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Background: A randomized, sham-controlled trial in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) ≥40% demonstrated reductions in pulmonary capillary wedge pressure (PCWP) with a novel transcatheter InterAtrial Shunt Device (IASD). Whether this hemodynamic effect will translate to an improvement in cardiovascular outcomes and symptoms requires additional study.Study Design and Objectives: REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP HF-II) is a multicenter, prospective, randomized, sham-controlled, blinded trial designed to evaluate the clinical efficacy of the IASD in symptomatic HF and elevated left atrial pressures. Up to 608 HF patients age ≥ 40 years with LVEF ≥40%, PCWP ≥25 mm Hg during supine ergometer exercise, and PCWP ≥5 mm Hg higher than right atrial pressure will be randomized 1:1 to the IASD versus sham control. Key exclusion criteria include hemodynamically significant valvular disease, evidence of pulmonary arterial hypertension, and right heart dysfunction. The primary endpoint is a hierarchical composite, analyzed by the Finkelstein-Schoenfeld methodology, that includes (1) cardiovascular mortality or first nonfatal ischemic stroke through 12 months; (2) total (first plus recurrent) HF hospitalizations or healthcare facility visits for intravenous diuretics up to 24 months, analyzed when the last randomized patient completes 12 months of follow-up; and (3) change in Kansas City Cardiomyopathy Questionnaire overall summary score from baseline to 12 months. Follow-up echocardiography will be performed at 6, 12, and 24 months to evaluate shunt flow and cardiac chamber size/function. Patients will be followed for a total of 5 years after the index procedure.Conclusions: REDUCE LAP-HF II is designed to evaluate the clinical efficacy of the IASD device in patients with symptomatic HF with elevated left atrial pressure and LVEF ≥40%. [ABSTRACT FROM AUTHOR]

In patients with atherosclerotic cardiovascular disease (ASCVD), guidelines recommend statins as first-line lipid-lowering therapy (LLT) with addition of nonstatin agents in those with persistently elevated low-density lipoprotein cholesterol levels.Methods: To estimate the cardiovascular (CV) risk reduction implications of treatment intensification, we used a previously reported simulation model with enhancements. An ASCVD cohort was developed from a US claims database. A Cox model was used to estimate baseline risk of CV events: myocardial infarction, ischemic stroke, unstable angina hospitalization, elective coronary revascularization, or cardiovascular death. Patients were sampled with replacement (bootstrapping) and entered the simulation model, which applied stepwise LLT intensification logic, with a goal of achieving low-density lipoprotein cholesterol less than 70 mg/dL at each step. CV risk reduction assumptions were based on published data. Two treatment intensification scenarios were investigated: ideal and real-world (which accounted for statin intolerance, nonadherence, and payer restrictions).Results: In a cohort of 1,000 patients with ASCVD, approximately 813 (809-818) would require treatment intensification with LLT under an ideal treatment intensification scenario. Before treatment intensification, 183 (179-187) events would be expected to occur over 5 years. With treatment intensification, 40 (34-45) of these events could be avoided. In a real-world scenario, about 818 (813-823) patients require treatment intensification with LLT, resulting in 29 (24-34) events avoided over 5 years.Conclusions: Intensification of LLT in an ASCVD population translates into a substantial number of CV events avoided. This simulation-based model could assist in assessing the potential benefits of various types of population-level LLT interventions. [ABSTRACT FROM AUTHOR]

Background: Kidney injury is common in patients with cardiovascular disease.Objectives: We determined whether blood measurement of kidney injury molecule-1 (KIM-1), would predict kidney outcomes in patients undergoing angiographic procedures for various indications.Methods: One thousand two hundred eight patients undergoing coronary and/or peripheral angiography were prospectively enrolled; blood was collected for KIM-1 measurement. Peri-procedural acute kidney injury (AKI) was defined as AKI within 48 hours of contrast exposure. Non-procedural AKI was defined as AKI beyond 48 hours. Development of chronic kidney disease (CKD) was defined as progression to an estimated glomerular filtration rate (eGFR) <60 milliliters/minute/1.73 m2 by study conclusion. Univariate and multivariable Cox proportional hazards models were used to identify predictors of non-procedural AKI, while univariate and multivariable logistic regression analysis was used to evaluate peri-procedural AKI and predictors of progression to CKD.Results: During mean follow up of 4 years, peri-procedural AKI occurred in 5.0%, non-procedural AKI in 27.3%, and 12.4% developed new reduction in eGFR <60 mL/min/1.73 m2. Higher KIM-1 concentrations were associated with prevalent comorbidities associated with risk in cardiovascular disease and worse left ventricular function. In adjusted analyses, elevated pre- and post-procedural KIM-1 concentrations predicted not only peri-procedural AKI (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.09-2·18, P = .01 and OR 1.54, 95% CI 1.10-2.15, P = .01, respectively) and non-procedural AKI (hazard ratio [HR] 1·49, 95% CI 1·24-1·78, P < .001 and HR 1.46, 95% CI 1.23-1.74, P < .001, respectively), but also progression to CKD (OR 1.99, 95% CI 1.32-2.99, P = .001 and OR 2·02, 95% CI 1·35-3·03, P = .001, respectively).Conclusions: In a typical at-risk population undergoing coronary and/or peripheral angiography, blood concentrations of KIM-1 may predict incident peri-procedural and non-procedural AKI, as well as progression to CKD. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is associated with increased liver- and cardiovascular disease (CVD)-related morbidity and mortality. In cross-sectional analyses, NAFLD clusters with several cardiometabolic traits including obesity,1,2 hypertension,3 diabetes,1 and dyslipidemia.3 However, liver fat is dynamic and changes over time. Aside from limited prior studies evaluating diet or exercise interventions, little is known about the association between changes in liver fat and the incidence of CVD risk factors. Additionally, previous studies often have limited follow-up; evaluate only select populations, such as individuals with obesity4,5 or diabetes6-8; and may not account for changes in weight or body mass index (BMI). The aim of the present study was to examine, in a longitudinal cohort, the natural history of liver fat change and the association with the incidence of multiple CVD risk factors. [ABSTRACT FROM AUTHOR]

Background: Traditional study design submitted to the Food and Drug Administration to test newer drug-eluting stents (DES) for marketing approval is the prospective randomized controlled trial. However, several DES have extensive clinical data from trials conducted outside the United States that have led to utilization of a novel design using the Bayesian approach. This design was proposed for testing DES with bioresorbable polymer compared with DES most commonly in use today that use durable polymers for drug elution.Study Design and Objectives: This prospective, multicenter, randomized, controlled trial is designed to assess the safety and efficacy of the Orsiro bioresorbable polymer sirolimus-eluting stent (BP SES). Up to 1,334 subjects with up to 3 de novo or restenotic coronary artery lesions who qualify for percutaneous coronary intervention with stenting will be randomized 2:1 to the BP SES versus the Xience durable polymer everolimus-eluting stent (DP EES). Data from this trial will be combined with data from 2 similarly designed trials that also randomize subjects to BP SES and DP EES (BIOFLOW II, N=452 and BIOFLOW IV, N=579) by using a Bayesian approach. The primary end point is target lesion failure at 12 months post index procedure, defined as cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization, and the primary analysis is a test of noninferiority of the BP SES versus DP EES on the primary end point according to a noninferiority delta of 3.85%. Secondary end points include stent thrombosis and the individual components of target lesion failure. Subjects will be followed for 5 years after randomization.Conclusions: The BIOFLOW V trial offers an opportunity to assess clinical outcomes in patients treated with coronary revascularization using the Orsiro BP SES relative to a commonly used DP EES. The use of a Bayesian analysis combines a large randomized cohort of patients 2 two smaller contributing randomized trials to augment the efficiency of the comparison. [ABSTRACT FROM AUTHOR]

Objectives This study sought to determine whether patients with peripheral arterial disease (PAD) experience different reductions in ischemic event and increases in bleeding events with extended duration dual antiplatelet therapy versus those without PAD. Background Patients with PAD have increased ischemic and bleeding risks after coronary stenting. Methods The DAPT (Dual Antiplatelet Therapy) study randomized 11,648 patients free from ischemic and bleeding events 12 months after coronary stenting to continued thienopyridine plus aspirin therapy for an additional 18 months versus aspirin therapy alone. The effects of continued thienopyridine on myocardial infarction (MI) or stent thrombosis, major adverse cardiovascular and cerebrovascular events (death, MI, or stroke) and bleeding (GUSTO [Global Utilization of t-PA and Streptokinase for Occluded Coronary Arteries] moderate or severe) were assessed among those with versus without PAD. Results Among 11,648 randomized patients, 649 (5.57%) had PAD. Between 12 and 30 months, randomized patients with PAD had higher rates of MI/stent thrombosis (6.03% vs. 2.92%; p < 0.001), major adverse cardiovascular and cerebrovascular events (11.65% vs. 4.62%; p < 0.001), and bleeding (4.86% vs. 1.74%; p < 0.001). Continued thienopyridine versus placebo was associated with consistent treatment effects for MI/stent thrombosis (with PAD, HR: 0.63; 95% CI: 0.32 to 1.22; without PAD, HR: 0.53; 95% CI: 0.42, 0.66; interaction p = 0.631), major adverse cardiovascular and cerebrovascular events (with PAD, HR: 1.06; 95% CI: 0.67 to 1.67; without PAD, HR: 0.70; 95% CI: 0.59 to 0.84; interaction p = 0.103), and bleeding (with PAD, HR, 1.82; 95% CI: 0.87 to 3.83; without PAD, HR: 1.66; 95% CI: 1.23 to 2.24; interaction p = 0.811). Conclusions Among patients undergoing coronary stenting, those with PAD have more ischemic and bleeding events versus those without PAD. Extended duration dual antiplatelet therapy is associated with consistent ischemic benefit and bleeding harm among patients with and without PAD. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this study was to characterize outcomes for everolimus-eluting stent (EES)–treated subjects according to treatment with continued thienopyridine plus aspirin versus aspirin alone 12 to 30 months after stenting. Background In the DAPT (Dual Antiplatelet Therapy) study, continued thienopyridine plus aspirin beyond 1 year after coronary stenting reduced ischemic events. Given low rates of stent thrombosis and myocardial infarction (MI) for current drug-eluting stents, we examined outcomes among EES-treated subjects in the DAPT study. Methods The DAPT study enrolled 25,682 subjects (11,308 EES-treated) after coronary stenting. Following 12 months of treatment with thienopyridine and aspirin, eligible subjects continued treatment with aspirin and 9,961 (4,703 with EES) were randomized to 18 months of continued thienopyridine or placebo. Stent type was not randomized, and the EES subset analysis was post hoc. Results Among EES-treated patients, continued thienopyridine reduced stent thrombosis (0.3% vs. 0.7%, hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.15 to 0.97; p = 0.04) and MI (2.1% vs. 3.2%, HR: 0.63, 95% CI: 0.44 to 0.91; p = 0.01) versus placebo but did not reduce a composite of death, MI, and stroke (4.3% vs. 4.5%, HR: 0.89, 95% CI: 0.67 to 1.18; p = 0.42), and increased moderate/severe bleeding (2.5% vs. 1.3%, HR: 1.79, 95% CI: 1.15 to 2.80; p = 0.01), and death (2.2% vs. 1.1%, HR: 1.80, 95% CI: 1.11 to 2.92; p = 0.02). Death due to cancer and not related to bleeding was increased (0.64% vs. 0.17%; p = 0.01). Conclusions In EES-treated subjects, significant reductions in stent thrombosis and MI and an increase in bleeding were observed with continued thienopyridine beyond 1 year compared with aspirin alone. (The Dual Antiplatelet Therapy Study [DAPT Study]); NCT00977938 ) [ABSTRACT FROM AUTHOR]

Objectives This study sought to compare rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE) (composite of death, myocardial infarction, or stroke) after coronary stenting with drug-eluting stents (DES) versus bare-metal stents (BMS) in patients who participated in the DAPT (Dual Antiplatelet Therapy) study, an international multicenter randomized trial comparing 30 versus 12 months of dual antiplatelet therapy in subjects undergoing coronary stenting with either DES or BMS. Background Despite antirestenotic efficacy of coronary DES compared with BMS, the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Many clinicians perceive BMS to be associated with fewer adverse ischemic events and to require shorter-duration dual antiplatelet therapy than DES. Methods Prospective propensity-matched analysis of subjects enrolled into a randomized trial of dual antiplatelet therapy duration was performed. DES- and BMS-treated subjects were propensity-score matched in a many-to-one fashion. The study design was observational for all subjects 0 to 12 months following stenting. A subset of eligible subjects without major ischemic or bleeding events were randomized at 12 months to continued thienopyridine versus placebo; all subjects were followed through 33 months. Results Among 10,026 propensity-matched subjects, DES-treated subjects (n = 8,308) had a lower rate of stent thrombosis through 33 months compared with BMS-treated subjects (n = 1,718, 1.7% vs. 2.6%; weighted risk difference −1.1%, p = 0.01) and a noninferior rate of MACCE (11.4% vs. 13.2%, respectively, weighted risk difference −1.8%, p = 0.053, noninferiority p < 0.001). Conclusions DES-treated subjects have long-term rates of stent thrombosis that are lower than BMS-treated subjects. (The Dual Antiplatelet Therapy Study [DAPT study]; NCT00977938 ) [ABSTRACT FROM AUTHOR]

Background: Hyperthyroidism has a well-described association with atrial fibrillation (AF). However, the relation of hypothyroidism to AF has had limited investigation. Hypothyroidism is associated with cardiovascular risk factors, subclinical cardiovascular disease, and overt cardiovascular disease, all of which predispose to AF. We investigated 10-year incidence of AF in a community-dwelling cohort. Methods: Among 6,653 Framingham heart Study participants, 5,069 participants, 52% female, with mean age of 57 ± 12 years, were eligible after excluding those with missing thyroid-stimulating hormone (TSH), TSH <0.45 μU/L (hyperthyroid), TSH >19.9 μU/L, or prevalent AF. Thyroid-stimulating hormone was categorized by range (≥0.45 to <4.5, 4.5 to <10.0, 10.0 to ≤19.9 μU/L) and by quartiles. We examined the associations between TSH and 10-year risk of AF using multivariable-adjusted Cox proportional hazards analysis. Results: Over 10-year follow-up, we observed 277 cases of incident AF. A 1-SD increase in TSH was not associated with increased risk of AF (hazard ratio 1.01, 95% CI 0.90-1.14, P = .83). In categorical analysis, using TSH ≥0.45 to <4.5 μU/L as the referent (equivalent to euthyroid state), we found no significant association between hypothyroidism and 10-year AF risk. Comparing the highest (2.6 < TSH < 19.9 μU/L) to lowest (0.45 < TSH < 1.3 μU/L) quartiles of TSH further did not identify a significant association between TSH levels and 10-year risk of AF. Conclusions: In conclusion, we did not identify a significant association between hypothyroidism and 10-year risk of incident AF in a community-based study. [Copyright &y& Elsevier]

Rationale and Objectives: Abdominal aortic calcification (AAC) can be quantified using computed tomography (CT), but imaging planes are prescribed based on bony landmarks, so that individual variation between the landmark and the aortoiliac junction can result in variable aortic coverage. In the Framingham CT substudy, we scanned a 15-cm (Z-direction) abdominal segment cranial to the S1 vertebral body. We sought to determine the range and distribution of length of aorta scanned and the distribution of AAC within the abdominal aorta and to compare burden of AAC measured from fixed-length segments versus AAC from all slices cranial to the aortoiliac bifurcation. Materials and Methods: AAC was quantified by modified Agatston score (AS) in 100 Framingham Heart Study participants (60 ± 13 years old, 51 men). We compared the AS measured from 5-cm and 8-cm segments with the ASALL (total visualized aorta). Results: Of 100, 73 participants had AAC >0. The total length of aorta imaged was ≥8 cm in 84% of participants. Qualitatively, 5-cm and 8-cm segments correctly identified 96% and 99%, respectively, of participants as having or not having AAC. Quantitatively, AS8cm was within 20% of ASALL in four-fifths and within 30% of ASALL in nine-tenths of participants. AS5cm more severely underestimated ASALL. Conclusion: The use of S1 as the caudal imaging landmark in a 15-cm slab yields ≥8 cm aortic coverage in most adults. Both 5-cm and 8-cm analysis strategies are comparable to analyzing the total visualized abdominal aorta for prevalent AAC, but only 8-cm segment analysis yields quantitatively similar measures of AAC. [Copyright &y& Elsevier]

Abstract: Purpose: To examine the relationship between objective treadmill test outcomes and subjective symptom outcomes among patients with claudication treated with stent revascularization (ST) compared with supervised exercise (SE). Materials and Methods: Five scales of the Peripheral Artery Questionnaire and Walking Impairment Questionnaire were correlated with peak walking time and treadmill claudication onset time. Results: The correlation between change in disease-specific quality of life (QOL) and change in peak walking time differed according to treatment group, with statistically significant correlations for all five scales for the ST group and weaker trends for the SE group, only one of which was statistically significant. In contrast, improvements in disease-specific QOL correlated well with increases in claudication onset time, with no significant interaction with treatment group for any of the five scales. Conclusions: Disease-specific QOL results at 6 months in the Claudication: Exercise Vs. Endoluminal Revascularization (CLEVER) study show that improved maximal treadmill walking in patients with claudication treated with SE correlated poorly with self-reported symptom relief. Conversely, patients treated with ST showed good correlation between improved maximal treadmill walking and self-reported symptom improvement. The correlation between claudication onset time and self-reported symptom relief was good across treatment groups. This finding indicates that traditional objective treadmill test outcomes may not correlate well with symptom relief in patients with claudication. Future studies should investigate these data and improve understanding of patient relevance of traditional objective treadmill-based treatment outcomes. [Copyright &y& Elsevier]

Objectives: The aim of this study was to determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer, and all-cause mortality. Background: The morbidity associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited. Methods: Participants from the Framingham Heart Study (n = 3,086; 49% women; mean age of 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography and were followed up longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 SD increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index. Results: Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (hazard ratio: 1.44; 95% confidence interval: 1.08 to 1.92; p = 0.01) and cancer (hazard ratio: 1.43; 95% confidence interval: 1.12 to 1.84; p = 0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality. Conclusions: Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat. [Copyright &y& Elsevier]

Objectives: The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat quantity. Background: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated with cardiometabolic risk independent of the quantity is uncertain. Methods: Participants were drawn from the Framingham Heart Study CT substudy. The VAT and SAT volumes were acquired by semiquantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield unit (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor. Results: Lower CT attenuation of VAT and SAT was correlated with higher body mass index levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1 SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR: 1.80), impaired fasting glucose (OR: 2.10), metabolic syndrome (OR: 3.65), and insulin resistance (OR: 3.36; all p < 0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome, and insulin resistance remained significant. Trends were similar but less pronounced for SAT and for men. There was evidence of an interaction between HU and fat volume among both women and men. Conclusions: Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity. [Copyright &y& Elsevier]

Current screening and detection of asymptomatic aortic aneurysms is based largely on uniform cut-point diameters. The aims of this study were to define normal aortic diameters in asymptomatic men and women in a community-based cohort and to determine the association between aortic diameters and traditional risk factors for cardiovascular disease. Measurements of the diameters of the ascending thoracic aorta (AA), descending thoracic aorta (DTA), infrarenal abdominal aorta (IRA), and lower abdominal aorta (LAA) were acquired from 3,431 Framingham Heart Study (FHS) participants. Mean diameters were stratified by gender, age, and body surface area. Univariate associations with risk factor levels were examined, and multivariate linear regression analysis was used to assess the significance of covariate-adjusted relations with aortic diameters. For men, the average diameters were 34.1 mm for the AA, 25.8 mm for the DTA, 19.3 mm for the IRA, and 18.7 mm for the LAA. For women, the average diameters were 31.9 mm for the AA, 23.1 mm for the DTA, 16.7 mm for the IRA, and 16.0 mm for the LAA. The mean aortic diameters were strongly correlated (p <0.0001) with age and body surface area in ageadjusted analyses, and these relations remained significant in multivariate regression analyses. Positive associations of diastolic blood pressure with AA and DTA diameters in both genders and pack-years of cigarette smoking with DTA diameter in women and IRA diameter in men and women were observed. In conclusion, average diameters of the thoracic and abdominal aorta by computed tomography are larger in men compared with women, vary significantly with age and body surface area, and are associated with modifiable cardiovascular disease risk factors, including diastolic blood pressure and cigarette smoking. [ABSTRACT FROM AUTHOR]

Background: Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris to acute myocardial infarction (AMI), and myocardial infarction size. However, trials of hospital administration of IV GIK to patients with ST-elevation myocardial infarction (STEMI) have generally not shown favorable effects possibly because of the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies. Objective: The IMMEDIATE Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK (1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and (2) administered in prehospital emergency medical service settings, rather than later, in hospitals, after emergency department evaluation. Design: The IMMEDIATE Trial was an emergency medical service–based randomized placebo-controlled clinical effectiveness trial conducted in13 cities across the United States that enrolled 911 participants. Eligible were patients 30 years or older for whom a paramedic performed a 12-lead electrocardiogram to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument indicated a ≥75% probability of ACS, and/or the thrombolytic predictive instrument indicated the presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately. Prespecified were the primary end point of progression of ACS to infarction and, as major secondary end points, the composite of cardiac arrest or in-hospital mortality, 30-day mortality, and the composite of cardiac arrest, 30-day mortality, or hospitalization for heart failure. Analyses were planned on an intent-to-treat basis, on a modified intent-to-treat group who were confirmed in emergency departments to have ACS, and for participants presenting with STEMI. Conclusion: The IMMEDIATE Trial tested whether GIK, when administered as early as possible in the course of ACS by paramedics using acute cardiac ischemia time-insensitive predictive instrument and thrombolytic predictive instrument decision support, would reduce progression to AMI, mortality, cardiac arrest, and heart failure. It also tested whether it would provide clinical and pathophysiologic information on GIK''s biological mechanisms. [Copyright &y& Elsevier]

Background: Choline is the precursor to the neurotransmitter acetylcholine. Loss of cholinergic neurons is associated with impaired cognitive function, particularly memory loss and Alzheimer disease (AD). Brain atrophy and white-matter hyperintensity (WMH) are also associated with impaired cognitive function and AD. Objective: The objective was to determine whether a relation exists between dietary choline intake, cognitive function, and brain morphology in a large, nondemented community-based cohort. Design: A dementia-free cohort of 1391 subjects (744 women, 647 men; age range: 36-83 y; mean ± SD age: 60.9 ± 9.29 y) from the Framingham Offspring population completed a food-frequency questionnaire administered from 1991 to 1995 (exam 5; remote intake) and from 1998 to 2001 (exam 7; concurrent intake). Participants underwent neuropsychological evaluation and brain MRI at exam 7. Four neuropsychological factors were constructed: verbal memory (VM), visual memory (VsM), verbal learning, and executive function. MRI measures included WMH volume (WMHV). Results: Performance on the VM and VsM factors was better with higher concurrent choline intake in multivariable-adjusted models for VM (average change in neuropsychological factor per 1-unit change in choline = 0.60; 95% CI: 0.29, 0.91; P < 0.01) and VsM (0.66; 95% CI: 0.19, 1.13; P < 0.01). Remote choline intake was inversely related to log-transformed WMHV (average change in log WMHV per 1-unit change in choline = −0.05; 95% CI: −0.10, −0.01; P = 0.02). Furthermore, an inverse association was observed between remote higher choline intake and presence of large WMVH (OR: 0.56; 95% CI: 0.34, 0.92; P = 0.01). Conclusion: In this community-based population of nondemented individuals, higher concurrent choline intake was related to better cognitive performance, whereas higher remote choline intake was associated with little to no WMHV. [ABSTRACT FROM AUTHOR]

Background: Drug-eluting stents (DES) are commonly used to treat obstructive coronary disease and avoid restenosis. Newer DES have been developed to improve effectiveness and safety. We describe a clinical trial to evaluate a DES with a novel polymer that may improve the antirestenosis effectiveness while maintaining the safety standards of currently Food and Drug Administration–approved DES. Methods: The RESOLUTE US Trial is a multicenter, nonrandomized trial prospectively designed to compare the Resolute zotarolimus-eluting stent (R-ZES) to the Food and Drug Administration–approved Endeavor ZES using patient-level historical control data, adjusting for baseline covariates through propensity score. The stents differ primarily in the polymer, which, in the R-ZES, is designed to elute zotarolimus over a longer period. The study will enroll up to 1,574 patients with ischemic heart disease due to de novo native coronary lesions suitable for 1- or 2-vessel treatment with stents from 2.25 to 4.0 mm in diameter. The primary end point is target lesion failure at 12 months postprocedure, defined as the composite of cardiac death, target-vessel myocardial infarction (MI), and clinically driven target lesion revascularization by percutaneous or surgical methods. Secondary end points include device, lesion and procedural success, death, MI, cardiac death and MI, composites of these clinical events, and stent thrombosis at each follow-up assessment up to 5 years postprocedure. Conclusions: The RESOLUTE US Trial (ClinicalTrials.gov #NCT00726453) is a prospective, multicenter, observational study with a patient-level historical control designed to assess the safety and efficacy of the R-ZES for the treatment of de novo lesions in native coronary arteries. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to evaluate the long-term safety of the zotarolimus-eluting stent (ZES) using a pooled analysis of pivotal trials. Background: Drug-eluting stents, compared with bare-metal stents (BMS), have reduced restenosis; however, individual trials of these stents have not had sufficient power to ascertain long-term safety. Methods: We combined patient level data from 6 prospective randomized single-arm multicenter trials involving 2,132 patients treated with ZES and 596 patients treated with a BMS control. The median follow-up was 4.1 years, with 5-year follow-up completed in 1,256 patients (97% of those eligible). The recommended minimum duration of dual antiplatelet therapy in these studies was 3 to 6 months regardless of stent type. An independent events committee adjudicated all events. The 2 treatment groups were compared after adjustment for between trial variation and for individual patient clinical and angiographic characteristics by propensity score. Results: The cumulative incidence of adverse events at 5 years for ZES and BMS were: death: 5.9% versus 7.6% (adjusted hazard ratio: 0.81, p = 0.34), cardiac death: 2.4 versus 3.7% (0.83, p = 0.57), myocardial infarction: 3.4 versus 4.8% (0.77, p = 0.37), target lesion revascularization: 7.0% vs. 16.5% (0.42, p < 0.001), stent thrombosis (definite or probable): 0.8 versus 1.7% (0.50, p = 0.21). After adjustment for variation in study and patient characteristics, there were no significant differences in stent thrombosis or the clinical safety event rates at 5 years between ZES and BMS. Conclusions: Over 5 years, there was no increased risk of death, myocardial infarction, or stent thrombosis, and there was a benefit of prevention of repeat revascularization procedures in ZES compared with BMS. (The ENDEAVOR Pharmacokinetic [PK] Registry: The Medtronic Endeavor Drug Eluting Coronary Stent System [ENDEAVOR PK]; NCT00314275) (The ENDEAVOR II Clinical Trial: The Medtronic Endeavor Drug Eluting Coronary Stent System in Coronary Artery Lesions [ENDEAVOR II]; NCT00614848) (The Medtronic Endeavor III Drug Eluting Coronary Stent System Clinical Trial [ENDEAVOR III]; NCT00217256) (The ENDEAVOR IV Clinical Trial: A Trial of a Coronary Stent System in Coronary Artery Lesions [ENDEAVOR IV]; NCT00217269) [Copyright &y& Elsevier]

Background: Mitral valve surgery is the standard of care for patients with symptomatic mitral regurgitation (MR) or asymptomatic MR with evidence of left ventricular dysfunction or dilation. Whether an endovascular approach to repair can offer comparable effectiveness with improved safety remains to be determined in randomized trials. Study Design: The EVEREST II Trial is a multicenter, randomized controlled trial to evaluate the benefits and risks of endovascular mitral valve repair using the MitraClip device compared with open mitral valve surgery (control) in patients with moderate or severe MR. Using a 2:1 randomization ratio, the trial is enrolling up to 186 MitraClip-treated subjects and 93 control subjects. Trial end points include a primary efficacy end point: the proportion of patients free from death, surgery for valve dysfunction, and with moderate-severe (3+) or severe (4+) MR at 12 months; the primary safety end point includes the proportion of patients with death, myocardial infarction, reoperation, nonelective cardiovascular surgery, stroke, renal failure, deep would infection, ventilation >48 hours, gastrointestinal complication, new permanent atrial fibrillation, septicemia, or transfusion of ≥2 U at 30 days or hospital discharge, whichever is longer. Conclusions: This randomized controlled trial is designed to evaluate the performance of endovascular mitral repair in comparison to open mitral valve surgery in patients with significant MR. [Copyright &y& Elsevier]

Objectives: To determine the association of long-term exposure to atherosclerosis risk factors with valvular calcification. Background: Traditional atherosclerosis risk factors have been associated with aortic and mitral valve calcium in cross-sectional studies, but long-term prospective data are lacking. Methods: This was a prospective, community-based cohort study with 27-year follow-up (median follow-up 26.9 years; range 23.1 to 29.6 years). Participants from the Framingham Offspring Study (n = 1,323, enrolled between 1971 and 1975, mean age at enrollment 34 ± 9 years; 52% women) underwent cardiac multidetector computed tomography assessment between 2002 and 2005. Associations between the long-term average of each cardiovascular risk factor and valve calcium were estimated using logistic regression. Results: Aortic valve calcium was present in 39% of participants and mitral valve calcium in 20%. In multivariable models, the odds ratio for aortic valve calcium associated with every SD increment in long-term mean total cholesterol was 1.74 (p < 0.0001); with every SD increment in high-density lipoprotein cholesterol, it was 0.77 (p = 0.002); and with every 9 cigarettes smoked per day, it was 1.23 (p = 0.002). Associations of similar magnitude were seen for mitral valve calcium. The mean of 3 serum C-reactive protein measurements was associated with mitral valve calcium (odds ratio: 1.29 per SD increment in C-reactive protein levels; p = 0.002). A higher Framingham risk score in early adulthood (40 years age or younger) was associated with increased prevalence and severity of aortic valve calcium measured 3 decades later. Conclusions: Exposure to multiple atherosclerotic risk factors starting in early to mid-adulthood is associated with aortic and mitral valve calcium. Studies evaluating early risk factor modification to reduce the burden of valve disease are warranted. [Copyright &y& Elsevier]

Abstract: Objective: Perivascular fat through the secretion of paracrine and pro-inflammatory mediators may play a role in obesity-mediated vascular disease. We sought to examine associations between adipose tissue depots immediately surrounding the thoracic aorta, metabolic risk factors, and vascular calcification. Methods: In participants free of cardiovascular disease (CVD) from the Framingham Heart Study Offspring cohort who underwent computed tomography (n =1067, mean age 59 years, 56.1% women), thoracic peri-aortic fat depots were quantified. Visceral abdominal tissue (VAT) and calcification of the thoracic and abdominal aorta were also measured. Results: Peri-aortic fat depots were correlated with body mass index, waist circumference (WC), VAT (all p <0.0001), hypertension (p =0.007), low HDL (p <0.0001), serum triglycerides (p <0.0001), impaired fasting glucose (p = 0.005), and diabetes (p =0.02). These associations generally remained significant after adjustment for BMI and WC (all p-values<0.05), but not after VAT adjustment. Thoracic aortic fat was associated with thoracic calcification in models containing VAT (OR 1.31, 95% CI 1.01–1.71, p =0.04), but was not significant after adjustment for CVD risk factors (OR 1.16, 95% CI 0.88–1.51, p =0.30). Thoracic aortic fat, however, was associated with abdominal aortic calcification (OR 1.48, 95% CI 1.11–1.98, p =0.008) and coronary artery calcification (OR 1.47, 95% CI 1.09–1.98, p =0.001) even in models including CVD risk factors and VAT. Conclusions: Thoracic peri-aortic fat is associated with measures of adiposity, metabolic risk factors, and coronary and abdominal aortic calcification. [Copyright &y& Elsevier]

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome (MetS). Alanine aminotransferase (ALT) levels are used to detect NAFLD and have also been associated with increased risk for MetS, diabetes mellitus, and cardiovascular disease (CVD). We studied the relationship between ALT levels and these disorders in a long-term follow-up study. Methods: Framingham Offspring Heart Study participants (n = 2812; mean age, 44 years; 56% women) were followed for the development of MetS, diabetes, CVD, and all-cause mortality using logistic regression (MetS, diabetes) or Cox proportional hazards models (CVD, all-cause mortality). Results: Among individuals at baseline, per 1 standard deviation increase in log ALT level, there were increased odds of the development of MetS (odds ratio [OR] 1.21, P < .001) and diabetes (OR, 1.48; P < .0001) over 20 years of follow-up. These findings also applied to participants with ALT levels within the normal range (MetS OR, 1.17; P = .006; diabetes OR, 1.34; P =.002). There was an increased risk of CVD in age/gender-adjusted models (hazard ratio, 1.23; P < .0001), but this was attenuated in multivariable-adjusted models (hazard ratio 1.05; P = .27); no association was observed for all-cause mortality. Aspartate aminotransferase levels were found to be associated with an increased risk of only diabetes. Conclusions: Both normal and increased levels of ALT are associated with long-term development of multiple metabolic disorders. These results indicate the potential for ALT values as biomarkers for the risk of metabolic disease. [Copyright &y& Elsevier]

Background: The CD40 receptor and its ligand (CD40L) are known to modulate both inflammation and thrombosis-2 processes important for the development and clinical expression of atherosclerosis. Circulating soluble CD40L (sCD40L) concentration predicts cardiovascular risk in selected patient samples. The purpose of this study was to determine the predictors of sCD40L in a large, community-based sample.Methods: We determined both serum and plasma sCD40L concentration in 3,259 participants (54% women) from the Framingham Offspring Study.Results: In multivariable models, advancing age was the only consistent (inverse) correlate of both serum and plasma sCD40L concentration. Overall, the variability explained by clinical covariates was very low for both measurements of sCD40L; with values of only 1.4% and 2.7% for serum and plasma, respectively. We observed that genetic factors accounted for a modest (12% serum; 14% plasma) amount of the adjusted variability in sCD40L.Conclusions: Circulating sCD40L concentration was poorly associated with known cardiovascular disease (CVD) risk factors and was modestly heritable. Determining if either serum or plasma sCD40L are predictive of CVD risk in the community will require longitudinal follow-up. [ABSTRACT FROM AUTHOR]

The Framingham Heart Study records of participants with atrial fibrillation (AF) during 1980 and 1994 were retrospectively reviewed to determine the prevalence of warfarin and aspirin use in AF. Anticoagulant use increased significantly in the 393 men and women (mean ages 72.5 and 79.0 years, respectively) who developed AF over the observation period: aspirin use increased from 14% to 39% in men and from 19% to 33% in women, and warfarin use increased from 10% to 39% in men and from 17% to 38% in women. There were no significant gender differences in anticoagulant use (p = 0.61), but participants using warfarin were younger. A total of 65 participants (17%) had major bleeding complications ≤5 years after initial AF. Age was not a significant predictor of bleeding. [Copyright &y& Elsevier]

Objectives: We sought to determine the clinical factors and heritability associated with inflammation measured as circulating levels of soluble-intercellular adhesion molecule-1 (sICAM-1) in a community-based cohort.Background: Several prospective studies indicate that circulating sICAM-1 is predictive of future cardiovascular events. However, in some studies this predictive value is lost after multivariable adjustment for traditional cardiovascular disease (CVD) risk factors. We addressed the heritability of sICAM-1 and its relation to CVD risk factors in a community-based cohort.Methods: We examined 3,295 subjects from the Framingham Heart Study and measured sICAM-1 levels. We then used linear and stepwise multivariable regression to determine predictors or sICAM-1 levels.Results: In age- and gender-adjusted regression models, increased sICAM-1 levels were positively associated with age, total/high-density lipoprotein cholesterol, systolic blood pressure, body mass index (BMI), blood glucose, diabetes, smoking, and prevalent CVD. In stepwise multivariable regression models, sICAM-1 levels remained associated with age, female gender, total/high-density lipoprotein cholesterol ratio, BMI, blood glucose, smoking, and prevalent CVD. The residual heritability of sICAM-1 was 24%.Conclusions: In addition to prevalent CVD, established CVD risk factors and non-traditional ones such as BMI were associated with systemic inflammation as determined by sICAM-1 levels. There also is significant heritability of sICAM-1, which suggests a genetic component to systemic inflammation. [Copyright &y& Elsevier]

Background: Atherosclerosis, a primary cause of myocardial infarction (MI), is an inflammatory disease. Aspirin use lowers risk of MI, probably through antithrombotic and antiinflammatory effects. Because serum ferritin (SF) can be elevated spuriously by inflammation, reported associations between elevated SF, used as an indicator of iron stores, and heart disease could be confounded by occult inflammation and aspirin use if they affect SF independently of iron status. Objective: We tested the hypothesis that aspirin use is associated with reduced SF. Design: We used analysis of covariance to investigate the relation between SF and categories of aspirin use in 913 elderly participants aged 67-96 y in the Framingham Heart Study. Results: After adjustment for sex, age, body mass index, smoking, alcohol use, concentrations of C-reactive protein and liver enzymes, white blood cell count, and use of nonaspirin nonsteroidal antiinflammatory drugs and other medications, subjects who took > 7 aspirins/wk had a significantly lower (by 25%) geometric mean SF than did nonusers, who took < 1 aspirin/wk (71 compared with 95 µg/L, respectively; P for trend = 0.004). This effect of aspirin on SF was more marked in diseased subjects than in healthy subjects (mean SF was 50% lower compared with 21% lower, respectively). Conclusions: Aspirin use is associated with lower SF. We suggest this effect results from possible increased occult blood loss and a cytokine-mediated effect on SF in subjects with inflammation, infection, or liver disease. The relations between aspirin, inflammation, and SF may confound epidemiologic associations between elevated SF, as an indicator of iron stores, and heart disease risk. [ABSTRACT FROM AUTHOR]

Background: Although iron deficiency occurs commonly in vulnerable groups of women of reproductive age, infants, and children, less is known about the iron nutriture of the elderly. Objective: Our objective was to evaluate the iron status of a noninstitutionalized, elderly US population, with a particular focus on 2 concerns unique to the elderly: 1) potential confounding effects of chronic disease on iron measures and 2) increased occurrence of elevated iron stores. Design: Multiple iron measures, including serum ferritin (SF), transferrin saturation, mean cell volume, and hemoglobin, were used to evaluate the prevalence of iron deficiency (ID), iron deficiency anemia (IDA), and other measures of iron nutriture in 1016 elderly white Americans aged 67-96 y from the Framingham Heart Study. "Diseased" subjects were defined as those with possible pathologically altered iron measures due to inflammation, infection, elevated liver enzymes, hereditary hemochromatosis, or cancer. The effect of altered iron status on various prevalence estimates was assessed. Results: The elderly subjects had a low prevalence of ID (2.7%), IDA (1.2%), and depleted iron stores (3%; SF < 12 μg/L). In contrast, 12.9% had elevated iron stores (SF > 300 μg/L in men and SF > 200 μg/L in women), of which only 1% was attributable to chronic disease. The prevalence of ID, IDA, and depleted iron stores was unaffected by the presence of chronic disease. Conclusions: The Framingham Heart Study cohort is an iron-replete elderly population with a high prevalence of elevated iron stores in contrast with a low prevalence of iron deficiency, with insignificant effects of chronic disease on these iron status estimates. The likely liability in iron nutriture in free-living, elderly white Americans eating a Western diet is high iron stores, not iron deficiency. [ABSTRACT FROM AUTHOR]

Many individuals presumed to have nonalcoholic fatty liver disease (NAFLD) consume moderate amounts of alcohol. Little is known about patterns of alcohol use in patients with NAFLD or how drinking behaviors affect liver fat. We conducted a cross-sectional study of 2475 participants of the Framingham Heart Study with hepatic steatosis, as determined by computed tomography. We performed multivariable-adjusted logistic regression models to evaluate the association between alcohol drinking patterns and hepatic steatosis. Models were adjusted for sociodemographic factors, diet, and the components of the metabolic syndrome. We excluded heavy alcohol users, defined as women who consume more than 14 alcohol drinks per week and men who consume more than 21 alcohol drinks per week. In our sample (mean age, 49.8 ± 10.2 y; 50.3% women), the prevalence of hepatic steatosis was 17.5%. The total number of alcohol drinks per week and the maximum drinks consumed per drinking day each were associated with hepatic steatosis (adjusted odds ratio [aOR], 1.15; 95% CI, 1.02–1.29 and aOR 1.15; 95% CI, 1.02–1.30). Binge drinking occurred in 25.4% of individuals with presumed NAFLD and was associated with an increased odds of hepatic steatosis (aOR, 1.45; 95% CI, 1.06–1.98) among alcohol users. In a beverage-specific analysis, alcohol use patterns were associated with hepatic steatosis among beer drinkers, but not among wine drinkers. In a cross-sectional study of participants of the Framingham Heart Study with hepatic steatosis, we observed an association between alcohol use and liver fat, even after excluding heavy alcohol users from our analysis. Alcohol use therefore appears to be a risk factor for NAFLD. Prospective studies are needed to validate these findings and determine if alcohol use should be a focus for research, prevention, and treatment of presumed NAFLD. [ABSTRACT FROM AUTHOR]

Vagus Nerve Stimulation (VNS) is meant to deliver Autonomic Regulation Therapy (ART) to neurological targets with sufficient neuromodulation (NM) to ameliorate chronic heart failure (CHF). VNS delivery consists of its intensity (a combination of pulse amplitude, pulse frequency, and pulse duration), polarity, duty cycle (DC; stimulation "on" time and "off" time), and mode (continuous, or intermittent and periodic). In the ANTHEM-HF Pilot Study patients with CHF and reduced ejection fraction (HFrEF), VNS intensity was up-titrated until a change in heart rate (HR) dynamics was objectively confirmed. This did not require any change in GDMT and was associated with significant improvements in LVEF, 6-minute walk distance (6MWD), Minnesota Living with HF (MLWHF) score, and HR variability. Qualitative and quantitative analyses used data from peer-reviewed publications and other sources in the public domain to compare VNS delivery in ANTHEM-HF, INOVATE-HF, and NECTAR-HF. (Table): Up-titration of VNS intensity was attempted in all 3 studies. In contrast to ANTHEM-HF, INOVATE-HF aimed only at peripheral neural targets. VNS intensity was delivered at a lower pulse frequency, and had a variable DC as a consequence of R-wave synchronization and only intermittent, periodic stimulation. In NECTAR-HF VNS intensity was delivered at a higher pulse frequency, and this was associated with intolerable adverse off-target effects which restricted VNS up-titration. Significant improvements in EF, 6MWD, MLWHF, and SDNN occurred in ANTHEM-HF relative to the other studies. VNS differed in ANTHEM-HF when compared to INOVATE-HF and NECTAR-HF. The neural targets, pulse frequencies for titration, and the DC for NM were different. VNS in ANTHEM-HF was clinically efficacious. The ongoing ANTHEM-HFrEF Pivotal Study uses a similar paradigm. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate safety and effectiveness of the iCAST Covered Stent for treatment of iliac artery atherosclerotic lesions.Materials and Methods: The iCARUS trial (ClinicalTrials.gov Identifier: NCT00593385) was a single-arm, prospective, multicenter study that enrolled 152 per protocol subjects at 25 sites in the United States and Germany. Subjects with multiple lesions and/or stents were eligible. The primary endpoint was the composite rate of death within 30 days, target lesion revascularization (TLR) within 9 months, or restenosis at 9 months after procedure. Secondary endpoints included major adverse vascular events (MAVEs), primary patency, freedom from TLR, and clinical success.Results: Device and acute procedural success were achieved in 98.7% and 92.7% of cases, respectively. MAVE rate was 4.6% at 30 days. The 9-month primary composite endpoint rate was 8.1% (10/123), which was below the performance goal of 16.57%. Nine-month primary patency, defined as continuous flow without revascularization, bypass, or target limb amputation, was 96.4%. Freedom from TLR at 9 months and 3 years was 97.2% and 86.6%, respectively. Early clinical success was seen in 88.7% of subjects at 30 days with sustained clinical benefit in 72.4% of subjects at 3 years.Conclusions: The iCARUS study demonstrated that the iCAST Covered Stent was safe and effective for treatment of atherosclerotic iliac artery lesions with sustained clinical benefit out to 3 years. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease is an inflammatory condition that results in progressive liver disease. It is unknown if individuals with hepatic steatosis, but not known to have liver disease, have higher serum concentrations of markers of systemic inflammation and oxidative stress. We collected data from 2482 participants from the Framingham Heart Study (mean age, 51 ± 11 y; 51% women) who underwent computed tomography and measurement of 14 serum markers of systemic inflammation. Heavy alcohol users were excluded. The liver:phantom ratio (a continuous parameter of liver attenuation relative to a calibration phantom) was used to identify individuals with radiographic evidence of liver fat. Primary covariates included age, sex, smoking, alcohol, aspirin use, hypertension, dyslipidemia, diabetes, and cardiovascular disease. Body mass index and visceral fat were secondary covariates. We used multivariable linear regression models to assess the association between liver fat and systemic inflammatory markers. In multivariable-adjusted models, liver fat was associated with the following inflammatory markers: high-sensitivity C-reactive protein (P <.001), urinary isoprostanes (P <.001), interleukin 6 (P <.001), intercellular adhesion molecule 1 (P <.001), and P-selectin (P =.002). Additional adjustment for body mass index or visceral fat attenuated the results slightly, although all associations remained statistically significant (P for all ≤.01). In a community-based cohort, individuals with hepatic steatosis without known liver disease had higher mean serum concentrations of systemic markers of inflammation. Studies are needed to determine whether treatment of hepatic steatosis reduces systemic inflammation. [ABSTRACT FROM AUTHOR]

Background & Aims Serum levels of aminotransferases are used as markers of nonalcoholic fatty liver disease in epidemiology research. However, it is not clear whether they can be used to identify patients with fatty liver. We investigated the accuracy of serum levels of aminotransferases in detection of hepatic steatosis. In addition, we derived a Framingham steatosis index (FSI) and tested its ability to identify patients with hepatic steatosis in an independent cohort. Methods We performed a cross-sectional study of 1181 members of the Framingham Third Generation Cohort (46.1% women; mean age, 50.3 ± 6.7 years). People with hepatic steatosis were identified by computed tomography that was performed from 2008 through 2011. We compared the abilities of levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the ratio of ALT:AST to identify people with hepatic steatosis by using c-statistic analyses. We performed a stepwise regression procedure to identify demographic and clinical factors that correlated with hepatic steatosis; we used these, along with biochemical factors associated with steatosis, to develop the FSI. We validated the FSI by using data from the third National Health and Nutrition Examination Survey. Results The prevalence of hepatic steatosis in the Framingham Third Generation Cohort was 26.8%. The ratio of ALT:AST identified people with hepatic steatosis with the highest c-statistic value (0.728); the value for only ALT was 0.706, and the value for only AST was 0.589. We derived the FSI on the basis of patient age, sex, body mass index, levels of triglycerides, hypertension, diabetes, and ratio of ALT:AST. The FSI identified patients with hepatic steatosis with a c-statistic value of 0.845. When it was applied to the third National Health and Nutrition Examination Survey cohort, the FSI identified patients with steatosis with a c-statistic value of 0.760 and was well-calibrated. Conclusions In an analysis of the Framingham Third Generation Cohort, we found the ratio of ALT:AST to identify people with hepatic steatosis more accurately than either ALT or AST alone. We used data from this cohort to develop and validate the FSI, which identifies patients with steatosis with a c-statistic value of about 0.8. [ABSTRACT FROM AUTHOR]

Background: We compared 30-day and 1-year survival among high-risk mitral regurgitation (MR) patients treated with the MitraClip (Abbott Vascular, Abbott Park, IL) with matched non-surgically treated patients from the Duke Echocardiography Laboratory Database (DELD).Methods and Results: High-risk patients with 3+/4+ MR managed non-surgically between years 2000 and 2010 in the longitudinal DELD were matched to high-risk MitraClip patients. Patient matching was performed using the method of nearest available Mahalanobis distance metric within calipers defined by the propensity score. Kaplan-Meier estimates and stratified Cox proportional hazards models were used to compare survival at 30 days and 1 year. Among 953 high-risk DELD patients available for matching, 30-day and 1-year mortality were 6.5% and 26.2%. Close matches were obtained for 239 of the 351 MitraClip patients. The 30-day mortality in MitraClip patients was lower (4.2%) when compared with matched DELD patients (7.2%). The 1-year relative risk of mortality of the MitraClip compared with non-surgical treatment was 0.64 (95% CI 0.45-0.91; log-rank P = .013). These results in favor of the MitraClip remained significant upon further adjustment for baseline differences between groups (P = .043).Conclusions: This matched comparison of severe MR patients at high surgical risk supports the safety of the MitraClip relative to medical therapy at 30 days and a survival benefit at 1 year. [ABSTRACT FROM AUTHOR]

Background Blood levels of high low-density lipoprotein cholesterol (LDL-C), high triglycerides (TG), and low high-density lipoprotein cholesterol (HDL-C) have been associated with increased risk of cardiovascular disease (CVD). The long-term comparative CVD risk associated with these 3 major lipid classes in various combinations is, however, unknown. Methods A total of 3,501 participants of the Framingham Offspring Study (mean age 51 ± 10 years, 56% women) without CVD at baseline were followed up for incident CVD between 1987 and 2011. Participants were grouped according to baseline lipid values into 8 distinct categories to compare the prognostic significance of values within an optimal range to Third Report of the National Cholesterol Educational Program–defined high LDL-C (>130 mg/dL), high TG (>150 mg/dL), and/or low HDL-C (<40 mg/dL) in various combinations using multivariable-adjusted Cox regression models. Results On follow-up (median 20.2 years), 724 (21%) had new-onset CVD. Adjusted for confounders and compared with the group with optimal lipid values, hazards ratios and population-attributable risks (PARs) were as follows: isolated low HDL-C, 1.93 (95% CI 1.37-2.71), PAR = 3.1%; isolated high LDL-C, 1.28 (1.03-1.59), PAR 6.4%; isolated high TG, 1.35 (0.91-1.98), PAR = 1.1% (not significant); low HDL-C and high LDL-C, 1.82 (1.33-2.49), PAR = 3.9%; low HDL-C and high TG, 1.74 (1.28-2.37), PAR = 3.9%; high LDL-C and high TG, 1.52 (1.12-2.07), PAR = 6.4%; and high LDL-C, high TG and low HDL-C 2.28 (1.73-3.02), PAR = 7.5%. Conclusions Aside from isolated hypertriglyceridemia, low levels of HDL-C, high levels of LDL-C, and high levels of TG in any combination were associated with increased risk of CVD. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF)–related symptoms and physical performance are relied upon to guide therapeutic management of patients with AF. We sought to understand whether AF predisposes to or is a result of physical disability and poor subjective health in the community. Methods: We studied relations between physical disability (Rosow-Breslau Functional Health Scale), subjective health (self-report) and incident AF, and the converse, in the Framingham Heart Study. Results: In 3,609 participants (age 73 ± 8 years, 59% women), a subset of 861 participants (24%) had prevalent physical disability at baseline. During 5.8 ± 1.8 years of follow-up, 555 participants (10-year age- and sex-adjusted incidence rate 13%) developed incident AF. Prevalent physical disability was related to incident AF (multivariable-adjusted hazard ratio 1.25, 95% CI 1.02-1.54, P = .03). In 3,525 participants, prevalent poor subjective health (n = 333) also was related to incident AF (n = 552, multivariable-adjusted hazard ratio 1.31, 95% CI 1.00-1.70, P = .048). Conversely, in 2,080 participants (age 69 ± 6 years, 55% women), interim AF (n = 106) was associated with newly reported physical disability (n = 573) at a follow-up examination (multivariable-adjusted odds ratio 1.58, 95% CI 1.08-2.31, P = .01). In 1,954 participants, interim AF (n = 96) likewise was related to newly reported poor subjective health (n = 224, multivariable-adjusted odds ratio 1.83, 95% CI 1.10-3.02, P = .02). Conclusions: Physical disability and poor subjective health were related to incident AF in a community-based cohort. Conversely, interim AF was related to newly reported physical disability and poor subjective health. Because AF guidelines incorporate symptoms, it is essential to clarify the temporality and mechanisms linking physical disability, subjective health, and AF. [Copyright &y& Elsevier]

Background: Dual antiplatelet therapy with aspirin and thienopyridines (clopidogrel or prasugrel) is required after placement of coronary stents to prevent thrombotic complications. Although current clinical practice guidelines recommend 12-month treatment after drug-eluting stent placement, even longer durations may prevent thrombotic events. Study Design: The Dual Antiplatelet Therapy (DAPT) Study is comparing the benefits and risks of 12 versus 30 months of dual antiplatelet therapy in preventing stent thrombosis or major adverse cardiovascular and cerebrovascular events in subjects undergoing percutaneous coronary intervention (PCI) for the treatment of coronary artery obstructive lesions. The DAPT Study is a multicenter, international, randomized, double-blind, placebo-controlled trial that will enroll 15,245 subjects treated with drug-eluting stent (DES) and 5,400 subjects treated with bare-metal stents (BMS). All subjects will receive 12 months of open-label thienopyridine treatment in addition to aspirin. After 12 months, subjects who are free from death, myocardial infarction, or stroke (MACCE), repeat revascularization, and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate or severe bleeding events will be randomized to receive either 18 additional months of thienopyridine (clopidogrel or prasugrel) (30 month DAPT arm) or placebo (12 month DAPT arm) plus aspirin. Coprimary end points are MACCE and stent thrombosis. The primary safety end point is GUSTO moderate or severe bleeding. Conclusions: This randomized trial is designed to define the relative safety and effectiveness of 12 versus 30 months of dual antiplatelet therapy across the broad spectrum of patients receiving coronary stents. [ABSTRACT FROM AUTHOR]

Background: The DAPT (Dual Antiplatelet Therapy) study enrolled patients after coronary stenting. Patients randomized to continued thienopyridine and aspirin after 12 months had lower ischemic risk but higher bleeding risk than those treated with placebo and aspirin.Objectives: This study sought to determine whether a decision tool (DAPT score) aids prescription of dual antiplatelet therapy duration in patients with or without prior myocardial infarction (MI) treated with coronary stents.Methods: Patients were categorized according to any history of MI before the index procedure or no history of MI. Risk differences during the randomized treatment period (12 to 30 months) for ischemic (MI and/or stent thrombosis) and bleeding (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries moderate/severe) events were compared according to DAPT score.Results: Rates of MI were 3.8% versus 2.4% (p = 0.01) for patients with any MI versus no MI. Continued thienopyridine reduced late MI compared with placebo regardless of MI history (hazard ratio [HR] for any MI: 0.46; p < 0.001; HR for no MI: 0.60; p = 0.003) and increased bleeding (HR: 1.86, p = 0.01 any MI; HR: 1.58, p = 0.01 no MI). DAPT scores ≥2 were associated with reductions in MI/stent thrombosis with continued thienopyridine compared with placebo (2.7% vs. 6.0%, p < 0.001 any MI; 2.6% vs. 5.2%, p = 0.002 no MI), with comparable bleeding rates. Among patients with DAPT scores <2 in both groups, continued thienopyridine was associated with significantly increased bleeding but similar rates of ischemia.Conclusions: Patients with previous MI have greater risk of late ischemic events than those with no MI history. The DAPT score improves prediction of patient benefit and harm from continued dual antiplatelet therapy beyond assessment of MI history alone. (The Dual Antiplatelet Therapy Study; NCT00977938). [ABSTRACT FROM AUTHOR]

The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care Trial of very early intravenous glucose-insulin-potassium (GIK) for acute coronary syndromes (ACS) in out-of-hospital emergency medical service (EMS) settings showed 80% reduction in infarct size at 30 days, suggesting potential longerterm benefits. Here we report 1-year outcomes. Prespecified 1-year end points of this randomized, placebo-controlled, double-blind, effectiveness trial included all-cause mortality and composites including cardiac arrest, mortality, or hospitalization for heart failure (HF). Of 871 participants randomized to GIK versus placebo, death occurred within 1 year in 11.6% versus 13.5%, respectively (unadjusted hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.57 to 1.23, p = 0.36). The composite of cardiac arrest or 1-year mortality was 12.8% versus 17.0% (HR 0.71, 95% CI 0.50 to 1.02, p = 0.06). The composite of hospitalization for HF or mortality within 1 year was 17.2% versus 17.2% (HR 0.98, 95% CI 0.70 to 1.37, p = 0.92). The composite of mortality, cardiac arrest, or HF hospitalization within 1 year was 18.1% versus 20.4% (HR 0.85, 95% CI 0.62 to 1.16, p = 0.30). In patients presenting with suspected ST elevation myocardial infarction, HRs for 1-year mortality and the 3 composites were, respectively, 0.65 (95% CI 0.33 to 1.27, p = 0.21), 0.52 (95% CI 0.30 to 0.92, p = 0.03), 0.63 (95% CI 0.35 to 1.16, p =0.14), and 0.51 (95% CI 0.30 to 0.87, p = 0.01). In patients with suspected acute coronary syndromes, serious end points generally were lower with GIK than placebo, but the differences were not statistically significant. However, in those with ST elevation myocardial infarction, the composites of cardiac arrest or 1-year mortality, and of cardiac arrest, mortality, or HF hospitalization within 1 year, were significantly reduced. [ABSTRACT FROM AUTHOR]

Diabetes mellitus and obesity are increasing in prevalence and are associated with an elevated risk of atrial fibrillation (AF). Given the aging of the United States population, AF is projected to concomitantly increase in prevalence in the upcoming decades. Both diabetes and obesity are associated with insulin resistance. Whether insulin resistance is an intermediate step for the development of AF is uncertain. We hypothesized that insulin resistance is associated with an increased risk of incident AF. We examined the association of insulin resistance with incident AF using multivariate Cox proportional hazards regression analysis adjusting for the established AF risk factors (i.e., age, gender, systolic blood pressure, hypertension treatment, PR interval, significant heart murmur, heart failure, and body mass index). Of the 3,023 eligible participants (55% women; mean age 59 years) representing 4,583 person-examinations (Framingham Offspring fifth and seventh examination cycles), 279 participants developed AF (9.3%) within ≤10 years of follow-up. With multivariate modeling, insulin resistance was not significantly associated with incident AF (hazard ratio comparing top quartile to other 3 quartiles of homeostatic model assessment index 1.18, 95% confidence interval 0.84 to 1.65, p = 0.34). In a community-based cohort with ≤10 years of follow-up, no significant association was observed between insulin resistance and incident AF. [ABSTRACT FROM AUTHOR]