Slow conduction through an arc of block: A basis for arrhythmia formation postmyocardial infarction.

INTRODUCTION: The electrophysiologic basis for characteristic rate-dependent, constant-late-coupled (390 + 54 milliseconds) premature ventricular beats (PVBs) present 4-5 days following coronary artery occlusion were examined in 108 anesthetized dogs. METHODS AND RESULTS: Fractionated/double potentials were observed in injured zone bipolar and composite electrograms at prolonged sinus cycle lengths (1,296 ± 396 milliseconds). At shorter cycle lengths, conduction of the delayed potential decremented, separating from the initial electrogram by a progressively prolonged isoelectric interval. With sufficient delay of the second potential following an isoelectric interval, a PVB was initiated. Both metastable and stable constant-coupled PVBs were associated with Wenckebach-like patterns of delayed activation following an isoelectric interval. Signal-averaging from the infarct border confirmed the presence of an isoelectric interval preceding the PVBs (N = 15). Pacing from the site of double potential formation accurately reproduced the surface ECG morphology (N = 15) of spontaneous PVBs. Closely-spaced epicardial mapping demonstrated delayed activation across an isoelectric interval representing "an arc of conduction block." Rate-dependent very slow antegrade conduction through a zone of apparent conduction block (N = 8) produced decremental activation delays until the delay was sufficient to excite epicardium distal to the original "arc of conduction block," resulting in PVB formation. CONCLUSION: The present experiments demonstrate double potential formation and rate-dependent constant-coupled late PVB formation in infarcted dog hearts. Electrode recordings demonstrate a prolonged isoelectric period preceding PVB formation consistent with very slow conduction (<70 mm/s) across a line of apparent conduction block and may represent a new mechanism of PVB formation following myocardial infarction.

Intermittent vs. Continuous Anticoagulation theRapy in patiEnts with Atrial Fibrillation (iCARE-AF): a randomized pilot study.

PURPOSE: We hypothesized that intermittent anticoagulation based on daily rhythm monitoring using the novel oral anticoagulants (NOACs) is feasible and safe among patients with paroxysmal atrial fibrillation (AF). METHODS: Patients with paroxysmal AF and ≥1 risk factors for stroke were randomized to either intermittent or continuous anticoagulation. Those in the intermittent group were instructed to transmit a daily ECG using an iPhone-based rhythm monitoring device. If AF was detected, patients received one of the NOACs for 48 h-1 week. Patients who failed to transmit an ECG for three consecutive days or more than 7 days total were crossed over to continuous anticoagulation. Patients in the continuous group received one of the NOACs. RESULTS: Fifty-eight patients were randomized to either intermittent (n = 29) or continuous anticoagulation (n = 29). Over a median follow-up of 20 months, 20 patients in the intermittent group failed to submit a daily ECG at least once (median three failed submissions). Four patients (14 %) crossed over to continuous anticoagulation due to failure to submit an ECG for three consecutive days. One stroke (continuous group) occurred during the study. Major bleeding occurred in two patients in the continuous and one patient in the intermittent group, after crossing over to continuous anticoagulation. In a prespecified per-protocol analysis, gastrointestinal bleeding was more frequent in the continuous group (16 vs. 0 %; p = 0.047). CONCLUSIONS: Intermittent anticoagulation based on daily rhythm monitoring is feasible and may decrease bleeding in low-risk patients with paroxysmal AF. A larger trial, adequately powered to detect clinical outcomes, is warranted.

Functional aspects of His bundle physiology and pathophysiology: Clinical implications.

In this review we present evidence from many experimental studies which challenge the concept of predestination of His bundle fibers. Using both intra- and extracellular His bundle pacing in the context of atrio-ventricular block and the development of bundle branch blocks these experimental studies provide the underlying mechanisms for the recent clinical findings showing the benefits of permanent His bundle pacing.

Spectral Analysis of Baseline Electrocardiogram During Atrial Fibrillation Predicts Response to Antiarrhythmic Drug Therapy in Patients With Persistent Atrial Fibrillation.

BACKGROUND: We evaluated the ability of spectral analysis of the baseline ECG during atrial fibrillation (AF) to predict the response of persistent AF to antiarrhythmic drug therapy. METHODS: Patients with persistent AF who were admitted for dofetilide loading were prospectively enrolled in the study. Atrial activity was extracted from the ECG using an Independent Component Analysis method and then subjected to a Modified Periodogram. The regularity index was computed as the ratio of the power in the dominant frequency and all its harmonics to the total power in the spectrum. Patients were followed at 1 month, 3 months and every 3 months thereafter. RESULTS: Of 28 patients enrolled in the study, 14 (50%) converted acutely to sinus rhythm during the 3-day hospital loading period. The clinical and echocardiographic characteristics of patients with and without acute pharmacologic conversion were similar. The regularity index was significantly higher in those who converted to sinus rhythm compared to those who did not (0.71 ± 0.20 vs. 0.38 ± 0.13, respectively; P < 0.0001). A regularity index ≥0.44 had a 79% sensitivity and 93% specificity to predict acute conversion and was associated with a nearly 5-fold increase in the acute conversion rate (odds ratio = 4.89; 95% confidence interval 1.74-13.75; P = 0.003). The regularity index was the only independent predictor of acute conversion. Neither acute conversion, nor the regularity index predicted sinus rhythm maintenance, after a median follow-up of 10 months. CONCLUSION: Increased regularity index predicts acute conversion of persistent AF during dofetilide loading, but does not predict long-term sinus rhythm maintenance.

Current concepts of anatomy and electrophysiology of the sinus node.

The sinoatrial node, or sinus node, of humans is the principal pacemaker of the heart. Over the last century, studies have unraveled the complex molecular architecture of the sinus node and the expression of unique ion channels within its specialized myocytes. Aim of this review is to describe the embriology, the anatomy, the histology and the electrophisiology of the sinus node.

The role of the autonomic ganglia in atrial fibrillation.

Recent experimental and clinical studies have shown that the epicardial autonomic ganglia play an important role in the initiation and maintenance of atrial fibrillation (AF). In this review, we present the current data on the role of the autonomic ganglia in the pathogenesis of AF and discuss potential therapeutic implications. Experimental studies have demonstrated that acute autonomic remodeling may play a crucial role in AF maintenance in the very early stages. The benefit of adding ablation of the autonomic ganglia to the standard pulmonary vein (PV) isolation procedure for patients with paroxysmal AF is supported by both experimental and clinical data. The interruption of axons from these hyperactive autonomic ganglia to the PV myocardial sleeves may be an important factor in the success of PV isolation procedures. The vagus nerve exerts an inhibitory control over the autonomic ganglia and attenuation or loss of this control may allow these ganglia to become hyperactive. Autonomic neuromodulation using low-level vagus nerve stimulation inhibits the activity of the autonomic ganglia and reverses acute electrical atrial remodeling during rapid atrial pacing and may provide an alternative non-ablative approach for the treatment of AF, especially in the early stages. This notion is supported by a preliminary human study. Further studies are warranted to confirm these findings.

Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation.

BACKGROUND: Transcutaneous low-level tragus electrical stimulation (LLTS) suppresses atrial fibrillation (AF) in canines. OBJECTIVES: This study examined the antiarrhythmic and anti-inflammatory effects of LLTS in humans. METHODS: Patients with paroxysmal AF who presented for AF ablation were randomized to either 1 h of LLTS (n = 20) or sham control (n = 20). Attaching a flat metal clip onto the tragus produced LLTS (20 Hz) in the right ear (50% lower than the voltage slowing the sinus rate). Under general anesthesia, AF was induced by burst atrial pacing at baseline and after 1 h of LLTS or sham treatment. Blood samples from the coronary sinus and the femoral vein were collected at those time points and then analyzed for inflammatory cytokines, including tumor necrosis factor alpha and C-reactive protein, using a multiplex immunoassay. RESULTS: There were no differences in baseline characteristics between the 2 groups. Pacing-induced AF duration decreased significantly by 6.3 ± 1.9 min compared with baseline in the LLTS group, but not in the control subjects (p = 0.002 for comparison between groups). AF cycle length increased significantly from baseline by 28.8 ± 6.5 ms in the LLTS group, but not in control subjects (p = 0.0002 for comparison between groups). Systemic (femoral vein) but not coronary sinus tumor necrosis factor (TNF)-alpha and C-reactive protein levels decreased significantly only in the LLTS group. CONCLUSIONS: LLTS suppresses AF and decreases inflammatory cytokines in patients with paroxysmal AF. Our results support the emerging paradigm of neuromodulation to treat AF.

High-dose cytosine arabinoside-induced symptomatic bradycardia.

Cardiac complications of high-dose cytosine arabinoside (HiDAC), although rare, predominantly include pericarditis, pericardial effusion and cardiomyopathy (with concurrent use of cyclophosphamide). Clinically significant arrhythmias associated with HiDAC, although reported in the literature, are rare. The following case report has for the first time used the Naranjo Scale to document a high-probability association (definite adverse drug reaction) of cytarabine with symptomatic sinus bradycardia.

Relationship between catheter contact force and radiofrequency lesion size and incidence of steam pop in the beating canine heart: electrogram amplitude, impedance, and electrode temperature are poor predictors of electrode-tissue contact force and lesion size.

BACKGROUND: Electrode-tissue contact force (CF) is believed to be a major factor in radiofrequency lesion size. The purpose of this study was to determine, in the beating canine heart, the relationship between CF and radiofrequency lesion size and the accuracy of predicting CF and lesion size by measuring electrogram amplitude, impedance, and electrode temperature. METHODS AND RESULTS: Eight dogs were studied closed chest. Using a 7F catheter with a 3.5 mm irrigated electrode and CF sensor (TactiCath, St. Jude Medical), radiofrequency applications were delivered to 3 separate sites in the right ventricle (30 W, 60 seconds, 17 mL/min irrigation) and 3 sites in the left ventricle (40 W, 60 seconds, 30 mL/min irrigation) at (1) low CF (median 8 g); (2) moderate CF (median 21 g); and (3) high CF (median 60 g). Dogs were euthanized and lesion size was measured. At constant radiofrequency and time, lesion size increased significantly with increasing CF (P<0.01). The incidence of a steam pop increased with both increasing CF and higher power. Peak electrode temperature correlated poorly with lesion size. The decrease in impedance during the radiofrequency application correlated well with lesion size for lesions in the left ventricle but less well for lesions in the right ventricle. There was a poor relationship between CF and the amplitude of the bipolar or unipolar ventricular electrogram, unipolar injury current, and impedance. CONCLUSIONS: Radiofrequencylesion size and the incidence of steam pop increase strikingly with increasing CF. Electrogram parameters and initial impedance are poor predictors of CF for radiofrequency ablation.

Atrial tachyarrhythmias induced by the combined effects of ß1/2-adrenergic autoantibodies and thyroid hormone in the rabbit.

Activating autoantibodies (AAb) to ß-adrenergic receptors (ßAR) are associated with atrial fibrillation in patients with Graves' disease. In the present study, we examined the interaction of thyroid hormone with ß1/2AR-AAb in inducing atrial tachyarrhythmias in the rabbit. Immunization of rabbits with a ß1AR or ß2AR second extracellular loop peptide produced high titers of ß1AR-AAb or ß2AR-AAb. Thyroid hormone in combination with ß1AR-AAb or ß2AR-AAb induced a significant number of sustained sinus tachycardia and atrial tachycardia, respectively. Both combinations resulted in significantly increased inductions of sustained arrhythmias compared to AAb alone. Thyroid hormone alone induced sustained sinus and junctional tachycardia. Sera from immunized rabbits specifically bound to and activated ß1AR or ß2AR in transfected cells in vitro. This study demonstrates thyroid hormone qualitatively accentuates the specific arrhythmogenic action of these AAb and quantitatively enhances their rate. Our data support a dual role of AAb and thyroid hormone in Graves'-associated tachyarrhythmias.

The Propensity for Inducing Atrial Fibrillation: A Comparative Study on Old versus Young Rabbits.

It is well established that atrial fibrillation (AF) is far more common in elderly humans. Autonomic activation is thought to be an operative mechanism for AF propensity. The aim of the study was to investigate the impact of age on atrial tachyarrhythmia induction in a rabbit model. Six old (aged 4-6 years) and 9 young (aged 3-4 months) New Zealand white rabbits were subjected to a catheter-based electrophysiological study. Atrial tachyarrhythmia susceptibility was tested by burst pacing before and after infusion of increasing concentrations of acetylcholine. Both young and old rabbits were in normal sinus rhythm at the beginning of the infusion/burst pacing protocol. The old rabbits had faster heart rates and a marked increase in atrial tachyarrhythmias compared to the young rabbits. Nonsustained and sustained AF events were more frequent in the old rabbits. No significant fibrosis was observed in the atria of either young or old rabbits. In conclusion, the old rabbits have a greater propensity for induction of AF. The significantly faster heart rates in the old rabbits suggest that dominant sympathetic activity may play an important role in the propensity for AF in this group.

Inducible cardiac arrhythmias caused by enhanced ß1-adrenergic autoantibody expression in the rabbit.

Previous studies demonstrated burst pacing and intravenous infusion of ACh induced sustained atrial tachycardia when rabbits were immunized to produce ß2-adrenergic receptor (ß2AR)-activating autoantibodies. The objective of this study was to examine the arrhythmogenic effect of ß1-adrenergic receptor (ß1AR)-activating autoantibodies in the rabbit. Eight New Zealand white rabbits were immunized with a ß1AR second extracellular loop peptide to raise ß1AR antibody titers. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization. Arrhythmia occurrence was determined in response to burst pacing before and after ACh infusion in incremental concentrations of 10 µM, 100 µM, and 1 mM. The baseline sinus heart rate before and after immunization averaged 149 ± 17 per min and 169 ± 16 per min, respectively (P < 0.05). In the preimmune studies, there were five sustained (≥10 s) arrhythmias in 32 induction attempts, which occurred in only four of eight rabbits. In the postimmune studies, there were 22 sustained arrhythmias in 32 induction attempts, which occurred in all eight rabbits (P < 0.0001 for the independent effect of immunization). Of the 22 sustained arrhythmias postimmunization, 15 were sinus tachycardia compared with only two before immunization (P < 0.01 for the independent effect of immunization). Postimmune (but not preimmune) rabbit sera demonstrated specific binding to ß1AR and induced significant ß1AR activation in transfected cells in vitro. No cross-reactivity with ß2AR was observed. In conclusion, in contrast with rabbits with ß2AR-activating autoantibodies that demonstrate predominantly atrial tachycardias, enhanced autoantibody activation of ß1AR in the rabbit leads to tachyarrhythmias mainly in the form of sustained sinus tachycardia.

Risk of coronary artery injury with radiofrequency ablation and cryoablation of epicardial posteroseptal accessory pathways within the coronary venous system.

BACKGROUND: Ablation of epicardial posteroseptal accessory pathways requires ablation within the coronary venous system. We assessed the risk of coronary artery (CA) injury with radiofrequency ablation (RFA) within the coronary venous system as a function of the distance between the CA and ablation site. We also examined the efficacy and safety of cryoablation close to a CA. METHODS AND RESULTS: Two-hundred forty patients underwent ablation for epicardial posteroseptal accessory pathways. Coronary angiography was performed before ablation in the last 169 patients and was repeated after ablation if performed in the coronary venous system within 5 mm of a significant CA. The distance between the ideal ablation site and closest CA was <2 mm in 100 (59%), 3 to 5 mm in 28 (16%), and >5 mm in 41 of 169 (25%) patients. CA injury was observed in 11 of 22 (50%) and 1 of 15 (7%) patients when RFA was performed within 2 and 3 to 5 mm of a CA, respectively. Cryoablation was performed in 26 patients with a significant CA located within 5 mm. Cryoablation alone eliminated epicardial posteroseptal accessory pathway conduction in 17 of 26 (65%) patients and in 8 patients with additional RFA without CA narrowing in any patient. During a follow-up period of 3 to 6 months, single procedure success rates were 90% and 77% for RFA and cryoablation at the ideal site, respectively. CONCLUSIONS: The risk of CA injury with RFA is correlated inversely with the distance from the ablation site. Cryoablation is a safe and reasonably effective alternative when a significant CA is located close to the ideal ablation site.

Wide complex tachycardia in the presence of class I antiarrhythmic agents: a diagnostic challenge.

We present two patients with paroxysmal atrial fibrillation on class 1C antiarrhythmic drugs without concomitant atrioventricular (AV) nodal blocking agents who developed atrial flutter with 1:1 AV conduction. Their electrocardiogram revealed wide complex tachycardia with rates >200/minute. Atrial flutter with 1:1 conduction in the presence of class IC antiarrhythmic drugs may present a diagnostic challenge. These cases illustrate the importance of coadministering an AV nodal blocking agent with class IC antiarrhythmic agents in patients with atrial fibrillation. The differential diagnosis of wide complex tachycardia in patients taking class IC agents should include atrial flutter with 1:1 AV conduction.

Inhibition of atrial fibrillation by low-level vagus nerve stimulation: the role of the nitric oxide signaling pathway.

PURPOSE: We examined the role of the phosphatidylinositol-3 kinase (PI3K)/nitric oxide (NO) signaling pathway in low-level vagus nerve stimulation (LLVNS)-mediated inhibition of atrial fibrillation (AF). METHODS: In 17 pentobarbital anesthetized dogs, bilateral thoracotomies allowed the attachment of electrode catheters to the superior and inferior pulmonary veins and atrial appendages. Rapid atrial pacing (RAP) was maintained for 6 h. Each hour, programmed stimulation was used to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3 h, RAP was overlapped with right LLVNS (50 % below that which slows the sinus rate). In group 1 (n = 7), LLVNS was the only intervention, whereas in groups 2 (n = 6) and 3 (n = 4), the NO synthase inhibitor N (G)-nitro-L-arginine methyl ester (L-NAME) and the PI3K inhibitor wortmannin, respectively, were injected in the right-sided ganglionated plexi (GP) during the last 3 h. The duration of acetylcholine-induced AF was determined at baseline and at 6 h. Voltage-sinus rate curves were constructed to assess GP function. RESULTS: LLVNS significantly decreased the acetylcholine-induced AF duration by 8.2 ± 0.9 min (p < 0.0001). Both L-NAME and wortmannin abrogated this effect. The cumulative WOV (the sum of the individual WOVs) decreased toward baseline with LLVNS (p < 0.0001). L-NAME and wortmannin blunted this effect during the fifth (L-NAME only, p < 0.05) and the sixth hour (L-NAME and wortmannin, p < 0.05). LLVNS suppressed the ability of GP stimulation to slow the sinus rate, whereas L-NAME and wortmannin abolished this effect. CONCLUSION: The anti-arrhythmic effects of LLVNS involve the PI3K/NO signaling pathway.

Atrial tachycardia provoked in the presence of activating autoantibodies to ß2-adrenergic receptor in the rabbit.

BACKGROUND: A recent clinical study of patients with inappropriate sinus tachycardia reported that autoantibodies to ß-adrenergic receptors (ß2ARs) could act as agonists to induce atrial arrhythmias. OBJECTIVE: To test the hypothesis that activating autoantibodies to the ß2AR in the rabbit atrium are arrhythmogenic. METHODS: Five New Zealand white rabbits were immunized with a ß2AR second extracellular loop peptide to raise ß2AR antibody titers. A catheter-based electrophysiologic study was performed on anesthetized rabbits before and after immunization. Arrhythmia occurrence was determined in response to burst pacing before and after the infusion of acetylcholine in incremental concentrations of 10 µM, 100 µM, and 1 mM at 1 mL/min. RESULTS: In the preimmune studies when ß2AR antibody titers were undetectable, of a total of 20 events, only 3 episodes of nonsustained (<10 seconds) atrial arrhythmias were induced. In the postimmune studies when ß2AR antibody titers ranged from 1:160,000 to 1:1.28 million, burst pacing induced 10 episodes of nonsustained or sustained (≥10 seconds) arrhythmias in 20 events (P = .04 vs preimmune; χ(2) and Fisher exact test). Taking into account only the sustained arrhythmias, there were 6 episodes in 20 events in the postimmune studies compared with 0 episodes in 20 events in the preimmune studies (P = .02). Immunized rabbits demonstrated immunoglobulin G deposition in the atria, and their sera induced significant activation of ß2AR in transfected cells in vitro compared to the preimmune sera. CONCLUSIONS: Enhanced autoantibody activation of ß2AR in the rabbit atrium leads to atrial arrhythmias mainly in the form of sustained atrial tachycardia.

Development and validation of a prognostic index for risk stratification of patients with early repolarization.

BACKGROUND: Early repolarization (ER) is associated with increased mortality in the general population. We sought to develop and validate a prognostic index (PI) of mortality in patients with ER. METHODS: We identified 852 consecutive patients (mean age 49 ± 12 years) with ER (J-point elevation ≥0.1 mV in inferior or lateral leads), from the VA electronic electrocardiogram (ECG) database. A random sample of age-matched patients with normal ECG was used as control (n = 257). The initial cohort was randomly split into a derivation and a validation cohort (2/3 and 1/3 of patients, respectively). A PI was derived from the weighed sum of the regression coefficients of each independent risk factor in the final model using Cox regression analysis. RESULTS: During a median follow-up of 6.4 years, 170 patients died. ER was associated with increased mortality compared to control (HR 1.49, 95% CI 1.05-2.12; P = 0.03). Older age, lower body mass index, non-African American race, current use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or sulfonyureas, prolonged corrected QT (QTc), and higher ER amplitude independently predicted all-cause mortality. Annualized mortality rates were 1.3%, 2.2%, and 3.7% in the low, intermediate, and high-risk groups, respectively, in the derivation cohort (log rank P < 0.0001) and 0.8%, 1.9%, and 4.1% in the low, intermediate, and high-risk groups, respectively, in the validation cohort (log rank P < 0.0001). Model discrimination was very good (c-statistic = 0.85 and 0.80 for derivation and validation cohort, respectively). CONCLUSIONS: A PI derived from simple clinical and ECG characteristics predicts mortality in patients with ER and may be used clinically for risk stratification.

The intrinsic autonomic nervous system in atrial fibrillation: a review.

The procedure of catheter ablation for the treatment of drug resistant atrial fibrillation (AF) has evolved but still relies on lesion sets intended to isolate areas of focal firing, mainly the myocardial sleeves of the pulmonary veins (PVs), from the rest of the atria. However the success rates for this procedure have varied inversely with the type of AF. At best success rates have been 20 to 30% below that of other catheter ablation procedures for Wolff-Parkinson-White syndrome, atrioventricular junctional re-entrant tachycardia and atrial flutter. Basic and clinical evidence has emerged suggesting a critical role of the ganglionated plexi (GP) at the PV-atrial junctions in the initiation and maintenance of the focal form of AF. At present the highest success rates have been obtained with the combination of PV isolation and GP ablation both as catheter ablation or minimally invasive surgical procedures. Various lines of evidence from earlier and more recent reports provide that both neurally based and myocardially based forms of AF can separately dominate or coexist within the context of atrial remodeling. Future studies are focusing on non-pharmacological, non-ablative approaches for the prevention and treatment of AF in order to avoid the substantive complications of both these regimens.