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Aim The Prevention of Arrhythmia Device Infection Trial (PADIT) infection risk score, developed based on a large prospectively collected data set, identified five independent predictors of cardiac implantable electronic device (CIED) infection. We performed an independent validation of the risk score in a data set extracted from U.S. healthcare claims. Methods and results Retrospective identification of index CIED procedures among patients aged ≥18 years with at least one record of a CIED procedure between January 2011 and September 2014 in a U.S health claims database. PADIT risk factors and major CIED infections (with system removal, invasive procedure without system removal, or infection-attributable death) were identified through diagnosis and procedure codes. The data set was randomized by PADIT score into Data Set A (60%) and Data Set B (40%). A frailty model allowing multiple procedures per patient was fit using Data Set A, with PADIT score as the only predictor, excluding patients with prior CIED infection. A data set of 54 042 index procedures among 51 623 patients with 574 infections was extracted. Among patients with no history of prior CIED infection, a 1 unit increase in the PADIT score was associated with a relative 28% increase in infection risk. Prior CIED infection was associated with significant incremental predictive value (HR 5.66, P, Graphical Abstract

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

SCN5A encodes the voltage-gated Na+ channel NaV1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence. This SNP was previously shown to reproducibly associate with cardiac electrophysiological parameters, but was not considered to be causal. Here, we show that miR-24 potently suppresses SCN5A expression and that rs1805126 modulates this regulation. We found that the rs1805126 minor allele associates with decreased cardiac SCN5A expression and that heart failure subjects homozygous for the minor allele have decreased ejection fraction and increased mortality, but not increased ventricular tachyarrhythmias. In mice, we identified a potential basis for this in discovering that decreased Scn5a expression leads to accumulation of myocardial reactive oxygen species. Together, these data reiterate the importance of considering the mechanistic significance of synonymous SNPs as they relate to miRs and disease, and highlight a surprising link between SCN5A expression and nonarrhythmic death in heart failure.

Syncope is difficult to definitively diagnose, even with tilt-table testing and beat-to-beat blood pressure measurements, the gold-standard. Both are qualitative, subjective assessments. There are subtypes of syncope associated with autonomic conditions for which tilt-table testing is not useful. Heart rate variability analyses also include too much ambiguity. Three subtypes of syncope are differentiated: vasovagal syncope (VVS) due to parasympathetic excess (VVS-PE), VVS with abnormal heart rate response (VVS-HR), and VVS without PE (VVS-PN). P&S monitoring (ANSAR, Inc., Philadelphia, PA) differentiates subtypes in 2727 cardiology patients (50.5% female; average age: 57 years; age range: 12–100 years), serially tested over four years (3.3 tests per patient, average). P&S monitoring noninvasively, independently, and simultaneously measures parasympathetic and sympathetic (P&S) activity, including the normal P-decrease followed by an S-increase with head-up postural change (standing). Syncope, as an S-excess (SE) with stand, is differentiated from orthostatic dysfunction (e.g., POTS) as S-withdrawal with stand. Upon standing, VVS-PE is further differentiated as SE with PE, VVS-HR as SE with abnormal HR, and VVS-PN as SE with normal P- and HR-responses. Improved understanding of the underlying pathophysiology by more accurate subtyping leads to more precise therapy and improved outcomes.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

Introduction Expert consensus holds that post-market, systematic surveillance of ICD leads is essential to ensure confirmation of adequate lead performance. GALAXY (NCT00836589) and CELESTIAL (NCT00810264) are ongoing multicenter, prospective, non-randomized registries conducted to confirm the long-term safety and reliability of Biotronik leads. Methods and results ICD and CRT-D patients are followed for Linox and Linox(smart) ICD lead performance and safety for 5 years post-implant. All procedural and system-related adverse events (AEs) were assessed at each follow-up, along with lead electrical parameters. An independent CEC of EPs adjudicated AEs to determine AE category and lead relatedness. The analysis used categories of lead observations per ISO 5841-2 (Third edition). A total of 3,933 leads were implanted in 3,840 patients (73.0% male, mean age 67.0 ± 12.2 years) at 146 US centers. The estimated cumulative survival probability was 96.3% at 5 years after implant for Linox leads and 96.6% at 4 years after implant for Linox(smart) leads. A comparison of the Linox and Linox(smart) survival functions did not find evidence of a difference (P = 0.2155). The most common AEs were oversensing (23, 0.58%), conductor fracture (14, 0.36%), failure to capture (13, 0.33%), lead dislodgement (12, 0.31%), insulation breach (10, 0.25%), and abnormal pacing impedance (8, 0.20%). Conclusions Linox and Linox(smart) ICD leads are safe, reliable and infrequently associated with lead-related AEs. Additionally, estimated cumulative survival probability is clinically acceptable and well within industry standards. Ongoing data collection will confirm the longer-term safety and performance of the Linox family of ICD leads.

Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Background: Recent data from SPRINT trial demonstrated that, intense systolic blood pressure (ISBP) control to Methods: Electronic medical records from 3 different ambulatory clinics were reviewed to identify hypertensive patients with at least 3 consecutive clinic visits. Patients with diabetes, with 120 mm Hg respectively. Results: 1644 non diabetic patients with HTN included in the analysis. 1389 (84.5%) patients had St-SBP control whereas only 255 (15.5%) patients had ISBP control. ISBP group had significantly lower mean (±SD) SBP compared to St-SBP group; 116(±6.4) mm Hg vs. 136(±11.6) mm Hg respectively; P Conclusion: There is significant variation in SBP control in non-diabetic hypertensive patients in clinical practice, despite comparable comorbid profile. Furthermore, ISBP control is not a common practice in real world. Quality improvement measures should focus on promoting ISBP control in non-diabetic hypertensive patients.

Background Cardiovascular autonomic neuropathy (CAN) is recognized as a significant health risk. Specific and sensitive measures of CAN are needed for early identification and treatment to avoid complications, preferably in the preclinical state. Objectives In this first of two articles, the patient cohort is described and two measures of autonomic function are reviewed: the traditional heart rate variability (HRV)-alone method and the newer parasympathetic and sympathetic (P&S) Method. These systems are then evaluated against known effects of the alpha/beta-adrenergic blocker, Carvedilol, and the selective beta-adrenergic blocker, Metoprolol, on P&S activity. Methods Serial autonomic nervous system test data from 147 type 2 diabetes mellitus patients from eight ambulatory clinics were analyzed. Patients were grouped according to whether a beta-blocker was (1) introduced, (2) discontinued or (3) continued without adjustment. Group 3 served as the control. HRV-alone parameters are computed according to standards. The P&S Method, which is a time–frequency analyses of concurrent respiratory activity and HRV, is elucidated, as developed at MIT and Harvard Medical School (1981). Results The HRV-alone demonstrated that introducing either medication increased low frequency (msec2) and standard deviation of the beat-to-beat (N-N) interval (msec), as expected. The other HRV parameter responses were not consistent with expectations. Similar inconsistencies occurred when either medication was discontinued. The P&S Method demonstrated that introducing or discontinuing either agent decreased or increased sympathetic activity, respectively, according to expectations. With ongoing treatment, resting parasympathetic activity decreased with Metoprolol but increased with Carvedilol. Conclusion Autonomic assessment fidelity was significantly higher with the P&S Method as validated by comparison with previously known physiology of the cardiovascular system.

Background Premature cardiac contractions are associated with increased morbidity and mortality. Though experts associate premature atrial contractions (PACs) and premature ventricular contractions (PVCs) with caffeine, there are no data to support this relationship in the general population. As certain caffeinated products may have cardiovascular benefits, recommendations against them may be detrimental. Methods and Results We studied Cardiovascular Health Study participants with a baseline food frequency assessment, 24‐hour ambulatory electrocardiography (Holter) monitoring, and without persistent atrial fibrillation. Frequencies of habitual coffee, tea, and chocolate consumption were assessed using a picture‐sort food frequency survey. The main outcomes were PACs/h and PVCs/hour. Among 1388 participants (46% male, mean age 72 years), 840 (61%) consumed ≥1 caffeinated product per day. The median numbers of PACs and PVCs/h and interquartile ranges were 3 (1–12) and 1 (0–7), respectively. There were no differences in the number of PACs or PVCs/h across levels of coffee, tea, and chocolate consumption. After adjustment for potential confounders, more frequent consumption of these products was not associated with ectopy. In examining combined dietary intake of coffee, tea, and chocolate as a continuous measure, no relationships were observed after multivariable adjustment: 0.48% fewer PACs/h (95% CI −4.60 to 3.64) and 2.87% fewer PVCs/h (95% CI −8.18 to 2.43) per 1‐serving/week increase in consumption. Conclusions In the largest study to evaluate dietary patterns and quantify cardiac ectopy using 24‐hour Holter monitoring, we found no relationship between chronic consumption of caffeinated products and ectopy.

Background Sudden cardiac death (SCD) from ventricular tachyarrhythmias accounts for approximately 450,000 annual deaths in the United States; many of these cases involve patients with chronic heart failure (HF). Prediction of which HF patients are most susceptible to SCD is difficult, and it is uncertain whether gene polymorphisms associated with HF outcomes are also linked to arrhythmic risk. Methods We evaluated 485 patients with chronic HF to see whether the angiotensin receptor type 1 (AT1R) 1166A/C or angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms were associated with a higher rate of ventricular arrhythmias requiring implantable cardioverter defibrillator (ICD) therapies over a 5-year period. We assessed the correlation between polymorphisms and antitachycardia pacing (ATP) and/or ICD shocks. Results Patients with AT1R-1166CC genotype had an increased rate of all events: ATP plus ICD shocks ( P = .02). There was no association between ACE I/D genotype and ICD therapies. Furthermore, circulating levels of microRNA-155 (miR-155), a microRNA known to posttranscriptionally regulate AT1R expression, were significantly decreased in the CC compared with the AC and AA genotypes and were associated with ICD events. Conclusion Our study suggests that the AT1R-1166CC genotype is associated with increased ICD therapies in patients with chronic HF, and the level of circulating miR-155 may be a potential marker for arrhythmic risk. Although these findings are novel, they will need replication and validation in larger cohorts of chronic HF patients.

Background Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. The etiology of DCM is genetically heterogeneous. Objectives We sought to define the prevalence of mutations in the RNA splicing protein RBM20 in a large cohort with DCM and to determine whether genetic variation in RBM20 is associated with clinical outcomes. Methods Subjects included in the Genetic Risk Assessment of Defibrillator Events (GRADE) study were aged at least 18 years, had an ejection fraction of ≤30%, and an implantable cardioverter-defibrillator (ICD). The coding region and splice junctions of RBM20 were screened in subjects with DCM; 2 common polymorphisms in RBM20 , rs942077 and rs35141404, were genotyped in all GRADE subjects. Results A total of 1465 subjects were enrolled in the GRADE study, and 283 with DCM were screened for RBM20 mutations. The mean age of subjects with DCM was 58 ± 13 years, 64% were males, and the mean follow-up time was 24.2 ± 17.1 months after ICD placement. RBM20 mutations were identified in 8 subjects with DCM (2.8%). Mutation carriers had a similar survival, transplantation rate, and frequency of ICD therapy compared with nonmutation carriers. Three of 8 subjects with RBM20 mutations (37.5%) had atrial fibrillation (AF), whereas 19 subjects without mutations (7.4%) had AF ( P = .02). Among all GRADE subjects, rs35141404 was associated with AF (minor allele odds ratio=0.62; 95% confidence interval=0.44–0.86; P = .006). In the subset of GRADE subjects with DCM, rs35141404 was associated with AF (minor allele odds ratio=0.58; P = .047). Conclusions Mutations in RBM20 were observed in approximately 3% of subjects with DCM. There were no differences in survival, transplantation rate, and frequency of ICD therapy in mutation carriers.

Inflammation and oxidative stress are associated with atrial fibrillation (AF). Statins have antioxidant and anti-inflammatory properties. We tested if atorvastatin reduced AF recurrence after DC cardioversion (CV) by modifying systemic oxidative stress and inflammation (NCT00252967).In a randomized, double-blinded, placebo-controlled trial, patients with atrial fibrillation/flutter (AF) were randomized to receive either atorvastatin 80 mg (n = 33) or placebo (n = 31) before CV. Treatment was continued for 12 months or until AF recurred. Serum oxidative stress markers (ratios of oxidized to reduced glutathione and cysteine, derivatives of reactive oxygen species, isoprostanes) and inflammatory markers (high-sensitivity C- reactive protein [hs-CRP], interleukin-6 [IL-6], interleukin-1β[IL-1β], tumor necrosis factor alpha [TNFα]) were measured at baseline and on follow-up. AF recurred in 22 (66.7%) of atorvastatin and 26 (83.9%) of placebo group (P = 0.2). The adjusted hazard ratio of having recurrence on atorvastatin versus on placebo was 0.99 (95% CI: 0.98-1.01, P = 0.3). There was no significant difference in the time to recurrence using Kaplan-Meier survival estimates (median [IR]: 29 [2-145] days versus 22 [7-70] days, P = 0.9). Although no significant effect was seen on oxidative stress, 2 of 4 inflammatory markers, IL-6 (adjusted OR: 0.59, 95% CI: 0.35-0.97, P = 0.04) and hs-CRP (adjusted OR: 0.59, 95% CI: 0.37-0.95, P = 0.03) were significantly lowered with atorvastatin. Cholesterol levels significantly decreased with atorvastatin (P = 0.03).High-dose atorvastatin did not reduce the recurrence of AF after CV. It reduced selective markers of inflammation without affecting systemic oxidative stress. Failure of atorvastatin to prevent AF recurrence may be due to its failure to affect oxidative stress.

Background: Cardiovascular implantable electronic device (CIED) infection rates are increasing faster than implantation rates. More effective antimicrobial prophylaxis may help reduce CIED infections and improve clinical outcomes. The AIGISRx antibacterial envelope is a polymer mesh implanted in the generator pocket with the CIED. After implantation it releases two antibiotics, minocycline and rifampin, that have been shown to reduce infections associated with other medical devices. The purpose of this retrospective cohort study is to determine the rate of CIED implantation success and CIED infection in procedures utilizing the antibacterial envelope. Methods: This study enrolled consecutive CIED procedures utilizing the antibacterial envelope at 10 US academic, community, and Veterans Affairs medical centers. Procedures following an explantation for a prior CIED infection or off-label use of the antibacterial envelope were excluded. Results: The 624 eligible procedures (age 70 ± 13 years, 68.1% men, 27.2% renal insufficiency, 35.4% oral anticoagulant use, 67.8% replacement/revision procedures) utilized pacemakers (35%), implantable cardioverter-defibrillators (ICD)(29%), and cardiac resynchronization therapy with defibrillator devices (CRT-D)(36%). Nearly half of the patients (49%) had at least three predefined risk factors for CIED infection. CIED implantation was successful in 621 procedures (99.5% [95% confidence interval (CI) 98.8‐99.9]). There were three major infections (0.48% [95%CI 0.17‐1.40]) after 1.9 ± 2.4 months followup. The infections followed one ICD revision and two CRT-D replacements. There were seven deaths; none was a result of the antibacterial envelope or the CIED procedure. Conclusions: CIED procedures that utilized an antibacterial envelope had a high rate of CIED implantation success (>99%). Although the follow-up to date is short, there was also a low rate of infection (

Study objectives To examine the relationship between sleep-disordered breathing (SDB) and cardiovascular disease among community-dwelling older adults. Previous studies have suggested relatively stronger associations between SDB and such morbidity in middle-aged, relative to elderly, populations. Design Cross-sectional analysis of an elderly ambulatory, non-clinic-based cohort (Bay Area Sleep Cohort, BASC) SETTING: Community population studied in a sleep laboratory Participants One hundred twenty-nine older adults (mean [+/- SD] age = 72.6 [8.3]) (78 women; 51 men). Interventions NA. Measurements Complete clinical history including list of current medications, physical examination, selected blood chemistries, multiple blood pressure measurements, 12-lead electrocardiogram, and 2 consecutive nights of polysomnography. Results Fifty-one individuals (40%) were taking 1 or more cardiovascular medications and 24 (19%) had an apnea-hypopnea index (AHI) of 10 or more per hour of sleep. Cardiovascular medication use was related to cardiac events or procedures, history of angina, higher systolic or diastolic blood pressure, and abnormal electrocardiogram. Logistic regression showed statistically significant association between cardiovascular medication use and AHI of 10 or greater per hour, independent of age, sex, and body mass index. Supplementary analyses indicated that rapid eye movement AHI of 10 or greater per hour was significantly associated with elevated diastolic blood pressure. Conclusions The results suggest that sleep-disordered breathing may contribute to increased cardiovascular morbidity in older adults.

Background: Atrial fibrillation (AF) has been associated with myocardial oxidative stress, and antioxidant agents have demonstrated antiarrhythmic benefit in humans. We compared serum markers of oxidation and associated inflammation in individuals with or without AF. Methods: Serum markers of oxidative stress and inflammation were compared in a cross-sectional, case-control design study of 40 male individuals, with or without persistent or permanent AF, who were matched for age, sex, diabetes, and smoking status, known confounding variables for the measurement of oxidative stress. We used derivatives of reactive oxidative metabolites (DROMs) and ratios of oxidized to reduced glutathione (Eh GSH) and cysteine (Eh CySH) to quantify oxidative stress. We also measured inflammatory markers, including high-sensitivity C-reactive protein, interleukins 1β and 6, and tumor necrosis factor α. Results: Univariate, conditional logistical regression analysis showed that oxidative stress but not inflammatory markers were statistically associated with AF (P Conclusions: These data suggest that oxidative stress markers may have predictive value in AF management.

Introduction: Cystic fibrosis is among the most common inherited disorders, with ∼ 3% of Caucasians being heterozygous for the common CFTR ΔF508 mutation. Cardiomyopathy is a major cause of morbidity and mortality. While a small preliminary study suggested that cardiomyopathy patients heterozygous for the CFTR ΔF508 mutation have poorer outcomes, the finding has not been replicated and it is not known whether the poor outcomes are related to sudden death and/or heart failure progression. Methods: We screened 1347 Caucasian cardiomyopathy subjects (EF 21%, 82% male, 75% ischemic) with implantable cardioverter defibrillators (ICDs) from the prospective, multicenter, NIH-funded Genetic Risk Assessment of Defibrillator Events (GRADE) study. CFTR ΔF508 alleles were discriminated by real time fluorescence PCR. GRADE subjects were followed for up to 5 years to the primary endpoint of freedom from appropriate ICD shocks and the secondary endpoints of death and death/heart transplant/VAD placement. The results were compared by genotype using Kaplan-Meier analysis and Log Rank testing. Results: Genotyping revealed 33 CFTR ΔF508 heterozygotes (allele frequency 2.4%). ΔF508 carriers were older (68 vs 64 yrs, p=0.03); more likely to be diabetic (55 vs 34%, p=0.02), to have had an MI (77 vs 57%, p=0.02), and to have a RBBB on ECG (18 vs 7%, p=0.03); and had lower EFs (19 vs 21%, p=0.01). CFTR ΔF508 carriers had markedly higher rates of death (HR>2; p Conclusion: We have confirmed that carrying one CFTR ΔF508 allele is associated with an increased mortality in cardiomyopathy patients, and that this is likely not due to increased arrhythmic death. These findings may have implications for the treatment of this high risk heart failure subgroup. Future studies are needed to determine whether the increased mortality stems from a cardiac and/or pulmonary etiology.

Mutations that disrupt the coding sequence of Nav1.5, the cardiac Na+ channel encoded by SCN5A, cause inherited arrhythmias and cardiomyopathy. Changes in Nav1.5 splice isoforms, localization and function have also been associated with prognosis in acquired heart disease. However, the role of genetic variants in SCN5A gene regulatory sequences (e.g. those modulating expression) remains poorly understood. MicroRNAs (miRs) have emerged as vital gene regulators in heart, having roles in cardiogenesis, contractile function, and disease. These small non-coding RNAs are loaded into Argonaute proteins to direct post-transcriptional gene suppression by base-pairing with target transcripts, and genetic variants altering miR binding sequences may influence disease. Here, we used high-throughput biochemical means (HITS-CLIP) to generate the first transcriptome-wide map of miR binding events in human heart (4000 sites across >2200 genes). Our query of the data uncovered >500 common SNPs residing in or nearby miR target sites. Among these, we identified a synonymous SNP (rs1805126, T/C) which alters a conserved miR-24 binding site in the terminal coding exon of SCN5A. We hypothesized that this SNP affects Nav1.5 expression and contributes to clinical outcomes in heart failure. In vitro experiments showed that miR-24 suppresses Na+ current on patch clamp analysis (~5-fold; p1800 subjects with EFs≤30% and implantable cardioverter defibrillators (ICDs) from GRADE, a prospective multicenter study of genetic modulators of heart failure outcomes. We found that CC homozygotes had worse survival rates than T-allele carriers (HR=1.5, p=0.001), but no change in appropriate ICD shocks, a surrogate for sudden death. Together, these data reveal a novel miR-24:SCN5A:SNP regulatory axis that points to a surprising link between cardiac Na+ channel levels and non-arrhythmic death in heart failure. Overall, this work represents a key advance in exploring the interface of cardiac miRs with genetics and disease, perhaps signifying a broader functional relevance for “silent” SNPs.

Sudden cardiac death (SCD) is a leading cause of mortality in patients with cardiomyopathy. Although angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) decrease cardiac mortality in these cohorts, their role in preventing SCD has not been well established. We sought to determine whether the use of ACEi or ARB in patients with cardiomyopathy is associated with a lower incidence of appropriate implantable cardiac defibrillator (ICD) shocks in the Genetic Risk Assessment of Defibrillator Events study that included subjects with an ejection fraction of ≤30% and ICDs. Treatment with ACEi/ARB versus no-ACEi/ARB was physician dependent. There were 1,509 patients (mean age [SD] 63 [12] years, 80% men, mean [SD] EF 21% [6%]) with 1,213 (80%) on ACEi/ARB and 296 (20%) not on ACEi/ARB. We identified 574 propensity-matched patients (287 in each group). After a mean (SD) of 2.5 (1.9) years, there were 334 (22%) appropriate shocks in the entire cohort. The use of ACEi/ARB was associated with lower incidence of shocks at 1, 3, and 5 years in the matched cohort (7.7%, 16.7%, and 18.5% vs 13.2%, 27.5%, and 32.0%; RR = 0.61 [0.43 to 0.86]; p = 0.005). Among patients with glomerular filtration rate (GFR)60 and 30 to 60 ml/min/1.73 m(2), those on no-ACEi/ARB were at 45% and 77% increased risk of ICD shock compared with those on ACEi/ARB, respectively. ACEi/ARB were associated with significant lower incidence of appropriate ICD shock in patients with cardiomyopathy and GFR ≥30 ml/min/1.73 m(2) and with neutral effect in those with GFR30 ml/min/1.73 m(2).

SCD is a leading cause of cardiac mortality in patients with cardiomyopathy (CM). ACEi/ARB antagonize the action of angiotensin-II, a known precursor of interstitial fibrosis associated with ventricular arrhythmia. While ACEi/ARB decrease mortality, their role in preventing SCD in patients with CM

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Cardiovascular implantable electronic device (CIED) infection rates are increasing faster than implantation rates. More effective antimicrobial prophylaxis may help reduce CIED infections and improve clinical outcomes. The AIGIS(Rx)(®) antibacterial envelope is a polymer mesh implanted in the generator pocket with the CIED. After implantation it releases two antibiotics, minocycline and rifampin, that have been shown to reduce infections associated with other medical devices. The purpose of this retrospective cohort study is to determine the rate of CIED implantation success and CIED infection in procedures utilizing the antibacterial envelope.This study enrolled consecutive CIED procedures utilizing the antibacterial envelope at 10 US academic, community, and Veterans Affairs medical centers. Procedures following an explantation for a prior CIED infection or off-label use of the antibacterial envelope were excluded.The 624 eligible procedures (age 70 ± 13 years, 68.1% men, 27.2% renal insufficiency, 35.4% oral anticoagulant use, 67.8% replacement/revision procedures) utilized pacemakers (35%), implantable cardioverter-defibrillators (ICD)(29%), and cardiac resynchronization therapy with defibrillator devices (CRT-D)(36%). Nearly half of the patients (49%) had at least three predefined risk factors for CIED infection. CIED implantation was successful in 621 procedures (99.5%[95% confidence interval (CI) 98.8-99.9]). There were three major infections (0.48%[95%CI 0.17-1.40]) after 1.9 ± 2.4 months follow-up. The infections followed one ICD revision and two CRT-D replacements. There were seven deaths; none was a result of the antibacterial envelope or the CIED procedure.CIED procedures that utilized an antibacterial envelope had a high rate of CIED implantation success (99%). Although the follow-up to date is short, there was also a low rate of infection (0.50%) in this population at high risk for CIED infection.

Recent studies demonstrate that statins decrease ventricular arrhythmias in internal cardioverter defibrillator (ICD) patients. The mechanism is unknown, but evidence links increased inflammatory and oxidative states with increased arrhythmias. We hypothesized that statin use decreases oxidation.Methods.304 subjects with ICDs were surveyed for ventricular arrhythmia. Blood was analyzed for derivatives of reactive oxygen species (DROMs) and interleukin-6 (IL-6).Results.Subjects included 252 (83%) men, 58% on statins, 20% had ventricular arrhythmias. Average age was 63 years and ejection fraction (EF) 20%. ICD implant duration was 29±27 months. Use of statins correlated with lower ICD events (r=0.12,P=.02). Subjects on statins had lower hsCRP (5.2 versus 6.3;P=.05) and DROM levels (373 versus 397;P=.03). Other factors, including IL-6 and EF did not differ between statin and nonstatin use, nor did beta-blocker or antiarrhythmic use. Multivariate cross-correlation analysis demonstrated that DROMs, statins, IL-6 and EF were strongly associated with ICD events. Multivariate regression shows DROMs to be the dominant predictor.Conclusion.ICD event rate correlates with DROMs, a measure of lipid peroxides. Use of statins is associated with reduced DROMs and fewer ICD events, suggesting that statins exert their effect through reducing oxidation.

Objective: To examine the relationship between enlarged left atrial volume and increased blood markers of oxidative stress in patients at high risk for atrial fi brillation. Design: This is a retrospective study where a single blood draw was taken from a cohort of patients with internal cardioverter-defi brillators, cardiomyopathy and ejection fraction (EF) ≤ 30%, and sent for markers of oxidative stress and infl ammation. Left atrial size was obtained from echocardiography. Setting: Single center, multi-hospital, cohort of 191 patients who underwent subgroup analysis; these patients are a subgroup of those enrolled in a larger, prospective trial, multicenter trial. Patients: See above Interventions: Single blood draw, retrospective database/chart review Outcome Measures: Levels of hsCRP, IL-6, TNF-, nitrotyrosine, reduced to oxidized cysteine ratio, reduced to oxidized glutathione ratio, derivatives of reactive oxygen metabolites (DROMS) Results: Under univariate analysis, BMI (= 0.003, r= 0.211), IL-6 (=0.03, r= 0.192) and cysteine ratio (=0.004, r=0.242) all correlated with LA enlargement. Binary logistic regression demonstrated that the single factor that best classifi ed normal vs. enlarged LA is cysteine (=.001). The binary logistic model itself is signifi cantly predictive, as indicated by an omnibus test of model coeffi cients (

Ventricular tachycardia (VT) is a leading cause of morbidity and mortality for many patients, with a significant emotional and economic burden caused by implantable cardioverter-defibrillator (ICD) shocks and the requirement of medication with significant side effects. Additionally, 10% of VT occurs in patients with no structural heart disease. Until quite recently, ablation for VT has been reserved as the procedure of last hope for those who have ongoing recurrences despite maximal medical therapy and who are traumatized by multiple ICD shocks [1]. However, recent advances in imaging technology and three-dimensional intracardiac mapping systems have significantly improved the safety and efficacy of VT ablation procedures. Thus, ablation for VT should no longer be reserved as a last-resort bailout procedure and should move into the realm of routine electrophysiology treatment.

Background In-hospital cardiac arrest has a poor prognosis despite active electrocardiography monitoring. The initial rhythm of approximately 25% of in-hospital cardiopulmonary resuscitation (CPR) events is pulseless ventricular tachycardia/ventricular fibrillation (VT/VF). Early defibrillation is an independent predictor of survival in CPR events caused by VT/VF. The automated external cardioverter defibrillator (AECD) is a device attached by pads to the chest wall that monitors, detects, and within seconds, automatically delivers electric countershock to an appropriate tachyarrhythmia. Study Objectives • To evaluate safety of AECD monitoring in hospitalized patients. • To evaluate whether AECDs provide earlier defibrillation than hospital code teams. Methods The study is a prospective trial randomizing patients admitted to the telemetry ward to standard CPR (code team) or standard CPR plus AECD monitoring (PowerHeart CRM). The AECD is programmed to deliver one 150 J biphasic shock to patients in sustained VT/VF. Data is collected using the Utstein criteria for cardiac arrest. The primary endpoint is time-to-defibrillation; secondary outcomes include neurological status and survival to discharge, with 3-year follow-up. Results To date, 192 patients have been recruited in the time period between 10/10/2006 to 7/20/2007. A total of 3,655 hours of telemetry data have been analyzed in the AECD arm. The AECD has monitored ambulatory telemetry patients in sinus rhythm, sinus tachycardia, supraventricular tachycardia, atrial flutter or fibrillation, with premature ventricular complexes and non-sustained VT without delivery of inappropriate shocks. One patient experienced sustained VT during AECD monitoring, who was successfully defibrillated (17 seconds after meeting programmed criteria). There are no events to report in the control arm. The patient survived the event without neurological complications. During the same time period, mean time to shock for VT/VF cardiac arrest occurring outside the telemetry ward was 230 ± 50 seconds. Conclusion AECD monitoring is safe and likely results in earlier defibrillation than standard telemetry monitoring. Trial Registration National Institutes of Health registration ID: NCT00382928

Background Little is known about long-term outcomes of patients who survive inhospital cardiac arrest. Methods We examined long-term survival after inhospital cardiac arrest and whether procedural changes that improved survival to discharge impacted long-term survival. Consecutive inhospital arrests in the Atlanta Veterans Affairs Medical Center (Atlanta, GA) from 1995 to 2004 (n = 732) were retrospectively analyzed. Data regarding the arrest was obtained, including age, left ventricular ejection fraction, medications, and comorbidities, presenting rhythm, location of arrest, code duration, and outcomes. Long-term mortality data was obtained based on chart and Social Security Death Index reviews. Further data was gathered on internal cardioverter-defibrillator presence and use in survivors. Results Overall, 49 subjects (6.6%) survived to discharge. Univariate analysis found that ventricular tachycardia/ventricular fibrillation and the use of β-blockers, angiotensin-converting enzyme inhibitors, and antiarrhythmics at the time of arrest were associated with increased survival, whereas advancing age and comorbidities were associated with a higher risk of mortality. Multivariate analysis determined that age, rhythm, and comorbidities independently affected survival. Implementation of a resuscitation program previously documented to improve survival to discharge did not translate to durable long-term survival. Three-year survival rate after discharge was only 41%. Alternatively, subjects with internal cardioverter-defibrillator showed a 36% improvement in 3-year survival rate to 77% ( P = .001). Conclusions Subjects with inhospital cardiac arrest have poor long-term prognoses. A strategy that improved inhospital survival did not alter long-term mortality rate. Thus, survival to discharge may not be a sufficient end point for future resuscitation trials.

Cardiovascular implantable electronic device system infection is a serious complication of cardiac device implantation and carries with it a risk of significant morbidity and mortality. In the last 15 years, expansions of indications for cardiac devices have resulted in much higher volumes of much sicker patients being implanted, carrying significant risk of infection. Coagulase (−) Staphylococcus and Staphylococcus aureus are responsible for the majority of these infections, and these organisms are increasingly resistant to methicillin. The Aigis™ envelop is a Food and Drug Administration–approved implantable mesh that is impregnated with antibiotics that can be placed in the surgical incision prior to closure. The antibiotics elute off the mesh for 7–10 days, providing in vivo surgical site coverage with rifampin and minocyclin. This paper reviews the three retrospective clinical trials published in peer-reviewed journals and the interim analysis of the two ongoing prospective trials that have been presented at international conferences. Overall consensus is that the Aigis™ offers significant risk reduction for cardiovascular implantable electronic device infection. We then give a comprehensive discussion of how to use the Aigis™ envelop in the clinical setting, comparing the manufacturer’s recommendations with our extensive clinical experience.

BACKGROUND Pacemakers and implanted cardioverter defibrillator (ICD) infection rates are rising. Renal insufficiency impairs immune function and is known to increase the risk of infection following implantation of orthopedic hardware. The purpose of the current study is to characterize the risk factors for pacemaker and ICD infection and to evaluate the role of renal insufficiency in this complication. METHODS AND RESULTS A large (n = 4,856) single center experience with pacemaker and ICD procedures was reviewed. Of these, 141 were extractions of infected devices and 76 of these patients had been implanted in the Emory system and had preimplant creatinine information available for analysis. These cases were compared to 76 control patients undergoing device implantation matched by date of implant who had no infective complications. Demographic and clinical data from both groups were compared using both univariate and multivariate analysis. The overall rate of infection was 1.5%. Patients with device infection were more likely to have congestive heart failure (CHF), be diabetic, have generator exchanges, and to take warfarin than controls. There was no difference in the prevalence of coronary disease, atrial fibrillation, steroid use, or malignancy between the two groups. Elevated creatinine (Cr > or = 1.5 mg/dL) was much more frequent in patients with infection than in controls (38% vs 12%, odds ratio 4.6, P < 0.001). Moderate to severe renal disease (GFR < or = 60 cc/min/1.73 m2) was the most potent risk factor for infection, with a prevalence of 42% in infected patients versus 13% in controls (odds ratio of 4.8). CONCLUSIONS Renal insufficiency dramatically increases the risk of infection complicating pacemaker or ICD surgery. This association should be part of the risk-benefit consideration prior to device implantation. Additional study of more extensive perioperative antibiotic therapy in this subset of patients is warranted.

Atrial fibrillation (AF) is the most common clinically significant arrhythmia seen by clinicians. Prevalence is as high as 9.0% in patients agedor = 80 years, and incidence is projected to be more than 5.6 million patients in the U.S. by 2050. Recently, new trials have challenged the traditional belief that rhythm control is inherently superior to rate control in these patients. This article reviews the basic tenets of treatment for AF and discusses how new trial data integrate into these protocols. A concise treatment algorithm is provided and new and upcoming more aggressive interventional treatment options are discussed. This review is designed to help the general practitioner decide how to treat patients in the outpatient setting, evaluate which patients should be hospitalized for management, and which patients should be referred to a cardiologist.

l n a j s a r f f m c In the current issue of Heart Rhythm, Tang et al provide new tool for the armamentarium in the fight against ardiac disease, a point-of-care test for the biomarker plasma erve growth factor (NGF). NGF is a secreted protein that nduces the differentiation and survival of neurons and is esponsible for the maintenance of sympathetic and sensory eurons in cardiac tissue. It primarily binds to and activates yrosine kinase receptor A (TrkA) and a low-affinity p75 eurotrophin receptor (p75NTR). At the cellular level, GF decreases calcium-dependent and calcium-indepenent potassium channels and appears to modulate the firing roperties of sympathetic neurons. These, in turn, may be elated to an interaction with cardiac arrhythmia. NGF is ecreted in proportion to the innervation density of cardiac issue, and developing neurons not exposed to NGF undergo poptosis. Several studies have shown that increased NGF evels lead to cardiac hypertrophy. The study by Tang et al demonstrates nicely that this new beroptic immunoassay can deliver NGF concentrations rom plasma in 5 minutes. Compared to the currently used nzyme-linked immunosorbent assay test, which takes days o weeks and requires significant user training, equipment, nd support personnel, this new assay makes serum NGF easurements ready for prime time use by the cardiac ommunity. But, is NGF ready for prime time? The 21 patients with atrial fibrillation/atrial flutter enolled in this comparison trial underwent radiofrequency blation. Previous work has documented that NGF levels ise acutely postoperatively. Preoperative and postoperaive NGF samples were highly comparable between the two easurement methods. The reliability of the test appears xcellent. Yet the question now is the utility of the test. The autonomic nervous system plays a role in the specrum of postmyocardial infarction (post-MI) risk for sudden ardiac death (SCD), particularly as evidenced by the surival conferred by pharmacologic beta-blockade. Clinically, ardiac reinnervation improves hemodynamic function. ardiac sympathetic activation of beta-adrenergic receptors ncreases systolic contractility and diastolic relaxation, and ccelerates atrioventricular conduction. However, the extent

A 62-year-old man without significant medical history presented to his doctor with repeated episodes of syncope. The episodes were always associated with micturition (often at night) and had caused falls resulting in head injury. His wife was particularly concerned, noting that he became apneic while sleeping. He was diagnosed with sleep apnea. A 24-hour Holter monitor was obtained …

Background: Recent in vitro studies on failing human heart muscle has suggested that ranolazine (RAN), a novel antianginal drug known to inhibit late sodium current, may improve diastolic dysfunction (DD) caused by hypertension (HTN)-induced oxidative stress. By improving DD, RAN can improve heart failure with preserved ejection fraction (HFPEF). Methods: Amouse model of DDwas developed by inducing mild HTN by unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and substituting drinking water with 1% NaCl. Control animals underwent sham operation and drank regular tap water. RAN 50 (mg/kg) was given orally twice a day. Weekly blood pressures (BPs) and heart rates (HRs) were measured using tail-cuff plethysmography. Cardiac function and left ventricular posterior wall thickness (LVPWd) were measured by echocardiogram under light anesthesia using isoflurane. Treatment durationwas for 3weeks and 7weeks. Pulmonary congestion was assessed by lung to body weight (L/BW) ratio. Results: Compared to controls, DOCA mice were hypertensive (BP 112 ±4 vs. 89±2 mmHg) and had DD evidenced by a low LV inflow propagation velocity Vp (28.1±0.5 vs. 47.2±1 cm/s⁎), a low mitral annulus early longitudinal velocity E' (2.70 vs. 4.40 cm/s⁎), and a high E/E' ratio (29.3±1.5 vs. 18.0±0⁎). DOCA mice had LVH as evidenced by high heart/BW ratio (6.22±0.15 vs. 4.90±0.22 mg/g⁎) and increased LVPWd (0.82±0.22 vs. 0.74±0.01 mm⁎). There was no systolic dysfunction in either group. RAN pretreatment effectively prevented DD and LVH in DOCA mice as evidenced by high E' (3.9 Vs 2.70 cm/s⁎), low E/E' (18.8±1.0⁎), high Vp (41±2Vs 28.1±0.5 cm/s⁎), lowheart/BW ratio (4.79±0.11 mg/g⁎), and low LVPWd thickness (0.76±0.01 vs. 0.82±0.02 mm⁎). RAN had no effect on HR [625±18 vs. 630±20 bpm, P=not significant (NS)]. RAN pretreatment effectively prevented development of heart failure in DOCA mice at 7 weeks as evidenced by significantly lower L/BW ratios when compared with untreated DOCA mice (0.41±0.002 vs. 0.52±0.02 mg/g⁎). Conclusions: RANhas prevented DD, LVH, and HFPEF in a hypertensive murine model of DD. Prevention of heart failure in our model warrants additional animal andhuman studies to further evaluate the therapeutic potential of RAN in HFPEF (Mean±S.E.M., ⁎Pb.05).

RAS inhibitors (RASIs/ACE inhibitors & ARBs) have reduced mortality in SHF (EF 45p) in randomized controlled trials. Since, AAs are underrepresented in these trials, whether these results are applicable to AAs with HFPEF is uncertain All cause mortality was