Comparison of electrogram characteristics in persistent atrial fibrillation.

INTRODUCTION: Multiple analysis techniques evaluate electrograms during atrial fibrillation (AF), but none have been established to guide catheter ablation. This study compares electrogram properties recorded from multiple right (RA) and left atrial (LA) sites. METHODS: Multisite LA/RA mapping (281 ± 176/239 ± 166 sites/patient) was performed in 42 patients (30 males, age 63 ± 9 years) undergoing first (n = 32) or redo-AF ablation (n = 10). All electrogram recordings were visually reviewed and artifactual signals were excluded leaving a total of 21 846 for analysis. Electrogram characteristics evaluated were cycle length (CL), amplitude, Shannon's entropy (ShEn), fractionation interval, dominant frequency, organizational index, and cycle length of most recurrent morphology (CLR ) from morphology recurrence plot analysis. RESULTS: Electrogram characteristics were correlated to each other. All pairwise comparisons were significant (p < .001) except for dominant frequency and CLR (p = .59), and amplitude and dominant frequency (p = .38). Only ShEn and fractionation interval demonstrated a strong negative correlation (r = -.94). All other pairwise comparisons were poor to moderately correlated. The relationships are highly conserved among patients, in the RA versus LA, and in those undergoing initial versus redo ablations. Antiarrhythmic drug therapy did not have a significant effect on electrogram characteristics, except minimum ShEn. Electrogram characteristics associated with ablation outcome were shorter minimum CLR , lower minimum ShEn, and longer mimimum CL. There was minimal overlap between the top 10 sites identified by one electrogram characteristic and the top 10 sites identified by the other 10 characteristics. CONCLUSION: Multiple techniques can be employed for electrogram analysis in AF. In this analysis of eight different electrogram characteristics, seven were poorly to moderately correlated and do not identify similar locations. Only some characteristics were predictive of ablation outcome. Further studies to consider electrogram properties, perhaps in combination, for categorizing and/or mapping AF are warranted.

Contemporary outcomes of acute ischemic stroke in atrial fibrillation patients on anticoagulation.

BACKGROUND: Long-term anticoagulation (AC) therapy reduces the risk of stroke in patients with Atrial Fibrillation (AF). However, data on the impact of AC on in-hospital stroke outcomes is lacking. METHODS: The National Inpatient Sample was used to identify adult inpatients with AF and a primary diagnosis of ischemic stroke between 2016 and 2020. Data was stratified between AC users and nonusers. A multivariate regression model was used to describe the in-hospital outcomes, adjusting for significant comorbidities. RESULTS: A total of 655,540 hospitalizations with AF and a primary hospitalization diagnosis of ischemic stroke were included, of which 194,560 (29.7 %) were on long-term AC. Patients on AC tended to be younger (mean age, 77 vs. 78), had a higher average CHA2DS2VASc score (4.48 vs. 4.20), higher rates of hypertension (91 % vs. 88 %), hyperlipidemia (64 % vs. 59 %), and heart failure (34 % vs. 30 %) compared to patients not on long-term AC. Use of AC was associated with decreased in-hospital mortality (aOR [95 % CI]: 0.62 [0.60-0.63]), decreased stroke severity (mean NIHSS, 8 vs. 10), decreased use of tPA (aOR 0.42 [0.41-0.43]), mechanical thrombectomy (aOR 0.85 [0.83-0.87]), intracranial hemorrhage (aOR 0.69 [0.67-0.70]), gastrointestinal bleeding (aOR 0.74 [0.70-0.77]), and discharge to skilled nursing facilities (aOR 0.90 [0.89-0.91]), compared to patients not on AC (P<0.001 for all comparisons). CONCLUSION: Among patients with AF admitted for acute ischemic stroke, AC use prior to stroke was associated with decreased in-hospital mortality, decreased stroke severity, decreased discharge to SNF, and fewer stroke-related and bleeding complications.

Network meta-analysis of His bundle, biventricular, or right ventricular pacing as a primary strategy for advanced atrioventricular conduction disease with normal or mildly reduced ejection fraction.

INTRODUCTION: Although right ventricular pacing (RVP) may impair ventricular function, it is commonly used for advanced atrioventricular block (AVB) and normal or mildly reduced ejection fraction (EF). We aimed to compare His bundle pacing (HBP), biventricular pacing (BiVP), and RVP for advanced AVB in patients with normal or mildly reduced EF. METHODS AND RESULTS: MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov, Scopus, and Web of Science were searched. Outcomes were all-cause death, heart failure hospitalizations (HFH), EF, left ventricular volumes, 6-minute walk test, and QRS duration. HBP or BiVP was compared with RVP. Subsequently, network meta-analysis compared the three pacing options. Our protocol was registered in PROSPERO (CRD42018094132). Six studies compared BiVP and RVP (704 vs 614 patients) and four compared HBP and RVP (463 vs 568 patients). Follow-up was 6 months to 5 years. There was significantly lower mortality and HFH with HBP or BiVP as compared with RVP (odds ratio [OR], 0.66, [0.51-0.85], P = .002; OR, 0.61 [0.45-0.82], P < .001, respectively]. HBP or BiVP also showed significant increase in EF and decrease in QRS duration (mean difference [MD], 5.27 [3.86-6.69], P < .001; MD -42.2 [-51.2 to -33.3], P < .001, respectively). In network meta-analysis, HBP and BiVP were associated with significantly improved survival compared to RVP, with surface under the cumulative ranking curve (SUCRA) probability of 79.4%, 69.4%, and 1.2% for HBP, BiVP, and RVP, respectively. For HFH, SUCRA probability was 91.5%, 57.2%, and 1.3%, respectively. CONCLUSION: HBP or BiVP were the superior strategies to reduce all-cause death and HFH for advanced AVB with normal or mildly reduced EF, with no significant difference between BiVP and HBP.

Systematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

BACKGROUND: Although large randomized clinical trials have found that primary prevention use of an implantable cardioverter-defibrillator (ICD) improves survival in patients with cardiomyopathy and heart failure symptoms, patients who receive ICDs in practice are often older and have more comorbidities than patients who were enrolled in the clinical trials. In addition, there is a debate among clinicians on the usefulness of electrophysiological study for risk stratification of asymptomatic patients with Brugada syndrome. AIM: Our analysis has 2 objectives. First, to evaluate whether ventricular arrhythmias (VAs) induced with programmed electrostimulation in asymptomatic patients with Brugada syndrome identify a higher risk group that may require additional testing or therapies. Second, to evaluate whether implantation of an ICD is associated with a clinical benefit in older patients and patients with comorbidities who would otherwise benefit on the basis of left ventricular ejection fraction and heart failure symptoms. METHODS: Traditional statistical approaches were used to address 1) whether programmed ventricular stimulation identifies a higher-risk group in asymptomatic patients with Brugada syndrome and 2) whether ICD implantation for primary prevention is associated with improved outcomes in older patients (>75 years of age) and patients with significant comorbidities who would otherwise meet criteria for ICD implantation on the basis of symptoms or left ventricular function. RESULTS: Evidence from 6 studies of 1138 asymptomatic patients were identified. Brugada syndrome with inducible VA on electrophysiological study was identified in 390 (34.3%) patients. To minimize patient overlap, the primary analysis used 5 of the 6 studies and found an odds ratio of 2.3 (95% CI: 0.63-8.66; P=0.2) for major arrhythmic events (sustained VAs, sudden cardiac death, or appropriate ICD therapy) in asymptomatic patients with Brugada syndrome and inducible VA on electrophysiological study versus those without inducible VA. Ten studies were reviewed that evaluated ICD use in older patients and 4 studies that evaluated unique patient populations were identified. In our analysis, ICD implantation was associated with improved survival (overall hazard ratio: 0.75; 95% confidence interval: 0.67-0.83; P<0.001). Ten studies were identified that evaluated ICD use in patients with various comorbidities including renal disease, chronic obstructive pulmonary disease, atrial fibrillation, heart disease, and others. A random effects model demonstrated that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.72; 95% confidence interval: 0.65-0.79; P<0.0001), and a second "minimal overlap" analysis also found that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.61-0.82; P<0.0001). In 5 studies that included data on renal dysfunction, ICD implantation was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.60-0.85; P<0.001).

Prevention of Stroke in Atrial Fibrillation After Coronary Stenting.

Background and Purpose- The optimal antithrombotic strategy to balance thromboembolic and bleeding events, especially acute stroke, for patients with atrial fibrillation following coronary stenting remains a matter of debate. We conducted a network meta-analysis to identify the antithrombotic regimen associated with the lowest rate of bleeding and thromboembolic events in atrial fibrillation after coronary stenting. Methods- PubMed, Scopus, and Cochrane Central were searched for randomized controlled trials and observational studies of patients with atrial fibrillation after coronary stenting. The outcomes of interest were stroke, myocardial infarction, major adverse cardiac events, mortality, and major bleeding. A network meta-analysis was performed comparing the available antithrombotic regimens in the literature. Results- Three randomized and 15 observational studies were included, with a total of 23 478 participants. Median follow-up was 2 years. Network meta-analysis demonstrated that vitamin K antagonist plus single antiplatelet therapy or direct-acting oral anticoagulant plus single antiplatelet therapy were the most effective regimens in preventing stroke. Direct-acting oral anticoagulant regimens were associated with lower major bleeding rates than vitamin K antagonist regimens. Regimens with dual antiplatelet therapy were associated with lower rates of myocardial infarction. Vitamin K antagonist plus dual antiplatelet therapy was associated with a lower mortality and low-dose direct-acting oral anticoagulants with decreased major cardiovascular adverse events. Conclusions- Direct-acting oral anticoagulant regimens were associated with less major bleeding and major cardiovascular adverse events, but vitamin K antagonists were associated with decreased mortality and stroke. These results suggest that the decision of antithrombotic therapy in patients with atrial fibrillation after percutaneous coronary intervention needs to be individualized.

A meta-analysis of arrhythmia endpoints in randomized controlled trials of transendocardial stem cell injections for chronic ischemic heart disease.

INTRODUCTION: The electrophysiologic impact of cell-based therapy on the injured myocardium remains highly controversial. We aimed to perform a meta-analysis of studies comparing arrhythmia burden following transendocardial stem cell therapy vs placebo in patients with chronic ischemic heart disease (CIHD). METHODS AND RESULTS: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. No restriction of stem cell type was specified. The outcomes included sustained supraventricular or ventricular arrhythmias (VAs), sudden cardiac death (SCD), and resuscitated sudden cardiac arrest (SCA). Effect sizes were reported as odds ratio (OR) and 95% CI. Poisson regression was used to account for zero-events data. Twelve randomized trials that included 736 patients (384 in the cell therapy group and 352 in the placebo group) were analyzed. Six different cell types were used. Follow-up ranged from 6 to 12 months. There was a significant decrease in risk of SCD in the cell therapy group, (FE OR, 0.19 [0.04, 0.93]; P = .04). In subgroup analysis, there was a significantly lower risk of SCD or resuscitated SCA in the cell therapy group limited to studies that did not use skeletal myoblasts, (FE OR, 0.23 [0.06, 0.83]; P = .03). There was no significant difference in the incidence of sustained VA between groups (FE OR, 0.91 [0.47, 1.77]; P = .8), even after stratifying by cell type. There was no difference in supraventricular arrhythmias between groups. CONCLUSION: Nonskeletal myoblast transendocardial cell therapy was associated with a significantly lower risk of SCD or resuscitated SCA compared to control, with no proarrhythmic effects.

Imaging the Propagation of the Electromechanical Wave in Heart Failure Patients with Cardiac Resynchronization Therapy.

BACKGROUND: Current electrocardiographic and echocardiographic measurements in heart failure (HF) do not take into account the complex interplay between electrical activation and local wall motion. The utilization of novel technologies to better characterize cardiac electromechanical behavior may lead to improved response rates with cardiac resynchronization therapy (CRT). Electromechanical wave imaging (EWI) is a noninvasive ultrasound-based technique that uses the transient deformations of the myocardium to track the intrinsic EW that precedes myocardial contraction. In this paper, we investigate the performance and reproducibility of EWI in the assessment of HF patients and CRT. METHODS: EWI acquisitions were obtained in five healthy controls and 16 HF patients with and without CRT pacing. Responders (n = 8) and nonresponders (n = 8) to CRT were identified retrospectively on the basis of left ventricular (LV) reverse remodeling. Electromechanical activation maps were obtained in all patients and used to compute a quantitative parameter describing the mean LV lateral wall activation time (LWAT). RESULTS: Mean LWAT was increased by 52.1 ms in HF patients in native rhythm compared to controls (P < 0.01). For all HF patients, CRT pacing initiated a different electromechanical activation sequence. Responders exhibited a 56.4-ms ± 28.9-ms reduction in LWAT with CRT pacing (P < 0.01), while nonresponders showed no significant change. CONCLUSION: In this initial feasibility study, EWI was capable of characterizing local cardiac electromechanical behavior as it pertains to HF and CRT response. Activation sequences obtained with EWI allow for quantification of LV lateral wall electromechanical activation, thus providing a novel method for CRT assessment.

Cryoballoon versus Radiofrequency Catheter Ablation in Atrial Fibrillation: A Meta-Analysis.

INTRODUCTION: Radiofrequency (RF) and cryoballoon (CB) catheter ablation are effective for pulmonary vein isolation (PVI) in atrial fibrillation (AF). This report presents an updated meta-analysis comparing the efficacy and safety of CB versus RF ablations in AF. METHODS: Databases and conference abstracts were systematically searched for studies that directly compared CB and RF PVI, and reported safety or efficacy outcomes in follow-up ≥12 months. Recurrent atrial tachyarrhythmias (AT) were defined as AF, atrial flutter, or atrial tachycardia. RESULTS: Twenty-two studies and 8,668 patients were included. Freedom from AT was not significantly different between CB and RF ablations in the pooled population (OR 1.12; 95%CI 0.97-1.29; P = 0.13) and in randomized trials (OR 1.0; 95%CI 0.65-1.56; P = 0.99). Second-generation CB (CB2; 78.1%) and contact-force (CF) sensing RF (78.2%) have improved procedure success rate as compared to first-generation technology (57.9% CB, 58.1% RF). As compared to CF-RF, CB2 demonstrated similar freedom from recurrent AT (OR 1.04; 95%CI 0.71-1.51; P = 0.84). The incidence of pericardial effusions (OR 0.44; 95%CI 0.28-0.69; P < 0.01), tamponade (OR 0.31; 95%CI 0.15-0.64; P < 0.01), and non-AF AT (OR 0.46; 95%CI 0.26-0.83; P < 0.01) were significantly lower with CB ablation, whereas transient phrenic nerve palsy was more incident after CB (OR 7.40; 95%CI 2.56-21.34; P < 0.01). CONCLUSION: There was comparable freedom from AT between CB and RF in patients with AF undergoing PVI. Additionally, freedom from AT was similar between CB2 and CF-RF. However, CB was associated with a lower incidence of pericardial effusions or tamponade, albeit with a higher rate of transient phrenic nerve palsies.

Electrogram morphology recurrence guided catheter ablation for repeat ablation of persistent atrial fibrillation.

BACKGROUND: There are no standard mapping approaches for patients with persistent atrial fibrillation (PeAF), particularly after failed prior catheter ablation (CA). In this study, we assess the feasibility of using Electrogram Morphology Recurrence (EMR) to guide ablation. METHODS: Ten patients with recurrent PeAF after prior CA underwent detailed mapping of both atria during PeAF using the PentaRay (4 mm interelectrode spacing) and 3D mapping with CARTO. At each site, 15 s recordings were made. Custom software identified each electrogram and cross-correlation was used to identify the most recurrent electrogram morphology from which the % recurrence and cycle length of the most repeatable morphology (CLR) was calculated. Sites of shortest CLR and sites within 5 ms of shortest CLR with recurrence ≥ 80% were used to inform CA strategy. RESULTS: A mean of 342.9 ± 131.9 LA and 328.6 ± 91.5 RA sites were recorded per patient. Nine had PV reconnection. Shortest CLR sites guided ablation in 6/10 patients while 1 patient failed to fulfill shortest CLR criteria, and another 3 did not undergo CA guided by shortest CLR due to operator preference. On 12-month follow-up, all 4 patients without shortest CLR guided CA had recurrent PeAF. Of the 6 patients with shortest CLR guided CA, 5 patients did not have recurrent PeAF (p = 0.048), although 1 had paroxysmal AF and 2 had atypical atrial flutter. CONCLUSION: EMR is a feasible, novel technique to guide CA in patients with PeAF. Further evaluation is needed to provide an electrogram-based method for mapping guided targeted ablation of key areas.

Electrogram Morphology Recurrence for Mapping Persistent Atrial Fibrillation: Initial vs Redo Catheter Ablation.

BACKGROUND: Electrogram (EGM) morphology recurrence (EMR) mapping of persistent atrial fibrillation (AF) quantifies consistency of activation and is expected to be high and rapid near AF drivers. OBJECTIVES: The purpose of this study was to compare EMR in left atria (LA) and right atria (RA) in patients undergoing first vs redo ablation for persistent AF. METHODS: Multisite LA/RA mapping (LA: 281 ± 176 sites/patient; RA: 239 ± 166 sites/patient) before persistent AF ablation was performed in 42 patients (30 males, age 63 ± 9 years) undergoing first (Group 1, n = 32) or redo ablation (Group 2, n = 10). After cross-correlation of each automatically detected EGM with every other EGM per recording, the most recurrent electrogram morphology was identified and its frequency (Rec%) and recurrence cycle length (CLR) were computed. RESULTS: In Groups 1 and 2, minimum CLR was 172.8 ± 26.0 milliseconds (LA: 178.2 ± 37.6 milliseconds, RA: 204.4 ± 34.0 milliseconds, P = 0.0005) and 186.5 ± 28.3 milliseconds (LA: 196.1 ± 38.1 milliseconds vs RA: 199.0 ± 30.2 milliseconds, P = 0.75), with Rec% 94.7% ± 10% and 93.8% ± 9.2%. Group 2 minimum CLR was not different from Group 1 (P = 0.20). Shortest CLR was in the LA in 84% of Group 1 and 50% of Group 2 patients (P = 0.04). Only 1 of 10 patients in Group 2 had the shortest CLR in the pulmonary veins (PVs) compared with 19 of 32 in Group 1 (P = 0.01). Most sites (77.6%) had Rec% <50%. CONCLUSIONS: EMR identified the shortest CLR sites in the PVs in 59% of patients undergoing initial persistent AF ablation, consistent with reported success rates of ∼50% for PV isolation. The majority of sites have low recurrence and may reflect bystander sites not critical for maintaining AF. EMR provides a robust new method for quantifying consistency and rapidity of activation direction at multiple atrial sites.

Comparison of in-hospital outcomes of patients undergoing catheter ablation for typical versus atypical atrial flutter.

BACKGROUND: Catheter ablation (CA) is indicated as definitive therapy for patients with either typical or atypical atrial flutter (TAFlutter and AAFlutter, respectively) which is unresponsive to medical therapy. There is a paucity of data regarding in-hospital outcomes of patients undergoing CA. METHODS: Retrospective study using the NIS to identify patients ≥18 years who underwent CA between 2015 and 2017. Individuals were identified using ICD-10-CM/PCS for TAFlutter, AAFlutter, and CA. RESULTS: A total of 17,390 patients underwent CA for Aflutter (33% AAFlutter and 67% TAFlutter). The TAFlutter group was younger (mean 65.9 years vs. 67.2 years), with less females (30% vs. 43%, p ≤ 0.001 for both) compared to the AAFlutter group. The TAFlutter group had a higher rate of diabetes, tobacco use, obesity, and chronic obstructive pulmonary disease (p ≤ 0.001 for all). The AAFlutter cohort had increased prior strokes and atrial fibrillation (p ≤ 0.001 for both). The mean CHA2DS2-VASc score was found to be 2.3 in AAFlutter compared to 2.1 in TAFlutter (p ≤ 0.001). There were significantly higher proportions of thromboembolic events, transfusions, and longer length of stay in the TAFlutter group (p ≤ 0.001 for all) with the AAFlutter group having significantly higher rates of cardioversion, implantation of cardiac devices, and increased hospital charges (p ≤ 0.001 for all); no significant difference was found in mortality after controlling for comorbidities. CONCLUSIONS: We found higher complication rates in CA for patients with TAFlutter, but no difference in in-hospital all-cause mortality. Variation in CA depending upon the mechanism of AFlutter may underlie these differences, and warrant further study.

Flecainide Toxicity Leading to Loss of Pacemaker Capture and Cardiac Arrest.

An 86-year-old man with paroxysmal atrial fibrillation on flecainide, a class IC antiarrhythmic, presented with cardiac arrest. The patient had extremely wide QRS complexes with inconsistent pacemaker capture on electrocardiography. Due to cardiac failure and renal failure, the patient developed progressive flecainide toxicity, which led to pacemaker failure, and ultimately, death. (Level of Difficulty: Beginner.).

Systematic Review for the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

BACKGROUND: Although large randomized clinical trials have found that primary prevention use of an implantable cardioverter-defibrillator (ICD) improves survival in patients with cardiomyopathy and heart failure symptoms, patients who receive ICDs in practice are often older and have more comorbidities than patients who were enrolled in the clinical trials. In addition, there is a debate among clinicians on the usefulness of electrophysiological study for risk stratification of asymptomatic patients with Brugada syndrome. AIM: Our analysis has 2 objectives. First, to evaluate whether ventricular arrhythmias (VAs) induced with programmed electrostimulation in asymptomatic patients with Brugada syndrome identify a higher risk group that may require additional testing or therapies. Second, to evaluate whether implantation of an ICD is associated with a clinical benefit in older patients and patients with comorbidities who would otherwise benefit on the basis of left ventricular ejection fraction and heart failure symptoms. METHODS: Traditional statistical approaches were used to address 1) whether programmed ventricular stimulation identifies a higher-risk group in asymptomatic patients with Brugada syndrome and 2) whether ICD implantation for primary prevention is associated with improved outcomes in older patients (>75 years of age) and patients with significant comorbidities who would otherwise meet criteria for ICD implantation on the basis of symptoms or left ventricular function. RESULTS: Evidence from 6 studies of 1138 asymptomatic patients were identified. Brugada syndrome with inducible VA on electrophysiological study was identified in 390 (34.3%) patients. To minimize patient overlap, the primary analysis used 5 of the 6 studies and found an odds ratio of 2.3 (95% CI: 0.63-8.66; p=0.2) for major arrhythmic events (sustained VAs, sudden cardiac death, or appropriate ICD therapy) in asymptomatic patients with Brugada syndrome and inducible VA on electrophysiological study versus those without inducible VA. Ten studies were reviewed that evaluated ICD use in older patients and 4 studies that evaluated unique patient populations were identified. In our analysis, ICD implantation was associated with improved survival (overall hazard ratio: 0.75; 95% confidence interval: 0.67-0.83; p<0.001). Ten studies were identified that evaluated ICD use in patients with various comorbidities including renal disease, chronic obstructive pulmonary disease, atrial fibrillation, heart disease, and others. A random effects model demonstrated that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.72; 95% confidence interval: 0.65-0.79; p<0.0001), and a second "minimal overlap" analysis also found that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.61-0.82; p<0.0001). In 5 studies that included data on renal dysfunction, ICD implantation was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.60-0.85; p<0.001).

Systematic review for the 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.

BACKGROUND: Although large randomized clinical trials have found that primary prevention use of an implantable cardioverter-defibrillator (ICD) improves survival in patients with cardiomyopathy and heart failure symptoms, patients who receive ICDs in practice are often older and have more comorbidities than patients who were enrolled in the clinical trials. In addition, there is a debate among clinicians on the usefulness of electrophysiological study for risk stratification of asymptomatic patients with Brugada syndrome. AIM: Our analysis has 2 objectives. First, to evaluate whether ventricular arrhythmias (VAs) induced with programmed electrostimulation in asymptomatic patients with Brugada syndrome identify a higher risk group that may require additional testing or therapies. Second, to evaluate whether implantation of an ICD is associated with a clinical benefit in older patients and patients with comorbidities who would otherwise benefit on the basis of left ventricular ejection fraction and heart failure symptoms. METHODS: Traditional statistical approaches were used to address 1) whether programmed ventricular stimulation identifies a higher-risk group in asymptomatic patients with Brugada syndrome and 2) whether ICD implantation for primary prevention is associated with improved outcomes in older patients (>75 years of age) and patients with significant comorbidities who would otherwise meet criteria for ICD implantation on the basis of symptoms or left ventricular function. RESULTS: Evidence from 6 studies of 1138 asymptomatic patients were identified. Brugada syndrome with inducible VA on electrophysiological study was identified in 390 (34.3%) patients. To minimize patient overlap, the primary analysis used 5 of the 6 studies and found an odds ratio of 2.3 (95% CI: 0.63-8.66; p=0.2) for major arrhythmic events (sustained VAs, sudden cardiac death, or appropriate ICD therapy) in asymptomatic patients with Brugada syndrome and inducible VA on electrophysiological study versus those without inducible VA. Ten studies were reviewed that evaluated ICD use in older patients and 4 studies that evaluated unique patient populations were identified. In our analysis, ICD implantation was associated with improved survival (overall hazard ratio: 0.75; 95% confidence interval: 0.67-0.83; p<0.001). Ten studies were identified that evaluated ICD use in patients with various comorbidities including renal disease, chronic obstructive pulmonary disease, atrial fibrillation, heart disease, and others. A random effects model demonstrated that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.72; 95% confidence interval: 0.65-0.79; p<0.0001), and a second "minimal overlap" analysis also found that ICD use was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.61-0.82; p<0.0001). In 5 studies that included data on renal dysfunction, ICD implantation was associated with reduced all-cause mortality (overall hazard ratio: 0.71; 95% confidence interval: 0.60-0.85; p<0.001).

GnRH stimulates expression of PACAP in the pituitary gonadotropes via both the PKA and PKC signaling systems.

Recent studies have demonstrated a clear role for pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of gonadotropin biosynthesis and secretion, both alone and in conjunction with GnRH. First defined as a hypothalamic releasing factor, PACAP subsequently has been identified in the gonadotrope subpopulation of the anterior pituitary gland, suggesting that PACAP may act as an autocrine-paracrine factor in this tissue. In initial studies, we determined that GnRH markedly stimulated endogenous PACAP mRNA levels and promoter-reporter activity in the mature gonadotrope cell line, LbetaT2. GnRH-stimulated rat PACAP promoter activity was blunted with deletion from position -915 to -402 and eliminated with further truncation to position -77 relative to the transcriptional start site. Site-directed mutagenesis demonstrated a functional requirement for a cAMP response element (CRE)-like site at position -205 and an activating protein-1 (AP-1)-like site at position -275, both of which bound CRE binding protein and AP-1 family members on EMSA. Treatment with pharmacological activators or inhibitors of second messenger signaling pathways implicated the protein kinase A, protein kinase C, and MAPK pathways in the GnRH response. In support of these in vitro data, we demonstrate that JunB binds to the rat PACAP gene promoter by chromatin immunoprecipitation assay and that small interfering RNA knockdown of JunB, cFos, and CRE binding protein factors blunts PACAP expression. In summary, these results further elucidate the complex functional interactions between PACAP and GnRH in the anterior pituitary. Specifically, these studies demonstrate that GnRH-stimulated PACAP gene expression is mediated via multiple signaling pathways acting on CRE/AP-1 sites in the proximal gene promoter. Because both PACAP and GnRH regulate gonadotropin biosynthesis and secretion, these results provide important insight into the critical fine tuning of gonadotrope function and, thereby, the maintenance of normal reproductive function.