Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group

Peripheral arterial disease (PAD) in the legs, measured noninvasively by the ankle-arm index (AAI) is associated with clinically manifest cardiovascular disease (CVD) and its risk factors. To determine risk of total mortality, coronary heart disease, or stroke mortality and incident versus recurrent CVD associated with a low AAI, we examined the relationship of the AAI to subsequent CVD events in 5888 older adults with and without CVD. The AAI was measured in 5888 participants >/=65 years old at the baseline examination of the Cardiovascular Health Study. All participants had a detailed assessment of prevalent CVD and were contacted every 6 months for total mortality and CVD events (including CVD mortality, fatal and nonfatal myocardial infarction, congestive heart failure, angina, stroke, and hospitalized PAD). The crude mortality rate at 6 years was highest (32.3%) in those participants with prevalent CVD and a low AAI (P<0.9), and it was lowest in those with neither of these findings (8.7%, P<0.01). Similar patterns emerged from analysis of recurrent CVD and incident CVD. The risk for incident congestive heart failure (relative risk [RR]=1.61) and for total mortality (RR=1.62) in those without CVD at baseline but with a low AAI remained significantly elevated after adjustment for cardiovascular risk factors. Hospitalized PAD events occurred months to years after the AAI was measured, with an adjusted RR of 5.55 (95% CI, 3.08 to 9.98) in those at risk for incident events. A statistically significant decline in survival was seen at each 0.1 decrement in the AAI. An AAI of <0.9 is an independent risk factor for incident CVD, recurrent CVD, and mortality in this group of older adults in the Cardiovascular Health Study.     

<Emphasis Type="Italic">TCF7L2</Emphasis> single nucleotide polymorphisms,cardiovascular disease and all-cause mortality: the Atherosclerosis Risk in Communities (ARIC) study

Aims/hypothesis We hypothesised that TCF7L2 single nucleotide polymorphisms (SNPs) are associated with cardiovascular disease (CVD) and that the associations differ in diabetic and non-diabetic persons. Methods Our analysis included black and white participants from the Atherosclerosis Risk in Communities study who were free of prevalent CVD at baseline and had been genotyped for rs7903146, rs12255372, rs7901695, rs11196205 and rs7895340 (n = 13,369). Cox proportional hazard regression was used to estimate the associations between polymorphisms and incident events; logistic and linear regression were used for associations with baseline risk factor levels. Results TCF7L2 SNPs were not significantly associated with incident coronary heart disease, ischaemic stroke, CVD, prevalent peripheral artery disease (PAD) or all-cause mortality in the full cohort or when stratified by race. Conclusions/interpretation In the whole cohort, TCF7L2 SNPs were not associated with incident CVD, all-cause mortality or prevalent PAD. This result suggests that the increased health risk associated with rs7903146 genotype is specific to diabetes.     

Fibroblast growth factor 23, the ankle-brachial index,and incident peripheral artery disease in the Cardiovascular Health Study

Background

Fibroblast growth factor 23 (FGF23) has emerged as a novel risk factor for mortality and cardiovascular events. Its association with the ankle-brachial index (ABI) and clinical peripheral artery disease (PAD) is less known.

Methods

Using data (N = 3143) from the Cardiovascular Health Study (CHS), a cohort of community dwelling adults >65 years of age, we analyzed the cross-sectional association of FGF23 with ABI and its association with incident clinical PAD events during 9.8 years of follow up using multinomial logistic regression and Cox proportional hazards models respectively.

Results

The prevalence of cardiovascular disease (CVD) and traditional risk factors like diabetes, coronary artery disease, and heart failure increased across higher quartiles of FGF23. Compared to those with ABI of 1.1–1.4, FGF23 per doubling at baseline was associated with prevalent PAD (ABI < 0.9) although this association was attenuated after adjusting for CVD risk factors, and kidney function (OR 0.91, 95% CI 0.76–1.08). FGF23 was not associated with high ABI (>1.4) (OR 1.06, 95% CI 0.75–1.51). Higher FGF23 was associated with incidence of PAD events in unadjusted, demographic adjusted, and CVD risk factor adjusted models (HR 2.26, 95% CI 1.28–3.98; highest versus lowest quartile). The addition of estimated glomerular filtration and urine albumin to creatinine ratio to the model however, attenuated these findings (HR 1.46, 95% CI, 0.79–2.70).

Conclusions

In community dwelling older adults, FGF23 was not associated with baseline low or high ABI or incident PAD events after adjusting for confounding variables. These results suggest that FGF23 may primarily be associated with adverse cardiovascular outcomes through non atherosclerotic mechanisms.     

The effect of novel cardiovascular risk factors on the ethnic-specific odds for peripheral arterial disease in the Multi-Ethnic Study of Atherosclerosis (MESA).

OBJECTIVES: The purpose of this study was to: 1) determine the significance and magnitude of associations between novel cardiovascular disease (CVD) risk factors and peripheral arterial disease (PAD) after adjustment for traditional risk factors; and 2) ascertain the extent to which novel risk factors explain the excess or lower risk for PAD in different ethnic groups. BACKGROUND: Previous reports have found a significant difference in the risk of PAD by ethnic group, with some of the risk difference attributed to different levels of traditional CVD risk factors. METHODS: A total of 6,814 individuals free of clinically apparent CVD were enrolled in the MESA (Multiethnic Study of Atherosclerosis) and underwent standardized testing for the presence of PAD by the ankle-brachial index. These subjects also had fasting blood drawn for serum cholesterol, glucose, and a number of novel biomarkers for CVD. Non-Hispanic whites were the largest ethnic group (38%), followed by African Americans (28%), Hispanics (22%), and Chinese (12%). RESULTS: In this cross-sectional analysis, 6,653 subjects with an ankle brachial index <1.40 were analyzed. The mean (SD) age was 62.2 (10.2) years, and 52.9% were women. Interleukin-6, fibrinogen, D-dimer, and homocysteine were significantly associated with PAD after adjustment for traditional CVD risk factors. Compared with non-Hispanic whites and after adjustment for traditional and "novel" risk factors, the odds for PAD were 1.47 (95% confidence interval [CI]: 1.07 to 2.02) times higher in African Americans, while being 0.45 (95% CI: 0.29 to 0.70) and 0.44 (95% CI: 0.24 to 0.78) in Hispanics and Chinese, respectively. CONCLUSIONS: Ethnic associations with PAD remained significant even after adjustment for traditional and novel risk factors. This suggests that unknown factors may account for the residual ethnic differences in PAD.     

Triglyceride-Rich Lipoprotein Cholesterol,Small Dense LDL Cholesterol,and Incident Cardiovascular Disease

BackgroundElevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease.ObjectivesThe purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD).MethodsIn a prospective case-cohort study within the Women’s Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein.ResultsThe risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR]_Q4: 3.05 [95% confidence interval (CI): 1.46 to 6.39]; p_trend = 0.002; PAD HR_Q4: 2.58 [95% CI: 1.18 to 5.63]; p_trend = 0.019), whereas sdLDL-C was significantly associated with MI alone (HR_Q4: 3.71 [95% CI: 1.59 to 8.63]; p_trend < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dl).ConclusionsTRL-C strongly associates with future MI and PAD events, whereas sdLDL-C strongly associates with MI alone. These findings signal that the cholesterol content of TRLs and sdLDL influence atherogenesis independently of low-density lipoprotein cholesterol, and high sensitivity C-reactive protein, with potentially different potency across vascular beds. (Women’s Health Study; NCT00000479)     

心血管疾病危险人群中微量白蛋白尿与颈动脉粥样硬化及外周动脉疾病的关系

目的评价存在心血管疾病危险因素但无明确心脑血管疾病的患者中,微量白蛋白尿(MA)与颈动脉粥样硬化(AS)及外周动脉疾病(PAD)的关系。方法采用横断面研究,277例住院有心血管疾病危险因素但无明确心脑血管疾病的患者,根据其尿白蛋白/肌酐(UACR)水平分为两组:微量白蛋白尿组(MA组,男:17 mg/g≤UACR≤250 mg/g;女:25 mg/g≤UACR≤355 mg/g)及不伴微量白蛋白尿组(NMA组,男:00.05)。结论心血管疾病高危患者中,伴MA者颈总动脉AS和PAD的危险性均增加,MA与颈总动脉AS的关系较与PAD的关系更加明显。     

Ultra-Processed Foods and Incident Cardiovascular Disease in the Framingham Offspring Study

BackgroundUltra-processed foods provide 58% of total energy in the U.S. diet, yet their association with cardiovascular disease (CVD) remains understudied.ObjectivesThe authors investigated the associations between ultra-processed foods and CVD incidence and mortality in the prospective Framingham Offspring Cohort.MethodsThe analytical sample included 3,003 adults free from CVD with valid dietary data at baseline. Data on diet, measured by food frequency questionnaire, anthropometric measures, and sociodemographic and lifestyle factors were collected quadrennially from 1991 to 2008. Data regarding CVD incidence and mortality were available until 2014 and 2017, respectively. Ultra-processed foods were defined according to the NOVA framework. The authors used Cox proportional hazards models to determine the multivariable association between ultra-processed food intake (energy-adjusted servings per day) and incident hard CVD, hard coronary heart disease (CHD), overall CVD, and CVD mortality. Multivariable models were adjusted for age, sex, education, alcohol consumption, smoking, and physical activity.ResultsDuring follow-up (1991 to 2014/2017), the authors identified 251, 163, and 648 cases of incident hard CVD, hard CHD, and overall CVD, respectively. On average, participants consumed 7.5 servings per day of ultra-processed foods at baseline. Each additional daily serving of ultra-processed foods was associated with a 7% (95% confidence interval [CI]: 1.03 to 1.12), 9% (95% CI: 1.04 to 1.15), 5% (95% CI: 1.02 to 1.08), and 9% (95% CI: 1.02 to 1.16) increase in the risk of hard CVD, hard CHD, overall CVD, and CVD mortality, respectively.ConclusionsThe current findings support that higher consumption of ultra-processed foods is associated with increased risk of CVD incidence and mortality. Although additional research in ethnically diverse populations is warranted, these findings suggest cardiovascular benefits of limiting ultra-processed foods.     

Joint effects of physical activity, body mass index, waist circumference and waist-to-hip ratio with the risk of cardiovascular disease among middle-aged Finnish men and women.

AIMS: To assess joint associations of physical activity and different indicators of obesity (body mass index, waist circumference, and waist-to-hip ratio) with the risk of cardiovascular disease (CVD). METHODS AND RESULTS: The study comprised 18,892 Finnish men and women aged 25-74 years without history of coronary heart disease, stroke, or heart failure at baseline. Physical activity, different indicators of obesity, education, smoking, blood pressure, total and high-density lipoprotein cholesterol and history of diabetes were measured at baseline. An incident CVD event was defined as the first stroke or coronary heart disease event or CVD death based on national hospital discharge and mortality register data. The median follow-up time was 9.8 years. Physical activity had a strong, independent, and inverse association with CVD risk in both genders. All obesity indicators had a significant direct association with CVD risk after adjustment for age, smoking, education and physical activity. Further adjustment for the obesity-related risk factors weakened the associations and they remained statistically significant in men only. Physical activity and the obesity indicators both predicted CVD risk in men, but in women the joint effect was inconsistent. CONCLUSION: Both regular physical activity and normal weight can reduce the risk of CVD. Physical inactivity seems to have an independent effect on CVD risk, whereas obesity increases the risk partly through the modification of other risk factors.     

Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER

Our purpose was to evaluate associations of single nucleotide polymorphisms (SNPs) at the low density lipoprotein (LDL) receptor (LDLR C44857T, minor allele frequency (MAF) 0.26, and A44964G, MAF 0.25, both in the untranslated region) and HMG-CoA reductase (HMGCR i18 T > G, MAF 0.019) gene loci with baseline lipid values, statin-induced LDL-cholesterol (C) lowering response, and incident coronary heart disease (CHD) and cardiovascular disease (CVD) on trial. Our population consisted of 5804 elderly men and women with vascular disease or one or more vascular disease risk factors, who were randomly allocated to pravastatin or placebo. Other risk factors and apolipoprotein (apo) E phenotype were controlled for in the analysis. Despite a prior report, no relationships with the HMGCR SNP were noted. For the LDLR SNPs C44857T and A44964G we noted significant associations of the rare alleles with baseline LDL-C and triglyceride levels, a modest association of the C44857T with LDL-C lowering to pravastatin in men, and significant associations with incident CHD and CVD of both SNPs, especially in men on pravastatin. Our data indicate that genetic variation at the LDLR locus can affect baseline lipids, response to pravastatin, and CVD risk in subjects placed on statin treatment.     

Serum Atrial Natriuretic Peptide,NPPA Promoter Methylation,and Cardiovascular Disease: A 10-year Follow-Up Study in Chinese Adults

Background:Atrial natriuretic peptide (ANP) has been associated with cardiovascular disease (CVD) and related risk factors, but the clinical application is limited and the underlying mechanisms are not very clear. Here, we aimed to examine whether proANP and its coding gene methylation were associated with CVD in the Chinese population.Methods:Serum proANP and peripheral blood DNA methylation of natriuretic peptide A gene (NPPA) promoter was quantified at baseline for 2,498 community members (mean aged 53 years, 38% men) in the Gusu cohort. CVD events were obtained during 10 years of follow-up. A competing-risks survival regression model was applied to examine the prospective associations of proANP and NPPA promoter methylation with incident CVD.Results:During follow-up, 210 participants developed CVD events, 50 participants died from non-cardiovascular causes, and 214 participants were lost. Per 1-nmol/L increment of serum proANP was associated with a 22% (HR = 1.22, 95%CI: 1.03–1.44, P = 0.025) higher risk of CVD during follow-up. Of the 9 CpG sites assayed, per 2-fold increment of DNA methylation at CpG3 (located at Chr1:11908299) was significantly associated with a half lower risk of CVD (HR = 0.50, 95%CI: 0.30–0.82, P = 0.006). The gene-based analysis found that DNA methylation of the 9 CpGs at NPPA promoter as a whole was significantly associated with incident CVD (P < 0.05).Conclusions:Increased proANP and hypomethylation at NPPA promoter at baseline predicted an increased future risk of CVD in Chinese adults. Aberrant DNA methylation of the NPPA gene may participate in the mechanisms of CVD.     

Association of glucose metabolism, smoking and cardiovascular risk factors with incident peripheral arterial disease: the DESIR study

AIMS: We determined the 6-year incidence of peripheral arterial disease (PAD) in a French population and assessed the association of glucose metabolism, smoking, cardiovascular risk factors and physical activity with incident PAD. METHODS: Participants from the French Data from a Epidemiological Study on the Insulin Resistance Syndrome (DESIR) were studied. Participants analysed were 30-65 years (at baseline) and had complete data (n=3805) after 6 years of follow-up. Diabetes was diagnosed according to the 1999 WHO criteria on the basis of fasting plasma glucose results or previous diagnosis of diabetes mellitus. The ankle brachial pressure index (ABPI) and a claudication question were used to classify PAD. RESULTS: The 6-year incidence of PAD (defined by ABPI<0.9 and or claudication present) among those with normal fasting glucose (NFG) and free of PAD at baseline was 5.1%. Among those with impaired fasting glucose (IFG) at baseline the incidence of PAD was 4.9% and among those with diabetes mellitus at baseline the incidence of PAD was 9.8%. The incidence of PAD among those who maintained NFG over 6 years was 4.7% and among those who progressed to diabetes over 6 years was 10.2%. Those who progressed from NFG or IFG to diabetes over 6 years were twice as likely to develop PAD compared to those who maintained NFG over 6 years, after adjustment for age and sex (OR (95% CI), 2.22 (1.12-4.42)). Independent risk factors for incident PAD using baseline population characteristics were diabetes (OR (95% CI) 2.11 (1.25-3.55)), systolic BP 122-135mmHg 1.06 (0.70-1.60), >135mmHg 1.54 (1.04-2.27) and current smoking 1.60 (1.10-2.34) after multivariate adjustment for age, sex, cholesterol, triglycerides and waist circumference. CONCLUSIONS: This French study shows that those who progress to diabetes are twice as likely to develop PAD, compared to those who maintain NFG. Peripheral arterial disease is a treatable condition and more aggressive management of atherosclerotic risk factors could reduce the numbers of people who develop PAD.     

The relative importance of systolic versus diastolic blood pressure control and incident symptomatic peripheral artery disease in women

Prospective data regarding risk factors for peripheral artery disease (PAD) are sparse, especially among women; the relative contribution of systolic versus diastolic blood pressure control for incident PAD has not been well studied. We evaluated the association of self-reported blood pressure control with incident symptomatic PAD in middle-aged and older women. We examined the relationship between reported hypertension and incident confirmed symptomatic PAD (n = 178) in 39,260 female health professionals aged ≥ 45 years without known vascular disease at baseline. Median follow-up was 13.3 years. Women were grouped according to presence of reported isolated diastolic (IDH), isolated systolic (ISH), or combined systolic-diastolic hypertension (SDH) using cut-points of 90 and 140 mmHg for diastolic and systolic blood pressure, respectively. SBP and DBP were modeled as continuous and categorical exposures. Multivariable-adjusted hazard ratios (HRs), including adjustment for cardiovascular risk factors, were derived from Cox proportional hazards models. Adjusted HRs compared to women without reported hypertension were 1.0 (0.4-2.8) for IDH, 2.0 (1.3-3.1) for ISH, and 2.8 (1.8-4.5) for SDH. There was a 43% increased adjusted risk per 10 mmHg of reported SBP (95% CI 27-62%) and a gradient in risk according to SBP category (< 120, 120-139, 140-159, and ≥ 160 mmHg); HRs were 1.0, 2.3, 4.3, and 6.6 (p-trend < 0.001), respectively. Reported DBP, while individually predictive in models excluding SBP, was not predictive after adjustment for SBP. In conclusion, these prospective data suggest a strong prognostic role for uncontrolled blood pressure and, particularly, uncontrolled systolic blood pressure in the development of peripheral atherosclerosis in women.     

Liver enzymes and risk of cardiovascular disease in the general population: A meta-analysis of prospective cohort studies

Background

Gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), commonly used markers of liver dysfunction, have been implicated with risk of cardiovascular disease (CVD). However, the strength and consistency of their associations in the general population have not been reliably quantified.

Methods

We synthesized available prospective epidemiological data on the associations of baseline levels of GGT, ALT, AST, and ALP with CVD [composite CVD, coronary heart disease (CHD), or stroke outcomes]. Relevant studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science up to December 2013. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random effects models.

Results

Twenty-nine unique cohort studies with aggregate data on over 1.23 million participants and 20,406 cardiovascular outcomes were included. The pooled fully adjusted RRs (95% CIs) for CVD were 1.23 (1.16–1.29) and 1.08 (1.03–1.14) per 1-standard deviation change in log baseline levels of GGT and ALP levels respectively. There was no evidence of an association of ALT or AST with CVD, however, ALT was somewhat inversely associated with CHD 0.95 (0.90–1.00) and positively associated with stroke 1.01 (1.00–1.02) in stratified analysis. Tests for nonlinearity were suggestive of linear relationships of GGT and ALP levels with CVD risk.

Conclusions

Baseline levels of GGT and ALP are each positively associated with CVD risk and in a log-linear fashion. There may be variations in the associations of ALT with cause-specific cardiovascular endpoints, findings which require further investigation.     

Cardiovascular Risk Factors and Incident Acute Renal Failure in Older Adults: The Cardiovascular Health Study

Background and objectives: Although the elderly are at increased risk for acute renal failure, few prospective studies have identified risk factors for acute renal failure in the elderly.Design, setting, participants, & measurements: The associations of cardiovascular disease risk factors, subclinical cardiovascular disease, and clinical coronary heart disease with the risk for development of acute renal failure were examined in older adults in the Cardiovascular Health Study, a prospective cohort study of community-dwelling older adults. Incident hospitalized cases of acute renal failure were identified through hospital discharge International Classification of Diseases, Ninth Revision codes and confirmed through physician diagnoses of acute renal failure in discharge summaries.Results: Acute renal failure developed in 225 (3.9%) of the 5731 patients during a median follow-up period of 10.2 yr. In multivariate analyses, diabetes, current smoking, hypertension, C-reactive protein, and fibrinogen were associated with acute renal failure. Prevalent coronary heart disease was associated with incident acute renal failure, and among patients without prevalent coronary heart disease, subclinical vascular disease measures were also associated with acute renal failure: Low ankle-arm index (≤0.9), common carotid intima-media thickness, and internal carotid intima-media thickness.Conclusions: In this large, population-based, prospective cohort study, cardiovascular risk factors and both subclinical and clinical vascular disease were associated with incident acute renal failure in the elderly.Acute renal failure (ARF) occurs most commonly in older adults and is associated with significant morbidity and mortality, with death rates among hospitalized patients ranging from 25 to >70% (1–4). Despite the prevalence of ARF in elderly adults, few studies have examined potential risk factors (5–7), and no studies have examined risk factors in the elderly. The limited data from small studies suggest that cardiovascular disease (CVD) risk factors, such as hypertension, diabetes, and inflammatory markers, and clinical CVD may be associated not only with chronic kidney disease (CKD) but also ARF. These associations may be particularly important in the elderly, in whom CVD is prevalent. We hypothesized that CVD risk factors and subclinical and clinical disease would be associated prospectively with the risk for development of ARF in older adults. To address these hypotheses, we evaluated the associations of these characteristics with incident ARF in the Cardiovascular Health Study (CHS), a large cohort study of older adults. If our hypotheses are correct, then prospective identification of risk factors for ARF in the elderly may suggest potential subgroups of this high-risk population that may merit additional attention or intervention.     

Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality

Previously diagnosed diabetes mellitus, newly diagnosed diabetes mellitus, and impaired glucose tolerance are important determinants of the risk of clinical cardiovascular disease (CVD). We have evaluated the relation of patients with subclinical CVD, diabetes, and impaired glucose tolerance and "normal" subjects and the risk of clinical CVD in the Cardiovascular Health Study. Diabetes (1343), impaired glucose tolerance (1433), and normal (2421) were defined by World Health Organization criteria at baseline in 1989 to 1990. The average follow-up was 6.4 years (mean age 73 years). Diabetics had a higher prevalence of clinical and subclinical CVD at baseline. Compared with diabetes in the absence of subclinical disease, the presence of subclinical CVD and diabetes was associated with significant increased adjusted relative risk of death (1.5, CI 0.93 to 2.41), relative risk of incident coronary heart disease (1.99, CI 1.25 to 3.19), and incident myocardial infarction (1.93, CI 0.96 to 3.91). The risk of clinical events was greater for participants with a history of diabetes compared with newly diagnosed diabetics at baseline. Compared with nondiabetic nonhypertensive subjects without subclinical disease, patients with a combination of diabetes, hypertension, and subclinical disease had a 12-fold increased risk of stroke. Fasting blood glucose levels were a weak predictor of incident coronary heart disease as were most other risk factors. Subclinical CVD was the primary determinant of clinical CVD among diabetics in the Cardiovascular Health Study.     

The prevalence of peripheral arterial disease in high risk subjects and coronary or cerebrovascular patients

Atherosclerosis is a generalized disease with considerable overlap of its coronary, carotid, and peripheral manifestations. As an indicator of multifocal atherosclerosis, peripheral arterial disease (PAD) is emerging as an important aid in risk stratification of patients with coronary artery (CAD) or cerebrovascular disease (CVD). Therefore, the aim of the study was to assess the prevalence of PAD in high risk subjects and its ability to identify coronary or cerebrovascular patients. A total of 952 (63.3% male; age 63.7 +/-10.7 years) patients at high cardiovascular risk (>or=2 risk factors), or with evidence of CAD or CVD were screened for PAD by means of ankle-brachial index (ABI) assessment; 226 patients were at high risk (>or=2 risk factors), 575 had CAD, and 151 had CVD. A total of 42% of patients with CAD and 36% of patients with CVD had PAD. In patients with CAD one half of cases of PAD were asymptomatic. Asymptomatic PAD (pathological ABI) was strongly associated with CAD and CVD, even after adjustment for age, gender, and other risk factors. No significant differences between CAD, PAD, and CVD patients were observed in terms of risk profiles. In conclusion, our findings confirm a high prevalence of both symptomatic and asymptomatic PAD in patients at high cardiovascular risk and its association with both CAD and CVD.     

Cytokines and clustered cardiovascular risk factors in children

The aim was to evaluate the possible role of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), low fitness, and fatness in the early development of clustering of cardiovascular disease (CVD) risk factors and insulin resistance. Subjects for this cross-sectional study were obtained from 18 schools near Copenhagen, Denmark. Two hundred ten 9-year-old children were selected for cytokine analysis from 434 third-grade children with complete CVD risk profiles. The subgroup was selected according to the CVD risk factor profile (upper and lower quartile of a composite CVD risk score). All the CVD risk factors and CRP differed between the high- and low-risk groups; but plasma glucose, TNF-α, and IL-6 had small and inconsistent differences. Strong associations were found between CVD risk scores and fitness (VO_2peak) or fatness. No associations were found between CVD risk scores and TNF-α and IL-6. C-reactive protein was associated with fitness, fatness, and CVD risk score. This study does not support an association between plasma IL-6 or TNF-α and low insulin sensitivity or clustering of CVD risk factors in a young cohort. Inflammation was more pronounced in fat and unfit children based on the association with CRP levels. The association between fitness and fatness variables, insulin resistance, and clustered risk could be caused by other mechanisms related to these exposures. The role of IL-6 remains unclear.     

Hemostatic factors as predictors of stroke and cardiovascular diseases: the FINRISK '92 Hemostasis Study.

We carried out a prospective cohort study to determine whether the plasma levels of fibrinogen, plasminogen, factor VII and lipoprotein (a) are predictors of ischemic stroke and all cardiovascular disease (CVD) events. The FINRISK '92 Hemostasis Study included a random sample of 2372 participants, who were followed-up from winter 1992 to 31 December 2001. During the follow-up, 75 ischemic stroke and 145 coronary events occurred. Of these, 169 were observed among participants free of known CVD at baseline. In this group, fibrinogen and plasminogen were positively associated with the risk of a CVD event with hazard ratios of 1.22 [95% confidence interval (CI), 1.05-1.41] and 1.22 (95% CI, 1.03-1.44), respectively, after adjusting for age, sex and conventional risk factors. Factor VII:C was associated with risk of a future CVD event only among persons with positive history of CVD at baseline (hazard ratio, 1.32; 95% CI, 1.00-1.73). Factor VII antigen was not associated with CVD risk. None of the measured hemostatic factors was a predictor of ischemic stroke events, with the possible exception of lipoprotein (a), which had a borderline significant association (hazard ratio, 1.25; 95% CI, 0.99-1.58). In conclusion, the present study supports the observations that fibrinogen and plasminogen are significant predictors of CVD events, independently of conventional risk factors.     

Markers of vascular inflammation are associated with the extent of atherosclerosis assessed as angiographic score and treadmill walking distances in patients with peripheral arterial occlusive disease

The importance of inflammation in atherosclerosis is well established in cardiovascular disease. However, limited data exist on the relationship between vascular inflammation and the severity of peripheral arterial occlusive disease (PAD). We investigated the relationship between biochemical markers of vascular inflammation and the diagnostic measures of PAD: ankle-brachial pressure index (ABI), maximum treadmill walking distance and angiographic score. In 127 patients (mean age 66 years; 64% males) with angiographically verified PAD, fasting blood samples were drawn for determination of selected soluble cell adhesion molecules, cytokines and chemokines. Tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and CD40 ligand (CD40L) were all significantly correlated with the angiographic score (p < 0.05 for all). After adjustment for relevant co-variates, MCP-1 and CD40L remained statistically significant (p < 0.01 for both). IL-6 was, independent of other risk factors, inversely correlated with the maximum treadmill walking distance (p < 0.01). Our cross-sectional study in PAD patients showed that the vascular inflammatory markers MCP-1, CD40L and IL-6 were significantly associated with the extent of atherosclerosis, assessed by angiographic score and maximum treadmill walking distance. These findings indicate that vascular inflammation is implicated in PAD, which might be of importance in future diagnosis and treatment of the disease.     

Heart rate-corrected QT interval prolongation predicts risk of coronary heart disease in black and white middle-aged men and women: the ARIC study

OBJECTIVES: We aimed to study the predictive value of heart rate-corrected QT interval (QTc) for incident coronary heart disease (CHD) and cardiovascular disease (CVD) mortality in the black and white general population, and to validate various QT measurements. BACKGROUND: QTc prolongation is associated with higher risk of mortality in cardiac patients and in the general population. Little is known about the association with incident CHD. No previous studies included black populations. METHODS: We studied the predictive value of QTc prolongation in a prospective population study of 14,548 black and white men and women, age 45 to 64 year. QT was determined by the NOVACODE program in the digital electrocardiogram recorded at baseline. RESULTS: In quintiles of QTc, cardiovascular risk profile deteriorated with longer QTc, and risk of CHD and CVD mortality increased. The high risk in the upper quintile was mostly explained by the 10% with the longest QTc. The age-, gender-, and race-adjusted hazard ratios for CVD mortality and CHD in subjects with the longest 10% relative to the other 90% of the gender-specific QTc distribution were 5.13 (95% confidence interval 3.80 to 6.94) and 2.14 (95% confidence interval 1.71 to 2.69), respectively. The increased risk was partly, but not completely, attributable to other risk factors or the presence of chronic disease. The association was stronger in black than in white subjects. Manual- and machine-coded QT intervals were highly correlated, and the method of rate correction did not affect the observed associations. CONCLUSIONS: Long QTc is associated with increased risk of CHD and CVD mortality in black and white healthy men and women.