Recent findings suggest that chronic kidney disease (CKD) may be associated with increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted.
Methods and Results
We pooled individual participant data from five community-based cohorts from Europe (HUNT2, PREVEND and Tromsø study) and United States (ARIC and CHS study) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria and CKD with objectively verified VTE. To estimate adjusted hazard ratios (HRs) for VTE, categorical and continuous spline models were fit using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1,178 VTE events occurred over 599,453 person-years follow-up. Relative to eGFR 100 mL/min/1.73m2, HRs for VTE were 1.29 (95%CI, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for 60, 1.82 (1.27-2.60) for 45 and 1.95 (1.26-3.01) for 30 mL/min/1.73m2. Compared with albumin-creatinine ratio (ACR) of 5.0 mg/g, the HRs for VTE were 1.34 (1.04-1.72) for 30 mg/g, 1.60 (1.08-2.36) for 300 mg/g and 1.92 (1.19-3.09) for 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted HR for CKD defined as eGFR <60 mL/min/1.73m2 or albuminuria ≥30 mg/g (vs. no CKD) was 1.54 (95%CI, 1.15-2.06). Associations were consistent in subgroups according to age, gender, and comorbidities as well as for unprovoked versus provoked VTE.
Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.
chronic kidney disease; deep vein thrombosis; epidemiology; pulmonary embolism; thromboembolism
Several studies have reported that taller individuals are at greater risk of venous thromboembolism (VTE). We hypothesized that longer leg length would be positively associated with incident VTE, and would explain the height association. LITE ascertained VTE in a prospective population-based sample of 21,860 individuals aged 45 and older. Leg length was measured as standing height minus sitting height. Cox regression models were adjusted for age, race, sex, waist circumference, diabetes, and factor VIII. To evaluate whether leg length was associated with VTE risk independent of height we standardized leg length and height per 1 standard deviation (SD), and then included them simultaneously in Cox regression models. A total of 641 incident VTE cases accrued over a median follow-up of 16 yrs. Participants in the highest quintile of leg length were at 59% (95% CI: 22%-108%) greater risk of VTE, relative to the lowest quintile. For height, risk was 45% (12%-88%) greater for those in the highest quintile, compared to the lowest. When leg length and height were modeled simultaneously leg length remained associated with VTE risk (HR per 1 SD: 1.21 (1.04-1.40) while height was unrelated (HR per 1 SD: 1.00 (0.86-1.16). To conclude, participants with longer legs were at greater risk of incident VTE, and leg length explained the relation of height to VTE. It remains to be established whether this finding is due to greater venous surface area, a larger number of venous valves, or greater hydrostatic pressure among individuals with longer legs.
height; leg length; venous thromboembolism; Atherosclerosis Risk in Communities Study (ARIC); Cardiovascular Health Study (CHS)
Apart from obesity, it remains controversial whether atherosclerosis and its cardiovascular risk disease (CVD) factors are associated with risk of venous thromboembolism (VTE). Using data from the Atherosclerosis Risk in Communities study (ARIC), we evaluated associations between CVD risk factors and incident VTE in a cohort of 15,340 participants who were free a history of VTE and/or anticoagulant use on enrolment. The CVD risk factors were updated during the follow-up period. Over a mean follow-up time of 15.5 years (237,375 person-years), 468 participants had VTE events. Adjusting for demographic variables and body mass index (BMI), current smokers were at greater risk [HR of 1.44 (95% CI: 1.12–1.86)] compared to non-smokers. There was a positive monotonic association between BMI and VTE risk. Individuals with a BMI ≥35 kg/m2 had a HR for VTE of 3.09 (95%CI: 2.26–4.23) compared to those with normal BMI (<25 kg/m2). Greater physical activity was associated with lower VTE risk in a demographic adjusted model; however, this association became non-significant following adjustment for BMI. Alcohol intake, diabetes, hypertension, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were not associated with VTE risk. In conclusion, among the well-established CVD risk factors, only current smoking and obesity were independently associated with VTE risk in this large cohort where risk factors were updated serially during follow-up. This finding corroborates that the pathogenesis of venous disease differs from that of atherosclerotic disease.
Deep-vein thrombosis; pulmonary embolism; risk factors
This study examined how adiposity influences racial/ethnic differences in diabetes incidence by exploring whether relations between anthropometric measures and incident diabetes vary by race/ethnicity. Data from the Multi-Ethnic Study of Atherosclerosis initiated in 2000 (n = 5,446 US men and women aged 45–84 years) were analyzed by using proportional hazards and Poisson regression. The diabetes incidence rate was 2/100 person-years (n = 479 cases). Interactions were present between race and anthropometry (P-interaction(race × body mass index) = 0.002). The slope of incident diabetes per anthropometric unit was greatest for Chinese, less for whites and Hispanics, and still less for blacks. For small waist, risk of incident diabetes was <1/100 person-years for all racial/ethnic groups. At intermediate waist levels, Chinese had the highest and whites the lowest rates of incident diabetes. At the respective 95th percentiles of waist circumference, risk of incident diabetes per 100 person-years was 3.9 for Chinese (104 cm), 3.5 for whites (121 cm), 5.0 for blacks (125 cm), and 5.3 for Hispanics (121 cm). Adiposity influenced relative diabetes occurrence across racial/ethnic groups, in that Chinese had a steeper diabetes risk per unit of adiposity. However, the generally low level of adiposity in Chinese led to a relatively low diabetes occurrence.
Asian continental ancestry group; body mass index; diabetes mellitus; waist circumference
Venous thromboembolism (VTE) recurs frequently. Greater height is associated with increased risk of incident VTE, but it is unclear if height is related to risk of VTE recurrence. Recurrent VTE is associated with substantial morbidity and mortality, thus identifying individuals at greatest risk of experiencing a recurrent event, who may benefit from extended anticoagulant therapy, is vitally important. Using data from the Iowa Women’s Health Study we explored whether greater height was associated with increased risk of VTE recurrence. Among 1691 women who experienced an initial VTE event 286 (16.9%) experienced a recurrent event. Risk of recurrence was 76% (95% CI: 16%–186%) higher among women ≥66 inches [~168 centimeters] tall relative to those ≤62 inches [~158 centimeters] tall, after adjustment for age and waist circumference. Future research should evaluate whether body height improves clinical prediction of VTE recurrence risk.
Thrombin is an enzyme essential to the acceleration of the coagulation cascade and the conversion of fibrinogen to clottable fibrin.
We evaluated the relation of basal peak thrombin generation to risk of future VTE, and determined whether associations were independent of other coagulation markers.
LITE ascertained VTE in two prospective population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). Peak thrombin generation was measured on stored plasma in a nested case-control sample (434 cases, 1,004 controls). Logistic regression was used to estimate the relation of peak thrombin generation to VTE, adjusted for age, sex, race, center and BMI. Mediation was evaluated by additionally adjusting for factor VIII and D-dimer.
Relative to the first quartile of peak thrombin generation, the odds ratio (95% CI) of VTE for those above the median was 1.74 (1.28–2.37). The association was modestly attenuated by adjustment for factor VIII and D-dimer 1.47 (1.05–2.05). Associations appeared stronger for idiopathic than for secondary VTE. Elevated peak thrombin generation more than added to the VTE risk associated with Factor V Leiden or low aPTT.
In this prospective study of two independent cohorts, elevated basal peak thrombin generation was associated with subsequent risk of VTE, independent of established VTE risk factors.
Longitudinal Investigation of Thromboembolism Etiology (LITE); thrombin generation; venous thromboembolism
Little is known about the role of diet in the development of venous thromboembolism (VTE). We explored the prospective relation of dietary patterns, food groups, and nutrients to incident VTE in older women.
In 1986, Iowa women aged 55–69 completed a mailed survey, including a 127-item food frequency questionnaire. These data were linked to Medicare data from 1986–2004, and International Classification of Disease discharge codes were used to identify hospitalized VTE cases. Cox regression analyses evaluated relations of 2 principal components-derived dietary patterns, 11 food groups, and 6 nutrients to VTE, adjusted for age, education, smoking status, physical activity, and energy intake.
Over 19 years of follow-up 1,950 of the 37,393 women developed VTE. Women consuming alcohol daily were at 26% (95% CI: 11%–38%) lower risk of VTE, as compared to nonconsumers. All alcoholic beverages types were in the direction of lower risk, however only beer and liquor were statistically significant. After basic adjustments coffee was inversely related to VTE, and diet soda and fish positively related. However, these associations were confounded, and became nonsignificant after adjustment for body mass index and diabetes. No associations were observed with consumption of ‘Western’ or ‘Prudent’ dietary patterns, fruit, vegetables, dairy, meat, refined grains, whole grains, regular soda, vitamins E, B6, B12, folate, omega-3 fatty acids, or saturated fat.
In this cohort of older women, greater intake of alcohol was associated with a lower risk of incident VTE. No other independent associations were seen between diet and VTE.
Venous thromboembolism; Diet; Alcohol; Iowa Women’s Health Study; Medicare
To assess whether markers of acculturation (birthplace, number of U.S. generations) and socioeconomic status (SES) are associated with carotid artery plaque, internal carotid intima-media thickness (IMT), and albuminuria, in four racial/ethnic groups.
Using Multi-Ethnic Study of Atherosclerosis data (n = 6,716; age: 45-84) and race-specific binomial regression models, we computed prevalence ratios, adjusted for demographics and traditional cardiovascular risk factors.
The adjusted U.S. to foreign-born prevalence ratio (99% CI) for carotid plaque was 1.20 (0.97, 1.39) in Whites, 1.91 (0.94, 2.94) in Chinese, 1.62 (1.28, 2.06) in Blacks, and 1.23 (1.15, 1.31) in Hispanics. Greater carotid plaque prevalence was also found among Whites, Blacks, and Hispanics with more generations of US residence (p<0.001). Lower educational attainment and/or income were associated with greater carotid plaque prevalence in Whites and Blacks. Similar associations were observed with IMT. There was also some evidence of an inverse association between albuminuria and SES, in Whites and Hispanics.
Greater U.S. acculturation and lower SES were associated with a higher prevalence of carotid plaque and IMT, while little association was found with albuminuria.
Despite reportedly having less tobacco exposure compared with whites, African Americans account for a disproportionate number of smoking-related deaths. The purpose of this study was to compare the prospective associations between smoking and cardiovascular risk in whites and African Americans. Smoking status was obtained on 14,200 participants from the Atherosclerosis Risk in Communities Study. Incidence of cardiovascular disease (CVD) was ascertained from 1987 through 2007. Adjusted Cox proportional hazard models were used to estimate the CVD incidence associated with smoking behavior. Over 17 years’ follow-up, there were 2,777 cardiovascular events. In men, compared with never smoking, current smoking was independently associated with 67% (95% confidence interval (CI): 43, 95) and 72% (95% CI: 30, 126) greater risk of CVD in whites and African Americans, respectively. In women, the smoking-related cardiovascular risk was higher: 136% (95% CI: 88, 196) and 169% (95% CI: 126, 219) in African-American and white women, respectively. Early age at smoking initiation was independently associated with increased risk among all participants irrespective of race. Smoking cessation during follow-up was equally beneficial in both whites and African Americans. African Americans who smoke incur a similar level of cardiovascular risk as white smokers and would derive the same benefits from quitting as whites.
age at smoking initiation; cardiovascular diseases; cigarette smoking; race
Deficient 25-hydroxyvitamin D [25(OH)D] levels are associated with cardiovascular disease (CVD) events and mortality. Both 25(OH)D deficiency and stroke are more prevalent among blacks. We examined whether low 25(OH)D contributes to the excess risk of fatal stroke in blacks compared to whites.
Research Methods and Procedures
The Third National Health and Nutrition Examination Survey, a probability sample of US civilians, measured 25(OH)D levels and CVD risk factors between 1988–1994. Vital status through December 2006 was obtained via linkage with the National Death Index. Among white and black adults without CVD reported at baseline (n=7981), Cox regression models were fit to estimate hazard ratios (HR) for fatal stroke by 25(OH)D status and race.
During a median of 14.1 years, there were 116 and 60 fatal strokes among whites and blacks respectively. The risk of fatal stroke was greater in blacks compared to whites in models adjusted for socio-economic status and CVD risk factors, [HR 1.60 (95% CI 1.01–2.53)]. Mean baseline 25(OH)D levels were significantly lower in blacks compared to whites (19.4 vs 30.8 ng/mL, respectively). In multivariable-adjusted models, deficient 25(OH)D levels <15 ng/mL were associated with fatal stroke among whites [HR 2.13 (1.01–4.50)] but not blacks [HR 0.93 (0.49–1.80)].
Vitamin D deficiency was associated with increased risk of stroke death in whites but not blacks. Although blacks had a higher rate of fatal stroke compared to whites, the low 25(OH)D levels in blacks were unrelated to stroke incidence and therefore 25(OH)D levels did not explain this excess risk.
vitamin D; stroke; racial differences
Multiple genetic loci have been associated with blood lipid levels. We tested the hypothesis that people with an unfavorable lipid gene profile would experience a greater increase in lipid levels and a higher incidence of abnormal lipid levels, relative to those with more favorable lipid gene profiles.
Methods and Results
9,328 European-descent individuals in ARIC (ages 45–64 y) were followed for 9 years. Separate gene scores were created for each lipid phenotype based on 95 loci identified in a published GWAS of >100,000 European-descent individuals. Adjusted linear and survival models were used to estimate associations with lipid levels and incidence of lipid-lowering medication or abnormal lipid levels. Age and sex interactions were also explored. The cross-sectional difference (mg/dL) per one standard deviation (SD) was −1.89 for HDL-C, 9.5 for LDL-C, and 22.8 for triglycerides (p<5 × 10−34 for all). Longitudinally, overall triglyceride levels rose over time, and each SD greater triglyceride gene score was associated with an average increase in triglyceride levels of 0.3 mg/dL (p=0.003) over 3-years. The HDL-C, LDL-C and total cholesterol gene scores were not related to change. All lipid gene scores were positively related to incidence of abnormal lipid levels over follow-up (HRs per SD ranged from 1.15–1.36).
Associations of genetic variants with lipid levels over time are complex, with the triglyceride gene score positively related to change in triglycerides levels. Similar longitudinal results were not observed for LDL-C or HDL-C levels. Unfavorable gene scores were nevertheless related to higher incidence of abnormal levels.
lipids; longitudinal trends; gene score; Atherosclerosis Risk in Communities (ARIC)
To testthe hypothesis that inflammation measured by white blood cell count (WBC) and C-reactive protein (CRP) is associated positively with incident heart failure (HF).
Using the Atherosclerosis Risk in Communities (ARIC) Study, we conducted separate Cox proportional hazards regression analyses for WBC (measured 1987 to 1989) and CRP (measured 1996 to 1998) in relation to subsequent heart failure occurrence. A total of 14,485 and 9,978 individuals were included in the WBC and CRP analyses, respectively.
There were 1647 participants that developed HF during follow up after WBC assessment and 613 developed HF after CRP assessment. After adjustment for demographic variables and traditional HF risk factors, the hazard ratio (95% CI)for incident HF across quintiles of WBC was 1.0, 1.10 (0.9-1.34), 1.27(1.05-1.53), 1.44(1.19-1.74), and 1.62(1.34-1.96) (p trend <0.001); hazard ratio across quintiles of CRP was 1.0, 1.03 (0.68-1.55), 0.99 (0.66-1.51), 1.40 (0.94-2.09) and 1.70 (1.14-2.53) (p trend 0.002). Granulocytes appeared to drive the relation between WBCs and heart failure [hazard ratios across quintiles: 1.0, 0.93(0.76-1.15), 1.26 (1.04-1.53), 1.67(1.39-2.01) and 2.19 (1.83-2.61) (p trend <0.0001)], while lymphocytes or monocytes were not related.
Greater levels of WBC (especially granulocytes) and CRP are associated with increased risk of heart failure in middle-aged adults, independent of traditional risk factors.
Prospective Study; Risk Factors; Heart Failure; Inflammation; C-Reactive Protein; Leukocytes; Granulocytes
Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.
arteries; cardiovascular diseases; elasticity; risk factors
To estimate the prevalence of ideal cardiovascular health and its relation to incident cardiovascular disease (CVD).
An American Heart Association committee recently set a goal to improve the cardiovascular heath of Americans by 20% by 2020. The committee developed definitions of “ideal,” “intermediate,” or “poor” cardiovascular health for adults and children based on seven CVD risk factors or health behaviors.
We used data from the Atherosclerosis Risk in Communities (ARIC) Study cohort, aged 45–64 years, to estimate the prevalence of ideal cardiovascular health in 1987–89 and the corresponding incidence rates of CVD. Incident CVD comprised stroke, heart failure, myocardial infarction, or fatal coronary disease.
Among 12,744 participants initially free of CVD, only 0.1% had ideal cardiovascular health, 17.4% had intermediate cardiovascular health, and 82.5% had poor cardiovascular health. CVD incidence rates through 2007 showed a graded relation with the ideal, intermediate, and poor categories and with the number of ideal health metrics present: rates were one tenth as high in those with six ideal health metrics (3.9 per 1,000 person-years) compared with zero ideal health metrics (37.1 per 1,000 person-years).
In this community-based sample, few adults in 1987–9 had ideal cardiovascular health by the new AHA definition. Those who had the best levels of cardiovascular health nevertheless sustained relatively few events. Clearly, to achieve the AHA goal of improving cardiovascular health by 20% by 2020, we will need to redouble nationwide primordial prevention efforts at the population and individual levels.
epidemiology; risk factors; cardiovascular disease; stroke; coronary disease
Background. The incidence of venous thromboembolism (VTE) is increased with severe kidney disease, but whether less-severe chronic kidney disease (CKD) increases the risk of VTE is less certain.
Methods. We studied this in a prospective cohort of 10 700 whites and African Americans, aged 53–75 years, attending Visit 4 (1996–98) of the Atherosclerosis Risk in Communities Study. Estimated glomerular filtration rate (eGFR) values were estimated from prediction equations based on serum creatinine (eGFRcreat) or cystatin C (eGFRcys). Normal kidney function was defined as eGFR ≥90 ml/min/1.73 m2, mildly decreased kidney function as eGFR between 60 and 89 ml/min/1.73 m2 and Stage 3 to 4 CKD as eGFR between 15 and 59 ml/min/1.73 m2. VTE occurrence (n = 228) was ascertained over a median of 8.3 years.
Results. For eGFRcys, the age-, race- and sex-adjusted hazard ratios of total VTE were 1.0, 1.40 and 1.94 (P trend = 0.003) for normal kidney function, mildly impaired kidney function and Stage 3 to 4 CKD, respectively. These respective hazard ratios were moderately attenuated to 1.0, 1.26 and 1.60 (P trend = 0.04) with adjustment for hormone replacement therapy, diabetes and body mass index. Associations between CKD based on eGFRcys and VTE were slightly stronger for idiopathic VTE than for secondary VTE. In contrast, CKD based on eGFRcreat was not associated with total VTE occurrence.
Conclusions. Stage 3 to 4 CKD, based on eGFRcys but not eGFRcreat, was associated with an approximately 1.6-fold increased risk of VTE.
chronic kidney disease; prospective study; pulmonary embolism; venous thromboembolism
To document the incidence, case-fatality, and recurrence of venous thromboembolism (VTE) in women, and to explore the relation of demographic, lifestyle, and anthropometric factors to VTE incidence.
In 1986 Iowa women aged 55–69 completed a mailed survey. These data were linked to Medicare data for 1986–2004 (n=40,377) to identify hospitalized VTE cases. Cox regression adjusted for age, education, smoking status, physical activity, and BMI.
2,137 women developed VTE, yielding an incidence rate of 4.04/1,000 person-years. The 28-day case-fatality was 7.7% and the 1-year recurrence, 3.4%. Educational attainment and age-at-menopause were inversely associated with VTE, as was physical activity, prior to BMI adjustment. The risk of secondary (particularly cancer-related) VTE was increased in smokers compared with never smokers. BMI, waist circumference, waist-hip-ratio height, and diabetes were positively associated with VTE risk. Hormone replacement therapy use was associated with increased risk of idiopathic VTE, while parity was unrelated.
VTE is a significant source of morbidity and mortality in older women. Risk was elevated among women who were smokers, physically inactive, overweight, and diabetic, indicating that lifestyle contributes to VTE risk.
The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n=462 in ARIC and n=174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated GFR, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% CI = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (versus above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.
albumin; prospective study; pulmonary embolism; venous thrombosis
The authors used data from the Multi-Ethnic Study of Atherosclerosis and latent trajectory class modeling to determine patterns of neighborhood poverty over 20 years (1980–2000 residential history questionnaires were geocoded and linked to US Census data). Using these patterns, the authors examined 1) whether trajectories of neighborhood poverty were associated with differences in the amount of subclinical atherosclerosis (common carotid intimal-media thickness) and 2) associated risk factors (body mass index, hypertension, diabetes, current smoking) at baseline (January 2000–August 2002). The authors found evidence of 5 stable trajectory groups with differing levels of neighborhood poverty (∼6%, 12%, 20%, 30%, and 45%) and 1 group with 29% poverty in 1980 and approximately 11% in 2000. Mostly for women, higher cumulative neighborhood poverty was generally significantly associated with worse cardiovascular outcomes. Trends generally persisted after adjustment for adulthood socioeconomic position and race/ethnicity, although they were no longer statistically significant. Among women who had moved during the 20 years, the long-term measure had stronger associations with outcomes (except smoking) than a single, contemporaneous measure. Results indicate that cumulative 20-year exposure to neighborhood poverty is associated with greater cardiovascular risk for women. In residentially mobile populations, single-point-in-time measures underestimate long-term effects.
body mass index; carotid artery, internal; diabetes mellitus; hypertension; models, statistical; residential mobility; retrospective studies; smoking
To examine the associations of three understudied hemostatic factors – D-dimer, factor VIIIc, and antiplasmin (PAP) complex -- with incident CVD and all cause mortality in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Hemostatic factors were measured at baseline in 45–84 year olds (n =6,391) who were free of clinically recognized CVD. Over 4.6 years of follow-up, we identified 307 CVD events, 207 hard coronary heart disease (CHD) events, and 210 deaths. D-dimer, factor VIIIc, and PAP were not associated with CVD incidence after adjustment for other risk factors. In contrast, each factor was associated positively with total mortality, and D-dimer and factor VIIIc were associated positively with cancer mortality. When modeled as ordinal variables and adjusted for risk factors, total mortality was greater by 33% (95% CI = 15–54%) for each quartile increment of D-dimer, 26% (11–44%) for factor VIIIc, and 20% (4–38%) for PAP. This prospective cohort study did not find D-dimer, factor VIIIc, or PAP to be risk factors for CVD. Instead, elevated levels of these three hemostatic factors were associated independently with increased risk of death. Elevated D-dimer and factor VIIIc were associated with increased cancer death.
cancer; cardiovascular disease; CHD; D-dimer; factor VIII; plasmin-antiplasmin
The role of inflammation in the causation of venous thromboembolism (VTE) is uncertain. In 10,505 participants of the Atherosclerosis Risk in Communities (ARIC) Study, we assessed the association of the systemic inflammation marker, elevated C-reactive protein (CRP), with incidence of VTE (n=221) over a median of 8.3 years of follow-up. Adjusted for age, race, and sex, the hazard ratios of VTE across quintiles of CRP were 1.0, 1.61, 1.16, 1.56, and 2.31 (p for trend p<0.0007). For CRP above the upper 10 percentile (≥8.55 mg/L), compared with the lowest 90% of CRP values, the hazard ratio of VTE was 2.07 (95% CI 1.47, 2.94). Further adjustment for baseline hormone replacement therapy, diabetes, and body mass index attenuated the hazard ratios only slightly. For example, the adjusted hazard ratio of VTE was 1.76 (95% CI 1.23, 2.52) for CRP above versus below the 90th percentile. In conclusion, this prospective, population-based study suggests elevated CRP is independently associated with increased risk of VTE.
C-reactive protein; prospective study; pulmonary embolus; venous thrombosis
Tissue factor pathway inhibitor (TFPI) inhibits tissue factor, a potent coagulation initiator. Limited evidence suggests that low TFPI levels are associated with increased risk of venous thrombosis (VTE). We measured total TFPI in a nested case-control study in the Longitudinal Investigation of Thromboembolism Etiology. Control subjects were frequency matched 2:1 to cases on age, sex, race, and cohort. Odds ratio for VTE by TFPI levels were computed using logistic regression models adjusting for age, race, sex, coagulation factors (factors VII, VIII, IX, XI, D-dimer), and body mass index. To evaluate for greater than additive interactions, we calculated the percent relative excess risk due to interaction between TFPI and other VTE risk factors. 534 cases of VTE occurred and matched to 1091 controls. Mean baseline TFPI in ng/mL (standard deviation) in those who developed VTE and controls was 36.4 (12.8) and 35.0 (11.1), respectively. Higher TFPI was associated with male sex, age, body mass index, factors VII, VIII, IX, XI, and D-dimer. TFPI level did not differ by ethnicity, factor V Leiden, or prothrombin G20210A. Compared with those in the upper 95%, the bottom 5% of TFPI had an age-, sex-, race-, and study-adjusted odds ratio (95% CI) of 1.35 (0.86, 2.12) for VTE. Adjusting for factors VII, VIII, IX, and XI the odds ratio was 1.93 (1.05, 3.53). Further addition of D-dimer and BMI to this model the odds ratio was 1.70 (0.98, 2.93). Low TFPI did not demonstrate greater than additive interaction with other VTE risk factors.
Venous Thrombosis; Tissue Factor Pathway Inhibitor; Epidemiologic Studies
Reduction in arterial elasticity marks progression toward cardiovascular morbidity and mortality. Variability in arterial elasticity may help account for race/ethnic and gender differences in cardiovascular risk.
Whites, African Americans, Hispanics and Chinese aged 45–84 years free of clinically recognized cardiovascular disease were recruited in six US communities.
We examined 3,316 women and 3,020 men according to race/ethnicity and sex.
Main Outcome Measures
Large (LAE) and small artery (SAE) elasticity, derived from radial artery diastolic pulse wave contour registration in all subjects in a supine position using tonometry. LAE and SAE were adjusted for ethnicity, age, clinical site, height, heart rate, blood pressure, antihypertensive medication and body mass index, diabetes, smoking, and circulating lipids.
Much of the sex difference in arterial elasticity was explained by height. After adjustment, LAE did not differ by race/ethnicity, but mean SAE in African Americans was 4.2 mL/mm Hg × 100 and 4.4 mL/mm Hg × 100 in Hispanics compared to means of 4.6 mL/mm Hg × 100 in Whites, and 4.8 mL/mm Hg × 100 in Chinese.
Reduced SAE may indicate earlier vascular disease in African Americans and Hispanics than other groups.
Blood Pressure; Arterial Elasticity; MESA Study
We determined associations between diet soda consumption and risk of incident metabolic syndrome, its components, and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis.
RESEARCH DESIGN AND METHODS
Diet soda consumption was assessed by food frequency questionnaire at baseline (2000–2002). Incident type 2 diabetes was identified at three follow-up examinations (2002–2003, 2004–2005, and 2005–2007) as fasting glucose >126 mg/dl, self-reported type 2 diabetes, or use of diabetes medication. Metabolic syndrome (and components) was defined by National Cholesterol Education Program Adult Treatment Panel III criteria. Hazard ratios (HRs) with 95% CI for type 2 diabetes, metabolic syndrome, and metabolic syndrome components were estimated, adjusting for demographic, lifestyle, and dietary confounders.
At least daily consumption of diet soda was associated with a 36% greater relative risk of incident metabolic syndrome and a 67% greater relative risk of incident type 2 diabetes compared with nonconsumption (HR 1.36 [95% CI 1.11–1.66] for metabolic syndrome and 1.67 [1.27–2.20] for type 2 diabetes). Of metabolic syndrome components, only high waist circumference (men ≥102 cm and women ≥88 cm) and high fasting glucose (≥100 mg/dl) were prospectively associated with diet soda consumption. Associations between diet soda consumption and type 2 diabetes were independent of baseline measures of adiposity or changes in these measures, whereas associations between diet soda and metabolic syndrome were not independent of these factors.
Although these observational data cannot establish causality, consumption of diet soda at least daily was associated with significantly greater risks of select incident metabolic syndrome components and type 2 diabetes.
An understanding of the relation in adolescents between serum homocysteine and foods rich in vitamin B-6, vitamin B-12, and folate is important because high homocysteine concentrations in childhood and adolescence may be a risk factor for later cardiovascular disease. However, little is known about the relation between food intake and homocysteine in adolescents.
Five years after national folic acid fortification of enriched grain products, cross-sectional relations between food intake and serum homocysteine concentrations were examined in 2695 adolescents [x̄ age: 18.3 (range: 15−20) y] enrolled in the Child and Adolescent Trial for Cardiovascular Health.
A nonfasting blood specimen was analyzed for serum homocysteine, folate, and vitamins B-6 and B-12. Dietary intake was assessed by using a food-frequency questionnaire. Multiple regression analyses were used to evaluate the relation of intakes of whole grains, refined grains, fruit, vegetables, dairy products, red and processed meats, and poultry with serum homocysteine concentrations after adjustment for demographic characteristics, lifestyle factors, and food intake.
Serum homocysteine concentrations were lower with greater intakes of whole grains (P for trend = 0.002), refined grains (P for trend = 0.02), and dairy foods (P for trend <0.001); were higher with greater intake of poultry (P for trend = 0.004); and were not related to intakes of fruit, vegetables, or red or processed meat. After additional adjustment for serum B vitamins, the relations of serum homocysteine with most food groups were attenuated.
These observational findings suggest a beneficial effect of whole-grain, refined-grain, and dairy products on serum homocysteine concentrations in an adolescent population.
Homocysteine; serum folate; cardiovascular disease; adolescents; food groups; whole grain