Peter W.F. Wilson

Metabolic Syndrome as a Precursor of Cardiovascular Disease and Type 2 Diabetes Mellitus

Background— The incidence of cardiovascular disease (CVD), coronary heart disease (CHD), and type 2 diabetes mellitus (T2DM) has not been well defined in persons with the metabolic syndrome (at least 3 of the following: abdominal adiposity, low HDL cholesterol, high triglycerides, hypertension, and impaired fasting glucose). The objective was to investigate risk for CVD, CHD, and T2DM according to metabolic syndrome traits. Methods and Results— The study followed a cohort of 3323 middle-aged adults for the development of new CVD, CHD, and T2DM over an 8-year period. In persons without CVD or T2DM at baseline, the prevalence of the metabolic syndrome (≥3 of 5 traits) was 26.8% in men and 16.6% in women. There were 174 incident cases of CVD, 107 of CHD, and 178 of T2DM. In men, the metabolic syndrome age-adjusted relative risk (RR) and 95% CIs were RR=2.88 (95% CI 1.99 to 4.16) for CVD, RR=2.54 (95% CI 1.62 to 3.98) for CHD, and RR=6.92 (95% CI 4.47 to 10.81) for T2DM. Event rates and RRs were lower in women for CVD (RR=2.25, 95% CI 1.31 to 3.88) and CHD (RR=1.54, 95% CI 0.68 to 3.53), but they were similar for T2DM (RR=6.90, 95% CI 4.34 to 10.94). Population-attributable risk estimates associated with metabolic syndrome for CVD, CHD, and T2DM were 34%, 29%, and 62% in men and 16%, 8%, 47% in women. Conclusions— Metabolic syndrome is common and is associated with an increased risk for CVD and T2DM in both sexes. The metabolic syndrome accounts for up to one third of CVD in men and approximately half of new T2DM over 8 years of follow-up.

Should C-Reactive Protein Be Added to Metabolic Syndrome and to Assessment of Global Cardiovascular Risk?

Of novel risk factors for cardiovascular disease currently under investigation, high-sensitivity C-reactive protein (hsCRP) is the most promising. To date, more than 20 prospective epidemiologic studies have demonstrated that hsCRP independently predicts vascular risk, 6 cohort studies have confirmed that hsCRP evaluation adds prognostic information beyond that available from the Framingham Risk Score, and 8 cohort studies have demonstrated additive prognostic value at all levels of metabolic syndrome or in the prediction of type 2 diabetes. In contrast to several other biomarkers that also reflect biological aspects of inflammation, hypofibrinolysis, and insulin resistance, hsCRP measurement is inexpensive, standardized, widely available, and has a decade-to-decade variation similar to that of cholesterol. Given the consistency of prognostic data for hsCRP and the practicality of its use in outpatient clinical settings, we believe the time has come for a careful consideration of adding hsCRP as a clinical criterion for metabolic syndrome and for the creation of an hsCRP-modified coronary risk score useful for global risk prediction in both men and women. Toward this end, we believe experts in the fields of epidemiology, prevention, vascular biology, and clinical cardiology should be convened to begin discussing the merits of this proposal.

New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study

The purpose of the present study was to assess the location, severity and progression of radiopaque lumbar aortic calcifications and to evaluate the utility of summary scores of lumbar calcification in a population-based cohort. Lateral lumbar films, obtained in 617 Framingham heart study participants, were analysed for the presence of abdominal aortic wall calcification in the region corresponding to the first through fourth lumbar vertebrae. The severity of the anterior and posterior aortic calcification were graded individually on a 0-3 scale for each lumbar segment and the results were summarized to develop four different composite scores: (1) affected segments score (range 0-4); (2) anterior and posterior affected score (range 0-8); and (3) antero-posterior severity score (range 0-24). The prevalence of aortic calcification was 37% in men and 27% in women at baseline and 86% in both genders at the follow-up exam 25 years later. During the follow-up interval, the mean of the affected segments score increased from 0.7 in men (0.5 in women) to 2.7 (2.8 in women), the mean of the anterior and posterior affected score from 1.2 (0.8 in women) (P = 0.012 for difference between genders) and the mean of the antero-posterior severity score increased from 1.5 (1.3 in women) to 9.3 (10.3 in women). The antero-posterior severity score offered a slight advantage over other composite scores and had the highest inter-rater intra-class correlations. In summary, lumbar aortic calcification can be graded and composite summary scores are reproducible. This technique appears to provide a simple, low cost assessment of subclinical vascular disease.

Association Between Increased Estrogen Status and Increased Fibrinolytic Potential in the Framingham Offspring Study

BACKGROUND Although extensive evidence indicates that estrogen is responsible for the markedly decreased cardiovascular risk of premenopausal women, the mechanism through which estrogen might exert its protective effect has not been adequately explained. Since thrombosis is now recognized to play an important role in the onset of cardiovascular disease, we investigated the relation between estrogen status and fibrinolytic potential, a determinant of thrombotic risk. METHODS AND RESULTS We determined levels of plasminogen activator inhibitor (PAI-1) antigen and tissue plasminogen activator (TPA) antigen in 1431 subjects from the Framingham Offspring Study. Fibrinolytic potential was compared between subjects with high estrogen status (premenopausal women and postmenopausal women receiving hormone replacement therapy) and low estrogen status (men and postmenopausal women not receiving hormone replacement therapy). In all comparisons, subjects with high estrogen status had greater fibrinolytic potential (lower PAI-1 levels) than subjects with low estrogen status. First, postmenopausal women receiving estrogen replacement therapy had lower levels of PAI-1 than those not receiving therapy (13.0 +/- 0.5 versus 19.5 +/- 1.0 ng/mL, P < .001). Second, premenopausal women had lower levels of PAI-1 than men of a similar age (14.8 +/- 0.6 versus 20.3 +/- 0.8 ng/mL, P < .001); this sex difference diminished when postmenopausal women not receiving hormone replacement therapy were compared with men of a similar age (19.6 +/- 0.7 versus 21.1 +/- 0.7 ng/mL, P = .089). Third, premenopausal women had markedly lower levels of PAI-1 antigen than postmenopausal women not receiving estrogen therapy (14.8 +/- 0.6 versus 19.5 +/- 1.0 ng/mL, P < .001). The between-group differences observed for TPA antigen were similar to those for PAI-1 antigen. CONCLUSIONS Each of these comparisons indicates that the cardioprotective effect of estrogen may be mediated, in part, by an increase in fibrinolytic potential. These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.

Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study

Osteoporosis is not a problem confined to women; it has important medical and socioeconomic consequences for men as well (1-3). With advancing age, men lose bone mineral density (4, 5), which leads to increased risk for fracture after minimal trauma (6). It is estimated that 13% of white men older than 50 years of age will experience a fracture during their lifetime (7). Approximately 30% of all hip fractures occur in men (8), and the morbidity and mortality after such fractures are much greater in men than in women (9-11). As the aging population grows worldwide, a better understanding of risk factors that contribute to low bone mineral density in elderly men will be needed. The effect of sex hormones on bone mineral density in elderly men is of particular interest because it could have diagnostic and therapeutic implications, as it does in women (12, 13). Both androgens and estrogens have been shown to be important for bone health in young men, but their role in elderly men is not as clear (14, 15). Testosterone, the predominant circulating androgen in men, is produced mainly by Leydig cells of the testes and is regulated by luteinizing hormone (16, 17). Hypogonadism in men, whether caused by primary or secondary failure of Leydig cell function, results in low testosterone levels. Young adult men who are hypogonadal because of medical conditions or castration have low bone mineral density (18-20); testosterone replacement improves bone mineral density in these men (19, 21). Given the association between hypogonadism and bone mineral density in young men and the decrease in serum testosterone levels with increasing age (22, 23), it has been assumed that hypogonadism related to aging explains low bone mineral density in elderly men. However, evidence to support this association remains weak. Results of studies that include men of a wide age range or hypogonadal men with an identifiable medical cause (such as orchiectomy or pituitary tumors) are not generalizable to elderly men from the general population. Among studies specifically of elderly men from the general population, several failed to show an association between testosterone levels and bone mineral density (24-28). It could be that an association with bone mineral density exists only below the normal reference range for testosterone (29) and that continuous measurement of testosterone levels, as was done in most studies, missed this relation. Previous studies may have also been limited by the fact that single measurements of sex hormones obtained at the same time as bone mineral density measurement may not adequately reflect the influence of these hormones on bone metabolism. Recent evidence suggests that estrogens may also be important for bone health in young and older men (14, 27, 28, 30-36). However, the magnitude of effect of estrogen levels on bone mineral density in elderly men is not known, nor is the relative effect of testosterone and estrogens clearly defined. Only a small fraction of estradiol, the major circulating form of estrogen, is produced directly by the testes; the main source is peripheral conversion of testosterone and adrenal sex steroids by the aromatase enzyme (17, 37). Thus, some or all of the effect of low testosterone on bone mineral density in elderly men could be explained by low estradiol levels. We examined the association of testosterone and estradiol status with bone mineral density among men from the Framingham Study, a population-based cohort with a large number of elderly men who had repeated measurement of sex hormones before bone mineral density assessment. We explored the association of a threshold effect of low testosterone level on bone mineral density in these men by considering different definitions of hypogonadism based on sex hormone measures. Methods The Framingham Study began in 1948 in Framingham, Massachusetts, with the initial goal of evaluating risk factors for heart disease in a population-based cohort (38). As part of this ongoing study, participants have received comprehensive medical examinations every 2 years. The Framingham Osteoporosis Study, designed to study risk factors for osteoporosis, started in 19881989 as a component of the 20th biennial examination and involved surviving members of the cohort, most of whom were white (39). We studied the 448 men of the cohort who had bone mineral density measurements in 19881989 and sex hormones measurements during previous biennial examinations. Assessment of Sex Hormones Total testosterone, total estradiol, and luteinizing hormone were measured in all male participants at four consecutive biennial examinations from 1981 to 1989. Serum samples were measured by using radioimmunoassay for total testosterone (Diagnostic Products Corp., Los Angeles, California; interassay coefficient of variation, 11%; reference range for young adult men, 10 to 35 nmol/L [3 to 10 ng/mL]), total estradiol (Diagnostic Products Corp.; lower limit of assay detection, 2 pg/mL; interassay coefficient of variation, 4%; reference range for young adult men, 7 to 184 pmol/L [2 to 50 pg/mL]), and luteinizing hormone (Serono Laboratories, Randolph, Massachusetts, in 1981 to 1983, then Diagnostic Products Corp. for the three biennial examinations from 1983 to 1989; intraclass correlation, 0.92; interassay coefficient of variation, 6%; reference range for young adult men, 3 to 13 IU/L). Data were originally collected in traditional units, and cutoff values were defined on the basis of these units. Conversions to SI units were performed in accordance with the publication policy of Annals of Internal Medicine. Assessment of Bone Mineral Density In 19881989, bone mineral density was measured at the proximal femur (femoral neck, Ward triangle, and trochanter) and lumbar spine by using dual-photon absorptiometry (LUNAR DP3, Lunar Corp., Madison, Wisconsin) and at the radial shaft (measured at the junction of the proximal two thirds and the distal one third of the radius) by using single-photon absorptiometry (LUNAR SP2, Lunar Corp.) (39). If participants had a history of fracture or hip joint replacement, the contralateral side was scanned. Because the lumbar spine was assessed during a callback examination, the number of participants for whom this measurement was available is smaller than that for the proximal femur or radial shaft. All bone mineral density scans were reviewed to ensure that correct placement and analysis were performed according to the manufacturers recommendations. Scans for which placement was incorrect, those that did not include the complete anatomic region of interest, and those found to include metal or other attenuating material were considered technically inadequate and were deleted. The coefficients of variation in normal persons for bone mineral density at the proximal femur were 2.6% for the femoral neck, 4.1% for Ward triangle, and 2.8% for the trochanter; the coefficients of variation were 2.2% and 2.0% for the lumbar spine and radial shaft, respectively. Assessment of Other Covariates Factors previously shown to be associated with bone mineral density in men were also assessed (15, 39-46). These variables were age, body mass index, serum 25-hydroxyvitamin D level, calcium intake, physical activity, cigarette smoking, alcohol intake, thiazide diuretic use, and glucocorticoid use. Age, body mass index, serum 25-hydroxyvitamin D, calcium intake, and physical activity were determined in 19881989 at the time of the bone mineral density assessment. Serum 25-hydroxyvitamin D was measured by using a competitive binding-protein assay (47) (interassay coefficient of variation, 10%) and was categorized as low (<50 nmol/L), medium (50 to 75 nmol/L), or high (>75 nmol/L). Information on dietary calcium intake, including supplements, was collected by using the Willett 126-item food frequency questionnaire (48, 49) and was categorized as low (<500 mg/d), moderate (500 to 1000 mg/d), or high (>1000 mg/d). Physical activity was assessed by using the Framingham Physical Activity Index, a weighted 24-hour score of typical daily activity based on hours spent performing heavy, moderate, light, or sedentary activity (50, 51). Information on smoking and alcohol intake was available from previous biennial examinations. Participants were characterized as current smokers if they smoked cigarettes during 1981 to 1989, former smokers if they reported smoking before 1981 but not between 1981 and 1989, and never-smokers if they reported no cigarette use since inception of the study in 1948. Alcohol intake was defined according to the average ounces of alcohol consumed per week between 1981 and 1989. Information on thiazide diuretic use among participants was available from three consecutive examinations from 1983 to 1989, and information on glucocorticoid use was available from all four examinations from 1981 to 1989. Statistical Analysis To examine the association between sex hormone status and bone mineral density, we averaged hormone values for each participant if measurements were available from at least three of four examinations from 1981 to 1989. We excluded one participant whose serum estradiol value was considered unreliable. All analyses were performed by using SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Gonadal Status and Bone Mineral Density Hypogonadism in men is the loss of testicular function, which includes primary and secondary failure of the Leydig cell function in the testes, leading to a deficiency in serum testosterone levels. Studying hypogonadal elderly men from the general population is difficult, however, because there are no standard definitions of hypogonadism, and symptoms and signs are not well correlated with hormonal status (52, 53). Therefore, to examine whether hypogonadism was associated with low bone mineral density in our population-based sample of elderly men, we created a definition based on the mean total testosterone o

Task force #1—identification of coronary heart disease risk: is there a detection gap?

In contrast to the relative ease of recognition and clarity of treatment and prevention strategies in patients with symptomatic coronary heart disease (CHD), a major problem of detection, treatment, and prevention of CHD exists in the large population who have no symptoms of heart disease yet are at

BMI vs. waist circumference for identifying vascular risk.

Objective: Current guidelines recommend measurement of both BMI and waist circumference (WC) in individuals with BMI between 25.0 and 34.9 kg/m2. We investigated the relative contributions of BMI and WC toward identifying risk of adverse vascular events in a community‐based sample.

Epidemiology of Hyperglycemia and Atherosclerosis

For three decades in the United States there has been a major decline in atherosclerotic cardiovascular mortality. It is clear, however, that control or prevention of diabetes has not contributed significantly to this decline since the National Health and Nutrition Examination Survey (NHANES) indicates a continued high prevalence of diabetes, largely undetected, among the general population (2). Despite improved diagnostic methods and better treatment, physicians continue to encounter a high rate of atherosclerotic cardiovascular sequelae in their diabetic patients.

Connective tissue growth factor and susceptibility to renal and vascular disease risk in type 1 diabetes.

OBJECTIVE We explored the relevance and significance of connective tissue growth factor (CTGF) as a determinant of renal and vascular complications among type 1 diabetic patients. METHODS AND RESULTS We measured the circulating and urinary levels of CTGF and CTGF N fragment in 1050 subjects with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study cohort. We found that hypertensive diabetic subjects have significantly higher levels of plasma log CTGF N fragment relative to normotensive subjects (P = 0.0005). Multiple regression analysis showed a positive and independent association between CTGF N fragment levels and log albumin excretion rate (P < 0.0001). In categorical analysis, patients with macroalbuminuria had higher levels of CTGF N fragment than diabetic subjects with or without microalbuminuria (P < 0.0001). Univariate and multiple regression analyses demonstrated an independent and significant association of log CTGF N fragment with the common and internal carotid intima-media thickness. The relative risk for increased carotid intima-media thickness was higher in patients with concomitantly elevated plasma CTGF N fragment and macroalbuminuria relative to patients with normal plasma CTGF N fragment and normal albuminuria (relative risk = 4.76; 95% confidence interval, 2.21-10.25; P < 0.0001). CONCLUSION These findings demonstrate that plasma CTGF is a risk marker of diabetic renal and vascular disease.

Magnesium intake is related to improved insulin homeostasis in the framingham offspring cohort

Objective: Higher dietary intake of magnesium may protect against development of type 2 diabetes. The aim of this study was to examine the association between dietary magnesium intake and metabolic risk factors for diabetes. Methods: We examined cross-sectional associations between magnesium intake and fasting glucose and insulin, 2-hour post-challenge plasma glucose and insulin, and insulin resistance assessed by the homeostasis model (HOMA-IR) in 1223 men and 1485 women without diabetes from the Framingham Offspring cohort. Magnesium intake was assessed by a food frequency questionnaire and magnesium intake was categorized into quintile categories. Geometric mean insulin, glucose, 2-hour post challenge plasma glucose and insulin concentrations and HOMA-IR were estimated across quintile categories of magnesium intake using Generalized Linear Models. Results: After adjustment for potential confounding factors, magnesium intake was inversely associated with fasting insulin (mean: 29.9 vs 26.7 μU/mL in the lowest vs highest quintiles of magnesium intake; P trend <0.001), post-glucose challenge plasma insulin (86.4 vs 72 μU/mL; P trend <0.001), and HOMA-IR (7.0 vs 6.2; P trend <0.001). No significant association was found between magnesium intake and fasting glucose or 2-hour post challenge glucose. Conclusions: Improved insulin sensitivity may be one mechanism by which higher dietary magnesium intake may reduce the risk of developing type 2 DM.