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More than 100 years after it was first invented, the 12-lead electrocardiogram (ECG) continues to occupy an important place in the diagnostic armamentarium of the practicing clinician. With the recognition of relatively rare but important clinical entities such as Wolff-Parkinson-White and the long QT syndrome, this clinical tool was firmly established as a test for assessing risk of sudden cardiac death (SCD). However, over the past two decades the role of the ECG in risk prediction for common forms of SCD, for example in patients with coronary artery disease, has been the focus of considerable investigation. Especially in light of the limitations of current risk stratification approaches, there is a renewed focus on this broadly available and relatively inexpensive test. Various abnormalities of depolarization and repolarization on the ECG have been linked to SCD risk; however, more focused work is needed before they can be deployed in the clinical arena. The present review summarizes the current knowledge on various ECG risk markers for prediction of SCD and discusses some future directions in this field., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Sudden cardiac arrest (SCA) is a major contributor to mortality, but data are limited among nonwhites. Identification of differences in clinical profile based on race may provide opportunities for improved SCA prevention., Methods and Results: In the ongoing Oregon Sudden Unexpected Death Study (SUDS), individuals experiencing SCA in the Portland, OR, metropolitan area were identified prospectively. Patient demographics, arrest circumstances, and pre-SCA clinical profile were compared by race among cases from 2002 to 2012 (for clinical history, n=126 blacks, n=1262 whites). Incidence rates were calculated for cases from the burden assessment phase (2002-2005; n=1077). Age-adjusted rates were 2-fold higher among black men and women (175 and 90 per 100 000, respectively) compared with white men and women (84 and 40 per 100 000, respectively). Compared with whites, blacks were >6 years younger at the time of SCA and had a higher prearrest prevalence of diabetes mellitus (52% versus 33%; P<0.0001), hypertension (77% versus 65%; P=0.006), and chronic renal insufficiency (34% versus 19%; P<0.0001). There were no racial differences in previously documented coronary artery disease or left ventricular dysfunction, but blacks had more prevalent congestive heart failure (43% versus 34%; P=0.04) and left ventricular hypertrophy (77% versus 58%; P=0.02) and a longer QTc interval (466±36 versus 453±41 milliseconds; P=0.03)., Conclusions: In this US community, the burden of SCA was significantly higher in blacks compared with whites. Blacks with SCA had a higher prearrest prevalence of risk factors beyond established coronary artery disease, providing potential targets for race-specific prevention., (© 2015 American Heart Association, Inc.)

Background: Recent canines studies have shown that iron deposition within chronic myocardial infarction (CMI) influences the electric behavior of the heart. To date, the link between the iron deposition and malignant ventricular arrhythmias in humans with CMI is unknown., Methods and Results: Patients with CMI (n=94) who underwent late-gadolinium-enhanced cardiac magnetic resonance imaging before implantable cardioverter-defibrillator implantation for primary and secondary preventions were retrospectively analyzed. The predictive values of hypointense cores (HIC) in balanced steady-state free precession images and conventional cardiac magnetic resonance imaging and ECG malignant ventricular arrhythmia parameters for the prediction of primary combined outcome (appropriate implantable cardioverter-defibrillator therapy, survived cardiac arrest, or sudden cardiac death) were studied. The use of HIC within CMI on balanced steady-state free precession as a marker of iron deposition was validated in a canine MI model (n=18). Nineteen patients met the study criteria with events occurring at a median of 249 (interquartile range of 540) days after implantable cardioverter-defibrillator placement. Of the 19 patients meeting the primary end point, 18 were classified as HIC+, whereas only 1 was HIC-. Among the cohort in whom the primary end point was not met, there were 28 HIC+ and 47 HIC- patients. Receiver operating characteristic curve analysis demonstrated an additive predictive value of HIC for malignant ventricular arrhythmias with an increased area under the curve of 0.87 when added to left ventricular ejection fraction (left ventricular ejection fraction alone, 0.68). Both cardiac magnetic resonance imaging and histological validation studies performed in canines demonstrated that HIC regions in balanced steady-state free precession images within CMI likely result from iron depositions., Conclusions: Hypointense cores within CMI on balanced steady-state free precession cardiac magnetic resonance imaging can be used as a marker of iron deposition and yields incremental information toward improved prediction of malignant ventricular arrhythmias., (© 2015 American Heart Association, Inc.)

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., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Unlabelled: : We previously reported the delivery of endothelial progenitor cells (EPCs) embedded in hyaluronic acid-based (HA)-hydrogels protects renal function during acute kidney injury (AKI) and promotes angiogenesis. We attempted to further ameliorate renal dysfunction by coembedding EPCs with renal mesenchymal stem cells (MSCs), while examining their paracrine influence on cytokine/chemokine release and proinflammatory macrophages. A live/dead assay determined whether EPC-MSC coculturing improved viability during lipopolysaccharide (LPS) treatment, and HA-hydrogel-embedded delivery of cells to LPS-induced AKI mice was assessed for effects on mean arterial pressure (MAP), renal blood flow (RBF), circulating cytokines/chemokines, serum creatinine, proteinuria, and angiogenesis (femoral ligation). Cytokine/chemokine release from embedded stem cells was examined, including effects on macrophage polarization and release of proinflammatory molecules. EPC-MSC coculturing improved stem cell viability during LPS exposure, an effect augmented by MSC hypoxic preconditioning. The delivery of coembedded EPCs with hypoxic preconditioned MSCs to AKI mice demonstrated additive improvement (compared with EPC delivery alone) in medullary RBF and proteinuria, with comparable effects on serum creatinine, MAP, and angiogenesis. Exposure of proinflammatory M1 macrophages to EPC-MSC conditioned medium changed their polarization to anti-inflammatory M2. Incubation of coembedded EPCs-MSCs with macrophages altered their release of cytokines/chemokines, including enhanced release of anti-inflammatory interleukin (IL)-4 and IL-10. EPC-MSC delivery to endotoxemic mice elevated the levels of circulating M2 macrophages and reduced the circulating cytokines/chemokines. In conclusion, coembedding EPCs-MSCs improved their resistance to stress, impelled macrophage polarization from M1 to M2 while altering their cytokine/chemokines release, reduced circulating cytokines/chemokines, and improved renal and vascular function when MSCs were hypoxically preconditioned., Significance: This report provides insight into a new therapeutic approach for treatment of sepsis and provides a new and improved strategy using hydrogels for the delivery of stem cells to treat sepsis and, potentially, other injuries and/or diseases. The delivery of two different stem cell lines (endothelial progenitor cells and mesenchymal stem cells; delivered alone and together) embedded in a protective bioengineered scaffolding (hydrogel) offers many therapeutic benefits for the treatment of sepsis. This study shows how hydrogel-delivered stem cells elicit their effects and how hydrogel embedding enhances the therapeutic efficacy of delivered stem cells. Hydrogel-delivered stem cells influence the components of the overactive immune system during sepsis and work to counterbalance the release of many proinflammatory and prodamage substances from immune cells, thereby improving the associated vascular and kidney damage., (©AlphaMed Press.)

Background: Endocardial mapping for scars and abnormal electrograms forms the most essential component of ventricular tachycardia ablation. The utility of ultra-high resolution mapping of ventricular scar was assessed using a multielectrode contact mapping system in a chronic canine infarct model., Methods: Chronic infarcts were created in five anesthetized dogs by ligating the left anterior descending coronary artery. Late gadolinium-enhanced magnetic resonance imaging (LGE MRI) was obtained 4.9 ± 0.9 months after infarction, with three-dimensional (3D) gadolinium enhancement signal intensity maps at 1-mm and 5-mm depths from the endocardium. Ultra-high resolution electroanatomical maps were created using a novel mapping system (Rhythmia Mapping System, Rhythmia Medical/Boston Scientific, Marlborough, MA, USA) Rhythmia Medical, Boston Scientific, Marlborough, MA, USA with an 8.5F catheter with mini-basket electrode array (64 tiny electrodes, 2.5-mm spacing, center-to-center)., Results: The maps contained 7,754 ± 1,960 electrograms per animal with a mean resolution of 2.8 ± 0.6 mm. Low bipolar voltage (<2 mV) correlated closely with scar on the LGE MRI and the 3D signal intensity map (1-mm depth). The scar areas between the MRI signal intensity map and electroanatomic map matched at 87.7% of sites. Bipolar and unipolar voltages, compared in 592 electrograms from four MRI-defined scar types (endocardial scar, epicardial scar, mottled transmural scar, and dense transmural scar) as well as normal tissue, were significantly different. A unipolar voltage of <13 mV correlated with transmural extension of scar in MRI. Electrograms exhibiting isolated late potentials (ILPs) were manually annotated and ILP maps were created showing ILP location and timing. ILPs were identified in 203 ± 159 electrograms per dog (within low-voltage areas) and ILP maps showed gradation in timing of ILPs at different locations in the scar., Conclusions: Ultra-high resolution contact electroanatomical mapping accurately localizes ventricular scar and abnormal myocardial tissue in this chronic canine infarct model. The high fidelity electrograms provided clear identification of the very low amplitude ILPs within the scar tissue and has the potential to quickly identify targets for ablation., (©2015 The Authors. Pacing and Clinical Electrophysiology Published by Wiley Periodicals, Inc.)

Background: Genome-wide association studies and candidate-gene based approaches have identified multiple common variants associated with increased risk of sudden cardiac death (SCD). However, the independent contribution of these individual loci to disease risk is modest., Objective: To investigate the cumulative effects of genetic variants previously associated with SCD risk., Methods: A total of 966 SCD cases from the Oregon-Sudden Unexpected Death Study and 1,926 coronary artery disease controls from the Wellcome Trust Case-Control Consortium were investigated. We generated genetic risk scores (GRS) for each trait composed of variants previously associated with SCD or with abnormalities in specific electrocardiographic traits such as QRS duration, QTc interval and heart rate. GRSs were calculated using a weighted approach based on the number of risk alleles weighted by the beta coefficients derived from the original studies. We also compared the highest and lowest quintiles for the GRS composed of SCD SNPs., Results: Increased cumulative risk was observed for a GRS composed of 14 SCD-SNPs (OR=1.17 [1.05-1.29], P = 0.002). The risk for SCD was 1.5 fold higher in the highest quintile when compared to the lowest quintile (OR = 1.46[1.11-1.92]). We did not observe significant associations with SCD for SNPs that determine electrocardiographic traits., Conclusions: A modest but significant effect on SCD risk was identified for a GRS composed of 14 previously associated SCD SNPs. While next generation sequencing methodology will continue to identify additional novel variants, these findings represent proof of concept for the additive effects of gene variants on SCD risk.

Background: Sports-associated sudden cardiac arrests (SCAs) occur mostly during middle age. We sought to determine the burden, characteristics, and outcomes of SCA during sports among middle-aged residents of a large US community., Methods and Results: Patients with SCA who were 35 to 65 years of age were identified in a large, prospective, population-based study (2002-2013), with systematic and comprehensive assessment of their lifetime medical history. Of the 1247 SCA cases, 63 (5%) occurred during sports activities at a mean age of 51.1±8.8 years, yielding an incidence of 21.7 (95% confidence interval, 8.1-35.4) per 1 million per year. The incidence varied significantly by sex, with a higher incidence among men (relative risk, 18.68; 95% confidence interval, 2.50-139.56) for sports SCAs compared with all other SCAs (relative risk 2.58; 95% confidence interval, 2.12-3.13). Sports SCA was also more likely to be a witnessed event (87% versus 53%; P<0.001) with cardiopulmonary resuscitation (44% versus 25%; P=0.001) and ventricular fibrillation (84% versus 51%; P<0.0001). Survival to hospital discharge was higher for sports-associated SCA (23.2% versus 13.6%; P=0.04). Sports SCA cases presented with known preexisting cardiac disease in 16% and ≥1 cardiovascular risk factors in 56%, and overall, 36% of cases had typical cardiovascular symptoms during the week preceding the SCA., Conclusions: Sports-associated SCA in middle age represents a relatively small proportion of the overall SCA burden, reinforcing the idea of the high-benefit, low-risk nature of sports activity. Especially in light of current population aging trends, our findings emphasize that targeted education could maximize both safety and acceptance of sports activity in the older athlete., (© 2015 American Heart Association, Inc.)

The development of new and specific treatment options for kidney disease in general and glomerular diseases in specific has lagged behind other fields like heart disease and cancer. As a result, nephrologists have had to test and adapt therapeutics developed for other indications to treat glomerular diseases. One of the major factors contributing to this inertia has been the poor understanding of disease mechanisms. One way to elucidate these disease mechanisms is to study the association between the cardinal manifestations of glomerular diseases. Because many of these patients develop nephrotic syndrome, understanding the relationship of proteinuria, the primary driver in this syndrome, with hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, edema, and lipiduria could provide valuable insight. The recent unraveling of the relationship between proteinuria and hypertriglyceridemia mediated by free fatty acids, albumin, and the secreted glycoprotein angiopoietin-like 4 (Angptl4) offers a unique opportunity to develop novel therapeutics for glomerular diseases. In this review, the therapeutic potential of mutant forms of Angptl4 in reducing proteinuria and, as a consequence, alleviating the other manifestations of nephrotic syndrome is discussed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: A growing literature suggests underutilization of the primary prevention implantable cardioverter-defibrillator (ICD); thus, factors influencing utilization need to be understood. We performed a comprehensive assessment of patient characteristics and health insurance status among subjects eligible for primary prevention ICD in a tertiary care center., Methods: From among a group of patients who met criteria for primary prevention ICD based on left ventricular dysfunction (LVEF ≤ 35%), ICD recipients (n = 110) were compared to ICD non-recipients (n = 110) to identify determinants of ICD implantation. We evaluated demographics, clinical profile including Charlson Comorbidity Index [CCI, categorized as low (≤3) or high (>3)] and health insurance status., Results: ICD recipients were younger (62.1±15.0 vs. 68.0±18.2; P = 0.01), with more males (80% vs. 65.5%; P = 0.01), higher NYHA class (II/III: 75.5% vs. 40.2%; P<0.001) and more likely to have supplemental private health insurance (61.8% vs. 46.4%; P = 0.02). CCI was not significantly different between the two groups (low CCI 61.8% vs. 62.7%; P = 0.89). In multivariable analysis, factors independently associated with ICD implantation were male sex (OR, 2.77, [1.31-5.85]; P = 0.01), age<75 (OR, 2.68, [1.30-5.50]; P = 0.01), private insurance (OR, 2.17, [1.08-4.36], P = 0.03) and NYHA Class II/III (OR, 5.91, [2.91-12.01]; P<0.001). Documentation of discussion about primary prevention ICD was absent in the majority (57.2%) of non-recipients., Conclusion: In a contemporary urban tertiary care setting, age, sex and heart failure symptom class were associated with ICD utilization, with socioeconomic/insurance status also potentially playing a role. These findings have implications for optimizing appropriate utilization of the prophylactic ICD and warrant follow-up in larger, more diverse populations.

Background: Obesity has been associated with significantly greater risk of sudden cardiac death (SCD); however, identifying the obese patient at highest risk remains a challenge. We evaluated the association between QRS fragmentation on the 12-lead electrocardiogram and SCD, in obese/overweight subjects., Methods and Results: In the ongoing prospective, community-based Oregon Sudden Unexpected Death Study (population approximately 1 million), we performed a case-control analysis, comparing obese/overweight SCD victims with obese/overweight controls from the same geographic region. Archived ECGs prior and unrelated to the SCD event were used for cases and all ECG measurements were assessed in blinded fashion. Fragmentation was defined as the presence of RSR' patterns and/or notching of the R/S wave in at least 2 contiguous leads. Analysis was limited to ECGs with QRS duration <120 ms. Overall prevalence of fragmentation was higher in cases (n=185; 64.9±13.8 years; 67.0% male) compared with controls (n=405; 64.9±11.0 years; 64.7% male) (34.6% versus 26.9%, P=0.06). Lateral fragmentation was significantly more frequent in cases (8.1% versus 2.5%; P<0. 01), with non-significant differences in anterior and inferior territories. Fragmentation in multiple territories (≥2) was also more likely to be observed in cases (9.7% versus 4.9%, P=0.02). In multivariable analysis with consideration of established SCD risk factors, lateral fragmentation was significantly associated with SCD (OR 2.84; 95% CI 1.01 to 8.02; P=0.05)., Conclusion: QRS fragmentation, especially in the lateral territory is a potential risk marker for SCD independent of the ejection fraction, among obese/overweight subjects in the general population., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

The overwhelming majority of sports-related sudden deaths occur among those older than 35 years of age. Because increasing numbers of older people are participating in organized endurance and competitive sporting events, the incidence of sports-related sudden death in older adults is expected to rise. Older athletes will approach clinical cardiologists for advice regarding their fitness for participation. It is important to recognize both that strenuous exercise is associated with a transient elevation in risk of sudden cardiac death and that appropriate training substantially reduces this risk. The approach to pre-participation screening for risk of sudden death in the older athlete is a complex issue and at present is largely focused on identifying inducible ischemia due to significant coronary disease. In this brief review, we summarize the current state of knowledge in this area with respect to epidemiology, mechanisms, and approaches to risk stratification, as viewed from the perspective of the consulting clinical cardiologist., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Sex hormones are known to have significant effects on the pathophysiology of cardiovascular disease., Objective: The purpose of this study was to study the association between sex hormone levels and sudden cardiac arrest (SCA)., Methods: In the ongoing Oregon Sudden Unexpected Death Study (catchment population approximately 1 million), cases of SCA were compared with matched controls. Testosterone and estradiol levels were measured from blood samples drawn at the time of the SCA event in cases and during a routine visit in controls., Results: Among cases (n = 149, age 64.1 ± 11.7 years, 73.2% male), compared to controls (n = 149, 64.2 ± 11.6 years, 72.5% male), median testosterone levels were significantly lower in males (4.4 vs 5.4 ng/mL, P = .01). Median estradiol levels were higher in male (68 vs 52 pg/mL, P <.001) and female cases (54 vs 36 pg/mL, P <.001). In multivariate analysis, higher testosterone levels were associated with lower SCA odds only in males (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.58-0.96, P = .02). Higher estradiol levels were associated with higher SCA odds in both males (OR 2.0, 95% CI 1.5-2.6, P <.001) and females (OR 3.5, 95% CI 1.9-6.4, P <.001). A higher testosterone/estrogen ratio was associated with lower SCA odds in males only (OR 0.5, 95% CI 0.4-0.7, P <.001). In a canine model of SCA, plasma testosterone levels were not significantly altered by the cardiac arrest event., Conclusion: We observed significant differences in sex hormone levels in patients who suffered SCA, with potential mechanistic implications. The role of sex hormones in the genesis of fatal ventricular arrhythmias warrants further exploration., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Nephrotic syndrome is recognized by the presence of proteinuria in excess of 3.5 g/24 h along with hypoalbuminemia, edema, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), and lipiduria. Each component has been investigated individually over the past four decades with some success. Studies published recently have started unraveling the molecular basis of proteinuria and its relationship with other components. We now have improved understanding of the threshold for nephrotic-range proteinuria and the pathogenesis of hypertriglyceridemia. These studies reveal that modifying sialylation of the soluble glycoprotein angiopoietin-like 4 or changing key amino acids in its sequence can be used successfully to treat proteinuria. Treatment strategies on the basis of fundamental relationships among different components of nephrotic syndrome use naturally occurring pathways and have great potential for future development into clinically relevant therapeutic agents., (Copyright © 2014 by the American Society of Nephrology.)

Background: Sudden cardiac arrest (SCA) is a significant public health problem, and rates of survival after resuscitation remain well below 10%. While several resuscitation-related factors are consistently associated with survival from SCA, the impact of specific comorbid conditions has not been assessed., Methods and Results: The Oregon Sudden Unexpected Study is an ongoing, multisource, community-based study in Portland, Oregon. Patients with SCA who underwent attempted resuscitation between 2002 and 2012 were included in this analysis if there were both arrest and prearrest medical records available. Information from the emergency medical services system, medical examiner, public health division, hospitals, and clinics was used to adjudicate SCA, evaluate comorbidities, and identify medical treatments. Univariate and multivariate analyses were performed to investigate the influence of prearrest comorbidities on survival to hospital discharge. Among 1466 included patients, established resuscitation-related predictors (Utstein factors) were associated with survival, consistent with prior reports. When a panel of prearrest comorbidities was evaluated along with Utstein factors, recognized coronary artery disease was significantly associated and predicted higher odds of survival (unadjusted odds ratio 1.5, P<0.001; adjusted odds ratio 1.5, P=0.02). In multivariable logistic models, prearrest coronary artery disease modified the survival effects of bystander cardiopulmonary resuscitation, but did not modify other Utstein factors., Conclusions: An established diagnosis of coronary artery disease was associated with 50% higher odds of survival from resuscitated SCA after adjustment for all arrest-related predictors. These findings raise novel potential mechanistic insights into survival after SCA, while highlighting the importance of early recognition and treatment of coronary artery disease., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Left ventricular (LV) diameter is routinely measured on the echocardiogram but has not been jointly evaluated with the ejection fraction (EF) for risk stratification of sudden cardiac death (SCD)., Methods and Results: From a large ongoing community-based study of SCD (The Oregon Sudden Unexpected Death Study; population ≈1 million), SCD cases were compared with geographic controls. LVEF and LV diameter, measured using the LV internal dimension in diastole (categorized as normal, mild, moderate, or severe dilatation using American Society of Echocardiography definitions) were assessed from echocardiograms prior but unrelated to the SCD event. Cases (n=418; 69.5±13.8 years), compared with controls (n=329; 67.7±11.9 years), more commonly had severe LV dysfunction (EF ≤35%; 30.5% versus 18.8%; P<0.01) and larger LV diameter (52.2±10.5 mm versus 49.7±7.9 mm; P<0.01). Moderate or severe LV dilatation (16.3% versus 8.2%; P=0.001) and severe LV dilatation (8.1% versus 2.1%; P<0.001) were significantly more frequent in cases. In multivariable analysis, severe LV dilatation was an independent predictor of SCD (odds ratio 2.5 [95% CI 1.03 to 5.9]; P=0.04). In addition, subjects with both EF ≤35% and severe LV dilatation had higher odds for SCD compared with those with low EF only (odds ratio 3.8 [95% CI 1.5 to 10.2] for both versus 1.7 [95% CI 1.2 to 2.5] for low EF only), suggesting that severe LV dilatation additively increased SCD risk., Conclusion: LV diameter may contribute to risk stratification for SCD independent of the LVEF. This readily available echocardiographic measure warrants further prospective evaluation., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100,000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery., Methods: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values., Findings: 292,982 (95% UI 261,017-327,792) maternal deaths occurred in 2013, compared with 376,034 (343,483-407,574) in 1990. The global annual rate of change in the MMR was -0·3% (-1·1 to 0·6) from 1990 to 2003, and -2·7% (-3·9 to -1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0·4% (0·2-0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1-1262·8) in South Sudan to 2·4 (1·6-3·6) in Iceland., Interpretation: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa., Funding: Bill & Melinda Gates Foundation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: To determine whether resuscitated cardiac arrest (CA) complicating ST elevation myocardial infarction (STEMI) impacts outcome, particularly in patients surviving to discharge., Background: Resuscitated CA complicating STEMI is associated with increased inpatient mortality. The impact on later prognosis is unclear., Methods: We analysed data from the UK Myocardial Ischaemia National Audit Project for STEMI patients admitted during January 2008-March 2010. We used survival analyses to assess the independent impact of resuscitated CA during the index episode on inhospital, 30 days, 1 year and medium term all-cause mortality., Results: Of 48 749 STEMI patients, 5308 (10.9%) were recorded as having a CA. Of these, 1557 (29.3%) died on the day of CA. In survivors, after covariate adjustment, resuscitated CA was associated with increased risk of death during the index admission (HR 4.05 (3.69 to 4.45) p<0.001). In patients surviving to discharge, a history of resuscitated CA was associated with increased risk of death to 30 days (HR 1.53 (1.18 to 2.00), p<0.001). However, beyond 30 days, resuscitated CA was not associated with increased mortality risk (1-year HR 0.95 (0.79 to 1.14, p=0.596); 3.5 years HR 0.90 (0.78 to 1.04), p=0.144). The influence of resuscitated CA on inhospital or 30-day mortality was similar whether CA occurred before or after hospital admission. Where the resuscitated CA rhythm was asystole, inhospital mortality was higher compared with ventricular arrhythmia (p<0.001) or pulseless electrical activity (p=0.011). Late resuscitated CA (occurring after the day of index STEMI) was associated with higher 30-day postdischarge mortality compared with early resuscitated CA (p=0.023)., Conclusions: STEMI complicated by resuscitated CA merits careful monitoring in the early period postevent. In contemporary practice, there is no impact of resuscitated CA on longer-term prognosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The National Institute of Diabetes and Digestive and Kidney Diseases-supported Kidney Research National Dialogue asked the scientific community to formulate and prioritize research objectives aimed at improved understanding of kidney function and disease progression. Over the past 2 years, 1600 participants posted almost 300 ideas covering all areas of kidney disease. An overriding theme that evolved through these discussions is the need to move beyond pathology to take advantage of basic science and clinical research opportunities to improve diagnostic classification and therapeutic options for people with primary glomerular disease. High-priority research areas included focus on therapeutic targets in glomerular endothelium and podocytes, regenerating podocytes through developmental pathways, use of longitudinal phenotypically defined disease cohorts to improve classification schemes, identifying biomarkers, disease-specific therapeutics, autoantibody triggers, and changing the clinical research culture to promote participation in clinical trials. Together, these objectives provide a path forward for improving clinical outcomes of glomerular disease., (Copyright © 2014 by the American Society of Nephrology.)

Background: Left ventricular hypertrophy (LVH) is associated with increased risk of sudden cardiac arrest (SCA). Whether LVH diagnosed by 12-lead ECG vs echocardiogram conveys identical or distinct risk information has not been previously evaluated., Objective: The purpose of this study was to compare the association between ECG vs echocardiographic LVH and SCA in the community., Methods: In a large, prospective population-based study (The Oregon Sudden Unexpected Death Study; population approximately 1 million), cases of SCA were compared to controls recruited from the same geographical area. The association between LVH and SCA was evaluated, specifically comparing LVH diagnosed by ECG vs echocardiogram., Results: Cases (n = 132, age 66.9 ± 13.5 years, 58.3% male) compared to controls (n = 211; age 66.2 ± 12 years, 59.2% male) were more likely to have both ECG LVH (12.1% vs 5.7%, P = .03) and echocardiographic LVH (35.0% vs 15.5%, P <.001). However, there was poor agreement between the tests (kappa statistic = 0.128). A large subgroup of patients with ECG LVH (57.1%) did not have echocardiographic LVH; conversely, 83.6% of patients with echocardiographic LVH did not have ECG LVH. In multivariate analysis, ECG LVH was significantly associated with SCA (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-6.0, P = .04). When echocardiographic LVH was added to the model, this association was only mildly attenuated (OR 2.4, 95% CI 1.0-6.0, P= .05), and echocardiographic LVH was also independently associated with SCA (OR 2.7, 95% CI 1.5-4.9, P = .001)., Conclusion: ECG and echocardiographic LVH may convey distinct risk information in patients with SCA, reflecting electrical vs anatomic remodeling. These findings have potential implications for SCA mechanisms and risk stratification., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to evaluate the role of congestive heart failure (CHF) in the association between atrial fibrillation (AF) and sudden cardiac death (SCD)., Background: Recent studies have reported the possibility of an independent association between AF and SCD. We hypothesized that a history of CHF is a significant confounder of this association., Methods: In a prospective case-control analysis from the community (The Oregon-SUDS [Sudden Unexpected Death Study], 2002 to 2012), SCD cases (n = 652) with clinical records available (including electrocardiography and/or echocardiography) were compared with age- and sex-matched control patients with coronary artery disease. The association between AF and SCD was analyzed using multivariable logistic regression and propensity score matching., Results: Cases (age 67.3 ± 11.7 years, 65% male) were more likely than control patients (age 67.2 ± 11.4 years, 65% male) to have a history of AF (p = 0.0001), myocardial infarction (p = 0.007), CHF (p < 0.0001), stroke (p < 0.0001), and diabetes (p < 0.0001). In multivariate analysis without considering CHF, AF was a significant predictor of SCD (odds ratio [OR]: 1.6; 95% confidence interval [CI]: 1.2 to 2.0; p = 0.002). However, in a model that included CHF, the AF-SCD association was no longer significant (OR: 1.1; 95% CI: 0.8 to 1.5; p = 0.45), whereas CHF was a significant predictor of SCD (OR: 3.1; 95% CI: 2.4 to 4.1; p < 0.0001). Results on the basis of propensity score matching were consistent., Conclusions: Our findings suggest that a history of CHF, including both systolic and diastolic symptomatic dysfunction, may partially explain the AF-SCD association., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Sudden cardiac death (SCD) is a leading cause of death in the United States, but the relative public health burden is unknown. We estimated the burden of premature death from SCD and compared it with other diseases., Methods and Results: Analyses were based on the following data sources (using most recent sources that provided appropriately stratified data): (1) leading causes of death among men and women from 2009 US death certificate reporting; (2) individual cancer mortality rates from 2008 death certificate reporting from the Centers for Disease Control and Prevention's National Program of Cancer Registries; (3) county, state, and national population data for 2009 from the US Census Bureau; and (4) SCD rates from the Oregon Sudden Unexpected Death Study (SUDS) population-based surveillance study of SCD between 2002 and 2004. Cases were identified from multiple sources in a prospectively designed surveillance program. Incidence, counts, and years of potential life lost for SCD and other major diseases were compared. The age-adjusted national incidence of SCD was 60 per 100 000 population (95% confidence interval, 54-66 per 100,000). The burden of premature death for men (2.04 million years of potential life lost; 95% uncertainty interval, 1.86-2.23 million) and women (1.29 million years of potential life lost; 95% uncertainty interval, 1.13-1.45 million) was greater for SCD than for all individual cancers and most other leading causes of death., Conclusions: The societal burden of SCD is high relative to other major causes of death. Accordingly, improved national surveillance with the goal of optimizing and monitoring SCD prevention and treatment should be a high priority.

Background: In cohort studies, elevated levels of plasma nonesterified free fatty acids (NEFAs) have been associated with increased risk of sudden cardiac death (SCD) in men, but blood samples were drawn several years before SCD., Objective: To confirm this relationship by evaluating levels of plasma NEFAs at the time of the SCD event in a group of both men and women., Methods: From the ongoing Oregon Sudden Unexpected Death Study, we compared levels of plasma NEFAs in 149 SCD cases presenting with ventricular fibrillation (mean age 64 ± 12 years; 73% men) and 149 age- and sex-matched controls with coronary artery disease. Plasma was processed from blood drawn at the time of arrest (cases) and at a routine visit (controls). The levels of plasma NEFAs were compared after categorizing into quartiles on the basis of control values. Conditional logistic regression was used to predict adjusted odds ratio for SCD associated with plasma NEFA levels per increased quartile., Results: The plasma NEFA levels were significantly higher in SCD cases than in controls (median 0.39 mmol/L [interquartile range 0.28-0.60 mmol/L] vs 0.32 mmol/L [interquartile range 0.20-0.49 mmol/L]; P = .002). There were no significant differences in body mass index, smoking, and diabetes. The odds ratio for SCD was 1.42 (95% confidence interval 1.14-1.78) per quartile increase in the plasma NEFA level (P = .002). Individuals with plasma NEFA levels above the prespecified cutoff point of 0.32 mmol/L were at increased risk of SCD (odds ratio 2.00; 95% confidence interval 1.20-3.34; P = .008)., Conclusion: These findings strengthen the role of plasma NEFA as a potential biomarker for the assessment of SCD risk., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation is the most common heart rhythm disorder in the world, with major public health impact especially due to increased risk of stroke and hospitalizations. The recently published results on epidemiology of atrial fibrillation from the Global Burden of Diseases, Injuries, and Risk Factors Study confirm the existence of a significant and progressive worldwide increase in the burden of atrial fibrillation. However, there appears to be regional variation in both the burden of atrial fibrillation and availability of epidemiological data regarding this condition. In this review, the authors identify issues that are unique to the developed versus developing regions and outline a road map for possible approaches to surveillance, management, and prevention of atrial fibrillation at the global level., (Copyright © 2014 World Heart Federation (Geneva). All rights reserved.)

Background: There is limited information on genetic factors associated with sudden cardiac arrest (SCA)., Objective: To assess the association of common variation in genes in fatty acid pathways with SCA risk., Methods: We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n = 2160) were from a repository of SCA in the greater Seattle area. Controls (n = 2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed permutation-based p-min tests to account for multiple comparisons within each gene. The SNP associations with a corrected P value of <.05 were then examined in a meta-analysis of these SNP associations in 9 replication studies totaling 2129 SCA cases and 23,833 noncases., Results: Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (95% confidence interval -21% to -5%) in the discovery phase and 9% lower SCA risk (95% confidence interval -16% to -1%) in the replication phase., Conclusions: While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation., (Copyright © 2014 Heart Rhythm Society. All rights reserved.)

Current drugs used to treat proteinuric disorders of the kidney have been borrowed from other branches of medicine, and are only partially effective. The discovery of a central, mechanistic role played by two different forms of the secreted glycoprotein angiopoietin-like 4 (Angptl4) in human and experimental glomerular disease has opened new treatment avenues. Localized upregulation of a hyposialylated form (lacks sialic acid residues) of Angptl4 secreted by podocytes induces the cardinal morphological and clinical manifestations of human minimal change disease, and is also being increasingly recognized as a significant contributor toward proteinuria in experimental diabetic nephropathy. Oral treatment with low doses of N-acetyl-D-mannosamine, a naturally occurring precursor of sialic acid, improves sialylation of Angptl4 in vivo, and reduces proteinuria by over 40%. By contrast, a sialylated circulating form of Angptl4, mostly secreted from skeletal muscle, heart and adipose tissue in all major primary glomerular diseases, reduces proteinuria while also causing hypertriglyceridemia. Intravenous administration of recombinant human Angptl4 mutated to avoid hypertriglyceridemia and cleavage has remarkable efficacy in reducing proteinuria by as much as 65% for 2 weeks after a single low dose. Both interventions are mechanistically relevant, utilize naturally occurring pathways, and represent new generation therapeutic agents for chronic kidney disease related to glomerular disorders.

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.

The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial αvβ5 integrin. Blocking the Angptl4-β5 integrin interaction or global knockout of Angptl4 or β5 integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.

We analyzed the Nationwide Inpatient Sample database from 2002 to 2010 to examine the temporal trends in incidence of acute kidney injury (AKI), AKI requiring dialysis, and associated in-hospital mortality in patients ≥75 years of age hospitalized with acute myocardial infarction and undergoing early (within 24 hours) percutaneous coronary intervention. Of 2,225,707 patients ≥75 years of age with acute myocardial infarction, 233,508 (10.5%) underwent early percutaneous coronary intervention, of which 21,961 (9.4%) developed AKI and 1,257 (0.54%) developed AKI requiring dialysis. From 2002 to 2010, the incidence of AKI increased from 5.6% to 14.2% (p for trend <0.001) and that for AKI requiring dialysis decreased (0.6% to 0.4%; p for trend 0.018). Compared with 2002, multivariable-adjusted odds ratios and 95% confidence intervals for AKI, AKI requiring dialysis, and in-hospital mortality in 2010 were 1.87 (1.71 to 2.05), 0.20 (0.15 to 0.27) and 0.74 (0.60 to 0.90), respectively. In conclusion, among hospitalized adults ≥75 years of age, from 2002 to 2010, there was an increase in AKI, but there was paradoxical decrease in AKI requiring dialysis and in-hospital mortality, potentially reflecting increased health-care provider awareness resulting in early recognition and implementation of renal-protective strategies and diagnosis-related group creep., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The purpose of this study was to identify risk factors for renal failure requiring hemodialysis and mortality in patients who developed contrast-induced nephropathy (CIN) after cardiac catheterization. Out of 13,742 patients who received cardiac catheterization at Westchester Medical Center/New York Medical College from 2005 to 2008, 268 patients (2%) with a discharge diagnosis of renal failure were screened for CIN. CIN was defined as either a >25% increase of the serum creatinine or an absolute increase in serum creatinine of 0.5 mg/dL within the first 48 hours of the procedure. Chart reviews were performed on 80 patients (1%) who met the criteria for CIN. The 80 patients in the study included 46 men and 34 women, mean age 69 ± 14 years. Of the 80 patients, 18 patients (23%) died, and 22 patients (28%) developed renal failure requiring hemodialysis. Stepwise logistic regression analysis showed that independent risk factors for mortality were the use of calcium channel blockers [odds ratio = 0.0025, 95% confidence interval (CI), 0.0001-0.1210, P < 0.01], catecholamine use (odds ratio = 71.2177, 95% CI, 4.2153-1203, P < 0.01), circulatory failure with lactic acidosis (odds ratio = 32.1405, 95% CI, 2.6331-392, P < 0.01), and renal failure requiring hemodialysis (odds ratio = 17.0376, 95% CI, 1.2344-235, P < 0.05). Significant independent risk factors for renal failure requiring hemodialysis were smoking (odds ratio = 0.06, 95% CI, 0.0045-0.8080, P < 0.05), N-acetylcysteine use (odds ratio = 0.08, 95% CI, 0.0148-0.4179, P < 0.01), anemia (odds ratio = 11.32, 95% CI, 2.57-50, P < 0.01), and circulatory failure with lactic acidosis (odds ratio = 9.76, 95% CI, 2.37-40, P < 0.01). Our data showed that risk factors for mortality in patients with CIN were catecholamine use, circulatory failure with lactic acidosis, and renal failure requiring hemodialysis. Risk factor for reducing mortality in patients with CIN was calcium channel blocker use. Significant risk factors for renal failure requiring hemodialysis were anemia, and circulatory failure with lactic acidosis. Risk factors for reducing renal failure requiring hemodialysis were N-acetylcysteine use and smoking.

Background: The prevalence rates and influencing factors for deployment of primary prevention implantable cardioverter defibrillators (ICDs) among subjects who eventually experience sudden cardiac arrest in the general population have not been evaluated., Methods and Results: Cases of adult sudden cardiac arrest with echocardiographic evaluation before the event were identified from the ongoing Oregon Sudden Unexpected Death Study (population approximately 1 million). Eligibility for primary ICD implantation was determined from medical records based on established guidelines. The frequency of prior primary ICD implantation in eligible subjects was evaluated, and ICD nonrecipients were characterized. Of 2093 cases (2003-2012), 448 had appropriate pre- sudden cardiac arrest left ventricular ejection fraction information available. Of these, 92 (20.5%) were eligible for primary ICD implantation, 304 (67.9%) were ineligible because of left ventricular ejection fraction >35%, and the remainder (52, 11.6%) had left ventricular ejection fraction ≤35% but were ineligible on the basis of clinical guideline criteria. Among eligible subjects, only 12 (13.0%; 95% confidence interval, 6.1%-19.9%) received a primary ICD. Compared with recipients, primary ICD nonrecipients were older (age at ejection fraction assessment, 67.1±13.6 versus 58.5±14.8 years, P=0.05), with 20% aged ≥80 years (versus 0% among recipients, P=0.11). Additionally, a subgroup (26%) had either a clinical history of dementia or were undergoing chronic dialysis., Conclusions: Only one fifth of the sudden cardiac arrest cases in the community were eligible for a primary prevention ICD before the event, but among these, a small proportion (13%) were actually implanted. Although older age and comorbidity may explain nondeployment in a subgroup of these cases, other determinants such as socioeconomic factors, health insurance, patient preference, and clinical practice patterns warrant further detailed investigation.

Background: While sudden cardiac arrest (SCA) rates increase with age, middle-aged adults (35-59 years) may comprise a significant proportion of SCA cases in the community (30-40%). However, there is a lack of studies evaluating SCA risk factors specifically associated with this age-group of the population., Methods: Using prospective multiple-source surveillance methodology we identified cases of SCA ≥35 years in the ongoing Oregon Sudden Unexpected Death Study (Portland, Oregon metropolitan area, population≈1,000,000). Out-of-hospital SCA cases, aged 35-59 years were compared to older SCA cases (≥60 years) in a comprehensive analysis of clinical profile of SCA., Results: The middle-aged (n=753) compared to older (n=1251) cases were more likely to be male, obese, have sleep apnea and seizure disorder (all p≤0.001); and were less likely to have a history of hypertension, diabetes mellitus, known coronary artery disease, congestive heart failure and syncope (all p<0.01). In multivariable analyses the middle-aged group had higher likelihood of male sex (O.R. 1.67, 95% C.I. 1.29-2.18), obesity (2.20, 1.52-3.19), sleep apnea (2.30, 1.44-3.68) and seizure disorder (2.69, 1.64-4.42); and lower rates of known coronary artery disease (0.57, 0.43-0.74) and congestive heart failure (0.35, 0.25-0.48)., Conclusions: SCA in the middle-aged adult was distinguishable from older subjects by higher rates of obesity, sleep apnea and seizure disorder; and lower prevalence of traditional clinical risk markers. With the growing epidemic of obesity, these findings have implications for SCA burden; and suggest the need for a clinical and investigational focus on SCA prediction and prevention in the middle-aged adult, that is distinct from older adults., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Among patients with epilepsy, sudden cardiac arrest (SCA) is a major cause of death. It is commonly thought that SCA in epilepsy occurs after a seizure, though the strength of evidence supporting this is limited. We sought to evaluate the relationship between seizures and SCA in patients with epilepsy., Methods and Results: From the ongoing Oregon Sudden Unexpected Death Study, cases of SCA identified using prospective, multisource ascertainment (Portland metropolitan area, Oregon; population≈1 million; February 1, 2002, to March 1, 2012) were evaluated for history of epilepsy. In the subset with witnessed SCA, clinical presentations were analyzed for evidence of seizure activity immediately before the event as well as lifetime clinical history, including nature of seizures before SCA. Only 34% of patients with history of epilepsy and a witnessed arrest had evidence of seizure activity before the arrest. Rates of survival to hospital discharge after attempted resuscitation were 2.7% in patients with history of epilepsy versus 11.9% for patients without epilepsy (P=0.014). Patients with epilepsy had a significantly lower rate of presentation with ventricular tachycardia/ventricular fibrillation as opposed to pulseless electrical activity/asystole (epilepsy, 26%; no epilepsy, 44%; P=0.002), despite nearly identical response times., Conclusions: In the majority (66%) of epilepsy patients, there was no relationship between seizure and SCA, implying that SCA in epilepsy patients often may not involve seizure as a trigger. The significantly worse rate of survival from SCA in epilepsy patients warrants urgent investigation.

Purpose: Iron deposition has been shown to occur following myocardial infarction (MI). We investigated whether such focal iron deposition within chronic MI lead to electrical anomalies., Methods: Two groups of dogs (ex-vivo (n = 12) and in-vivo (n = 10)) were studied at 16 weeks post MI. Hearts of animals from ex-vivo group were explanted and sectioned into infarcted and non-infarcted segments. Impedance spectroscopy was used to derive electrical permittivity ([Formula: see text]) and conductivity ([Formula: see text]). Mass spectrometry was used to classify and characterize tissue sections with (IRON+) and without (IRON-) iron. Animals from in-vivo group underwent cardiac magnetic resonance imaging (CMR) for estimation of scar volume (late-gadolinium enhancement, LGE) and iron deposition (T2*) relative to left-ventricular volume. 24-hour electrocardiogram recordings were obtained and used to examine Heart Rate (HR), QT interval (QT), QT corrected for HR (QTc) and QTc dispersion (QTcd). In a fraction of these animals (n = 5), ultra-high resolution electroanatomical mapping (EAM) was performed, co-registered with LGE and T2* CMR and were used to characterize the spatial locations of isolated late potentials (ILPs)., Results: Compared to IRON- sections, IRON+ sections had higher[Formula: see text], but no difference in[Formula: see text]. A linear relationship was found between iron content and [Formula: see text] (p<0.001), but not [Formula: see text] (p = 0.34). Among two groups of animals (Iron (<1.5%) and Iron (>1.5%)) with similar scar volumes (7.28% ± 1.02% (Iron (<1.5%)) vs 8.35% ± 2.98% (Iron (>1.5%)), p = 0.51) but markedly different iron volumes (1.12% ± 0.64% (Iron (<1.5%)) vs 2.47% ± 0.64% (Iron (>1.5%)), p = 0.02), QT and QTc were elevated and QTcd was decreased in the group with the higher iron volume during the day, night and 24-hour period (p<0.05). EAMs co-registered with CMR images showed a greater tendency for ILPs to emerge from scar regions with iron versus without iron., Conclusion: The electrical behavior of infarcted hearts with iron appears to be different from those without iron. Iron within infarcted zones may evolve as an arrhythmogenic substrate in the post MI period.

Importance: Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy., Objectives: To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries., Design: We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages., Results: US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th., Conclusions and Relevance: From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.

Background: Higher levels of resting heart rate (HR) have been associated with sudden cardiac death (SCD) but mechanisms are poorly understood. We hypothesized that severe left ventricular systolic dysfunction (LVSD) and HR-modulating drugs explain the HR-SCD relationship., Objective: To evaluate the relationship between HR, severe LVSD, HR-modulating drugs, and SCD in the community by using a case-control approach., Methods: From the ongoing Oregon Sudden Unexpected Death Study, SCD cases (n = 378) aged ≥35 years and with electrocardiogram-documented resting HR were compared to 378 age- and gender-matched control subjects with coronary artery disease (mean age 68 ± 13 years; 69% man). Associations with SCD were assessed by using multivariable logistic regression., Results: Mean resting HR was significantly higher among SCD cases compared to controls (7.5 beats/min difference; P < .0001). HR was a significant determinant of SCD after adjustment for significant comorbidities and medications (odds ratio for 10 beats/min increase 1.26; 95% confidence interval 1.14-1.38; P < .0001). After considering LVSD, resting HR was slightly attenuated but remained significantly associated with SCD (P = .005). In addition to diabetes and digoxin as well as pulmonary and renal disease, LVSD was also independently associated with SCD (odds ratio 1.79; 95% confidence interval 1.11-2.87; P = .02)., Conclusions: Contrary to expectations, the significant relationship between increased resting HR and SCD persisted even after adjustment for LVSD and HR-modulating drugs. These findings suggest a potential role for additional novel interventions/therapies that modulate autonomic tone., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Both schizophrenia and epilepsy have been linked to increased risk of sudden cardiac death (SCD). We hypothesized that DNA variants within genes previously associated with schizophrenia and epilepsy may contribute to an increased risk of SCD., Objective: To investigate the contribution to SCD susceptibility of DNA variants previously implicated in schizophrenia and epilepsy., Methods: From the ongoing Oregon Sudden Unexpected Death Study, comparisons were performed among 340 SCD cases presenting with ventricular fibrillation and 342 controls. We tested for the association between 17 single-nucleotide polymorphisms (SNPs) mapped to 14 loci previously implicated in schizophrenia and epilepsy by using logistic regression and assuming additive, dominant, and recessive genetic models., Results: The minor allele of the nonsynonymous SNP rs10503929 within the neuregulin 1 gene was associated with SCD under all 3 investigated models, with the strongest association for the recessive genetic model (recessive P = 4.01 × 10(-5), odds ratio [OR] 4.04; additive P = 2.84 × 10(-7), OR 1.9; and dominant P = 9.01 × 10(-6), OR 2.06). To validate our findings, we further explored the association of this variant in the Harvard Cohort SCD study. The SNP rs10503929 was associated with an increased risk of SCD under the recessive genetic model (P = .0005, OR 2.7). This missense variation causes a methionine to threonine change and functional effects are currently unknown., Conclusions: The observed association between a schizophrenia-related neuregulin 1 gene variant and SCD may represent the first evidence of coexisting genetic susceptibility between 2 conditions that have an established clinical overlap. Further investigation is warranted to explore the molecular mechanisms of this variant in the pathogenesis of SCD., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Left ventricular hypertrophy (LVH) has been associated with increased risk of sudden cardiac death (SCD), and improvements in risk stratification methodology are warranted., Methods: We evaluated electrocardiographic intervals as potential markers of SCD risk in LVH. Corrected QT, QRS, and JT intervals were evaluated in consecutive cases with SCD and LVH from the ongoing Oregon Sudden Unexpected Death study who underwent a 12-lead electrocardiogram (EKG) and echocardiogram prior to and unrelated to the SCD event. Comparisons of age, gender, body mass index, LV ejection fraction, and EKG intervals together with clinical conditions (hypertension and diabetes) were conducted with geographically matched controls that had coronary artery disease but no history of ventricular arrhythmias or cardiac arrest. LVH was determined using the modified American Society of Echocardiography equation for LV mass. Independent samples t-test, Pearson's chi-square test, and multiple logistic regression were used for statistical comparisons., Results: Of the 109 cases and 49 controls who met study criteria, age, gender, and comorbidities were similar among cases and controls. The mean LV mass index was not significantly different in cases compared to controls. However mean QTc (470.6 ± 53.6 ms vs 440.7 ± 38.7 ms; P < 0.0001) and QRS duration (113.6 ± 30.0 ms vs 104.9 ± 18.7 ms; P = 0.03) were significantly higher in cases than controls. In logistic regression analysis, prolonged QTc was the only EKG interval significantly associated with SCD (OR 1.72 [1.23-2.40])., Conclusion: Prolonged QTc was independently associated with SCD among subjects with LVH and merits further evaluation as a predictor of SCD in LVH., (©2012, Wiley Periodicals, Inc.)