Background: Advanced generation ablation technologies have been developed to achieve more effective pulmonary vein isolation (PVI) and minimize arrhythmia recurrence after atrial fibrillation (AF) ablation. Methods: We randomly assigned 346 patients with drug-refractory paroxysmal AF to contact force–guided radiofrequency ablation (CF-RF; n=115), 4-minute cryoballoon ablation (Cryo-4; n=115), or 2-minute cryoballoon ablation (Cryo-2; n=116). Follow-up was 12 months. The primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) between days 91 and 365 after ablation or a repeat ablation procedure at any time. Secondary end points included freedom from symptomatic arrhythmia and AF burden. All patients received an implantable loop recorder. Results: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring was 53.9%, 52.2%, and 51.7% with CF-RF, Cryo-4, and Cryo-2, respectively ( P =0.87). One-year freedom from symptomatic atrial tachyarrhythmia defined by continuous rhythm monitoring was 79.1%, 78.2%, and 73.3% with CF-RF, Cryo-4, and Cryo-2, respectively ( P =0.26). Compared with the monitoring period before ablation, AF burden was reduced by a median of 99.3% (interquartile range, 67.8%–100.0%) with CF-RF, 99.9% (interquartile range, 65.3%–100.0%) with Cryo-4, and 98.4% (interquartile range, 56.2%–100.0%) with Cryo-2 ( P =0.36). Serious adverse events occurred in 3 patients (2.6%) in the CF-RF group, 6 patients (5.3%) in the Cryo-4 group, and 7 patients (6.0%) in the Cryo-2 group, with no significant difference between groups ( P =0.24). The CF-RF group had a significantly longer procedure duration but significantly shorter fluoroscopy exposure ( P <0.001 vs cryoballoon groups). Conclusions: In this multicenter, randomized, single-blinded trial, CF-RF and 2 different regimens of cryoballoon ablation resulted in no difference in 1-year efficacy, which was 53% by time to first recurrence but >98% burden reduction as assessed by continuous cardiac rhythm monitoring. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01913522.

The anti-inflammatory actions of the mitochondrial peripheral benzodiazepine receptor (PBR) agonist PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide] were investigated in human microglia. Application of the microglial inflammatory stimulus lipopolysaccharide (LPS, at 100 ng/mL for 3 h), induced enhancement of the expressions of the inducible enzyme, cyclooxygenase-2 (COX-2) and the pro-inflammatory cytokine, tumor necrosis factor-a (TNF-a). PK11195 (at 50 lM) significantly inhibited the LPSinduced up-regulation of both inflammatory factors; at a lower concentration of PK11195 (2 lM) expression of TNF-a, but not COX-2, was reduced. Production of both factors, using immunocytochemistry for COX-2 and ELISA for TNF-a, was markedly reduced with 50 lM of PK11195 added to LPS solution. Acute application of LPS induced a transient increase in intracellular Ca 2+ [Ca 2+ ] i exhibiting both a slow development and recovery in kinetic behavior. This increase in [Ca 2+ ] i consisted primarily of a Ca 2+ influx component accompanied by a smaller mobilization from intracellular Ca 2+ stores. In the presence of PK11195, the amplitude of the [Ca 2+ ] i response induced by LPS was reduced by 54%. Another mitochondrial agent cyclosporin A (CsA), which also acts at the permeability transition pore (PTP) of mitochondrial membrane but at a site different from the PBR, was ineffective in reducing either the LPS-induced expression of COX-2 and TNF-a or the endotoxin increase in [Ca 2+ ] i . These results indicate that the mitochondrial effector PK11195 is a specific and effective agent for inhibiting LPS-induced microglial expressions of COX-2 and TNF-a and that modulation of Ca 2+ -mediated signaling pathways could be involved in the anti-inflammatory actions. Keywords: cyclooxygenase-2, human microglia, intracellular calcium, lipopolysaccharide, mitochondrial effector, PK11195, tumor necrosis factor-a. Microglia are resident cells of the CNS that serve a functional role as scavenger cells similar to that of peripheral macrophages. These cells have been implicated as key mediators of inflammation in the CNS, during which microglia proliferate and contribute to the inflammatory process by phagocytosis and secretion of cytokines, eicosanoids and other agents (McGeer and McGeer 1995). Although inflammation of the CNS is intended as a homeostatic means to contain damage to neural tissue, such damage may occur from the inflammatory process itself (McGeer and McGeer 1995;Rogers and Griffin 1998). In this case microglial responses to inflammatory stimuli in the brain may actually exacerbate, rather than inhibit, neuronal damage. Abbreviations used: [Ca 2+ ] i , intracellular calcium concentration; COX-2, cyclooxygenase-2; CsA, cyclosporin A; DAPI, 4,6-diaminodino-2-phenylindole; DMEM, Dulbecco's modified Eagle's medium; ER, endoplasmic reticulum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LPS, lipopolysaccharide; PBS, phosphate-buffered saline; PBR, peripheral benzodiazepine receptor; PK11195...

Context Many patients have palpitations and seek advice from general practitioners. Differentiating benign causes from those resulting from clinically significant cardiac arrhythmia can be challenging and the clinical examination may aid in this process.Objective To systematically review the accuracy of historical features, physical examination, and cardiac testing for the diagnosis of cardiac arrhythmia in patients with palpitations. MEDLINE (1950 to August 25, 2009 and EMBASE (1947 to August 2009) searches of English-language articles that compared clinical features and diagnostic tests in patients with palpitations with a reference standard for cardiac arrhythmia. Of the 277 studies identified by the search strategy, 7 studies were used for accuracy analysis and 16 studies for diagnostic yield analysis. Two authors independently reviewed articles for study data and quality and a third author resolved disagreements. Data Source, Study Selection, and Data ExtractionData Synthesis Most data were obtained from single studies with small sample sizes. A known history of cardiac disease (likelihood ratio [LR], 2.03; 95% confidence interval [CI], 1.33-3.11), having palpitations affected by sleeping (LR, 2.29; 95% CI, 1.33-3.94), or while the patient is at work (LR, 2.17; 95% CI, 1.19-3.96) slightly increase the likelihood of a cardiac arrhythmia. A known history of panic disorder (LR, 0.26; 95% CI, 0.07-1.01) or having palpitations lasting less than 5 minutes (LR, 0.38; 95% CI, 0.22-0.63) makes the diagnosis of cardiac arrhythmia slightly less likely. The presence of a regular rapid-pounding sensation in the neck (LR, 177; 95% CI, 25-1251) or visible neck pulsations (LR, 2.68; 95% CI, 1.25-5.78) in association with palpitations increases the likelihood of a specific type of arrhythmia (atrioventricular nodal reentry tachycardia). The absence of a regular rapid-pounding sensation in the neck makes detecting the same arrhythmia less likely (LR, 0.07; 95% CI, 0.03-0.19). No other features significantly alter the probability of clinically significant arrhythmia. Diagnostic tests for prolonged periods of electrocardiographic monitoring vary in their yield depending on the modality used, duration of monitoring, and occurrence of typical symptoms during monitoring. Loop monitors have the highest diagnostic yield (34%-84%) for identifying an arrhythmia.Conclusions While the presence of a regular rapid-pounding sensation in the neck or visible neck pulsations associated with palpitations makes the diagnosis of atrioventricular nodal reentry tachycardia likely, the reviewed studies suggest that the clinical examination is not sufficiently accurate to exclude clinically significant arrhythmias in most patients. Thus, prolonged electrocardiographic monitoring with demonstration of symptom-rhythm correlation is required to make the diagnosis of a cardiac arrhythmia for most patients with recurrent palpitations.

The effects of extracellular acidification on Ca 2ϩ -dependent signaling pathways in human microglia were investigated using Ca 2ϩ -sensitive fluorescence microscopy. Adenosine triphosphate (ATP) was used to elicit Ca 2ϩ responses primarily dependent on the depletion of intracellular endoplasmic reticulum (ER) stores, while platelet-activating factor (PAF) was used to elicit responses primarily dependent on store-operated channel (SOC) influx of Ca 2ϩ . The duration of transient responses induced by ATP was not significantly different in standard physiological pH 7.4 (mean duration 30.2 Ϯ 2.5 s) or acidified pH 6.2 (mean duration 31.7 Ϯ 2.8 s) extracellular solutions. However, the time course of the PAF response at pH 7.4 was significantly reduced by 87% with external pH at 6.2. These results suggest that acidification of extracellular solutions inhibits SOC entry of Ca 2ϩ with little or no effect on depletion of ER stores. Changes of extracellular pH over the range from 8.6 to 6.2 during the development of a sustained SOC influx induced by PAF resulted in instantaneous modulation of SOC amplitude indicating a rapidly reversible effect of pH on this Ca 2ϩ pathway. Whole-cell patch clamp recordings showed external acidification blocked depolarization-activated outward K ϩ current indicating cellular depolarization may be involved in the acid pH inhibition. Since SOC mediated influx of Ca 2ϩ is strongly modulated by membrane potential, the electrophysiological data suggest that acidification may act to inhibit SOC by cellular depolarization. These results suggest that acidification observed during cerebral ischemia may alter microglial responses and functions. GLIA 36:22-30, 2001.

Background There is a relative paucity of data linking inappropriate implantable cardioverter-defibrillator (ICD) shocks to adverse clinical outcomes. Objective To examine the association between inappropriate ICD shocks and mortality or heart transplantation in a large population cohort. Design, setting, patients A cohort study which included all subjects who underwent ICD implantation between 1998 and 2008 and were followed up at our institution. Main outcome measures Multivariable Cox regression analyses were conducted to investigate the effect of inappropriate shocks on the risk of death and heart transplantation. Appropriate and inappropriate ICD therapies were modelled as time-dependent covariates. Results A total of 1698 patients were included. During a median follow-up of 30 months, there were 246 (14.5%) deaths and 42 (2.5%) heart transplants. The incidence of inappropriate shocks was 10% at 1 year and 14% at 2 years. In the adjusted model, inappropriate shocks were not associated with death or transplantation (HR=0.97, 95% CI 0.70 to 1.36, p value=0.873). In contrast, appropriate shocks were associated with adverse outcomes (HR=3.11, 95% CI 2.41 to 4.02, p value<0.001). The lack of association between inappropriate shocks and outcomes persisted for those with severely impaired left ventricular function (ejection fraction <30%) and for those receiving multiple inappropriate treatments. Conclusions In this study, we observed no association between inappropriate ICD shocks and increased mortality or heart transplantation, even among those with severely impaired cardiac function. These findings question whether inappropriate ICD shocks lead to adverse outcomes.