Kathryn A. Britton

Ectopic fat depots and cardiovascular disease.

Obesity is increasingly recognized as a heterogeneous condition with variable cardiovascular risk in the setting of similar levels of body mass index. Ectopic fat depots may contribute to obesity-mediated vascular disease and explain part of this risk differential. This review will explore the current understanding of the biology of ectopic adipose tissue storage, its quantification and classification, and existing research supporting an association between ectopic fat and cardiovascular disease. Obesity is associated with significant cardiovascular morbidity and mortality, and is recognized as a major public health concern.1,2 Although useful clinically and in epidemiologic studies, the classification of obesity using body mass index (BMI) does not fully encompass the complex biology of excess adiposity. Excess body fat is now recognized as a heterogeneous condition in which individuals with similar levels of BMI may have distinct metabolic and cardiovascular disease risk.2 Variation in body fat distribution provides 1 potential explanation for some of the risk differential that persists after accounting for BMI and standard risk factors.3 The study of ectopic adipose tissue depots, which surround organs and blood vessels, focuses on the quantification of these different fat depots and their potential systemic and local consequences. Waist circumference was one of the earliest means of quantifying body fat distribution, and some clinical guidelines have recommended measurement of waist circumference to provide additional information regarding cardiovascular risk.4 However, waist circumference consists of both subcutaneous adipose (SAT) (classically nonectopic) and visceral adipose tissue (VAT) (classically ectopic). This is important because VAT is associated with more adverse levels of metabolic risk factors compared with SAT.5 In addition, seminal work in mice has shown that transplantation of SAT, but not VAT, to an intra-abdominal site resulted in beneficial effects on metabolism.6 Taken together, these findings suggest that information about …

Perivascular adipose tissue and vascular disease

Abstract Perivascular adipose tissue is a local deposit of adipose tissue surrounding the vasculature. Perivascular adipose tissue is present throughout the body and has been shown to have a lo al effect on blood vessels. The influence of perivascular adipose tissue on the vasculature changes with increasing adiposity. This article describes the anatomy and pathophysiology of p ivascular adipose tissue and the experimental evidence supporting its local adverse effect on the vasculature. Methods for quantifying perivascular adipose tissue in free-living populationswill be described. Finally, the epidemiological literature demonstrating an association between perivascular adipose tissue and cardiometabolic disease will be explored.

Normal systolic blood pressure and risk of heart failure in US male physicians

Heart failure (HF) is a major public health issue and hypertension is a major predictor of HF. Observational studies have demonstrated a continuous and graded relationship between ‘normal’ systolic blood pressure (SBP) and cardiovascular disease. However, limited data are available on the relationship between normotensive SBP and the risk of HF.

Prevalence, Distribution, and Risk Factor Correlates of High Thoracic Periaortic Fat in the Framingham Heart Study

Background Thoracic periaortic adipose tissue (TAT) is associated with atherosclerosis and cardiovascular disease (CVD) risk factors and may play a role in obesity‐mediated vascular disease. We sought to determine the prevalence, distribution, and risk factor correlates of high TAT. Methods and Results Participants from the Framingham Heart Study (n=3246, 48% women, mean age 51.1 years) underwent multidetector computed tomography; high TAT and visceral adipose tissue (VAT) were defined on the basis of sex‐specific 90th percentiles in a healthy referent sample. The prevalence of high TAT was 38.1% in women and 35.7% in men. Among individuals without high VAT, 10.1% had high TAT. After adjustment for age and VAT, both women and men with high TAT in the absence of high VAT were older and had a higher prevalence of CVD (P<0.0001) compared with those without high TAT. In addition, men in this group were more likely to be smokers (P=0.02), whereas women were more likely to have low high‐density lipoprotein cholesterol (P=0.005). Conclusions Individuals in our community‐based sample with high TAT in the absence of high VAT were characterized by an adverse cardiometabolic profile. This adipose tissue phenotype may identify a subset of individuals with distinct metabolic characteristics.

High-Molecular-Weight and Total Adiponectin Levels and Incident Symptomatic Peripheral Artery Disease in Women: A Prospective Investigation

Background— Adiponectin is linked to reduced diabetes risk and may be antiatherogenic, yet clinical data show no consistent relationship with incident cardiovascular events, especially among women. To our knowledge, no prior prospective studies have evaluated adiponectin, including high-molecular-weight (HMW) adiponectin, and incident peripheral artery disease (PAD). Methods and Results— We evaluated the relationship of total adiponectin, HMW adiponectin, and the HMW-to-total adiponectin ratio with incident symptomatic PAD in a prospective, nested case-control study conducted within the Womens Health Study (n=110 cases, n=230 controls, frequency matched in strata defined by 5-year age categories, smoking, fasting status, and follow-up time; median cohort follow-up=13.2 years). Baseline median levels of HMW and total adiponectin were significantly lower in women developing PAD than in those remaining event free (HMW: 3.3 versus 3.8 &mgr;g/mL, P=0.0005; total: 5.6 versus 7.4 &mgr;g/mL, P<0.0001). The ratio did not differ significantly between groups. Age-adjusted PAD odds ratios (95% confidence intervals) across tertiles were 1.0, 0.66 (0.39–1.13), and 0.40 (0.22–0.74) for HMW and 1.0, 0.74 (0.43–1.25), and 0.35 (0.18–0.65) for total adiponectin (Ptrend=0.004 and 0.001, respectively). Results were similar after adjustment for traditional cardiovascular risk factors, use of postmenopausal hormone therapy, high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, leptin, hemoglobin A1c, and fasting insulin (adjusted odds ratio and 95% confidence interval for HMW: 1.0, 0.62 [0.29–1.34], 0.30 [0.12–0.74]; total: 1.0, 0.46 [0.22–1.00], 0.30 [0.12–0.76]; Ptrend=0.01 for both). Conclusions— Total and HMW adiponectin are inversely associated with incident PAD among initially healthy women. These prospective data support a protective role for this adipokine in peripheral atherosclerosis development.

Thoracic Periaortic and Visceral Adipose Tissue and Their Cross-sectional Associations with Measures of Vascular Function

Objective: Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) were associated with vascular function.

Metabolic syndrome and risk of incident peripheral artery disease: the cardiovascular health study.

Prior studies evaluating metabolic syndrome (MetS) and incident peripheral artery disease (PAD) have been limited by use of modified MetS criteria and restriction to clinical PAD end points. We investigated MetS and risk of developing a low ankle-brachial index (ABI) and clinical PAD in the Cardiovascular Health Study, a population-based cohort of adults aged ≥65 years. Participants with MetS met at least 3 of 5 Adult Treatment Panel III criteria. Baseline C-reactive protein-MetS or fibrinogen-MetS were defined as presence of 3 of 6 components, with elevated C-reactive protein (>3 mg/L) or fibrinogen (>341 mg/dL) as a sixth component. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15, was assessed among a subset of 1899 individuals with 2 ABI measurements 6 years apart. Over a median follow-up of 13.7 years, 4632 individuals were followed up for clinical PAD, defined as revascularization or diagnosed claudication. Adult Treatment Panel III MetS was associated with both incident low ABI (risk ratio, 1.26; 95% confidence interval [CI], 1.00–1.58) and clinical PAD (hazard ratio, 1.47; 95% CI, 1.11–1.94). Incorporating C-reactive protein or fibrinogen into Adult Treatment Panel III criteria identified an additional 16% to 20% of individuals as having MetS, and both C-reactive protein-MetS and fibrinogen-MetS were associated with incident low ABI (risk ratio, 1.36; 95% CI, 1.07–1.72 and risk ratio, 1.43; 95% CI, 1.13–1.81, respectively) and clinical PAD (hazard ratio, 1.56; 95% CI, 1.17–2.08 and hazard ratio, 1.55; 95% CI, 1.17–2.07, respectively). Among Adult Treatment Panel III MetS criteria, risk of PAD was most strongly associated with hypertension.

No Association between Hemoglobin A1c and In-Hospital Mortality in Patients with Diabetes and Acute Myocardial Infarction

BACKGROUND Patients with diabetes have increased in-hospital mortality following acute myocardial infarction (AMI), with studies suggesting higher risk with both hypoglycemia and hyperglycemia. We assessed whether a J-shaped relation exists between hemoglobin A1c (A1C) in patients with diabetes and AMI. METHODS We assessed the associations between A1C and in-hospital mortality using data from a nationwide sample of AMI patients who had both prior diabetes and measurement of A1C (N = 15,337). RESULTS When evaluated continuously, we observed no evidence of a J-shaped relation between A1C and in-hospital mortality in multivariable analysis (test for linearity P = .89). Patients with lowest (<5.5%) and highest A1C (≥9.5%) had a crude mortality rate of 4.6% and 2.8%, respectively, compared with 3.8% among those in the referent A1C category (6.5% to <7%). In multivariable regression, we observed no association between low A1C (<5.5%, odds ratio 0.81, 95% CI 0.47-1.39) or high A1C (A1C ≥9.5, odds ratio 1.31, 95% CI 0.94-1.83) and mortality as compared with the referent group. These findings can only be generalized to the subset of patients with diabetes who had A1C assessed during their hospitalization; these patients tended to be healthier than those in whom A1C was not assessed. CONCLUSION In this large contemporary cohort of patients with diabetes presenting with AMI, we did not observe a J-shaped association between A1C and mortality.

Insulin Resistance and Incident Peripheral Artery Disease in the Cardiovascular Health Study

Type 2 diabetes is a risk factor for peripheral artery disease (PAD), and insulin resistance is a key feature of diabetes and pre-diabetes. No longitudinal epidemiological study has examined the relation between insulin resistance and PAD. Our study analyzed the association of quartiles of the homeostatic model of insulin resistance (HOMA-IR) and the development of PAD defined by two methods. PAD was first defined as the development of an abnormal ankle–brachial index (ABI) (dichotomous outcome) after 6 years of follow-up. PAD was alternatively defined as the development of clinical PAD (time-to-event analysis). The study samples included adults over the age of 65 years who were enrolled in the Cardiovascular Health Study, had fasting measurements of insulin and glucose, had ABI measurements, and were not receiving treatment for diabetes. Multivariable models were adjusted for potential confounders, including age, sex, field center and cohort, body mass index (BMI), smoking status, alcohol use, and exercise intensity. Additional models adjusted for potential mediators, including blood pressure, lipids, kidney function, and prevalent vascular disease. In the ABI analysis (n = 2108), multivariable adjusted models demonstrated a positive relation between HOMA-IR and incident PAD (odds ratio = 1.80 comparing the 4th versus 1st quartile of HOMA-IR, 95% confidence interval [CI] 1.20–2.71). In the clinical PAD analysis (n = 4208), we found a similar relation (hazard ratio = 2.30 comparing the 4th versus 1st quartile of HOMA-IR, 95% CI 1.15–4.58). As expected, further adjustment for potential mediators led to some attenuation of effect estimates. In conclusion, insulin resistance is associated with a higher risk of PAD in older adults.

Physical activity and the risk of becoming overweight or obese in middle aged and older women

Although public health campaigns stress leisure time physical activity (LTPA) as essential for obesity prevention, few epidemiological studies have focused on the association of specific types and intensities of LTPA and the clinical endpoints of overweight and obesity. Therefore, we prospectively assessed whether moderate‐ and vigorous‐intensity as well as total LTPA were associated with the risk of becoming either overweight or obese using a prospective cohort design of 19,003 women enrolled in the Womens Health Study (WHS). Women reported their participation in walking and LTPA at baseline. During a median follow‐up of 11.6 years, 7,865 women became overweight or obese. In multivariable‐adjusted models that included demographic, lifestyle, and dietary factors, both vigorous‐intensity and total LTPA showed a modest inverse relationship with the development of overweight/obesity. The hazard ratios (HR) and 95% confidence interval (CI) for the highest categories of vigorous‐intensity LTPA (>2,000 kcal/week) and total LTPA (>3,000 kcal/week) compared with no LTPA were 0.79 (0.71–0.89) and 0.87 (0.78–0.96), respectively. In addition, a greater percentage of total LTPA spent performing vigorous intensity activities was associated with a lower risk of overweight/obesity (multivariable HR 0.93, 95% CI 0.87–0.98 for performing >50% compared with <50% of activity as vigorous). In conclusion, higher amounts of total LTPA should be encouraged to prevent obesity. Among those willing to participate in vigorous LTPA, and for whom such activities are not contraindicated, vigorous LPTA should be encouraged.