Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

Effects of heart failure and diabetes mellitus on long-term mortality after coronary revascularization (from the BARI Trial).

This study evaluated the effect of heart failure (HF) and ejection fraction (EF) at baseline on long-term cardiac mortality in patients undergoing coronary revascularization and investigated the effect of diabetes mellitus (DM) on mortality. We evaluated long-term outcomes of patients without HF, HF and a preserved EF, and HF and a decreased EF who underwent revascularization with percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery after enrollment in the Bypass Angioplasty Revascularization Investigation (BARI) trial. Ten years after initial revascularization, cumulative rates of freedom from cardiac death were 90% in patients without HF, 75% in patients with HF and a preserved EF, and 59% in patients with HF and a decreased EF (p <0.001, 3-way comparison). In diabetic patients with HF and a preserved EF, there was a significant increase in cardiac mortality compared with patients without HF (p <0.001); however, this relation was not seen in patients without DM. In conclusion, patients with HF and a preserved EF have increased mortality over 10 years compared with those without HF. Only in patients with DM did HF with preserved EF confer additional risk.

Cardiac troponin I predicts short-term mortality in vascular surgery patients.

BACKGROUND: Cardiac troponin I (cTnI) is a highly sensitive and specific marker for myocardial injury that predicts outcomes in patients with acute coronary syndromes. Cardiovascular complications are the leading cause of morbidity and mortality in patients who have undergone vascular surgery. However, postoperative surveillance with cardiac enzymes is not routinely performed in these patients. We evaluated the association between postoperative cTnI levels and 6-month mortality and perioperative myocardial infarction (MI) after vascular surgery. METHODS AND RESULTS: Two hundred twenty-nine patients having aortic or infrainguinal vascular surgery or lower extremity amputation were included in this study. Blood samples were analyzed for cTnI immediately after surgery and the mornings of postoperative days 1, 2, and 3. An elevated cTnI was defined as serum concentrations >1.5 ng/mL in any of the 4 samples. Twenty-eight patients (12%) had postoperative cTnI >1.5 ng/mL, which was associated with a 6-fold increased risk of 6-month mortality (adjusted OR, 5.9; 95% CI, 1.6 to 22.4) and a 27-fold increased risk of MI (OR, 27.1; 95% CI, 5.2 to 142.7). Furthermore, we observed a dose-response relation between cTnI concentration and mortality. Patients with cTnI >3.0 ng/mL had a significantly greater risk of death compared with patients with levels < or =0.35 ng/mL (OR, 4.9; 95% CI, 1.3 to 19.0). CONCLUSIONS: Routine postoperative surveillance for cTnI is useful for identifying patients who have undergone vascular surgery who have an increased risk for short-term mortality and perioperative MI. Further research is needed to determine whether intervention in these patients can improve outcome.

The role of metabolic syndrome, adiposity, and inflammation in physical performance in the Health ABC Study.

BACKGROUND: Metabolic syndrome (MetS) and functional limitation have been linked, but whether and how specific components of MetS and associated factors, such as inflammation, drive this relationship is unknown. METHODS: Data are from 2,822 men and women, aged 70-79 years, participating in the Health, Aging, and Body Composition (Health ABC) study and followed for 5 years. Presence of MetS at baseline was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Interleukin-6, C-reactive protein, and body fat mass were measured at baseline. Measures of physical performance, including 400-m walk time, 20-m walking speed, and the Health ABC physical performance battery (PPB) were obtained at baseline and examination years 2, 4, and 6. RESULTS: A total of 1,036 (37%) individuals met criteria for MetS. MetS was associated with poorer physical performance at baseline. Effect estimates between MetS and gait speed, and components of the Health ABC PPB (standing balance and repeated sit-to-stand performance) were modestly attenuated after adjustment for inflammation. All associations were attenuated to nonsignificance after adding total body fat mass to the model. Longitudinal analyses yielded similar results. Individual MetS component analysis revealed that abdominal obesity explained the largest fraction of the variation in physical performance. CONCLUSIONS: Although inflammatory biomarkers partially accounted for the relationship between MetS and aspects of physical performance, overall findings implicate adiposity as the primary factor explaining poorer physical performance in older adults with MetS.

Associations of visceral and liver fat with the metabolic syndrome across the spectrum of obesity: the AGES-Reykjavik study.

Visceral adipose tissue (VAT) is a key pathogenic fat depot in the metabolic syndrome (MetS), but liver fat (LF) may also play an important role. We evaluated associations of VAT and LF with MetS in normal weight, overweight, and obese men and women (BMI <25, 25-29.9, and ≥30 kg/m2, respectively). This analysis included 2,495 participants from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study with computed tomography measurements for VAT and LF. MetS was defined by ≥3 of the following: larger abdominal circumference, hypertension, elevated triglyceride (TG), low high-density lipoprotein (HDL), impaired fasting glucose (IFG), and microalbuminuria. We estimated the odds of MetS per 1-s.d. increase in VAT and LF, adjusting for key covariates. VAT was associated with an increased odds of MetS in normal weight, overweight, and obese women (odds ratios (OR) = 2.78, 1.63, and 1.43, respectively; all P < 0.01) that diminished in magnitude with increasing BMI (VAT × BMI class interaction P < 0.001). In men, VAT was related to MetS only among the overweight (OR = 1.69, P < 0.01). LF was associated with MetS in the overweight and obese groups in women (OR = 1.38 and 1.45; both P < 0.001) and in men (OR = 1.38, P = 0.01; and OR = 1.27, P = 0.10), but not in the normal weight groups. These BMI-specific relationships persisted when both fat depots were included in the model. VAT and LF were associated with MetS independently of each other, and these relationships were modified by BMI class such that, VAT was the more important depot at lower levels of obesity and LF at higher levels. Importantly, fatty liver may be a novel metabolic risk factor in overweight and obese individuals.

Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

Body fat distribution and inflammation among obese older adults with and without metabolic syndrome.

The protective mechanisms by which some obese individuals escape the detrimental metabolic consequences of obesity are not understood. This study examined differences in body fat distribution and adipocytokines in obese older persons with and without metabolic syndrome. Additionally, we examined whether adipocytokines mediate the association between body fat distribution and metabolic syndrome. Data were from 729 obese men and women (BMI ≥ 30 kg/m(2)), aged 70-79 participating in the Health, Aging and Body Composition (Health ABC) study. Thirty-one percent of these obese men and women did not have metabolic syndrome. Obese persons with metabolic syndrome had significantly more abdominal visceral fat (men: P = 0.04; women: P < 0.01) and less thigh subcutaneous fat (men: P = 0.09; women: P < 0.01) than those without metabolic syndrome. Additionally, those with metabolic syndrome had significantly higher levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1) than individuals without metabolic syndrome. Per standard deviation higher in visceral fat, the likelihood of metabolic syndrome significantly increased in women (odds ratio (OR): 2.16, 95% confidence interval (CI): 1.59-2.94). In contrast, the likelihood of metabolic syndrome decreased in both men (OR: 0.56, 95% CI: 0.39-0.80) and women (OR: 0.49, 95% CI: 0.34-0.69) with each standard deviation higher in thigh subcutaneous fat. These associations were partly mediated by adipocytokines; the association between thigh subcutaneous fat and metabolic syndrome was no longer significant in men. In summary, metabolically healthy obese older persons had a more favorable fat distribution, characterized by lower visceral fat and greater thigh subcutaneous fat and a more favorable inflammatory profile compared to their metabolically unhealthy obese counterparts.

Factors related to the selection of surgical versus percutaneous revascularization in diabetic patients with multivessel coronary artery disease in the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) trial.

OBJECTIVES: We evaluated demographic, clinical, and angiographic factors influencing the selection of coronary artery bypass graft (CABG) surgery versus percutaneous coronary intervention (PCI) in diabetic patients with multivessel coronary artery disease (CAD) in the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) trial. BACKGROUND: Factors guiding selection of mode of revascularization for patients with diabetes mellitus and multivessel CAD are not clearly defined. METHODS: In the BARI 2D trial, the selected revascularization strategy, CABG or PCI, was based on physician discretion, declared independent of randomization to either immediate or deferred revascularization if clinically warranted. We analyzed factors favoring selection of CABG versus PCI in 1,593 diabetic patients with multivessel CAD enrolled between 2001 and 2005. RESULTS: Selection of CABG over PCI was declared in 44% of patients and was driven by angiographic factors including triple vessel disease (odds ratio [OR]: 4.43), left anterior descending stenosis >or=70% (OR: 2.86), proximal left anterior descending stenosis >or=50% (OR: 1.78), total occlusion (OR: 2.35), and multiple class C lesions (OR: 2.06) (all p < 0.005). Nonangiographic predictors of CABG included age >or=65 years (OR: 1.43, p = 0.011) and non-U.S. region (OR: 2.89, p = 0.017). Absence of prior PCI (OR: 0.45, p < 0.001) and the availability of drug-eluting stents conferred a lower probability of choosing CABG (OR: 0.60, p = 0.003). CONCLUSIONS: The majority of diabetic patients with multivessel disease were selected for PCI rather than CABG. Preference for CABG over PCI was largely based on angiographic features related to the extent, location, and nature of CAD, as well as geographic, demographic, and clinical factors. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI 2D]; NCT00006305).

The effect of coronary artery bypass grafting on specific causes of long-term mortality in the Bypass Angioplasty Revascularization Investigation.

OBJECTIVES: We sought to examine the effect of revascularization with coronary artery bypass grafting on specific causes of death in the Bypass Angioplasty Revascularization Investigation cohort. Although the effect of coronary revascularization on long-term mortality has been previously described, there are limited data describing its effect on specific causes of death in patients with coronary artery disease. Evaluation of cause of death might help elucidate disease mechanisms and be useful for developing treatment strategies. METHODS: In the Bypass Angioplasty Revascularization Investigation randomized trial and registry, 3610 patients underwent initial revascularization with coronary artery bypass grafting or balloon angioplasty and were followed for an average of 7.7 years. Causes of all deaths were classified by an independent committee. RESULTS: Among 3610 revascularized patients, 2239 underwent coronary artery bypass grafting as an initial or subsequent procedure. Over 7.7 years of follow-up, 3% of all patients died of sudden cardiac death, 3% died of myocardial infarction-related death, 2% died of congestive heart failure and other cardiac causes, and 9% died of noncardiac causes. Coronary artery bypass grafting (vs no coronary artery bypass grafting) was associated with a significantly lower risk of sudden cardiac death (relative risk, 0.60; P = .01) but was not significantly associated with any other causes of long-term mortality. CONCLUSIONS: In the Bypass Angioplasty Revascularization Investigation coronary artery bypass grafting significantly decreased the risk of sudden cardiac death but not any other cause of long-term mortality. Because major risk factors for sudden cardiac death have historically favored a revascularization strategy of coronary artery bypass grafting over angioplasty, evaluation of the current practice of extending angioplasty as an alternative to coronary artery bypass grafting in similar high-risk subgroups is paramount.

Sensitivity of routine intensive care unit surveillance for detecting myocardial ischemia.

OBJECTIVE: To assess the effectiveness of routine intensive care unit surveillance compared with frequent 12-lead electrocardiogram monitoring for detecting electrocardiogram evidence suggestive of prolonged myocardial ischemia in vascular surgery patients. DESIGN: Prospective cohort trial. SETTING: Intensive care unit. PARTICIPANTS: We studied 149 patients undergoing elective infrainguinal or aortic vascular surgery who were admitted to the intensive care unit postoperatively. INTERVENTIONS: Patients were simultaneously monitored with a 10-electrode/12-lead electrocardiogram obtained every 2 mins (criterion standard) and routine intensive care unit surveillance that included standard monitoring (five-electrode/two-lead electrocardiogram with ST segment trends and routine 12-lead electrocardiogram) and clinical assessment for detecting myocardial ischemia. The results of the criterion standard were not available to the caregivers. MEASUREMENTS AND MAIN RESULTS: We measured the ability of routine intensive care unit surveillance to detect the first 20 mins of electrocardiogram evidence suggestive of myocardial ischemia, defined as ST segment depression or elevation of >/=1 mm in two consecutive leads, during the first postoperative day. Seventeen patients (11%) had electrocardiogram evidence suggestive of prolonged myocardial ischemia, the majority of which occurred in leads V2-V4. The sensitivity of routine intensive care unit surveillance for detecting the first episode of electrocardiogram evidence suggestive of prolonged myocardial ischemia in a patient was 12% (95% confidence interval, 7-17%), and the specificity was 98% (95% confidence interval, 95-100%) with a positive predictive value of 40% (95% confidence interval, 32-48%), a negative predictive value of 90% (95% confidence interval, 85-94%), a positive likelihood ratio of 6, and a negative likelihood ratio of 1. The sensitivity of routine intensive care unit surveillance for detecting all episodes was 3% (95% confidence interval, 2-3%) and the specificity 99% (95% confidence interval, 99-100%) per 20-min monitoring interval, with a positive predictive value of 17% (95% confidence interval, 16-18%), negative predictive value of 95% (95% confidence interval, 95-96%), positive likelihood ratio of 3, and negative likelihood ratio of 1. CONCLUSIONS: Routine intensive care unit surveillance has low sensitivity for detecting electrocardiogram evidence suggestive of prolonged myocardial ischemia compared with frequent 12-lead electrocardiograms. Because detecting electrocardiogram evidence suggestive of prolonged postoperative myocardial ischemia is important, physicians should consider alternative strategies to detect myocardial ischemia.