Angiotensin receptor type 1 single nucleotide polymorphism 1166A/C is associated with malignant arrhythmias and altered circulating miR-155 levels in patients with chronic heart failure.

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.

Statin therapy for the prevention of atrial fibrillation trial (SToP AF trial).

BACKGROUND: 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). METHODS AND RESULTS: 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-1ß[IL-1ß], 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). CONCLUSIONS: 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.

Implantation success and infection in cardiovascular implantable electronic device procedures utilizing an antibacterial envelope.

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 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. 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 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. 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 (<0.50%) in this population at high risk for CIED infection.

The genomics of heart failure: design and rationale of the HERMES consortium.

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 × 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.

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. 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 unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Sleep-disordered breathing and cardiovascular disease in the Bay Area Sleep Cohort.

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.

Improved Patient Outcomes by Normalizing Sympathovagal Balance: Differentiating Syncope-Precise Subtype Differentiation Leads to Improved Outcomes.

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.

A common variant alters SCN5A-miR-24 interaction and associates with heart failure mortality.

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.

Multi-ethnic genome-wide association study for atrial fibrillation.

Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. 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.

Long-term survival after successful inhospital cardiac arrest resuscitation.

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 beta-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.

Clinical use of antibacterial mesh envelopes in cardiovascular electronic device implantations.

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.

Left Ventricular Dilatation Increases the Risk of Ventricular Arrhythmias in Patients With Reduced Systolic Function.

BACKGROUND: Reduced left ventricular (LV) ejection fraction increases the risk of ventricular arrhythmias; however, LV ejection fraction has a low sensitivity to predict ventricular arrhythmias. LV dilatation and mass may be useful to further risk-stratify for ventricular arrhythmias. METHODS AND RESULTS: Patients from the Genetic Risk of Assessment of Defibrillator Events (GRADE) study (N=930), a study of heart failure subjects with defibrillators, were assessed for appropriate implantable cardioverter-defibrillator shock and death, heart transplant, or ventricular assist device placement by LV diameter and mass. LV mass was divided into normal, mild, moderate, and severe classifications. Severe LV end-diastolic diameter had worse shock-free survival than normal and mild LV end-diastolic diameter (P=0.0002 and 0.0063, respectively; 2-year shock free, severe 74%, moderate 80%, mild 91%, normal 88%; 4-year shock free, severe 62%, moderate 69%, mild 72%, normal 81%) and freedom from death, transplant, or ventricular assist device compared with normal and moderate LV end-diastolic diameter (P<0.0001 and 0.0441, respectively; 2-year survival: severe 78%, moderate 85%, mild 82%, normal 89%; 4-year survival: severe 55%, moderate 64%, mild 63%, normal 74%). Severe LV mass had worse shock-free survival than normal and mild LV mass (P=0.0370 and 0.0280, respectively; 2-year shock free: severe 80%, moderate 81%, mild 91%, normal 87%; 4-year shock free: severe 68%, moderate 73%, mild 76%, normal 76%) but no association with death, transplant, or ventricular assist device (P=0.1319). In a multivariable Cox proportional hazards analysis adjusted for LV ejection fraction, LV end-diastolic diameter was associated with appropriate implantable cardioverter-defibrillator shocks (hazard ratio 1.22, P=0.020). LV end-diastolic diameter was associated with time to death, transplant, or ventricular assist device (hazard ratio 1.29, P=0.0009). CONCLUSIONS: LV dilatation may complement ejection fraction to predict ventricular arrhythmias. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02045043.

Effect of angiotensin-converting enzyme inhibitors and receptor blockers on appropriate implantable cardiac defibrillator shock in patients with severe systolic heart failure (from the GRADE Multicenter Study).

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 GFR <30 ml/min/1.73 m(2).

Concise review of atrial fibrillation: treatment update considerations in light of AFFIRM and RACE.

Atrial fibrillation (AF) is the most common clinically significant arrhythmia seen by clinicians. Prevalence is as high as 9.0% in patients aged > or = 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.

Differential effects of adrenergic antagonists (Carvedilol vs Metoprolol) on parasympathetic and sympathetic activity: a comparison of measures.

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 (msec(2)) 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.

Differential effects of adrenergic antagonists (Carvedilol vs Metoprolol) on parasympathetic and sympathetic activity: a comparison of clinical results.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is recognized as a significant health risk, correlating with risk of heart disease, silent myocardial ischemia or sudden cardiac death. Beta-blockers are often prescribed to minimize risk. OBJECTIVES: In this second of two articles, the effects on parasympathetic and sympathetic activity of the alpha/beta-adrenergic blocker, Carvedilol, are compared with those of the selective beta-adrenergic blocker, Metoprolol. METHODS: Retrospective, 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. RESULTS: Introducing Carvedilol or Metoprolol decreased heart rate and blood pressure, and discontinuing them had the opposite effect. Parasympathetic activity increased with introducing Carvedilol. Sympathetic activity increased more after discontinuing Carvedilol, suggesting better sympathetic suppression. With ongoing treatment, resting parasympathetic activity decreased with Metoprolol but increased with Carvedilol. CONCLUSION: Carvedilol has a more profound effect on sympathovagal balance than Metoprolol. While both suppress sympathetic activity, only Carvedilol increases parasympathetic activity. Increased parasympathetic activity may underlie the lower mortality risk with Carvedilol.

Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy.

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.

Statins Decrease Oxidative Stress and ICD Therapies.

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.