Search

Background: Cardiac implantable electronic device (CIED) infection has a high mortality. Previous investigations showed reduced postoperative infections using skin preparation with chlorhexidine, preoperative intravenous antibiotics, and a TYRX-a antibacterial envelope. The additional benefit of antibiotic pocket wash and postoperative antibiotics has not been systematically studied. Methods: The ENVELOPE trial (A Randomized trial of Stand-Alone Use of the Antimicrobial Envelope in High-Risk Cardiac Device Patients) was a prospective, multicenter, randomized, controlled trial enrolling patients undergoing CIED procedures with ≥2 risk factors for infection. The control arm received standard chlorhexidine skin preparation, intravenous antibiotics, and the TYRX-a antibiotic envelope. The study arm received pocket wash (500 mL antibiotic solution) and postoperative antibiotics for 3 days along with the prophylactic control measures. The primary end point was CIED infection and system removal at 6 months. Results: One thousand ten subjects (505 per arm) were enrolled and randomized. Patients were seen in person for a wound check with digital photo 2 weeks postimplant and at 3 and 6 months. CIED infection rate was low in both groups (1.0% control arm and 1.2% study arm, P =0.74). In the 11 subjects with infection and system removal, the time to study end point was 107±92 days with a PADIT (Prevention of Arrhythmia Device Infection Trial) score of 7.4 and a 64% 1-year mortality. Prior history of CIED infection independently predicted CIED system removal at 6 months in all subjects (odds ratio, 9.77, P =0.004). Of 11 infections requiring system removal, 5 were in the setting of pocket hematoma. Conclusions: The use of antibiotic pocket irrigation and postoperative oral antibiotics provides no additional benefit to the prophylactic measures of chlorhexidine skin preparation, preoperative intravenous antibiotics, and an antibiotic envelope in reducing CIED infection. Postoperative hematoma is a major risk factor for infection, driven by the use of antiplatelet and anticoagulant medications. The strongest predictor of CIED removal at 6 months, regardless of intervention, was prior CIED infection. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02809131.

Background: Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods: To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from −3 to −8 in a prior independent genetic association study. Results: Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13–1.46; P =1.5×10 −4 ) to 1.67 (25 variants; 95% confidence interval, 1.47–1.90; P =9.3×10 −15 ). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629–0.811; maximum ΔC statistic from clinical score alone, 0.009–0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39–4.58; P =2.7×10 −3 ). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20–4.40; P =0.01). Conclusions: Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.

Efficacy of Bio-Absorbable Antibacterial Envelope Introduction Cardiac implantable electronic device (CIED) infections are potentially preventable complications associated with high morbidity, mortality, and cost. A recently developed bio-absorbable antibacterial envelope (TYRX™-A) might prevent CIED infections in high-risk subjects. However, data regarding safety and efficacy have not been published. Methods and Results In a single-center retrospective cohort study, we compared the prevalence of CIED infections among subjects with ≥2 risk factors treated with the TYRX™-A envelope (N = 135), the nonabsorbable TYRX™ envelope (N = 353), and controls who did not receive an envelope (N = 636). Infection was ascertained by individual chart review. The mean (95% confidence interval) number of risk factors was 3.08 (2.84–3.32) for TYRX™-A, 3.20 (3.07–3.34) for TYRX™, and 3.09 (2.99–3.20) for controls, P = 0.3. After a minimum 300 days follow-up, the prevalence of CIED infection was 0 (0%) for TYRX™-A, 1 (0.3%) for TYRX™, and 20 (3.1%) for controls (P = 1 for TYRX™-A vs. TYRX™, P = 0.03 for TYRX™-A vs. controls, and P = 0.002 for TYRX™ vs. controls). In a propensity score-matched cohort of 316 recipients of either envelope and 316 controls, the prevalence of infection was 0 (0%) and 9 (2.8%), respectively, P = 0.004. When limited to 122 TYRX™-A recipients and 122 propensity-matched controls, the prevalence of CIED infections was 0 (0%) and 5 (4.1%), respectively, P = 0.024. Conclusions Among high-risk subjects, the TYRX™-A bio-absorbable envelope was associated with a very low prevalence of CIED related infections that was comparable to that seen with the nonabsorbable envelope.

The MICRA leadless pacing system (Medtronic, Inc, Minneapolis, Minnesota) delivers VVI pacing implanted through a 23-F sheath via a femoral approach. We present feasibility of MICRA implantation via a right internal jugular (RIJ) vein approach in a patient with an inferior vena cava (IVC) filter

Background Atrial fibrillation (AF) is a mechanistically heterogeneous disorder, and the ability to identify sub-phenotypes (“endophenotypes”) of AF would assist in the delivery of personalized medicine. We used the clinical response to pulmonary vein isolation (PVI) to identify a sub-group of patients with non-PV mediated AF and sought to define the clinical associations. Methods Subjects enrolled in the Vanderbilt AF Ablation Registry who underwent a repeat AF ablation due to arrhythmia recurrence were analyzed on the basis of PV reconnection. Subjects who had no PV reconnection were defined as “non-PV mediated AF”. A comparison group of subjects were identified who had AF that was treated with PVI-only and experienced no arrhythmia recurrence >12 months. They were considered a group enriched for “PV-mediated AF”. Univariate and multivariable binary logistic regression analysis was performed to investigate clinical associations between the PV and non-PV mediated AF groups. Results Two hundred and twenty nine subjects underwent repeat AF ablation and thirty three (14%) had no PV reconnection. They were compared with 91 subjects identified as having PV-mediated AF. Subjects with non-PV mediated AF were older (64 years [IQR 60,71] vs. 60 [52,67], P = 0.01), more likely to have non-paroxysmal AF (82% [N = 27] vs. 35% [N = 32], P

Cardiac implantable electronic device (CIED) infections are becoming increasingly more common. CIED infections are associated with considerable morbidity, mortality, and cost. Rates of CIED infections are lowest when devices are implanted in high-volume centers by experienced operators. Careful antimicrobial stewardship at the time of CIED implantation is crucial to prevent infections. Evidence-based strategies to prevent CIED infections include the use of prophylactic antibiotics, chlorhexidine-alcohol skin preparation, and antibiotic-impregnated pulse generator envelopes.

Single nucleotide polymorphisms (SNPs) at chromosome 4q25 (near PITX2) are strongly associated with atrial fibrillation (AF). We assessed whether a 4q25-tagging SNP (rs2200733) is associated with PR interval duration in patients with lone and typical AF and controls. Patients with lone (n = 169) and typical (n = 269) AF enrolled in the Vanderbilt AF registry and controls (n = 1,403) derived from the Vanderbilt DNA Biobank were studied. Carriage of the rs2200733T allele (CT or TT genotype) was more common in patients with lone (39%) than typical (25%) AF or controls (21%, p0.01 for both comparisons). In both AF cohorts, we observed an association between genotype and PR interval duration (median PR interval for CC, CT, and TT: 162, 178, and 176 ms, respectively, for lone, p = 0.038 and 166, 180, and 196 ms, respectively, for typical, p = 0.001). After adjustment for covariates, the association between T allele and PR prolongation persisted, with mean effect size of 10.9, 12.8, and 4.4 ms for patients with lone and typical AF and controls, respectively (p0.05 for each comparison). We found that a common 4q25 AF susceptibility allele (rs2200733) is associated with PR interval prolongation in patients with lone and typical AF and controls with no AF. Given that prolonged PR interval is an established risk factor for AF, this observation, in the context of previously described functional effects of PITX2 deficiency, provides further knowledge about the pathophysiological link of 4q25 variants with AF.

Comparison of Extraction of Recalled Defibrillator Leads Introduction The FDA has issued class I advisories for Medtronic Sprint Fidelis® and St. Jude Medical RiataTM ICD lead families. Transvenous RiataTM ICD lead extraction is typically considered higher risk than Fidelis® extraction, based on longer duration from implant, presence of externalized conductors and lack of silicone backfill in the SVC and RV coils. However, published data comparing procedural outcomes between these leads are limited. Methods Records were reviewed for all patients undergoing transvenous extraction of Sprint Fidelis® or RiataTM ICD leads at the Vanderbilt Heart and Vascular Institute from July 2006 to April 2013 to ascertain indication for extraction, procedural details, complications, and 30-day mortality. Results There were significant differences between those undergoing extraction of a Sprint Fidelis® (n = 145) or RiataTM lead (n = 47). In the RiataTM group, device-related endocarditis was a more common indication for extraction, the mean duration of implant was longer, and larger excimer laser sheaths were required. Lead malfunction was a more common indication in the Fidelis® group. There were no statistically significant differences in median procedure duration, procedural success (97.9% vs 95.7%, P = 0.41), median length of hospital stay (1 day vs 1 day, P = 0.23), procedural complication rate (5.5% vs 10.6%, P = 0.23) or 30-day mortality (2.1% vs 2.1%, P = 0.98). Analyses excluding patients with device infection revealed similar results. Conclusion Despite differences in baseline characteristics, this study indicates that Medtronic Sprint Fidelis® and St. Jude RiataTM ICD leads have similar procedural outcomes with transvenous lead extraction.

Introduction The incidence of cardiac implantable electronic device (CIED) infections has risen rapidly since 2004. A commercially available minocycline and rifampin impregnated antibacterial envelope has been associated with a low CIED infection rate. We performed a retrospective cohort study analyzing CIED infection rates in patients receiving an antibacterial envelope. Methods Prospectively applied criteria for use of the antibacterial envelope included ≥2 of the following: diabetes, renal insufficiency, anticoagulation, chronic corticosteroid use, fever or leukocytosis at the time of implantation, prior CIED infection, ≥3 leads (cardiac resynchronization therapy or abandoned leads), pacemaker dependence, or early pocket reentry. CIED infection rate was compared to a cohort of patients with matched risk factors and a CIED implanted prior to use of the antibacterial envelope. Results A total of 260 antibacterial envelopes were implanted from November 1, 2009 to April 30, 2012. The mean number of CIED infection risk factors was 2.8 ± 1.2. The control cohort (N = 639) was matched for mean number of CIED infection risk factors (2.8 ± 1.2), though individual risk factors differed. After a minimum of 90 days of follow-up, there was one CIED infection among patients who received an antibacterial envelope (0.4%), compared to 19 (3%) in controls (odds ratio [95% confidence interval] 0.13 [0.02–0.95], P = 0.04). This difference persisted after adjustment for covariates (0.09 [0.01–0.73], P = 0.02) and propensity score matching (0.11 [0.01–0.85], P = 0.04). Conclusions In patients prospectively identified at high risk for CIED infection, use of a commercially available antibacterial envelope was associated with a marked reduction in CIED infections when compared to a matched control cohort.

Background: In patients with acute coronary syndrome (ACS), elevated levels of soluble CD40 ligand (sCD40L) are associated with increased risk of cardiovascular events. We evaluated sCD40L levels and future cardiovascular events in patients not experiencing ACS. Methods: Serum sCD40L levels were measured in 909 patients undergoing angiography. A three-way matching scheme (age, gender and catheterization time period) identified 303 patients with coronary artery disease (CAD) who experienced a cardiac event within 1 year (CAD/event), 303 patients with CAD free of events (CAD/no event) and 303 patients without CAD and free of events (no CAD). Results: Average age was 64 ± 11 years; 74% were males. Median (± SE) sCD40L levels were higher for no CAD patients (335 ± 60 pg/ml) compared to CAD (248 ± 65 pg/ml, p = 0.01) and to CAD/event (233 ± 63 pg/ml, p < 0.001). There was no significant difference in median sCD40L levels between CAD/no event and CAD/event patients. Higher sCD40L quartiles were associated with a significant decrease in the risk of CAD/event versus no CAD (quartile 4 versus quartile 1: odds ratio = 0.59, p = 0.03). There was a nonsignificant trend towards a decreased risk of CAD as compared to no CAD, and for CAD/event versus CAD. Conclusions: In non-ACS patients, higher sCD40L levels were associated with a decreased risk of CAD. This novel interaction of sCD40L raises interesting questions for CAD pathogenesis.

ObjectivesThe objective of this study was to identify associations of the cholesteryl ester transfer protein (CETP) gene with coronary artery disease (CAD) with tagging (t) single nucleotide polymorphisms (SNPs) chosen to optimally account for intra-genic variation.BackgroundThe CETP gene plays a critical role in lipoprotein metabolism, but the common and well-studied TaqIB variant is inconsistently predictive of CAD.MethodsFrom a deoxyribonucleic acid bank of 10,020 individuals, nondiabetic nonsmoking patients (n = 4,811) with angiographically defined, clinically significant CAD (≥70% stenosis) or normal coronaries were genotyped for 11 CETPtSNPs. Myocardial infarction (MI) and lipid levels were evaluated as secondary end points.ResultsAnalysis of single tSNPs, corrected for multiple comparisons (p < 0.00485), identified allele +1086A to be associated with CAD (p = 0.0034). Suggestive allelic and significant genotypic associations were found for −631AA (odds ratio [OR] = 3.95, p = 0.004 vs. CC) and +2389GA (OR = 1.21, p = 0.003 vs. GG). Haplotype analysis by linkage disequilibrium (LD) group revealed a CAD association for LD group B (p = 0.0025 across T+1086A, C+878T, C+408T) and near significance for LD group A (p = 0.013 across C-631A, MspI, G+2389A). A weak protective trend for TaqIB was eliminated by adjustment for other tSNPs, and haplotype analyses suggested that TaqIB was simply a marker for other tSNPs or haplotypes. No tSNP or haplotype associations with MI were found.ConclusionsMultiple, less common SNPs and haplotype variants underlie CETP-related CAD risk, for which the common TaqIB variant is simply a poor marker. The occurrence of risk-related variants on separate haplotypes suggests genetic-risk complexity and allelic heterogeneity. (Database Registry of the Intermountain Heart Collaborative Study; http://clinicaltrials.gov/ct/show/NCT00406185?order=1; NCT00406185).

Background— Postoperative atrial fibrillation (PoAF) is common after coronary artery bypass grafting. We previously showed that atrial fibrillation susceptibility single nucleotide polymorphisms (SNPs) at the chromosome 4q25 locus are associated with PoAF. Here, we tested the hypothesis that a combined clinical and genetic model incorporating atrial fibrillation risk SNPs would be superior to a clinical-only model. Methods and Results— We developed and externally validated clinical and clinical/genetic risk models for PoAF. The discovery and validation cohorts included 556 and 1164 patients, respectively. Clinical variables previously associated with PoAF and 13 SNPs at loci associated with atrial fibrillation in genome-wide association studies were considered. PoAF occurred in 30% and 29% of patients in the discovery and validation cohorts, respectively. In the discovery cohort, a logistic regression model with clinical factors had good discrimination, with an area under the receiver operator characteristic curve of 0.76. The addition of 10 SNPs to the clinical model did not improve discrimination (area under receiver operator characteristic curve, 0.78; P =0.14 for difference between the 2 models). In the validation cohort, the clinical model had good discrimination (area under the receiver operator characteristic curve, 0.69) and addition of genetic variables resulted in a marginal improvement in discrimination (area under receiver operator characteristic curve, 0.72; P Conclusions— We developed and validated a model for the prediction of PoAF containing common clinical variables. Addition of atrial fibrillation susceptibility SNPs did not improve model performance. Tools to accurately predict PoAF are needed to risk stratify patients undergoing coronary artery bypass grafting and identify candidates for prophylactic therapies.

Whereas C-reactive protein (CRP) is a nonspecific marker of coronary artery disease (CAD) and cardiovascular (CV) events, Lp-PLA2 may be a nonvariable inflammatory biomarker. We evaluated the independent association of lipoprotein-associated phospholipase A2 (Lp-PLA2) to angiographic CAD and CV events adjusting for standard factors, lipids, and CRP.Lipoprotein-associated phospholipase A2 (PLAC test, diaDexus, Inc, San Francisco, CA) and CRP were measured from samples donated by consecutive consenting patients (N = 1493) enrolled in the registry of the Intermountain Heart Collaborative Study. All patients underwent coronary angiography (1996-1998) for CAD determination and were followed for 6.7 +/- 0.5 years (range 5.7-7.9 years) for CV events (death [including all-cause, CAD, and non-CAD CV death], myocardial infarction, and cerebrovascular accident).Lipoprotein-associated phospholipase A2 weakly correlated with lipids (low-density lipoprotein: r = 0.22, P.001; high-density lipoprotein: r = -0.13, P.001), but not CRP (r = 0.03, P = .26). Increasing quartile (Q) of Lp-PLA2 predicted greater the presence of CAD (vs Q1) for Q2 (adjusted odds ratio [OR] 1.15, 95% CI 0.78-1.71, P = .48), for Q3 (OR 1.53, 95% CI 1.02-2.31, P = .042), and for Q4 (OR 2.44, 95% CI 1.58-3.79, P.001), although CRP was also predictive (vs Q1, Q2: OR 1.47, P = .057; Q3: OR 1.93, P = .002; Q4: OR 3.43, P.001). In Cox regression, Lp-PLA2 predicted CAD death (vs Q1; Q2: adjusted hazard ratio [HR] 1.27, 95% CI 0.58-2.78, P = .55; Q3: HR 2.18, 95% CI 1.04-4.57, P = .04; Q4: HR 1.73, 95% CI 0.84-3.61, P = .14).Lipoprotein-associated phospholipase A2 was confirmed to predict the presence of CAD, even among patients undergoing coronary angiography. Uniquely, Lp-PLA2 predicted the risk of CAD death, but not all-cause death, myocardial infarction, or cerebrovascular accident.

Background: QT interval prolongation and risk of torsades de pointes have been associated with abrupt heart rate (HR) slowing after cardioversion from atrial fibrillation (AF) or AV nodal ablation. The degree to which the QT interval prolongs with abrupt changes in HR, and the underlying mechanisms, are poorly understood. We quantified ΔQT interval during cessation of rapid pacing and examined the relationship between QT and circulating neurohormonal and inflammatory markers. Methods: Eleven subjects with dual chamber pacemakers and intact AV conduction were atrially-paced at 90/min for 10 min, 60 min, and 1 week (Figure). Biomarkers were sampled during and after pacing. The relationships between QT, pacing stage, and biomarker levels were analyzed with a mixed effect model. QT intervals were compared for the 20 RR intervals before and 100 RR intervals after each pacing stage. Results: QT intervals prolonged after cessation of rapid pacing: 6.4 ms (95% confidence interval 4.9-7.8 ms) after 10 min (P0.1 for all comparisons). Conclusion: Abrupt decreases in HR were associated with QT prolongation. QT interval changes correlated with several neuroendocrine and inflammatory biomarkers, though there were no inter-individual differences in biomarker levels before and after pacing. These findings may partially explain the increased risk of torsade de points after restoration of sinus rhythm from AF.

Background: Atrial fibrillation (AF) contributes to substantial morbidity, mortality, and healthcare costs. Accurate prediction of incident AF might enhance patient care and improve outcomes. We aimed to externally validate the AF risk model developed by the CHARGE-AF investigators utilizing a large repository of electronic medical records (EMR). Methods: Using a database of de-identified EMRs, we conducted a retrospective cohort study of subjects serially followed in internal medicine clinics at our institution (minimum 3 visits in a 24 month window). Subjects were followed for incident AF from 2005 until 2010. We applied the published CHARGE-AF Cox proportional hazards model beta coefficients to our cohort. Predictors included age, race, height, weight, systolic and diastolic blood pressure, treatment for hypertension, smoking status, diabetes, heart failure, history of myocardial infarction, left ventricular hypertrophy, and PR interval. Calibration and discrimination were assessed by generating calibration plots and calculating C-statistics. Results: The study included 33,494 subjects with median age 57 years (25th to 75th percentile: 49 - 67), 57% women, 86% whites, and 14% African Americans. During the mean follow-up period of 4.8 ± 0.85 years, 2455 (7.3%) subjects developed AF. After correcting for baseline hazard, the CHARGE-AF model over-predicted AF at the highest risk deciles but was otherwise well-calibrated (Figure) and showed good discrimination, with a C-statistic of 0.746 (95% confidence interval: 0.738 to 0.754). Conclusion: From clinical factors readily accessible in a large de-identified EMR repository, we externally validated the CHARGE-AF risk prediction model to identify individuals at risk for developing AF in an ambulatory setting. These data not only provide strong validation for the CHARGE-AF risk prediction tool, but also indicate that the tool, and thus primary prevention strategies, can be implemented in an EMR context.

A common variant of the adenosine monophosphate deaminase (AMPD)-1 gene (C34T) results in enzymatic inactivity and may increase adenosine in cardiac muscle and confer cardioprotection through ischemic preconditioning.We hypothesized that AMPD1 carriers with ischemic heart failure (HF) in the Beta-Blocker Evaluation of Survival Trial (BEST) might have a relative survival advantage. Patients (n = 1038, 20% black) with ischemic (58%) and nonischemic (42%) HF were followed for an average of 2.0 years for cardiovascular mortality. DNA was purified from blood using phenol/chloroform. Genotyping was performed by polymerase chain reaction with 5' exonuclease chemistry. Differences in survival were assessed by comparing Kaplan-Meier curves with the log-rank test. Genotype frequencies differed by ethnicity (P.001) but not by disease etiology. AMPD1 genotype did not significantly modify survival in the entire study population (hazard ratio [HR] = 0.91, 95% CI = 0.61-1.37), among ischemics (HR = 0.73, CI = 0.44-1.22, P = .23), or ischemic non-blacks (HR = 0.74, CI = 0.44-1.24, P = .25). Genotype did not modify the effect of bucindolol on mortality.Results of this study failed to confirm a reported survival benefit among HF patients carrying the AMPD1 T-allele. However, further studies in larger, more homogeneous populations should explore the possibility of a modest survival advantage for patients with ischemic HF.

A medium-sensitivity assay for C-reactive protein (CRP) was compared with a high-sensitivity, enhanced immunoturbidimetric assay in 803 angiographically studied patients. Different absolute CRP values were found by the assays, but there was a high correlation by quartile rank and similar predictive values for death and myocardial infarction. This suggests that the conclusions of previous studies performed using the medium-sensitivity assay are still valid but that cross-study comparisons should use percentile rank.

For many patients with atrial fibrillation, ventricular rate control with atrioventricular (AV) nodal blockers is considered first-line therapy, although response to treatment is highly variable. Using an extreme phenotype of failure of rate control necessitating AV nodal ablation and pacemaker implantation, we conducted a genome-wide association study (GWAS) to identify genomic modulators of rate control therapy. Cases included 95 patients who failed rate control therapy. Controls (n = 190) achieved adequate rate control therapy with ≤2 AV nodal blockers using a conventional clinical definition. Genotyping was performed on the Illumina 610-Quad platform, and results were imputed to the 1000 Genomes reference haplotypes. A total of 554,041 single-nucleotide polymorphisms (SNPs) met criteria for minor allele frequency (>0.01), call rate (>95%), and quality control, and 6,055,224 SNPs were available after imputation. No SNP reached the canonical threshold for significance for GWAS of p −8 . Sixty-three SNPs with p −5 at 6 genomic loci were genotyped in a validation cohort of 130 cases and 157 controls. These included 6q24.3 (near SAMD5/SASH1 , p = 9.36 × 10 −8 ), 4q12 ( IGFBP7 , p = 1.75 × 10 −7 ), 6q22.33 (C6orf174, p = 4.86 × 10 −7 ), 3p21.31 ( CDCP1 , p = 1.18 × 10 −6 ), 12p12.1 ( SOX5 , p = 1.62 × 10 −6 ), and 7p11 ( LANCL2 , p = 6.51 × 10 −6 ). However, none of these were significant in the replication cohort or in a meta-analysis of both cohorts. In conclusion, we identified several potentially important genomic modulators of rate control therapy in atrial fibrillation, particularly SOX5 , which was previously associated with heart rate at rest and PR interval. However, these failed to reach genome-wide significance.

Importance Atrial fibrillation (AF) contributes to substantial morbidity, mortality, and health care expenditures. Accurate prediction of incident AF would enhance AF management and potentially improve patient outcomes. Objective To validate the AF risk prediction model originally developed by the Cohorts for Heart and Aging Research in Genomic Epidemiology–Atrial Fibrillation (CHARGE-AF) investigators using a large repository of electronic medical records (EMRs). Design, Setting, and Participants In this prediction model study, deidentified EMRs of 33 494 individuals 40 years or older who were white or African American and had no history of AF were reviewed and analyzed. The participants were followed up in the internal medicine outpatient clinics at Vanderbilt University Medical Center for incident AF from December 31, 2005, until December 31, 2010. Adjusting for differences in baseline hazard, the CHARGE-AF Cox proportional hazards model regression coefficients were applied to the EMR cohort. A simple version of the model with no echocardiographic variables was also evaluated. Data were analyzed from October 31, 2013, to January 31, 2014. Main Outcomes and Measures Incident AF. Predictors in the model included age, race, height, weight, systolic and diastolic blood pressure, treatment for hypertension, smoking status, type 2 diabetes, heart failure, history of myocardial infarction, left ventricular hypertrophy, and PR interval. Results Among the 33 494 participants, the median age was 57 (interquartile range, 49-67) years; 57% of patients were women, 43% were men, 85.7% were white, and 14.3% were African American. During the mean (SD) follow-up of 4.8 (0.9) years, 2455 individuals (7.3%) developed AF. Both models had poor calibration in the EMR cohort, with underprediction of AF among low-risk individuals and overprediction of AF among high-risk individuals (10th and 90th percentiles for predicted probability of incident AF, 0.005 and 0.179, respectively). The full CHARGE-AF model had a C index of 0.708 (95% CI, 0.699-0.718) in our cohort. The simple model had similar discrimination (C index, 0.709; 95% CI, 0.699-0.718; P = .70 for difference between models). Conclusions and Relevance Despite reasonable discrimination, the CHARGE-AF models showed poor calibration in this EMR cohort. This study highlights the difficulties of applying a risk model derived from prospective cohort studies to an EMR cohort and suggests that these AF risk prediction models be used with caution in the EMR setting. Future risk models may need to be developed and validated within EMR cohorts.

The incidence of cardiac implantable electronic device (CIED) infections has risen rapidly since 2004. A commercially available minocycline and rifampin impregnated antibacterial envelope has been associated with a low CIED infection rate. We performed a retrospective cohort study analyzing CIED infection rates in patients receiving an antibacterial envelope.Prospectively applied criteria for use of the antibacterial envelope included ≥2 of the following: diabetes, renal insufficiency, anticoagulation, chronic corticosteroid use, fever or leukocytosis at the time of implantation, prior CIED infection, ≥3 leads (cardiac resynchronization therapy or abandoned leads), pacemaker dependence, or early pocket reentry. CIED infection rate was compared to a cohort of patients with matched risk factors and a CIED implanted prior to use of the antibacterial envelope.A total of 260 antibacterial envelopes were implanted from November 1, 2009 to April 30, 2012. The mean number of CIED infection risk factors was 2.8 ± 1.2. The control cohort (N = 639) was matched for mean number of CIED infection risk factors (2.8 ± 1.2), though individual risk factors differed. After a minimum of 90 days of follow-up, there was one CIED infection among patients who received an antibacterial envelope (0.4%), compared to 19 (3%) in controls (odds ratio [95% confidence interval] 0.13 [0.02-0.95], P = 0.04). This difference persisted after adjustment for covariates (0.09 [0.01-0.73], P = 0.02) and propensity score matching (0.11 [0.01-0.85], P = 0.04).In patients prospectively identified at high risk for CIED infection, use of a commercially available antibacterial envelope was associated with a marked reduction in CIED infections when compared to a matched control cohort.

The implantation of cardiac implantable electronic devices (CIED) to prevent sudden cardiac death, ameliorate chronic congestive heart failure, and correct bradycardia has grown rapidly in the past decade. Bacterial infection of the device hardware (pacemaker or implantable cardioverter defibrillator [ICD] pulse generator, and intravascular wires or leads), including the tissue pocket, is rising at an even faster rate. The source infection inoculation typically occurs at the time the device is implanted, revised, or when a device generator replacement occurs. This risk is clearly related to patient and procedure-specific factors, and is reviewed in the present paper. Prophylactic preoperative antibiotics, strict sterile technique, and limiting procedure times may reduce infection risk. A novel Antibacterial Envelope (AIGISRx ® , TYRX Inc., Monmouth Junction, NJ, USA) that is directly implanted with the device generator to provide site-specific therapy could significantly lower infection risk in certain high-risk cases. This may potentially reduce inpatient mortality related to endocarditis and sepsis, and lower healthcare costs related to CIED extraction and re-implantation, which can exceed $1 million per case.

Background : Inflammation plays a role in the development and progression of coronary artery disease (CAD), with circulating markers of vascular inflammation being used in risk assessment including high sensitivity C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A 2 (LpPLA 2 ). While hsCRP responds to the systemic inflammatory stimulus of acute myocardial infarction (AMI), LpPLA 2 has been proposed to be more vascular-specific and to vary minimally based upon clinical presentation. To test this hypothesis, we evaluated both biomarkers among CAD patients presenting with stable angina (SA), unstable angina (USA) or acute myocardial infarction (AMI). Methods : LpPLA 2 (PLAC TM test, diaDexus, Inc.) and hsCRP were measured from samples donated by consenting patients (N=1,010) enrolled in the registry of the Intermountain Heart Collaborative Study that underwent angiographic evaluation for CAD. Patients were categorized by presentation status (SA=637; USA=205; and AMI=168), stratified according to median levels of LpPLA 2 (350.2 ng/mL) and hsCRP above and below 3 mgl/L and followed for 7.5 ± 2.4 years for CAD death. Results : Age averaged 64 ± 12 years and 70% were male. While median hsCRP (mg/L) levels differed significantly by presentation [2.86, 2.80, and 13.7 for SA, USA, and AMI, respectively (p2 (ng/mL) levels [350.2, 353.1, and 348.1 for SA, USA, and AMI, respectively (p=0.67)], did not. LpPLA 2 was not only a better predictor of CAD death among the entire cohort (LpPLA 2 : adjusted Hazard Ratio [HR]= 1.47, p=0.04; hsCRP: adjusted HR=0.95, p=0.81), it was a better predictor among patients presenting with AMI (LpPLA 2 : adjusted HR3 1.80, p=0.30; hsCRP adjusted HR=0.76, p=0.63). Conclusions : Among CAD patients, LpPLA 2 varies minimally among differing presentations compared to hsCRP and is a better a predictor of CAD death among those presenting with AMI. This information supports the hypothesis that LpPLA 2 is a vascular specific marker of inflammation and independent of transient systemic inflammatory effects.

Warfarin has a narrow therapeutic range and wide inter-individual dosing requirements that may be related to functional variants of genes affecting warfarin metabolism (i.e., CYP2C9) and activity (i.e., vitamin K epoxide reductase complex subunit 1-VKORC1). We hypothesized that variants in these two genes explain a substantial proportion of variability in stable warfarin dose and could be used as a basis for improved dosing algorithms.Consecutive consenting outpatients (n = 213) with stable INR (2-3) for1 month were enrolled. Buccal DNA was extracted using a Qiagen mini-column and CYP2C9*2 and VKORC1 genotyping performed by the Taqman 3' nuclease assay. Sequencing for CYP2C9*3, genotyping was done using Big Dye v3.1 terminator chemistry Dose by genotype was assessed by linear regression.Weekly warfarin dose averaged 30.8 +/- 13.9 mg/week; average INR was 2.42 +/- 0.72. CYP2C9*2/*3 genotype distribution was: CC/AA (wild-type [WT]) = 71.4%, CT/AA = 18.3%, CC/AC = 9.4%, and CT/AC = 1%; VKORC1 genotypes were CC (WT) = 36.6%, CT = 50.7%, and TT = 12.7%. Warfarin doses (mg/week) varied by genotype: for CYP2C9, 33.3 mg/week for WT (CC/AA), 27.2 mg/week for CT/AA (P = 0.04 vs. WT), 23.0 mg/week for CC/AC (P = 0.003), and 6.0 mg/week for CT/AC (P0.001), representing dose reductions of 18-31% for single and 82% for double variant carriers; for VKORC1: 38.4 mg/week for WT (CC), 28.6 mg/week for CT (P0.001 vs. WT), 20.95 mg/week for TT (P0.001). In multiple linear regression, genotype was the dominant predictor of warfarin dose (P = 2.4 x 10(-15)); weak predictors were age, weight, and sex. Genotype-based modeling explained 33% of dose-variance, compared with 12% for clinical variables alone.In this large prospective study of warfarin genetic dose-determinants, carriage of a single or double CYP2C9 variant, reduced warfarin dose 18-72%, and of a VKORC1 variant by 65%. Genotype-based modeling explained almost one-half of dose-variance. A quantitative dosing algorithm incorporating genotypes for 2C9 and VKORC1 could substantially improve initial warfarin dose-selection and reduce related complications.

Summary Full characterization of intragenic variation may improve candidate gene associations. This study selected tagging (t) single nucleotide polymorphisms (SNPs) to comprehensively represent genetic variability in the cholesteryl ester transfer protein (CETP) gene. Nineteen SNPs were identified in 50 unrelated individuals in the SNP discovery phase, and 13 intronic SNPs were added from the literature. These 32 SNPs were genotyped in 339 apparently healthy individuals and 190 coronary artery disease (CAD) patients. Using phased haplotypes, linkage disequilibrium (LD) structure was characterized and tSNPs selected using a principal component analysis (PCA) method. In healthy individuals, seven LD groups were identified that accounted for 93.4% of the observed genetic variation. These LD groups highlighted a complex LD structure for CETP, including both recombination and mutation, and eleven tSNPs were selected. Among CAD patients the results were essentially the same. Results from PCA using diploid genotype data were reasonably comparable. Finally, the selected tSNPs successfully represented the association evidence discovered for all of the other SNPs studied. This study provides an optimal set of tSNPs for association analyses of CETP. The observed complexity of LD structure highlights the importance of using methods, such as PCA, that allow for multiple dynamics in intragenic LD structure.

Background: Rare variants in cardiac sodium channel genes have been associated with atrial fibrillation (AF) and Brugada syndrome. Given the characteristic Brugada ECG, we tested the hypothesis that AF patients carrying rare variants encoding cardiac sodium channels are more likely to have right precordial ST-segment elevation than AF patients carrying wildtype alleles. Methods: ECG parameters were measured for 86 AF patients who harbored a rare variant (minor allele frequency o0.01) in a cardiac sodium channel gene (SCNA5, SCNB1, SCNB2, or SCN10A) and 102 AF patients who were sequenced but did not carry a rare variant (controls). A total of 508 sinus rhythm, ambulatory ECGs were analyzed using custom software. Results: Median age was 50.5 years (interquartile range [IQR] 41–59 years), and 65% of patients were male. Median ST-segment elevation was significantly higher in variant carriers than in controls: 0.69 mm (IQR 0.31– 0.96 mm) vs 0.4 mm (0.21–0.8 mm) (P 1⁄4 .007). This difference remained highly significant after adjustment for age and sex (P 1⁄4 .0003). ST elevationZ1.5 mm was seen in 9.3% of carriers but in only 2% of controls (P 1⁄4 .05). ST-segment elevation Z1 mm was more common among rare variant carriers (22%) than in controls (14%), although the difference in proportions was not statistically significant (P 1⁄4 .18). The specificity of ST elevation Z1.5 mm as a marker for sodium channel subunit gene variants was 98%, although the sensitivity was only 9%. Conclusions: Among patients with AF, ST-segment elevation on routine, ambulatory 12-lead ECGs was more common and more pronounced in carriers of rare variants in genes encoding cardiac sodium channel subunits than in noncarriers. Marked ST elevation (Z1.5 mm) may serve as an ECG endophenotype for AF patients who harbor sodium channel subunit gene variants.

Background Coronary artery disease (CAD) and, increasingly, diabetes are recognized as having an inflammatory basis. Membrane toll-like receptors (TLRs) activate signaling pathways that up-regulate inflammation. We evaluated whether the Asp299Gly polymorphism in the TLR4 gene, which impairs inflammatory responses, is associated with reduced vascular inflammation (assessed by C-reactive protein [CRP]) and a decreased risk for CAD and diabetes. Methods 1894 patients without acute myocardial infarction undergoing coronary angiography were studied. Genotyping was performed by real-time polymerase chain reaction. CAD was defined as ≥70% stenosis. Diabetes was diagnosed by patients' referring physicians. CRP was measured by fluorescence polarization immunoassay. Regression analyses adjusted for traditional cardiac risk factors. Results Patients averaged 64 ± 11 years of age, and 69% were male. Asp299Gly genotype frequencies were: AA=0.911 (n = 1725), AG=0.086 (n = 164), and GG=0.003 (n = 5), in keeping with Hardy-Weinberg equilibrium. CRP was lower among G-allele carriers (median = 1.11 mg/dL) than wild-type (AA) subjects (1.23 mg/dL, adjusted P = .044). G-allele carriers also had a lower prevalence of CAD (65% vs. 73%, OR=0.67, CI=0.46–0.99, adjusted P = .048) and diabetes (11% vs. 18%, OR=0.63, CI=0.42–0.95, adjusted P = .029), which persisted in multivariate logistic regression analyses. 299Gly carriage did not affect clinical outcomes nor interact with statin therapy. Conclusions The TLR4 299Gly allele was associated with reduced CRP levels and, in parallel, a decreased risk of angiographic CAD and clinical diabetes. These findings suggest that down-regulation of innate immune responsiveness could beneficially modify CAD and diabetes risk and might provide a novel basis for genetic risk stratification and therapeutic targeting.

Variants at the 9p21 locus have been associated with coronary heart disease, but their precise disease phenotype and utility for clinical risk assessment are uncertain.Consenting patients with early-onset angiographic coronary artery disease (CAD) (n = 1,011) were compared with matched subjects (n = 545) free of angiographic disease and with a random population sample (n = 565). Cases and controls were genotyped for 4 variants, and ORs for angio-CAD were determined. Findings were validated in a separate set of cases and controls (n = 1,452).Alleles were highly correlated (r(2)or = 0.9), and all predicted angio-CAD compared with both control groups. Genotype at rs2383206 (minor allele frequency 45.9%), the most predictive (P.0001), was associated with an adjusted odds ratio for angio-CAD of 1.39 (95% CI, 1.05-1.85) for heterozygote and 1.73 (1.26-2.37) for homozygote risk-allele carriers and explained 21% of population attributable risk and was independent of traditional risk factors and myocardial infarction. For the comparison of combined cases versus combined control samples (N = 3,573), CAD was predicted by high-risk allele homozygosity at P = 9 x 10(-8). Despite this, extent of disease was not increased. Applied to patients with intermediate Framingham risk scores, 9p21 genotyping modified risk classification in 24%.Variants at the 9p21 locus robustly predict angiographic CAD prevalence, independent of standard risk factors, but not CAD extent or myocardial infarction; provide pathophysiological insights; and may be clinically useful in refining coronary heart disease risk classification.