atrial flutter. A 20-pole halo catheter placed around the tricuspid annulus and a decapole catheter placed in the coronary sinus were used for mapping during initiation to determine type of flutter induced and the site of unidirectional block during initiation. RESULTS: Atrial flutter was induced in 52 (6.2%) of 838 attempted inductions. Of these, 33 were counterclockwise and 20 were clockwise. Of the 20 inductions resulting in clockwise flutter, 18 were from the trabeculated right atrium, whereas all the counterclockwise inductions were from the smooth right atrium. In all but the two inductions, the site of unidirectional block was identified between the os of the coronary sinus and the low lateral right atrium for both counterclockwise and clockwise flutter, in the same isthmus at which ablation is targeted. CONCLUSIONS: Even in patients with clinical counterclockwise flutter, clockwise flutter is frequently induced before ablation and is dependent on the site of induction: Pacing from the smooth right atrium induces counterclockwise flutter, whereas pacing from the trabeculated right atrium induces clockwise flutter. The site of the unidirectional block during the initiation of either form of flutter is in the low right atrium isthmus.

"Cristal tachycardias": origin of right atrial tachycardias from the crista terminalis identified by intracardiac echocardiography.

OBJECTIVES: We sought to use intracardiac echocardiography (ICE) to identify the anatomic origin of focal right atrial tachycardias and to define their relation with the crista terminalis (CT). BACKGROUND: Previous studies using ICE during mapping of atrial flutter and inappropriate sinus tachycardia have demonstrated an important relation between endocardial anatomy and electrophysiologic events. Recent studies have suggested that right atrial tachycardias may also have a characteristic anatomic distribution. METHODS: Twenty-three consecutive patients with 27 right atrial tachycardias were included in the study. ICE was used to facilitate activation mapping in relation to endocardial structures. A 20-pole catheter was positioned along the CT under ICE guidance. ICE was also used to assist in guiding detailed mapping with the ablation catheter in the right atrium. RESULTS: Of 27 focal right atrial tachycardias, 18 (67%, 95% confidence interval [CI] 46% to 83%) were on the CT (2 high medial, 8 high lateral, 6 mid and 2 low). ICE identified the location of the tip of the ablation catheter in immediate relation to the CT in all 18 cases. The 20-pole mapping catheter together with echocardiographic visualization of the CT provided a guide to the site of tachycardia origin along this structure. Radiofrequency ablation was successful in 26 (96%) of 27 (95% CI 81% to 100%) right atrial tachycardias. CONCLUSIONS: This study demonstrates that approximately two thirds of focal right atrial tachycardias occurring in the absence of structural heart disease will arise along the CT. Recognition of this common distribution may potentially facilitate mapping and ablation of these tachycardias.

Postextrasystolic U wave augmentation, a new marker of increased arrhythmic risk in patients without the long QT syndrome.

OBJECTIVES: We attempted to determine the correlation between the presence of postextrasystolic changes in the STU segment and a history of sustained ventricular arrhythmias. BACKGROUND: Postextrasystolic U wave augmentation (a marked increment in U wave amplitude after premature ventricular complexes [PVCs]) is an adverse prognostic sign in the "pause-dependent long QT syndrome." However, the prevalence of postextrasystolic changes in patients without the long QT syndrome is unknown. METHODS: We compared the configuration of the STU segment of the postextrasystolic beat (the sinus beat after a PVC) with the STU configuration during sinus rhythm in three patient groups: 1) 41 patients with spontaneous ventricular tachycardia/fibrillation (VT/VF) (VT/VF group), 2) 63 patients with heart disease and high grade ventricular arrhythmias (control group), and 3) 29 patients with high grade ventricular arrhythmias but no heart disease (reference group). RESULTS: Postextrasystolic T wave changes did not correlate with a history of ventricular tachyarrhythmias. However, postextrasystolic U wave changes were more common among the patients with VT/VF than among control subjects (39% vs. 8.7%, p < 0.001). By logistic multiple regression analysis, a low left ventricular ejection fraction (p < 0.001) and postextrasystolic U wave changes (p < 0.005) were independent predictors of ventricular tachyarrhythmias. CONCLUSIONS: Postextrasystolic T wave changes are common and lack predictive value. Postextrasystolic U wave changes may be a specific marker of a tendency to the development of spontaneous ventricular arrhythmias. Prospective studies should be performed to confirm this association.

Results of radiofrequency catheter ablation for atrial flutter.

RF catheter ablation for symptomatic typical atrial flutter is associated with a high procedural success rate, but a second RF procedure may be required in up to one third of subjects, particularly those with right atrial enlargement. In those subjects with both established AF and flutter, RF ablation for atrial flutter may decrease the recurrence rate of AF. However, patients remain at risk for the development of newly documented AF, most likely secondary to the high incidence of underlying structural heart disease.

Naltrexone blocks the post-shock increase of ethanol consumption.

Attention has recently focused on the possibility of an interaction between ethanol and the endorphin system. In this study the opiate blocker naltrexone prevents the expected post-shock increase of ethanol consumption. This provides further evidence that endogenous opiates are involved in the voluntary drinking of ethanol in rats.

The laboratory evaluation and role of catheter ablation for patients with atrial flutter.

The anatomic substrate for atrial flutter has now been recognized, and improved methods for catheter ablation have been developed. Using mapping techniques such as entrainment mapping, recognizing the different types of flutter that can occur, and testing for conduction block with pacing after ablation, long-term cure of atrial flutter can be achieved in most patients with catheter ablation. Not only is catheter ablative cure of atrial flutter the treatment of choice for drug-refractory patients, but also may now be offered as an alternative to drug therapy.

A high-temporal resolution algorithm for quantifying organization during atrial fibrillation.

Atrial fibrillation (AF) has been described as a "random" or "chaotic" rhythm. Evidence suggests that AF may have transient episodes of temporal and spatial organization. We introduce a new algorithm that quantifies AF organization by the mean-squared error (MSE) in the linear prediction between two cardiac electrograms. This algorithm calculates organization at a finer temporal resolution. (approximately 300 ms) than previously published algorithms. Using canine atrial epicardial mapping data, we verified that the MSE algorithm showed nonfibrillatory rhythms to be significantly more organized than fibrillatory rhythms (p < .00001). Further, we compared the sensitivity of MSE to that of two previously published algorithms by analyzing AF with simulated noise and AF manipulated with vagal stimulation or by adenosine administration to alter the character of the AF. MSE performed favorably in the presence of noise. While all three algorithms distinguished between low and high vagal AF, MSE was the most sensitive in its discrimination. Only MSE could distinguish baseline AF from AF with adenosine. We conclude that our algorithm can distinguish different levels of organization during AF with a greater temporal resolution and sensitivity than previously described algorithms. This algorithm could lead to new ways of analyzing and understanding AF as well as improved techniques in AF therapy.

Conduction barriers in human atrial flutter: correlation of electrophysiology and anatomy.

Animal models of atrial flutter and early mapping studies of human atrial flutter have suggested the importance of barriers in this reentrant arrhythmia. The consistency of rate and morphology of typical atrial flutter suggest a common anatomic substrate for this arrhythmia. The unique endocardial architecture of the right atrium provides anatomic barriers around which reentry occurs. In typical human atrial flutter, the crista terminalis, eustachian ridge, and tricuspid annulus have been identified as barriers to conduction. The importance of conduction barriers, methodology for defining barriers, the anatomic substrate for these barriers, and the role of these barriers in other atrial arrhythmias are discussed.

Role of right atrial endocardial structures as barriers to conduction during human type I atrial flutter. Activation and entrainment mapping guided by intracardiac echocardiography.

BACKGROUND: The importance of barriers in atrial flutter has been demonstrated in animals. We used activation and entrainment mapping, guided by intracardiac echocardiography (ICE), to determine whether the crista terminalis (CT) and eustachian ridge (ER) are barriers to conduction during typical atrial flutter in humans. METHODS AND RESULTS: In eight patients, ICE was used to guide the placement of 20-pole and octapolar catheters along the CT and interatrial septum and a roving catheter to nine sites: just posterior (1) and anterior (2) to the CT along the lateral right atrium, at the fossa ovalis (3), and just posterior and anterior to the ER at the low posterolateral (4 and 5), low posterior (6 and 7), and low posteromedial (8 and 9) right atrium. Entrainment was performed, and each site was considered within the flutter circuit if the postpacing interval-flutter cycle length (PPI-FCL) and the stimulus time-activation time (stim time-act time) were < 10 msec. Split potentials were recorded along the CT with components activated in a low-to-high pattern and a high-to-low pattern. Conduction times, as percentage of FCL, were significantly different at sites on either side of the CT and ER: site 1 (33 +/- 13%) and site 2 (43 +/- 12%) (P = .02), site 4 (48 +/- 24%) and site 5 (75 +/- 8.9%) (P = .02), and site 6 (22 +/- 10%) and site 7 (82 +/- 5.3%) (P = .0009). During entrainment, no surface fusion was observed at sites 5, 7, or 9. The PPI-FCL and stim time-act time were not significantly different than 0 at sites 2, 7, 5, or 9, indicating that they were within the flutter circuit, whereas sites 1, 3, 4, and 6 were not. CONCLUSIONS: ICE enabled the correlation of functional electrophysiological properties with specific anatomic landmarks, identifying the CT and ER as barriers to conduction during human atrial flutter.

Pathological findings following slow pathway ablation for AV nodal reentrant tachycardia.

INTRODUCTION: AV nodal reentrant tachycardia is routinely cured using radiofrequency catheter ablation techniques. However, there remains controversy as to whether the reentrant circuit for this tachycardia exists solely in the AV node or whether perinodal atrial tissues are vital to the circuit. In addition, the effects of radiofrequency ablation of the slow pathway of AV nodal reentrant tachycardia on the AV node are not known. We examined an autopsy specimen to determine the anatomical location and extent of AV nodal damage of radiofrequency slow pathway ablation for cure of AV nodal reentrant tachycardia. METHODS AND RESULTS: A 64-year-old woman with confirmed AV nodal reentrant tachycardia underwent a successful "slow pathway" AV modification with a single radiofrequency application. Five months after the procedure, the patient died from a spontaneous intracranial hemorrhage. Postmortem gross pathological examination of the heart was performed. The heart was then sectioned and stained for histologic examination. On gross examination, a pale lesion 0.5 cm in diameter was seen on the endocardial surface adjacent to the tricuspid annulus, approximately 0.85 cm anterior to the coronary sinus os and 1.15 cm from the apex of the triangle of Koch where the AV node resides. Histologic examination revealed a right atrial lesion composed of connective tissue and fat. The compact AV node and surrounding transitional cells were unaffected histologically, with normal atrial cells lying between the AV node and the lesion. CONCLUSION: Ablation of the slow pathway to cure AV nodal reentrant tachycardia does not produce any gross or histologic damage to the AV node, suggesting that the AV nodal reentrant circuit does not exist in its entirety in the AV node.

Regional entrainment of atrial fibrillation in man.

INTRODUCTION: The feasibility of entrainment of macroreentrant atrial arrhythmias such as atrial flutter is well documented. Recently, it has been shown that regional entrainment of atrial fibrillation is feasible in dogs. METHODS AND RESULTS: Three patients with chronic atrial fibrillation underwent electrophysiologic evaluation with attempted entrainment of atrial fibrillation prior to successful endocardial atrial defibrillation. A 16-pole catheter was positioned in the trabeculated right atrium, and in two patients a multipolar catheter was positioned along the septum. In addition, two large surface area defibrillation catheters were placed, one in the lateral right atrium and one in the coronary sinus. Regional entrainment was attempted in the right atrium and from the catheter in the coronary sinus. Entrainment was achieved in the right atrium in all three patients over a cycle length range of 28, 17, and 13 msec, respectively, and over a radius of atrial tissue of at least 2.8 cm. Regional entrainment was demonstrated from the coronary sinus in one patient during simultaneous right atrial entrainment. Termination of atrial fibrillation during entrainment was not observed. CONCLUSION: Regional entrainment of chronic atrial fibrillation is feasible in humans.

Use of intracardiac echocardiography in interventional electrophysiology.

Intracardiac echocardiography is emerging as a potentially useful tool during RF ablation procedures. There are a number of potential benefits of direct endocardial visualization during RF ablation including: (1) precise anatomical localization of the ablation catheter tip in relation to important endocardial structures, which cannot be visualized with fluoroscopy; (2) reduction in fluoroscopy time; (3) evaluation of catheter tip tissue contact; (4) confirmation of lesion formation and identification of lesion size and continuity; (5) immediate identification of complications; and (6) as a research tool to help in understanding the critical role played by specific endocardial structures in arrhythmogenesis. This article will review existing data and speculate as to possible future roles for intracardiac echocardiography in interventional electrophysiology.