Practice Variation in Anticoagulation Prescription and Outcomes After Device-Detected Atrial Fibrillation.

BACKGROUND: Device-detected atrial fibrillation (AF) is associated with increased risk of stroke; however, there are no clearly defined thresholds of AF burden at which to initiate oral anticoagulation (OAC). We sought to describe OAC prescription practice variation in response to new device-detected AF and the association with outcomes. METHODS: We performed a retrospective cohort study using data from the Veterans Health Administration linked to remote monitoring data that included day-level AF burden. We included patients with cardiac implantable electronic devices and remote monitoring from 2011 to 2014, CHA2DS2-VASc score ≥2, and no prior stroke or OAC receipt in the preceding 2 years. We determined the proportion of patients prescribed OAC within 90 days after new device-detected AF across a range of AF thresholds (≥6 minutes to >24 hours) and examined site variation in OAC prescription. We used multivariable Cox proportional hazards regressions to determine the association of OAC prescription with stroke by device-detected AF burden. RESULTS: Among 10 212 patients with cardiac implantable electronic devices, 4570 (45%), 3969 (39%), 3263 (32%), and 2469 (24%) had device-detected AF >6 minutes, >1 hour, >6 hours, and >24 hours, respectively. For device-detected AF >1 hour, 1712 patients met inclusion criteria (72±10 years; 1.5% female; CHA2DS2-VASc score 4.0±1.4; HAS-BLED score 2.6±1.1). The proportion receiving OAC varied based on device-detected AF burden (≥6 minutes: 272/2101 [13%]; >1 hour: 273/1712 [16%]; >6 hours: 263/1279 [21%]; >24 hours: 224/818 [27%]). Across 52 sites (N=1329 patients), there was substantial site-level variation in OAC prescription after device-detected AF >1 hour (median, 16%; range, 3%-67%; median odds ratio, 1.56 [95% credible interval, 1.49-1.71]). In adjusted models, OAC prescription after device-detected AF >24 hours was associated with reduced stroke risk (hazard ratio, 0.28; 95% CI, 0.10-0.81; P=0.02), although the propensity-adjusted model was significant when AF lasted at least 6 minutes. CONCLUSIONS: Among veterans with cardiac implantable electronic devices, device-detected AF is common. There is large practice variation in 90-day OAC initiation after new device-detected AF, with low rates of treatment overall, even for episodes that last >24 hours. The strongest association of OAC with reduction in stroke was observed after device-detected AF >24 hours. Randomized trials are needed to confirm these observational findings.

Depression and outcome among veterans with implantable cardioverter defibrillators with or without cardiac resynchronization therapy capability.

BACKGROUND: The impact of depression on outcome in implantable cardioverter defibrillator (ICD) recipients has not been fully appreciated. We assessed the prevalence of depression and its association with heart failure (HF) outcome among veterans with ICDs. METHODS AND RESULTS: Patients enrolled between January 2005 and January 2010 in the Outcomes among Veterans with Implantable Defibrillators Registry were studied. We examined the cross-sectional association of depression with severity of HF functional class as well as the association of depression with the composite outcome of mortality or HF hospitalization over a mean follow-up time of 2.7 years. There were 3,862 patients enrolled. Patients with depression (1,162, 43%) were younger (63.1 ± 9.4 years vs 66.6 ± 9.9 years, P < 0.001), more likely to have a history of tobacco or alcohol abuse (P < 0.0001) or atrial fibrillation (P = 0.05) while having a higher ejection fraction (28.3% vs 27.4%, P = 0.03). Depression was associated with advanced HF class at time of implant; odds ratio (OR; vs class I) for class III: 1.65 (confidence interval [CI] 1.17-2.33), class IV: 1.73 (95% CI 1.08-2.76). Death or HF hospitalization was more likely to occur in patients with depression (35.2% vs 32.0%, HR: 1.15 [95% CI 0.99-1.33]). The predictive value of depression was stronger after multivariable adjustment; HR: 1.25 (95% CI 1.05-1.49). CONCLUSION: Depression was prevalent among veterans with ICDs. Depression was associated with severity of HF. The predictive value of associated depression was significant after multivariable adjustment.

P2X7 receptor-mediated release of excitatory amino acids from astrocytes.

Astrocyte glutamate release can modulate synaptic activity and participate in brain intercellular signaling. P2X7 receptors form large ion channels when activated by ATP or other ligands. Here we show that P2X7 receptors provide a route for excitatory amino acid release from astrocytes. Studies were performed using murine cortical astrocyte cultures. ATP produced an inward current in patch-clamped astrocytes with properties characteristic of P2X7 receptor activation: the current was amplified in low divalent cation medium, blocked by pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and more potently activated by 3'-O-(4-benzoyl)benzoyl ATP (BzATP) than by ATP itself. Measurement of current reversal potentials showed the relative BzATP-induced permeabilities to different substrates to be Na+, 1 > Cl-, 0.34 > N-methyl-D-glucamine, 0.27 > L-glutamate, 0.15 approximately D-aspartate, 0.16. Astrocytes exposed to BzATP also became permeable to Lucifer yellow, indicating a large channel opening. Release of L-glutamate and D-aspartate through P2X7 channels was confirmed using radiolabeled tracers. As with the inward current, release of glutamate and D-aspartate was induced by BzATP more potently than ATP, amplified in Ca2+/Mg2+-free medium, and blocked by PPADS or oxidized ATP. Efflux through P2X7 channels is a previously unrecognized route of ligand-stimulated, nonvesicular astrocyte glutamate release.

Surface electrocardiographic characteristics of right and left atrial flutter.

BACKGROUND: There is little information about the surface expression of non-cavotricuspid isthmus (CTI)-dependent right atrial (RA) or left atrial (LA) flutter circuits. METHODS AND RESULTS: We retrospectively evaluated 32 episodes (in 26 patients) of atypical RA and 22 episodes (in 21 patients) of LA flutter. The surface ECG of 13 patients with lower-loop reentry was similar to that of their pattern during counterclockwise (CCW) CTI atrial flutter (AFL), except for decreased amplitude of the terminal forces in the inferior leads. In 11 of 24 episodes characterized by high or multiple breaks over the crista, the ECG showed changes that depended on the initial activation sequence of the LA. In 7 of 8 episodes of upper-loop reentry, the ECG pattern completely mimicked that for clockwise (CW) CTI AFL. All 11 patients with an LA septal circuit showed a typical ECG pattern characterized by prominent forces in lead V1 with flat deflections in the other surface leads. Eleven patients with other LA circuits had a more variable pattern but showed decreased voltage in the inferior leads compared with that of a group with CCW-CTI AFL (1.6+/-1 vs 2.68+/-0.7 mV, respectively; P<0.05). CONCLUSIONS: The RA surface-ECG patterns different from those of CCW or CW-CTI could still be CTI dependent. In contrast, a typical CW-CTI surface pattern was always seen in patients with upper-loop reentry, which was non-CTI dependent. LA AFL circuits had either flat or low-amplitude forces in the inferior leads.

Atrial Fibrillation Burden and Short-Term Risk of Stroke: Case-Crossover Analysis of Continuously Recorded Heart Rhythm From Cardiac Electronic Implanted Devices.

BACKGROUND: The temporal relationship of atrial fibrillation (AF) and stroke risk is controversial. We evaluated this relationship via a case-crossover analysis of ischemic strokes in a large cohort of patients with cardiac implantable electronic devices. METHODS AND RESULTS: We identified 9850 patients with cardiac implantable electronic devices remotely monitored in the Veterans Administration Health Care System between 2002 and 2012. There were 187 patients with acute ischemic stroke and continuous heart rhythm monitoring for 120 days before the stroke (age, 69±8.4 years; 98% with an implantable defibrillator). We compared each patient's daily AF burden in the 30 days before stroke (case period) with their AF burden during days 91 to 120 pre stroke (control period). Defining positive AF burden as ≥5.5 hours of AF on any given day, 156 patients (83%) had no positive AF burden in both periods and, in fact, had little to no AF; 15 (8%) patients had positive AF burden in both periods. Among the discordant (informative) patients, 13 exceeded 5.5 hours of AF in the case period but not in the control period, whereas 3 had positive AF burden in the control but not in the case period (warfarin-adjusted odds ratio for stroke, 4.2; 95% confidence interval, 1.5-13.4). Odds ratio for stroke was highest (17.4; 95% confidence interval, 5.39-73.1) in the 5 days immediately after a qualifying occurrence of AF and decreased toward 1.0 as the period after the AF occurrence increased beyond 30 days. CONCLUSIONS: In this population with continuous heart rhythm recording, multiple hours of AF had a strong but transient effect raising stroke risk.

Optimizing the detection of bidirectional block across the flutter isthmus for patients with typical isthmus-dependent atrial flutter.

The purpose of this study was to show that multipolar electrographic recordings along the subeustachian isthmus (SI) can better differentiate slow conduction from complete isthmus block after atrial flutter ablation, leading to a lower incidence of recurrent atrial flutter (Afl). Despite the presence of various techniques to identify bidirectional conduction block (BDB) after isthmus ablation for typical Afl, several studies, including a report from a national registry, suggest that radiofrequency ablation is still associated with a 15% recurrence rate. Thus, techniques that can distinguish slow conduction from complete isthmus block have the potential for reducing long-term recurrences. We evaluated patients who underwent radiofrequency ablation for typical isthmus-dependent Afl. Patients were separated into 2 groups. Group A underwent assessment of BDB with conventional methods. In group B, BDB was assessed by placing a multipolar catheter along the floor of the SI, pacing adjacent to the line of radiofrequency application, and assessing electrographic activation on either side. One hundred thirty-one cases of Afl ablation were analyzed (86 in group A, 45 in group B). Over a mean follow-up period of 17 months, recurrence rates of Afl were 16.5% in group A and 4.3% in group B (p = 0.043). Thus, assessment of BDB by placement of a multipolar catheter across the SI after ablation of typical Afl is associated with a significant reduction in long-term recurrence of Afl.

Significance of bundle branch block during atrioventricular nodal reentrant tachycardia.

There are very limited data on the effects of bundle branch block (BBB) in patients with atrioventricular nodal reentrant tachycardia (AVNRT). Studies in a total of 155 patients with 162 episodes of AVNRT were retrospectively analyzed. A total of 38 patients (25%) developed spontaneous right BBB, whereas 5 (3%) developed left BBB during tachycardia. Five of the 38 (13%) with right BBB showed near identical prolongation of both the ventriculoatrial (VA) (15 +/- 5 ms; 10 to 23) and His to atrial intervals (HA) (14 +/- 4 ms; 10 to 20) with an identical atrial activation sequence for both right BBB or normal QRS tachycardia complexes. In contrast, all 5 patients with left BBB showed a decrease in the VA (-18 +/- 11 ms; 10 to 36) with unchanged HA comparing left BBB to normal QRS patterns during AVNRT. The magnitude of prolongation of the His to ventricular interval (HV) during left BBB (19 +/- 12 ms; 10 to 40) was nearly identical to the decrease in the VA. In conclusion, prolongation of VA and HA with unchanged HV in patients with AVNRT and right BBB suggests that right BBB is due to a block in the fibers in close proximity to the His recording site. The data suggest that fibers in the His bundle are predestined to activate the right bundle branch, and in AVNRT the lower turnaround point may be within the His bundle.

The year in review of clinical cardiac electrophysiology.

This past year saw multiple important advances in the field clinical cardiac electrophysiology. Seminal articles describing new anticoagulant drugs for stroke prevention in atrial fibrillation were published. New results that raise questions regarding the safety of dronedarone and several new promising techniques in AF ablation were described. Important articles that refine our understanding of the risk of sudden death among Wolff-Parkinson-White patients were published. In the basic and translational sciences, the application of gene therapy to the study and potential treatment of arrhythmias was described, whereas genetic determinants important to the optimal treatment of inherited arrhythmia syndromes were further elucidated. Issues relevant to cardiac rhythm device therapy included investigations into the St. Jude Riata lead, new applications of device monitoring, predicting response to cardiac resynchronization therapy, and the use of pacemakers for vasovagal syncope.

Long-term electrical survival analysis of Riata and Riata ST silicone leads: National Veterans Affairs experience.

BACKGROUND: A medical device advisory issued by St Jude Medical in November 2011 estimated 0.63% all-cause abrasion rate on their Riata and Riata ST silicone high-voltage lead families (Riata/ST), leading to Food and Drug Administration class I recall. We performed an independent comparative, long-term electrical survival analysis of Riata/ST and 3 other high-voltage lead families in a large national cohort of patients. OBJECTIVE: To evaluate long-term electrical survival of Riata/ST leads relative to other commonly evaluated high-voltage leads. METHODS: Failure rates of Riata/ST, Sprint Quattro Secure (Quattro), Sprint Fidelis (Fidelis), and Endotak Reliance G/SG (Endotak) leads from the Veterans Administration's National Cardiac Device Surveillance Center database, consisting of 24,145 patients with remote transmissions since 2003, were analyzed. Survival Probabilities were determined with Kaplan-Meier survival analysis and compared using the log-rank test. RESULTS: Of 1,403 Riata/ST, 6,091 Quattro, 5,073 Fidelis, and 2,401 Endotak leads identified, 5-year survival probability of Riata/ST leads (97.5%) was significantly lower than that of Quattro (99.3%) and Endotak (99.4%) leads (P <.0001) but higher than that of Fidelis leads (89.6%) (P <.0001). Riata ST leads showed a 5-year survival of 95.5% (95% confidence interval 92.4-97.4) compared to 98.4% (95% confidence interval 97.1-99.1) in Riata leads (P = .003). CONCLUSIONS: There is decreased survival probability of Riata/ST leads compared to other contemporary high-voltage leads, with decreased survival of Riata ST silicone compared to Riata lead series. Careful long-term follow-up should be maintained in patients with Riata/ST leads in order to prevent inappropriate shocks or failed device interventions. Our results were determined in advance of Food and Drug Administration class I recall, which suggested that large-scale remote monitoring may be an effective tool for continued implantable cardioverter-defibrillator system surveillance.

Dual-chamber implantable cardioverter-defibrillator selection is associated with increased complication rates and mortality among patients enrolled in the NCDR implantable cardioverter-defibrillator registry.

OBJECTIVES: The aim of this study was to compare single- versus dual-chamber implantable cardioverter-defibrillator (ICD) implantation and complication rates in a large, real-world population. BACKGROUND: The majority of patients enrolled in ICD efficacy trials received single-chamber devices. Although dual-chamber ICDs offer theoretical advantages over single-chamber defibrillators, the clinical superiority of dual-chamber models has not been conclusively proven, and they may increase complications. METHODS: The National Cardiovascular Data Registry ICD Registry was used to examine the association between baseline characteristics and device selection in 104,049 patients receiving single- and dual-chamber ICDs between January 1, 2006, and December 31, 2007. A longitudinal cohort design was then used to determine in-hospital complication rates. RESULTS: Dual-chamber devices were implanted in 64,489 patients (62%). Adverse events were more frequent with dual-chamber than with single-chamber device implantation (3.17% vs. 2.11%, p < 0.001), as was the rate of in-hospital mortality (0.40% vs. 0.23%, p < 0.001). After adjusting for demographics, medical comorbidities, diagnostic test data, and ICD indication, the odds of any complication (odds ratio: 1.40; 95% confidence interval: 1.28 to 1.52; p < 0.001) and in-hospital mortality (odds ratio: 1.45; 95% confidence interval: 1.20 to 1.74; p < 0.001) were increased with dual-chamber versus single-chamber ICD implantation. CONCLUSIONS: In this large, multicenter cohort of patients, dual-chamber ICD use was common. Dual-chamber device implantation was associated with increases in periprocedural complications and in-hospital mortality compared with single-chamber defibrillator selection.

Electrophysiologic properties of para-Hisian atrial tachycardia.

BACKGROUND: Focal atrial tachycardia (AT) originates from preferential sites, including the tricuspid and mitral annuli. AT arising from the atrioventricular annuli is initiated and terminated with programmed stimulation and is, in general, adenosine and verapamil sensitive. Para-Hisian AT arising from the apex of the triangle of Koch has been considered to be a distinct entity, characterized by unique electrophysiological properties. OBJECTIVE: We sought to more fully delineate the electrophysiological and electrocardiographic properties of para-Hisian AT in a large series of patients. METHODS: The study population consisted of 38 patients (63 ± 15 years; 23 female) with AT from the para-Hisian region. The ATs were focal and originated from the anteroseptal tricuspid annulus, in close proximity to the His bundle recording. Proximity to the His bundle was confirmed by electrogram recordings, fluoroscopy, and centrifugal activation during three-dimensional mapping. RESULTS: The mean AT cycle length was 421 ± 69 ms. AT was associated with a distinct P-wave morphology that was significantly narrower than the P wave during sinus rhythm. Adenosine (5.0 ± 1.5 mg) terminated AT in 34/35 patients. Intravenous verapamil terminated AT in three of three patients. Catheter ablation was attempted in 30 patients and was successful in 26 (87%). CONCLUSION: The para-Hisian region is a source of focal AT, with properties consistent with AT arising circumferentially along the tricuspid and mitral annuli, and should be considered a subset of this broader group of "annular" ATs. The electropharmacologic findings in para-Hisian AT are mechanistically consistent with cyclic AMP-mediated triggered activity.

Using the initial vector from surface electrocardiogram to distinguish the site of outflow tract tachycardia.

BACKGROUND: The purpose of this study is to determine whether initial vector force might best distinguish tachycardias arising from the right ventricular (RV) outflow tract (OT) versus aortic sinus cusps (ASCs). METHODS: Among 45 patients with OT tachycardia, we measured the time from the earliest QRS onset in any lead to local onset and to the first QRS peak/nadir in each surface leads during VT. We compared the earliest phase differences among patients with foci in RVOT (n = 32) and in ASCs (n = 13) (determined by ablation), using unpaired t-tests. We determined the optimum cut-points by analyzing the receiver-operator characteristics curves, and derived an algorithm to discriminate ASC from RVOT foci. RESULTS: Compared with an RVOT focus, origin in the ASC was associated with lower likelihood that the earliest lead of QRS activation was V2 (4/13 [12%] vs 29/32 [88%], P = 0.0001), later initial peak/nadir in III (110 +/- 19 vs 93 +/- 16 ms, P = 0.0026) and V2 (75 +/- 26 vs 42 +/- 19 ms, P < 0.0001). After determining the optimum cut-points for each, we found that the presence of any one of these findings discriminated well between RVOT and ASC foci (sensitivity 92%, specificity 88%, positive predictive value 75%, and negative predictive value 97%). The sensitivity and specificity using standard ECG criteria were inferior to the vector approach. CONCLUSIONS: The ECG phase differences during VT can distinguish the origin of OT-VT. Earliest onset or first peak/nadir in V2 and early initial peak/nadir in the inferior leads suggest a RVOT focus.

Reentry within the cavotricuspid isthmus: an isthmus dependent circuit.

BACKGROUND: We describe a new cavotricuspid isthmus (CTI) circuit. METHODS: This study includes 8 patients referred for atrial flutter (AFL) ablation whose tachycardia circuit was confined to the septal CTI and the os of the coronary sinus (CS(OS)) region. Entrainment mapping was performed within the CTI, CS(OS), and other right atrial annular sites (tricuspid annulus (TA)). Electroanatomic mapping was available in 2 patients. RESULTS: Sustained AFL occurred in all patients with mean tachycardia cycle length (TCL) of 318 +/- 54 (276 - 420) ms. During tachycardia, fractionated or double potentials were recorded at either the septal CTI and/or the region of CS(OS) in all, and concealed entrainment with post-pacing interval (PPI)--TCL < or = 25 ms occurred in this area; but manifest entrainment with PPI > TCL was demonstrated from the anteroinferior CTI and other annular sites in 7/8 patients. In one, tachycardia continued with conduction block at the anteroinferior CTI during ablation. Up to three different right atrial activation patterns (identical TCL) were observed. The tachycardia showed a counterclockwise (CCW) pattern in 6, a clockwise pattern in 2, and simultaneous activation of both low lateral right atrium and septum in 5. Electroanatomic mapping was available in 2, showing an early area arising from the septal CTI in 1, and a CCW activation sequence along the TA in another. Radiofrequency application to the septal CTI terminated tachycardia in 4, and tachycardia no longer inducible in all. CONCLUSIONS: We describe a tachycardia circuit confined to the septal CTI/CS(OS) region, and hypothesize that this circuit involves slow conduction within the CTI and around the CS(OS), which acts as a central obstacle.

Site specificity of transverse crista terminalis conduction in patients with atrial flutter.

INTRODUCTION: The causes of transcristal conduction (TC) in patients with atrial flutter (AFL) are unknown. METHODS AND RESULTS: In two groups of patients referred for AFL ablation, 36 had cavotricuspid isthmus (CTI) dependent flutter (Group I) and 24 had lower (n = 21) or upper loop reentry (n = 5) (Group II). After ablation, isthmus block was evaluated by pacing from the coronary sinus (CS) and low lateral right atrium and by alternative techniques, including mapping with electrodes spanning the CTI or electroanatomic mapping. After bidirectional CTI block was verified, 21/36 (58%) in Group I showed TC with CS pacing, including low TC in 16 (including 11 showing "pseudo" CTI conduction), higher TC in 6 and multiple breaks in 3. However, 8 with low TC during CS pacing showed unidirectional block by pacing outside of the CS os. Twelve (50%) in Group II had TC during CS pacing after bidirectional CTI block, with low TC in 5 (2 mimicking residual CTI conduction) and higher breaks in 9. There was no significant difference in the incidence of TC during CS pacing after CTI block between groups. In seven autopsied hearts, the muscle orientation between the proximal CS musculature and Eustachian ridge were examined. Muscular connections between the CS and Eustachian ridge coursing toward the orifice of inferior vena cava were found in one of the hearts. CONCLUSIONS: It is concluded that in patients with bidirectional CTI block, pacing from the CS may be associated with TC mimicking a conduction leak through the isthmus. Pacing just outside the CS os helps distinguish pseudo from true isthmus block.

Alpha(1)-adrenoceptor subtypes mediate negative inotropy in myocardium from alpha(1A/C)-knockout and wild type mice.

Cardiac alpha(1)-adrenoceptors (AR) have two predominant subtypes (alpha(1A)-AR and alpha(1B)-AR) however, their roles in regulating contraction are unclear. We determined the effects of stimulating alpha(1A)-AR (using the subtype-selective agonist A61603) and alpha(1B)-AR (using a gene knockout mouse lacking alpha(1A)-AR) separately, and together (using phenylephrine) on Ca(2+) transients, intracellular pH, and contraction of mouse cardiac trabeculae. Stimulation of alpha(1)-AR subtypes separately or together caused a triphasic contractile response. After a transient ( approximately 3%) force rise (phase 1), force declined markedly (phase 2), then partially recovered (phase 3). In phase 2, the force decline (% of initial) with combined alpha(1A)-AR plus alpha(1B)-AR stimulation (50+/-3%) was more than with separate subtype stimulation (P<0.01), suggesting alpha(1A)-AR and alpha(1B)-AR mediate additive effects during phase 2. Force decline in phase 2 paralleled decreases of Ca(2+) transients that were reduced more with combined vs. separate subtype stimulation. During phase 3 the final force reduction was similar with stimulation of alpha(1A)-AR (20+/-5%), or alpha(1B)-AR (20+/-3%), or both (26+/-4%) suggesting alpha(1A)-AR and alpha(1B)-AR mediate non-additive effects during phase 3. In contrast, Ca(2+) transients recovered fully in phase 3 suggesting reduced force in phase 3 involved decreased myofilament Ca(2+)-sensitivity. Decreased Ca(2+)-sensitivity was not mediated by changes of intracellular pH since this was not affected by alpha(1)-AR stimulation. In contrast to mouse trabeculae, rat trabeculae demonstrated a positive inotropic response to alpha(1)-AR stimulation. In conclusion, for mouse myocardium in vitro both alpha(1)-adrenoceptor subtypes mediate negative inotropy involving decreased Ca(2+) transients and a decreased Ca(2+) sensitivity that does not involve altered intracellular pH.