Genetic Susceptibility for Atrial Fibrillation in Patients Undergoing Atrial Fibrillation Ablation.

BACKGROUND: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. METHODS: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. RESULTS: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13). CONCLUSIONS: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Left atrial booster pump function is an independent predictor of subsequent life-threatening ventricular arrhythmias in non-ischaemic cardiomyopathy.

AIMS: Left atrial (LA) function helps to preserve cardiac output and to control pulmonary capillary wedge pressure in the setting of left ventricular (LV) impairment, but little is known about the contribution of the LA function to ventricular arrhythmia. We sought whether LA booster pump function was associated with arrhythmias in patients undergoing primary prevention implantable cardioverter-defibrillator (ICD) implantation for non-ischaemic dilated cardiomyopathy (NICM), independent of global longitudinal strain (GLS) and mechanical dispersion (MD). METHODS AND RESULTS: We identified 124 NICM patients (56 ± 13, 67 male) who underwent echocardiography pre-ICD implantation for primary prevention. The main outcome measure was appropriate ICD therapy (anti-tachycardia pacing or shock). The mitral A-wave was used as an LA functional marker. MD was defined as standard deviation of time to peak strain of each segment. Over a median follow-up of 3.8 ± 2.2 years, 36 patients had appropriate ICD therapy, including 23 shocks. Patients with appropriate ICD therapy had lower A-wave velocity (P < 0.001), larger LA volume (P < 0.001), and impaired circumferential MD (P = 0.006), but similar ejection fraction (EF) (P = 0.40) and GLS (P = 0.11). In sequential Cox proportional hazards models, A-wave, E/A ratio, and GLS were significantly associated with outcomes, independent of age, sex, and cardiac resynchronization therapy defibrillator or left bundle branch block. In nested Cox models, mitral A-wave had a prognostic value incremental to models with LV systolic (EF and GLS) and diastolic functional parameters (E/A, E/e', and LA volume) and MD. CONCLUSION: LA booster pump function was an independent and incremental predictor of arrhythmias in NICM over GLS and MD, and may aid better risk stratification in this population.

The impact of changing antiseptic skin preparation agent used for cardiac implantable electronic device (CIED) procedures on the risk of infection.

BACKGROUND: Cardiac implantable electronic device (CIED) infection is a major complication that is associated with increased morbidity and mortality. Recent data suggested a relationship between the antiseptic agent used for skin preparation at time of CIED procedure and risk for infection. METHODS: On April 30, 2011, we changed the antiseptic agent used for skin preparation at our tertiary care facility from chlorhexidine-alcohol to povidone-iodine for all CIED procedures. We retrospectively reviewed records of all patients who underwent CIED procedure 1 year before and after the change. CIED infection was defined as pocket or endovascular systemic infection that required removal within 1 year of the index procedure. We examined if the change affected the risk of CIED infection. RESULTS: A total of 2,792 patients underwent 2,840 CIED procedures; 1,748 (61.5%) had implantable cardioverter defibrillator procedures and 1,092 (38.4%) had permanent pacemaker procedures. Chlorhexidine-alcohol agent was used in 1,450 (51.1%) procedures, and povidone-iodine agent was used in 1,390 (48.9%). After 1 year of follow-up, 31 patients (1.09%) developed CIED infection that required system removal. The 1-year infection rate was 1.1% among both antiseptic agent groups and there were no significant differences in the infection presentations among both groups (P = 0.950). Multivariate Cox proportional hazards regression model showed that risk factors for infection within 1 year included age, diabetes, and African American race. CONCLUSION: In one large cohort of patients undergoing CIED procedures, the antiseptic agent used for skin preparation (chlorhexidine-alcohol vs povidone-iodine) was not associated with increased risk of developing CIED infection.

Protected from torsades de pointes? What psychiatrists need to know about pacemakers and defibrillators.

BACKGROUND: Consultation-liaison (C-L) psychiatrists are frequently asked to initiate and manage psychotropic drugs, some of which can delay cardiac repolarization, prolong the QT interval, and increase the risk of torsades de pointes (TdP). This task is complicated by the growing number of patients with cardiovascular implantable electronic devices (CIED) [i.e., permanent pacemakers (PPM), implantable cardioverter defibrillators (ICD), and cardiac resynchronization therapy devices (CRT)]. The precise protective role of CIEDs in the prevention and treatment of TdP is not well-defined. METHODS: We review practical tips for assessment of the QT interval in patients with paced rhythms, as well as the basic operative principles of CIEDs. We examine the available clinical evidence for the use of CIEDs in patients at risk for TdP. RESULTS: Most CIEDs have a pacing function that, when utilized appropriately, can offer partial protection against TdP by prevention of bradycardia. Defibrillators deliver shocks and are reasonably effective at terminating TdP; however, recurrent shocks are common and are associated with significant physical and psychological morbidity. CONCLUSIONS: CIEDs are important tools in the management of drug-induced ventricular arrhythmias in spite of significant limitations. The C-L psychiatrist should remain vigilant in recognizing and managing patients at risk for TdP, and refrain from over-reliance on CIEDs regardless of type or settings. Ultimately, the presence of a CIED should serve as a marker of increased risk of TdP.

QRS fragmentation is not associated with poor response to cardiac resynchronization therapy.

BACKGROUND: QRS fragmentation (fQRS) has been shown to be a marker of scar in patients with left ventricular dysfunction. Whether fQRS is associated with progressive left ventricular remodeling and increased mortality in patients receiving cardiac resynchronization therapy (CRT) is unclear. METHODS: We reviewed the preimplant and follow-up echocardiograms in 233 patients undergoing the new implantation of a CRT device between December 2001 and November 2006. Patients were included if they had a pre-CRT ECG with appropriate filter settings (filter 0.16-100 or 0.16-150 Hz, 25 mm/s, 10 mm/mV), a left ventricular ejection fraction (LVEF) ≤40%, and New York Heart Association class II-IV symptoms on standard medical therapy. The 12-lead electrocardiogram (ECG) was interpreted by two blinded reviewers for the presence of fQRS. Remodeling end points, including changes in LVEF and left ventricular end-diastolic (LVEDV) and systolic (LVESV) volumes, were compared between patients with and without contiguous fQRS, and an assessment of all-cause mortality was made. RESULTS: Two hundred thirty-two patients met inclusion criteria, of which 50 demonstrated fQRS in contiguous leads. There was no difference in improvement in LVEF (%) (7.9 ± 12.9 vs 6.8 ± 11.0, P = 0.60) or reduction in LVEDV (mL) (-30.1 ± 57.2 vs -15.7 ± 47.6) or LVESV (mL) (-33.7 ± 58.1 vs -22.7 ± 50.6, P = 0.40) between patients with and without contiguous fQRS. At a mean follow-up of 4.4 ± 1.9 years, there were a total of 89 deaths, 22 (44.0%) in patients with contiguous fQRS and 67 (36.8%) without (log rank P = 0.31). CONCLUSIONS: QRS fragmentation is not a predictor of progressive ventricular remodeling or mortality in heart failure patients undergoing CRT.

The impact of age and gender on cardiac resynchronization therapy outcome.

BACKGROUND: Cardiac resynchronization therapy (CRT) outcome varies significantly among patients. We aimed to determine the impact of age, gender, and heart failure etiology on the long-term outcome of patients receiving CRT. METHODS: A total of 117 patients with drug-refractory heart failure, New York Heart Association (NYHA) Class III or IV, and a wide QRS complex, who received CRT, were followed for one year. Long-term outcome was measured as a combined end point of hospitalization for heart failure and/or all cause mortality. Efficacy of CRT was compared between men and women, between older and younger patients, and between patients with ischemic and nonischemic heart disease. Time to the primary end point was estimated by the Kaplan-Meier method and comparisons were made using the Breslow-Wilcoxon test. RESULTS: Baseline clinical characteristics were comparable between gender, age, and heart failure etiology subgroups. There was no significant difference in the combined end point between older versus younger (age >70, (n = 71), versus age < 70, (n = 46), P = 0.52); both genders (men, n = 91 vs women, n = 26, P = 0.46) and etiology of the cardiomyopathy (ischemic (n = 79) vs nonischemic (n = 38), P = 0.12). Substratification of the genders by the etiology of the cardiomyopathy, showed that women with ischemic cardiomyopathy (IW, n = 10) had a trend to a worse outcome compared to the other groups i.e., nonischemic women (NIW, n = 16), ischemic men (IM, n = 69), and nonischemic men (NIM, n = 22), P = 0.04. After adjusting for potential covariates, a Cox regression analysis showed no significant difference between the groups (P = 0.61). CONCLUSIONS: CRT outcome appears independent of age, gender, and heart failure etiology in this single institution study.

Polymorphisms in the novel gene acyloxyacyl hydroxylase (AOAH) are associated with asthma and associated phenotypes.

BACKGROUND: The gene encoding acyloxyacyl hydroxylase (AOAH), an enzyme that hydrolyzes secondary fatty acyl chains of LPS, is localized on chromosome 7p14-p12, where evidence for linkage to total IgE (tIgE) concentrations and asthma has been previously reported. OBJECTIVE: We hypothesized that variants in AOAH are associated with asthma and related phenotypes. Because both AOAH and soluble CD14 respond to LPS, we tested for gene-gene interaction. METHODS: We investigated the association between 28 single nucleotide polymorphisms throughout the AOAH gene and asthma, concentrations of tIgE, the ratio of IL-13/IFN-gamma, and soluble CD14 levels among 125 African Caribbean, multiplex asthmatic pedigrees (n = 834). Real-time PCR was used to assess whether AOAH cDNA expression differed with AOAH genotype. RESULTS: Significant effects were observed for all 4 phenotypes and AOAH markers in 3 distinct regions (promoter, introns 1-6, and the intron 12/exon 13 boundary/intron 13 region) by means of single-marker and haplotype analyses, with the strongest evidence for a 2-single-nucleotide-polymorphism haplotype and log[tIgE] (P = .006). There was no difference in AOAH expression levels by AOAH genotype for any of the markers. Comparing genotypic distributions at both the AOAH marker rs2727831 and CD14(-260)C >T raises the possibility of gene-gene interaction (P = .006-.036). CONCLUSION: Our results indicate that polymorphisms in markers within the AOAH gene are associated with risk of asthma and associated quantitative traits (IgE and cytokine levels) among asthmatic subjects and their families in Barbados, and there is an interactive effect on tIgE and asthma concentrations between an AOAH marker and the functional CD14(-260)C >T polymorphism. CLINICAL IMPLICATIONS: AOAH is a novel innate immunity candidate gene associated with asthma and related phenotypes in an African ancestry population.

Clinical course and long-term follow-up of patients receiving implantable cardioverter-defibrillators.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are increasingly used for primary and secondary prevention of sudden cardiac death. Defibrillators were introduced into clinical practice in 1980. Since that time, factors affecting long-term survival and the natural history of defibrillator patients have not been described. OBJECTIVES: The purpose of this study was to identify clinical predictors of long-term survival in patients receiving ICDs. METHODS: The prognostic value of several clinical variables on the likelihood of survival or appropriate ICD therapy in 1,382 consecutive patients receiving ICDs from 1980 to 2003 were evaluated. Data were collected at the time of device implantation, and follow-up was completed through March 2005. RESULTS: In 70 +/- 51 months of follow-up (range 0-282 months), 792 patients died and 421 patients received appropriate ICD therapy at least once. Age, left ventricular ejection fraction, New York Heart Association (NYHA) functional class, Charlson comorbidity index, and antiarrhythmic drug use correlated with mortality. beta-Blocker and angiotensin-converting enzyme inhibitor use was associated with improved survival. Only NYHA functional class correlated with ICD therapy. Patients free of shocks for the first 5 years after ICD implantation had continued risk of arrhythmia recurrence. CONCLUSION: The heart failure characteristics of patients predicted ICD shock probability and survival better than the arrhythmia characteristics or the underlying heart disease. Antiarrhythmic drug use was associated with increased mortality. Beta-blocker and angiotensin-converting enzyme inhibitor use was associated with improved survival. A measurable arrhythmic risk even after prolonged shock-free intervals indicates the need for continued ICD therapy in all patients with appropriate ICD indications.

Polymorphisms in the novel gene acyloxyacyl hydoxylase (AOAH) are associated with asthma and associated phenotypes

BACKGROUND: The gene encoding acyloxyacyl hydrolase (AOAH), an enzyme that hydrolyzes secondary fatty acyl chains of LPS, is localised on chromosome 7p14-p12, where evidence for linkage to total IgE (tIgE) concentrations and asthma has been previously reported. OBJECTIVE: We hypothesized that variants in AOAH are associated with asthma and related phenotypes. Because both AOAH and soluble CD14 respond to LPS, we tested for gene-gene interaction. METHODS: We investigated the association between 28 single nucleotide polymorphisms throughout the AOAH gene and asthma, concentrations of tIgE, the ratio of IL-13/IFN-y, and soluble CD14 levels among 125 African Caribbean, multiplex asthmatic pedigrees (n=834). Real-time PCR was used to assess whether AOAH cDNA expression differed with AOAH genotype. RESULTS: Significant effects were observed for all 4 phenotypes and AOAH markers in 3 distinct regions (promoter, introns 1-6, and the intron 12/exon 13 boundary/intron 13 region) by means of single-marker and haplotype analyses, with the strongest evidence for a 2-single-nucleotide-polymorphism haplotype and log [tIgE] (P=.006). There was no difference in AOAH expression levels by AOAH genotype for any of the markers. Comparing genotypic distributions at both the AOAH marker rs2727831 and CD14(-260)C>T raises the possibility of gene-gene interaction (P=.006-.036). CONCLUSION: Our results indicate that polymorphisms in markers within the AOAH gene are associated with risk of asthma and associated quantitative traits (IgE and cytokine levels) among asthmatic subjects and their families in Barbados, and there is an interactive effect on tIgE and asthma concentrations between an AOAH marker and the functional CD14(-260)C>T polymorphism. CLINICAL IMPLICATIONS: AOAH is a novel innate immunity candidate gene associated with asthma and related phenotypes in an African ancestry population.