Sumeet S. Chugh

Worldwide Epidemiology of Atrial Fibrillation A Global Burden of Disease 2010 Study

Background— The global burden of atrial fibrillation (AF) is unknown. Methods and Results— We systematically reviewed population-based studies of AF published from 1980 to 2010 from the 21 Global Burden of Disease regions to estimate global/regional prevalence, incidence, and morbidity and mortality related to AF (DisModMR software). Of 377 potential studies identified, 184 met prespecified eligibility criteria. The estimated number of individuals with AF globally in 2010 was 33.5 million (20.9 million men [95% uncertainty interval (UI), 19.5–22.2 million] and 12.6 million women [95% UI, 12.0–13.7 million]). Burden associated with AF, measured as disability-adjusted life-years, increased by 18.8% (95% UI, 15.8–19.3) in men and 18.9% (95% UI, 15.8–23.5) in women from 1990 to 2010. In 1990, the estimated age-adjusted prevalence rates of AF (per 100 000 population) were 569.5 in men (95% UI, 532.8–612.7) and 359.9 in women (95% UI, 334.7–392.6); the estimated age-adjusted incidence rates were 60.7 per 100 000 person-years in men (95% UI, 49.2–78.5) and 43.8 in women (95% UI, 35.9–55.0). In 2010, the prevalence rates increased to 596.2 (95% UI, 558.4–636.7) in men and 373.1 (95% UI, 347.9–402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2–95.4) in men and 59.5 (95% UI, 49.9–74.9) in women. Mortality associated with AF was higher in women and increased by 2-fold (95% UI, 2.0–2.2) and 1.9-fold (95% UI, 1.8–2.0) in men and women, respectively, from 1990 to 2010. There was evidence of significant regional heterogeneity in AF estimations and availability of population-based data. Conclusions— These findings provide evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010, with significant public health implications. Systematic, regional surveillance of AF is required to better direct prevention and treatment strategies.

Epidemiology of Sudden Cardiac Death: Clinical and Research Implications

The current annual incidence of sudden cardiac death in the United States is likely to be in the range of 180,000 to 250,000 per year. Coinciding with the decreased mortality from coronary artery disease, there is evidence pointing toward a significant decrease in rates of sudden cardiac death in the United States during the second half of the 20th century. However, the alarming rise in prevalence of obesity and diabetes in the first decade of the new millennium both in the United States and worldwide, would indicate that this favorable trend is unlikely to persist. We are likely to witness a resurgence of coronary artery disease and heart failure, as a result of which sudden cardiac death will have to be confronted as a shared and indiscriminate, worldwide public health problem. There is also increasing recognition of the fact that discovery of meaningful and relevant risk stratification and prevention methodologies will require careful prospective community-wide analyses, with access to large archives of DNA, serum, and tissue that link with well-phenotyped databases. The purpose of this review is to summarize current knowledge of sudden cardiac death epidemiology. We will discuss the significance and strengths of community-wide evaluations of sudden cardiac death, summarize recent observations from such studies, and finally highlight specific potential predictors that warrant further evaluation as determinants of sudden cardiac death in the general population.

Sudden Cardiac Death Prediction and Prevention Report From a National Heart, Lung, and Blood Institute and Heart Rhythm Society Workshop

Despite the significant decline in coronary artery disease (CAD) mortality in the second half of the 20th century,1 sudden cardiac death (SCD) continues to claim 250 000 to 300 000 US lives annually.2 In North America and Europe the annual incidence of SCD ranges between 50 to 100 per 100 000 in the general population.3,–,6 Because of the absence of emergency medical response systems in most world regions, worldwide estimates are currently not available.7 However, even in the presence of advanced first responder systems for resuscitation of out-of-hospital cardiac arrest, the overall survival rate in a recent North American analysis was 4.6%.8 SCD can manifest as ventricular tachycardia (VT), ventricular fibrillation (VF), pulseless electric activity (PEA), or asystole. In a significant proportion of patients, SCD can present without warning or a recognized triggering mechanism. The mean age of those affected is in the mid 60s, and at least 40% of patients will suffer SCD before the age of 65.4 Consequently, enhancement of methodologies for prediction and prevention of SCD acquires a unique and critical importance for management of this significant public health issue. Prediction and prevention of SCD is an area of active investigation, but considerable challenges persist that limit the efficacy and cost-effectiveness of available methodologies.7,9,10 It was recognized early on that optimization of SCD risk stratification will require integration of multi-disciplinary efforts at the bench and bedside, with studies in the general population.11,–,13 This integration has yet to be effectively accomplished. There is also increasing awareness that more investigation needs to be directed toward identification of early predictors of SCD.14 Significant advancements have occurred for risk prediction in the inherited channelopathies15,–,17 and …

Quantification of Diffuse Myocardial Fibrosis and Its Association With Myocardial Dysfunction in Congenital Heart Disease

Background—The etiology of ventricular dysfunction in adult congenital heart disease (ACHD) is not well understood. Diffuse fibrosis is a likely common final pathway and is quantifiable using MRI. Methods and Results—Patients with ACHD (n=50) were studied with cardiac MRI to quantify systemic ventricular volume and function and diffuse fibrosis. The fibrosis index for a single midventricular plane of the systemic ventricle was quantified by measuring T1 values for blood pool and myocardium before and after administration of gadolinium (0.15 mmol/kg) and then adjusted for hematocrit. Results were compared to healthy volunteers (normal controls, n=14) and patients with acquired heart failure (positive controls, n=4). Patients studied (age, 37±12 years; female sex, 40%) included 11 with a systemic right ventricle (RV), 17 with tetralogy of Fallot, 10 with cyanosis, and 12 with other lesions. The fibrosis index was significantly elevated in patients with ACHD compared to normal controls (31.9±4.9% versus 24.8±2.0%; P=0.001). Values were highest in patients with a systemic RV (35.0±5.8%; P<0.001) and those who were cyanotic (33.7±5.6%; P<0.001). The fibrosis index correlated with end-diastolic volume index (r=0.60; P<0.001) and ventricular ejection fraction (r=−0.53; P<0.001) but not with age or oxygen saturation in patients who were cyanotic. Late gadolinium enhancement did not account for the differences seen. Conclusions—Patients with ACHD have evidence of diffuse, extracellular matrix remodeling similar to patients with acquired heart failure. The fibrosis index may facilitate studies on the mechanisms and treatment of myocardial fibrosis and heart failure in these patients.

Meta-Analysis of Obstructive Sleep Apnea as Predictor of Atrial Fibrillation Recurrence After Catheter Ablation

The association between obstructive sleep apnea (OSA) and atrial fibrillation (AF) is strong and is now well established. However, studies on the role of OSA on AF recurrence after catheter ablation have yielded conflicting results. The aim of the present study was to investigate the role of OSA on AF recurrence after catheter-based pulmonary vein isolation. We performed a data search on the PubMed, Web of Science, and the Cochrane databases for studies published by August 2010. In addition, we manually searched the conference proceedings of the European Society of Cardiology, American College of Cardiology, and American Heart Association for related abstracts. After the initial search returned 402 reports, we identified 6 studies with a total of 3,995 patients that met our inclusion criteria. Overall, patients with OSA have a 25% greater risk of AF recurrence after catheter ablation than those without OSA (risk ratio 1.25, 95% confidence interval 1.08 to 1.45, p = 0.003). Subgroup analysis showed that OSA diagnosed using polysomnography is a strong predictor of AF recurrence (risk ratio 1.40, 95% confidence interval 1.16 to 1.68, p = 0.0004) but not when OSA was diagnosed using the Berlin questionnaire (risk ratio 1.07, 95% confidence interval 0.91 to 1.27, p = 0.39). In conclusion, patients with OSA have significantly greater AF recurrence rates after pulmonary vein isolation. In addition to other factors, a diagnosis of OSA merits special consideration when evaluating patients for catheter-based AF ablation.

Prolonged Tpeak-to-Tend Interval on the Resting ECG Is Associated With Increased Risk of Sudden Cardiac Death

Background— Early studies indicate that prolongation of the interval between the peak and the end of the T wave (Tpeak to Tend [TpTe]) on the 12-lead ECG is a marker of ventricular arrhythmogenesis. However, community-based studies have not been conducted. Methods and Results— TpTe and other ECG predictors were evaluated in the ongoing Oregon Sudden Unexpected Death Study based in the Portland, Oregon, metropolitan area using a case-control design. Cases of sudden cardiac death (SCD) (n=353; mean age, 66.6 years; 95% CI, 65.1 to 68.1 years; 67% men) were compared with living controls with coronary artery disease (n=342; mean age, 64.7 years; 95% CI, 63.4 to 66.0 years; 69% men) from the same region. Analysis of TpTe and selected ECG intervals was limited to sinus rhythm 12-lead ECGs. For cases, these were obtained before and unrelated to SCD. Independent-samples t tests and multiple logistic regression were used. Mean TpTe was significantly greater in cases (89.4 ms; 95% CI, 87.7 to 91.2 ms; P<0.0001) than in controls (76.1 ms; 95% CI, 74.8 to 77.4 ms). The other ECG intervals (corrected QT interval [QTc], QRS duration [QRSD], and TpTe/QT ratio) also were significantly prolonged among cases versus controls (P⩽0.01). TpTe remained a significant predictor of SCD after adjusting for age, sex, QTc, QRSD, and left ventricular function. Odds of SCD increased more with a 1-SD increase in TpTe (12 ms) among subjects with prolonged QRSD (odds ratio, 3.49; 95% CI, 2.06 to 5.91) than with a 1-SD increase in TpTe among subjects with normal QRSD (odds ratio, 1.96; 95% CI, 1.65 to 2.32). TpTe remained significantly associated with SCD in subjects with normal QTc. Conclusions— Prolongation of the TpTe interval measured in lead V5 was independently associated with SCD, with particular utility when the QTc was normal or not measurable because of prolonged QRSD.

Determinants of Prolonged QT Interval and Their Contribution to Sudden Death Risk in Coronary Artery Disease: The Oregon Sudden Unexpected Death Study

Background— In a recent cohort study, prolongation of the corrected QT interval (QTc) was associated with an independent increased risk of sudden cardiac death (SCD). We evaluated determinants of prolonged QTc and the relationship of prolonged QTc to SCD risk among patients with coronary artery disease in the general population. Methods and Results— A case-control design was used. Cases were SCD patients with coronary artery disease among a metropolitan area of 1 000 000 residents (2002 to 2006); controls were area residents with coronary artery disease but no history of SCD. All cases were required to have an ECG suitable for QTc analysis before and unrelated to the occurrence of SCD. A total of 373 cases and 309 controls met criteria for analysis. Mean QTc was significantly longer in cases than in controls (450±45 versus 433±37 ms; P<0.0001). In a multivariate model, gender, diabetes mellitus, and QTc-prolonging drugs were significant determinants of QTc prolongation in controls. In a logistic regression model predicting SCD, diabetes mellitus (odds ratio, 1.97; 95% confidence interval, 1.32 to 2.96) and use of QTc-prolonging drugs (odds ratio, 2.90; 95% confidence interval, 1.92 to 4.37) were significant predictors of SCD among subjects with normal or borderline QTc. However, abnormally prolonged QTc in the absence of diabetes and QT-prolonging medications was the strongest predictor of SCD (odds ratio, 5.53; 95% confidence interval, 3.20 to 9.57). Conclusions— Diabetes mellitus and QTc-affecting drugs determined QTc prolongation and were predictors of SCD in coronary artery disease. However, idiopathic abnormal QTc prolongation was associated with 5-fold increased odds of SCD. A continued search for novel determinants of QTc prolongation such as genomic factors is likely to enhance risk stratification for SCD in coronary artery disease.

A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone

BACKGROUND Published case reports have associated the therapeutic use of methadone with the occasional occurrence of sudden cardiac death. Because of the established utility of this drug and with the eventual goal of enhancing safety of use, we performed a community-based study to evaluate this association. METHODS During a 4-year period, we prospectively evaluated all patients who consecutively had sudden cardiac death and underwent investigation by the medical examiner in the metropolitan area of Portland, Ore. Case subjects of interest were those with a therapeutic blood level of methadone (<1 mg/L), and case comparison subjects were those with no methadone identified. Patients with recreational drug use or any drug overdose were excluded from either group. Detailed autopsies were conducted, including the detection and quantification of all substances in the blood. RESULTS A total of 22 sudden cardiac death cases with therapeutic levels of methadone (mean 0.48+/-0.22 mg/L; range 0.1-0.9 mg/L) were identified (mean age 37.0+/-10 years, 68% were male) and compared with 106 consecutive sudden cardiac death cases without evidence of methadone (mean age 42+/-13 years, 69% were male). The most common indication for methadone use was pain control (n=12, 55%). Among cases receiving methadone therapy, sudden death-associated cardiac abnormalities were identified in only 23% (n=5), with no clear cause of sudden cardiac death in the remaining 77% (n=17). Among cases with no methadone, sudden death-associated cardiac abnormalities were identified in 60% (n=64, P=.002). CONCLUSION The significantly lower prevalence of cardiac disease in the case group implicates methadone, even at therapeutic levels, as a likely cause of sudden death. These findings point toward an association between methadone and occurrence of sudden death in the community. Clinical safeguards and further prospective studies specifically designed to enhance safety of methadone use are warranted.

Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction

Sudden cardiac death from ventricular fibrillation during acute myocardial infarction is a leading cause of total and cardiovascular mortality. To our knowledge, we here report the first genome-wide association study for this trait, conducted in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at 21q21 (rs2824292, odds ratio = 1.78, 95% CI 1.47–2.13, P = 3.3 × 10−10). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (controls) (odds ratio = 1.49, 95% CI 1.14–1.95, P = 0.004). The closest gene to this SNP is CXADR, which encodes a viral receptor previously implicated in myocarditis and dilated cardiomyopathy and which has recently been identified as a modulator of cardiac conduction. This locus has not previously been implicated in arrhythmia susceptibility.

Predicting Survival After Out-of-Hospital Cardiac Arrest: Role of the Utstein Data Elements

STUDY OBJECTIVE Survival after out-of-hospital cardiac arrest depends on the links in the chain of survival. The Utstein elements are designed to assess these links and provide the basis for comparing outcomes within and across communities. We assess whether these measures sufficiently predict survival and explain outcome differences. METHODS We used an observational, prospective data collection, case-series of adult persons with nontraumatic out-of-hospital cardiac arrest from December 1, 2005, through March 1, 2007, from the multisite, population-based Resuscitation Outcomes Consortium Epistry-Cardiac Arrest. We used logistic regression, receiver operating curves, and measures of variance to estimate the extent to which the Utstein elements predicted survival to hospital discharge and explained outcome variability overall and between 7 Resuscitation Outcomes Consortium sites. Analyses were conducted for all emergency medical services-treated cardiac arrests and for the subset of bystander-witnessed patient arrests because of presumed cardiac cause presenting with ventricular fibrillation or ventricular tachycardia. RESULTS Survival was 7.8% overall (n=833/10,681) and varied from 4.6% to 14.7% across Resuscitation Outcomes Consortium sites. Among bystander-witnessed ventricular fibrillation or ventricular tachycardia, survival was 22.1% overall (n=323/1459) and varied from 12.5% to 41.0% across sites. The Utstein elements collectively predicted 72% of survival variability among all arrests and 40% of survival variability among bystander-witnessed ventricular fibrillation. The Utstein elements accounted for 43.6% of the between-site survival difference among all arrests and 22.3% of the between-site difference among the bystander-witnessed ventricular fibrillation subset. CONCLUSION The Utstein elements predict survival but account for only a modest portion of outcome variability overall and between Resuscitation Outcomes Consortium sites. The results underscore the need for ongoing investigation to better understand characteristics that influence cardiac arrest survival.