Plasminogen activator inhibitor-1 and the risk of Type 2 diabetes mellitus in American Indians: the Strong Heart Study.
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Diabetes Mellitus, Type 2↗
Biomedical subjects
R P Tracy
Publications and source records attributed to R P Tracy.
Soluble intracellular adhesion molecule-1 is associated with cardiovascular disease risk and mortality in older adults.
BACKGROUND: Intracellular adhesion molecule-1 (ICAM-1) regulates leukocyte-endothelial attachment, a process crucial to atherosclerosis. Circulating soluble ICAM-1 (sICAM-1) may serve as a marker of cardiovascular disease (CVD) progression. OBJECTIVES: We examined the association of sICAM-1 with measures of subclinical CVD and risk of incident CVD events and death in older men and women (age > or = 65 years) from the Cardiovascular Health Study. METHODS: Selected participants were free of clinical CVD at baseline. Non-exclusive incident case groups were angina (n = 534), myocardial infarction (n = 304), stroke (n = 327), and death (n = 842; CVD death = 310). A total 643 subjects were free of events during follow-up. RESULTS: sICAM-1 was positively associated with C-reactive protein, interleukin-6 and fibrinogen and measures of subclinical CVD in these older men and women. In Cox regression models adjusted for age, gender, and race, increasing levels of sICAM-1 were associated with increased risk of all cause mortality in men and women. Hazard ratios (95% confidence intervals) for a one standard deviation increase in sICAM-1 (89.7 ng mL(-1)) were 1.3 (1.1-1.4) in men and 1.2 (1.1-1.3) in women. sICAM-1 was associated with increased risk of CVD death in women (1.2; 1.0-1.5), but not men (1.1; 0.9-1.3). There were no associations of sICAM-1 with non-fatal CVD events. CONCLUSIONS: While sICAM-1 was associated with death in older men and women, there was a more marked association between sICAM-1 and CVD death in women.
Aged↗
Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
BACKGROUND: Previous genotype-phenotype association studies of fibrinogen have been limited by incomplete knowledge of genomic sequence variation within and between major ethnic groups in FGB, FGA, and FGG. METHODS: We characterized the linkage disequilibrium patterns and haplotype structure across the human fibrinogen gene locus in European- and African-American populations. We analyzed the association between common polymorphisms in the fibrinogen genes and circulating levels of both 'functional' fibrinogen (measured by the Clauss clotting rate method) and total fibrinogen (measured by immunonephelometry) in a large, multi-center, bi-racial cohort of young US adults. RESULTS: A common haplotype tagged by the A minor allele of the well-studied FGB-455 G/A promoter polymorphism (FGB 1437) was confirmed to be strongly associated with increased plasma fibrinogen levels. Two non-coding variants specific to African-American chromosomes, FGA 3845 A and FGG 5729 G, were each associated with lower plasma fibrinogen levels. In European-Americans, a common haplotype tagged by FGA Thr312Ala and several other variant alleles across the fibrinogen gene locus was strongly associated with decreased fibrinogen levels as measured by functional assay, but not by immunoassay. Overall, common polymorphisms within the three fibrinogen genes explain < 2% of the variability in plasma fibrinogen concentration. CONCLUSIONS: In young adults, fibrinogen multi-locus genotypes are associated with plasma fibrinogen levels. The specific single nucleotide polymorphism and haplotype patterns for these associations differ according to population and also according to phenotypic assay. It is likely that a substantial proportion of the heritable component of plasma fibrinogen concentration is due to genetic variation outside the three fibrinogen genes.
Adolescent↗
Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.
CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.
Adult↗
The prospective association between adiponectin and coronary artery disease among individuals with type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study.
AIMS/HYPOTHESIS: Recent findings suggest the potential involvement of adiponectin in obesity, diabetes and cardiovascular disease. We assessed the prospective association between adiponectin concentration and coronary artery disease in individuals with type 1 diabetes. METHODS: Participants were identified from the Pittsburgh Epidemiology of Diabetes Complications cohort, a prospective follow-up study of childhood-onset type 1 diabetes. At baseline, subjects had a mean age of 28 years, and a mean diabetes duration of 19 years. Cases (determined by physician-diagnosed angina, confirmed myocardial infraction, stenosis >or=50%, ischemic ECG or revascularization) were matched to the control subjects with respect to sex, age and diabetes duration. Samples and risk factors for analyses were identified from the earliest exam prior to incidence in cases. Sera and information on all covariates were available for 28 cases and 34 control subjects. Proportional hazards models were constructed including matching variables. RESULTS: Compared with those in men, adiponectin concentrations were elevated in females (p=0.009) and among individuals with macroalbuminuria (p=0.04). In multivariable analyses (adjusting for standard risk factors as well as lipoprotein measurements determined by nuclear magnetic resonance spectroscopy, E-selectin or antioxidants), adiponectin inversely predicted the incidence of coronary artery disease (hazard ratio=0.37 per 1 SD increase, 95% CI 0.19-0.73, p=0.004). CONCLUSIONS/INTERPRETATION: The results suggest that increased adiponectin concentration is prospectively associated with a lower risk of coronary artery disease type 1 diabetes. The potential of adiponectin determination as a useful marker of, and potential therapeutic target for, coronary artery disease prevention in type 1 diabetes should be further explored.
Adiponectin↗
Respiratory muscle strength and the risk of incident cardiovascular events.
BACKGROUND: Maximal inspiratory pressure (MIP) is a measure of inspiratory muscle strength. The prognostic importance of MIP for cardiovascular events among elderly community dwelling individuals is unknown. Diminished forced vital capacity (FVC) is a risk factor for cardiovascular events which remains largely unexplained. METHODS: MIP was measured at the baseline examination of the Cardiovascular Health Study. Participants had to be free of prevalent congestive heart failure (CHF), myocardial infarction (MI), and stroke. RESULTS: Subjects in the lowest quintile of MIP had a 1.5-fold increased risk of MI (HR 1.48, 95% CI 1.07 to 2.06) and cardiovascular disease (CVD) death (HR 1.54, 95% CI 1.09 to 2.15) after adjustment for non-pulmonary function covariates. There was a potential inverse relationship with stroke (HR 1.36, 95% CI 0.97 to 1.90), but there was little evidence of an association between MIP and CHF (HR 1.22, 95% CI 0.93 to 1.60). The addition of FVC to models attenuated the HR associated with MIP only modestly; similarly, addition of MIP attenuated the HR associated with FVC only modestly. CONCLUSIONS: A reduced MIP is an independent risk factor for MI and CVD death, and a suggestion of an increased risk for stroke. This association with MIP appeared to be mediated through mechanisms other than inflammation.
Cardiovascular Diseases↗
Emerging relationships of inflammation, cardiovascular disease and chronic diseases of aging.
The last 10 y have seen an enormous surge in research focused on inflammation and atherosclerotic heart disease. In parallel, inflammation (used as a term to represent a broad array of response systems) has become a topic of interest in a number of different areas of chronic disease including type II diabetes, cognitive decline and frailty, among others. These discoveries are opening up many new opportunities for risk assessment. For example, markers of inflammation such as C-reactive protein are becoming established as important additions in helping to define those at the greatest risk of progressive vascular disease. These discoveries are also important in the area of risk management. Older medications now in wide use are being found to have previously unknown anti-inflammatory effects (eg, statins); these effects are now viewed as being important to the overall effectiveness of these compounds. In addition, the many different aspects of inflammation provide a wealth of targets for new therapeutics, which will be increasingly important as the population continues to age. Although daunting in complexity, studies on the relation of inflammation to disease have already proven useful, and hold promise for providing fundamental advances in both basic biology and clinical medicine.
Aged↗
Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly.
Elevated circulating plasminogen activator inhibitor-1 (PAI-1) may increase risk of cardiovascular disease (CVD). The 4G allele of the 4G/5G PAI-1 promoter polymorphism is associated with higher levels of PAI-1. We examined the association of PAI-1 4G/5G genotype and CVD events in the elderly participants of the Cardiovascular Health Study (CHS). We measured 4G/5G genotype in a nested case-control study within the CHS. Cases included incident angina, myocardial infarction (MI), and stroke. 4G/5G genotype was not found to be associated with markers of fibrinolysis or CVD risk in the selected elderly cohort. There were no differences in genotype frequencies by case-control status (5G/5G frequency 16-22%; chi2P= 0.07). The 5G allele was not associated with incident CVD events when individuals with at least one 5G allele were compared to 4G/4G homozygotes. The presence of at least one 4G allele was likewise not associated with incident CVD when those with 4G/4G and 4G/5G genotypes were compared to 5G/5G homozygotes. Our results suggest that the PAI-1 4G/5G promoter polymorphism is not associated CVD risk factors or incident CVD events in the elderly.
Aged↗
C-reactive protein is more strongly related to post-glucose load glucose than to fasting glucose in non-diabetic subjects; the Insulin Resistance Atherosclerosis Study.
AIMS: It has been suggested that cardiovascular disease may be more strongly related to post-challenge glycaemia than to fasting glucose concentrations. We hypothesized that subclinical inflammation, as indicated by elevated serum levels of C-reactive protein (CRP), may partially explain the association of cardiovascular disease with post-challenge glycaemia. METHODS: We studied the relationship of CRP (measured with a highly sensitive immunoassay) with fasting glucose and 2-h glucose concentrations during an oral glucose tolerance test in non-diabetic subjects from the Insulin Resistance Atherosclerosis Study. RESULTS: Spearman correlation analyses and multiple linear regression analyses showed a significant association of both fasting glucose and 2-h glucose concentrations with CRP levels, after adjusting for demographic covariates (age, sex, ethnicity, clinical centre; Spearman correlation coefficients: r = 0.18 for fasting glucose, r = 0.27 for 2-h glucose, both P < 0.0001). However, after additional adjustment for body mass index and waist-hip ratio only 2-h glucose (and not fasting glucose) was significantly related to CRP (r = 0.03 for fasting glucose, P = NS; r = 0.14 for 2-h glucose, P < 0.0001). Adding insulin sensitivity to the multivariate models further weakened the relationship of CRP to 2-h glucose (r = 0.07, P < 0.05). CRP mean values increased by 2-h glucose category (normal vs. impaired glucose tolerance vs. isolated post-challenge hyperglycaemia). CONCLUSIONS: Chronic, subclinical inflammation, as indicated by elevated circulating CRP levels, is more strongly associated with post-challenge glycaemia than with fasting glucose levels in non-diabetic subjects. This association is partially independent of body fat and insulin resistance.
Adipose Tissue↗
Is type 2 diabetes a chronic inflammatory/autoimmune disease?
The classification of diabetes mellitus into 2 main types, defined as Type 1 and 2 diabetes (T1DM, T2DM) relies mostly on the requirement of insulin therapy and on the presence of detectable immunologic abnormalities. However, this distinction is far from straightforward and there is considerable overlap between these 2 types of diabetes. Islet cell autoimmunity, which is characteristic of T1DM, appears in fact to be present in up to 10-15% of subjects diagnosed clinically with T2DM. In the UK Prospective Diabetes Study (UKPDS), it was reported that in patients diagnosed with in T2DM, the presence of autoantibodies to the enzyme glutamic acid decarboxylase (GAD) and cytoplasmic islet cell antibodies (ICA) were a predictor of insulin requirement as compared with patients not carrying these autoantibodies. These results are strikingly similar to a number of prospective studies carried out in childhood diabetes. If islet cell autoimmunity is truly present in 10-15% of subjects clinically diagnosed with T2DM, up to two million Americans might have an unidentified autoimmune form of T2DM, a prevalence similar to that of recent onset childhood diabetes. In addition, we found that in a subset of T2DM patients, a pronounced activation of the acute phase response that seems to be associated with islet cell autoimmunity. These results may in part explain the defect in insulin secretion as well as insulin resistance seen in T2DM. The identification of a subgroup of individuals at risk of developing T2DM using autoantibody as well as inflammatory markers is of public health interest, not only for the correct classification of diabetes, but also because immunomodulatory therapeutic strategies could potentially be instituted sufficiently early in a large number of patients diagnosed as having T2DM and most likely delay the onset of insulin requirement and the complications related with hyperglycemia.
Acute-Phase Reaction↗
Role of tumor necrosis factor-alpha and interleukin-6 in the effects of hormone replacement therapy and raloxifene on C-reactive protein in postmenopausal women.
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Analysis of Variance↗
Association of C-reactive protein with markers of prevalent atherosclerotic disease.
Recent prospective studies have demonstrated that elevated C-reactive protein (CRP) is a marker of increased risk of atherothrombotic clinical events. We examined in a large, cross-sectional family-based study (n = 875 men, 948 women) whether serum CRP was associated with prevalent coronary heart disease (CHD), the ankle/brachial blood pressure index, or carotid intima-media thickness, an indicator of subclinical atherosclerosis as assessed by B-mode ultrasound. CRP was associated with many other cardiovascular risk factors, particularly markers of obesity and insulin resistance, markers of inflammation and acute phase reaction, and hormone replacement therapy. Adjusted for age and family type, there was a weak positive association of CRP with carotid intima-media thickness in both genders and with prevalent CHD in women. However, adjustment for other risk factors completely eliminated the associations. For example, among women, the risk factor-adjusted mean values of intima-media thickness across quartiles of CRP were 0.76, 0.74, 0.75, and 0.76 mm (p >0.5). In men there was a weak inverse association between CRP and ankle/brachial blood pressure index, independent of other risk factors, but no such association in women. Our findings indicate that CRP is not strongly and independently associated with prevalent atherosclerosis. Because CRP has been associated with clinical events, it could be that elevated CRP may be a stronger marker of thrombotic risk than of the degree of atherosclerosis.
Age Factors↗
Serum levels of C-reactive protein are associated with obesity, weight gain, and hormone replacement therapy in healthy postmenopausal women.
The authors evaluated the cross-sectional and prospective associations between the serum concentration of C-reactive protein and measures of obesity and fat distribution, hormone replacement therapy (HRT) use, and serum sex hormones in postmenopausal women from the Healthy Women Study (Allegheny County, Pennsylvania, 1998). The authors tested the hypothesis that C-reactive protein levels would be higher among HRT users and among women with greater body mass index, waist circumference, or visceral fat. There were 207 women in the study who were > or =8 years postmenopausal (101 HRT users and 106 HRT nonusers). The median levels of C-reactive protein were 3.01 mg/liter in HRT users compared with 1.74 mg/liter in nonusers (p = 0.002). C-reactive protein levels were strongly positively correlated with measures of body size, fatness, fat distribution, and weight gain among HRT users and nonusers. C-reactive protein was also positively correlated with serum estrone levels (r(s) = 0.38) among HRT nonusers. The highest level of C-reactive protein was found among HRT users in the highest quartile of visceral fat (4.29 mg/liter) compared with women not on HRT and in the lowest quartile of visceral fat (0.96 mg/liter). The use of HRT and measures of overall body fatness are important correlates of C-reactive protein among postmenopausal women.
Adipose Tissue↗
T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia.
BACKGROUND: T cells are implicated in atherosclerosis, but little is known about the genetic control or molecular pathways, especially under conditions of mild hypercholesterolemia. METHODS AND RESULTS: BALB/c mice, making a CD4+ Th2 (IL-4+) cell response, express both MHC class II antigens (IA(d), IE(d)) and are atherosclerosis-resistant. C57Bl/6 mice produce a CD4+ Th1 (interferon [IFN]gamma+) response, express IA(b) but no IE, and are atherosclerosis-prone. To evaluate T helper-cell phenotype in fatty streak formation, wild-type C57Bl/6 mice (IA(b)+IE-) and transgenic mice, either AB(o), IA(b)-IE-; ABEalpha, IA-IE(k)+; or BL:TG:Ealpha, IA(b)+IE(k)+, were fed a high-cholesterol diet for 16 weeks and evaluated histomorphometrically for aortic lesions. Lesion size in AB(o), ABEalpha, and BL:TG:Ealpha strains was decreased by 54%, 79%, and 82%, respectively, compared with wild-type, correlating with decreased Th1 and increased Th2 expression and suggesting that T helper-cell phenotype is important in fatty lesion development. Decreasing Th1 cells by antibodies (alpha-CD4) or cytokines (IL-4) also caused >/=80% reductions in lesion size. Immunohistology revealed IFN-gamma, but not IL-4, colocalized with activated macrophages. Confirming these findings in a different mouse strain, BALB/c Stat 6 knockout mice (Th2 cell-deficient) developed aortic lesions comparable to C57Bl/6 mice on the same diet. CONCLUSIONS: In mildly hypercholesterolemic C57Bl/6 mice, presence of IA(b) and absence of IE regulated CD4+ T helper-cell phenotype; fatty lesions were proportional to IFNgamma+ Th1 cells in both C57Bl/6 and BALB/c strains. IFN-gamma may participate through macrophage activation, whereas IL-4 may act to limit Th1-cell response.
Animals↗
Sudden cardiac death, genes, and arrhythmogenesis: consideration of new population and mechanistic approaches from a National Heart, Lung, and Blood Institute workshop, Part II.
This is Part II of a 2-part article dealing with malignant ventricular arrhythmias, which are the leading mechanism of death in common cardiac diseases. Genetic population studies directed at discovering common proximal sources of inherited molecular risk most directly linked to arrhythmia initiation and propagation would appear to have considerable potential in helping reduce cardiovascular mortality.
Arrhythmias, Cardiac↗
Sudden cardiac death, genes, and arrhythmogenesis : consideration of new population and mechanistic approaches from a national heart, lung, and blood institute workshop, part I.
Malignant ventricular arrhythmias are the leading mechanism of death in patients with acute and chronic cardiac pathologies. The extent to which inherited mutations and polymorphic variation in genes determining arrhythmogenic mechanisms affect these patients remains unknown, but based on recent population studies, this risk appears significant, deserving much greater investigation. This report summarizes a National Heart, Lung, and Blood Institute workshop that considered sources of genetic variation that may contribute to sudden cardiac death in common cardiac diseases. Evidence on arrhythmogenic mechanisms in recent population studies suggests a significant portion of the risk of sudden cardiac death in such broad populations may be unrelated to traditional risk factors for predisposing conditions such as atherosclerosis, hypertension, and diabetes and instead may involve unrecognized genetic and environmental interactions that influence arrhythmic susceptibility more directly. Additional population and genetic studies directed at discovering the sources of inherited molecular risk that are most directly linked to arrhythmia initiation and propagation, in addition to studies on previously well-described risk factors, would appear to have considerable potential for reducing premature cardiovascular mortality.
Arrhythmias, Cardiac↗
Summary of the scientific conference on dietary fatty acids and cardiovascular health: conference summary from the nutrition committee of the American Heart Association.
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American Heart Association↗
Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study.
Inflammation is thought to play a central role in the etiology and outcome of atherosclerosis. Animal studies as well as in vitro and in vivo human studies suggest that host factors modulate the magnitude and extent of inflammatory responses. We investigated familial aggregation of three systemic markers of inflammation (C-reactive protein (CRP), white blood cell count (WBC), and albumin) in a large, cross-sectional study conducted in four US communities. We found evidence of substantial heritability (35-40%) for CRP levels as well as for WBC and albumin levels. Negligible spouse correlations suggested little influence of shared household environment on these traits. The combination of sociodemographic factors (age, center, education), behavioral and lifestyle factors (cigarette smoking, alcohol intake, hormone replacement therapy), obesity and fat patterning, and prevalent diabetes explained 13-30% the interindividual variability of these traits. There was no evidence that these inflammation phenotypes were linked to a microsatellite marker in the interleukin-1 gene cluster on chromosome 2q, a region that includes several candidate genes for chronic inflammatory diseases. Our findings suggest that CRP levels, albumin levels, and WBC are determined at least partially by genetic factors. Further efforts to identify gene loci affecting these traits are warranted.
Adult↗