Plasma fibrin D-dimer levels and risk of stable coronary artery disease: results of a large case-control study

Increased levels of fibrin D-dimer are indicative of a hypercoagulable state, as found in acute coronary syndromes. Few well-controlled studies have assessed D-dimers in patients with stable coronary artery disease (CAD). We measured levels of D-dimers (in ng/mL by enzyme-linked immunosorbent assay) in 312 patients with angiographically proved CAD and stable angina pectoris and in 477 age- and sex-matched healthy blood donors. Demographic characteristics were assessed by a standardized questionnaire, and a complete lipid profile was performed for all subjects. In addition, a variety of other markers of hemostasis and inflammation were measured. The distribution of D-dimer levels was skewed to the right, and plasma median levels were higher in cases than in controls (median: 11.2 vs 2.8 ng/mL; P<0.001). In controls, correlations of D-dimer were found with fibrinogen, plasma viscosity, and interleukin-6. In logistic regression analysis, the age- and sex-adjusted odds ratio (OR) for the presence of CAD was 2.6 (95% confidence interval [CI], 1.9 to 3.5) when the highest quartile of the D-dimer distribution was compared with the combined lower 3 quartiles. The OR did not change appreciably after controlling for nonlipid risk factors (OR, 2.7; 95% CI, 1.9 to 3.9) and remained significant after further adjustment for other hemostatic parameters (OR, 2.4; 95% CI, 1.7 to 3.3) and markers of inflammation (OR, 2.1; 95% CI, 1.5 to 2.9). Plasma D-dimer levels are strongly and independently associated with the presence of CAD in patients with stable angina pectoris. These results support the concept of a contribution of intravascular fibrin to atherothrombogenesis.     

Predictive value of C-reactive protein on 30-day and 1-year mortality in acute coronary syndromes: an analysis from the ACUITY trial

We sought to evaluate the association between C-reactive protein (CRP) sampled on admission and short- and long-term mortality in patients with acute coronary syndromes (ACS) undergoing early invasive treatment. Baseline levels of CRP were determined in 2,974 patients with moderate and high-risk ACS undergoing an early invasive treatment strategy in the large-scale randomized ACUITY trial. The relationship of CRP to 30-day and 1-year clinical outcomes were assessed according to quartiles of CRP values. Patients with CRP levels in the fourth quartile compared to the first quartile had significantly higher 30-day mortality (2.3 vs. 0.3%, P = 0.0004) and 1-year mortality (5.5 vs. 2.8%, P = 0.0003). CRP level as a continuous variable was associated with 30-day mortality (OR [95% CI] for one unit increase in logarithmically transformed CRP level = 1.42 [1.08-1.89], P = 0.01) and 1-year mortality (OR [95% CI] = 1.24, [1.04-1.47], P = 0.02). By multivariable analysis, higher baseline CRP levels independently predicted 30-day and 1-year mortality, a relationship that was particularly strong for patients with the highest quartile of CRP (OR [95% CI] = 5.19 [1.14-23.68], P = 0.009). In troponin-positive patients, increasing quartiles of CRP were associated with a trend for 30-day mortality (P (trend) = 0.08) and a significant increase in 1-year mortality (P (trend) = 0.02); this relationship was not present in troponin-negative patients. Baseline CRP level is a powerful independent predictor of both early and late mortality in patients with ACS being treated with an early invasive strategy, especially in troponin positive patients.     

Inflammation and Thrombosis Biomarkers and Incident Frailty in Postmenopausal Women

Background

The immune and blood coagulation systems have been implicated in the pathophysiology of the geriatric syndrome of frailty, but limited prospective data examining the relationship of clotting/inflammation biomarkers to risk of incident frailty exist.

Methods

This prospective analysis was derived from a nested case-control study within the Women's Health Initiative. Among women 65 to 79 years free of frailty at enrollment, we randomly selected 900 incident cases from those developing frailty within 3 years; 900 non-frail controls were individually matched on age, ethnicity, and blood collection date. Biomarkers assessed for risk of incident frailty included fibrinogen, factor VIII, D-dimer, C-reactive protein, interleukin-6, and tissue plasminogen activator (t-PA).

Results

When examined by quartiles in multivariable adjusted models, higher D-dimer and t-PA levels were each associated with increased risk of frailty (P trend = .04). Relative to the lowest quartile, the odds ratios for frailty compared with the upper quartile were 1.52 (95% confidence interval, 1.05-2.22) for t-PA and 1.57 (95% confidence interval, 1.11-2.22) for D-dimer. For women having high t-PA and high D-dimer compared with women having lower levels of both biomarkers, the odds of frailty was 2.20 (1.29-3.75). There was little evidence for association between coagulation factor VIII, fibrinogen, C-reactive protein, or interleukin-6 levels and incident frailty.

Conclusion

This prospective analysis supports the role of markers of fibrin turnover and fibrinolysis as independent predictors of incident frailty in postmenopausal women.     

The Relationship of Psychosocial Factors to Total Mortality Among Older Japanese-American Men: The Honolulu Heart Program

OBJECTIVE: To examine the predictive value of psychosocial factors as risk factors for all-cause mortality. DESIGN: A community-based longitudinal cohort study: The Honolulu Heart Program. SETTING: Population-based study conducted in Oahu, Hawaii. PARTICIPANTS: Three thousand four hundred and ninety-seven men age 71 to 93 were examined and followed prospectively for all-cause mortality for an average of 6 years. MEASUREMENTS: Psychosocial data were obtained using the Lubben Social Networks Scale (LSNS). The LSNS consists of 10 items-family relationships (three items), relationships with friends (three items), and interdependent social supports and living arrangements (four items). We divided the LSNS score into quartiles for comparison, with the first quartile representing the lowest social support and the fourth quartile representing the highest social support. RESULTS: A significant dose-response relationship was noted with LSNS score and total mortality: 33.8% in the first quartile died over the follow-up period, 23.4% in the second, 18% in the third, and 15.7% in the fourth (P < .001). Six-year age-adjusted mortality rates were 66.2, 45.7, 37.8, and 33.7 per 1,000 person years in the first, second, third, and fourth, respectively (P < .001). Using age-adjusted Cox proportional hazards models, with the first quartile of LSNS as the reference group, relative risk for mortality was 0.69 (95% confidence interval (CI) = 0.58-0.82), 0.57 (95% CI = 0.47-0.70), and 0.52 (95% CI = 0.43-0.64) in the second, third, and fourth quartiles, respectively. Cox models were repeated, controlling for age and smoking status, and low LSNS scores remained significantly associated with higher mortality (P = .0001). CONCLUSIONS: Our findings suggest that social networks were significantly independently associated with 6-year all-cause mortality in this cohort of older Japanese-American men. Social interventions in old age may reduce early mortality.     

Renal function and cardiovascular mortality in elderly men: the role of inflammatory, procoagulant, and endothelial biomarkers.

AIMS: To assess the extent to which inflammatory, procoagulant, and endothelial biomarkers modify the relationship between diminished renal function and cardiovascular mortality. METHODS AND RESULTS: Prospective study of 4029 men aged 60-79 years followed up for a mean period of 6 years, during which 304 cardiovascular deaths occurred. Predicted estimated glomerular filtration rate (eGFR) was used as a measure of renal function. Reduced eGFR was associated with increased prevalence of established cardiovascular risk factors [cardiovascular disease, diabetes, hypertension, left ventricular (LV) hypertrophy, and dyslipidaemia] and higher levels of inflammatory markers [interleukin 6 (IL-6), C-reactive protein], endothelial markers [von Willebrand factor (vWF) and tissue plasminogen activator], activated coagulation markers (fibrin D-dimer), and blood viscosity. Cardiovascular mortality risk increased with decreasing levels of eGFR, particularly among men with eGFR <60 mL/min per 1.73 m(2) even after adjustment for established risk factors (adjusted RR 1.49, 95% CI 1.10, 2.03; <60 vs. > or =70 mL/min per 1.73 m(2)). The association was attenuated after further adjustment for vWF, D-dimer, and IL-6 (adjusted RR 1.34, 95% CI 0.98-1.82). CONCLUSION: Mild-to-moderate renal insufficiency is associated with significantly increased cardiovascular mortality in elderly men, which is partly explained by the increased prevalence of established risk factors, markers of coagulation, endothelium, and inflammation.     

Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.

PURPOSE: To investigate whether interleukin-6 and C-reactive protein levels predict all-cause and cause-specific mortality in a population-based sample of nondisabled older people. SUBJECTS AND METHODS: A sample of 1,293 healthy, nondisabled participants in the Iowa 65+ Rural Health Study was followed prospectively for a mean of 4.6 years. Plasma interleukin-6 and C-reactive protein levels were measured in specimens obtained from 1987 to 1989. RESULTS: Higher interleukin-6 levels were associated with a twofold greater risk of death [relative risk (RR) for the highest quartile (> or = 3.19 pg/mL) compared with the lowest quartile of 1.9 [95% confidence interval, CI, 1.2 to 3.1]). Higher C-reactive protein levels (> or = 2.78 mg/L) were also associated with increased risk (RR = 1.6; CI, 1.0 to 2.6). Subjects with elevation of both interleukin-6 and C-reactive protein levels were 2.6 times more likely (CI, 1.6 to 4.3) to die during follow-up than those with low levels of both measurements. Similar results were found for cardiovascular and noncardiovascular causes of death, as well as when subjects were stratified by sex, smoking status, and prior cardiovascular disease, and for both early (<2.3 years) and later follow-up. Results were independent of age, sex, body mass index, and history of smoking, diabetes, and cardiovascular disease, as well as known indicators of inflammation including fibrinogen and albumin levels and white blood cell count. CONCLUSIONS: Higher circulating levels of interleukin-6 and C-reactive protein were associated with mortality in this population-based sample of healthy older persons. These measures may be useful for identification of high-risk subgroups for anti-inflammatory interventions.     

DHEAS levels and mortality in disabled older women: the Women's Health and Aging Study I

BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) is an endogenously produced sex steroid that has been hypothesized to have anti-aging effects. Low DHEAS levels are associated with mortality in older men, but the relationship between DHEAS levels and mortality in women is not clearly defined. METHODS: The relationship between serum DHEAS level and 5-year mortality was analyzed in a cohort of 539 disabled women aged 65-100 years enrolled in the Women's Health and Aging Study I (WHAS I). Using Cox proportional hazard models, we calculated multivariate-adjusted mortality risks by DHEAS quartiles and by DHEAS continuously, allowing for a nonlinear relationship. We also examined cause-specific mortality. RESULTS: We found a U-shaped relationship between DHEAS level and mortality. After adjusting for multiple covariates, women in the top and bottom DHEAS quartiles had a more than 2-fold higher 5-year mortality than did those in the middle quartiles (hazard ratio, 2.15; 95% confidence interval [CI], 1.17-3.98 for the top quartile and 2.05; 95% CI, 1.27-3.32 for the bottom quartile, each compared to the third quartile). Women with higher DHEAS levels tended to have greater cancer mortality, whereas those with lower DHEAS tended to have greater cardiovascular mortality. CONCLUSION: Disabled older women with either low or high levels of DHEAS are at greater risk for death than are those with intermediate levels. More research is needed to determine if targeted dehydroepiandrosterone supplementation would provide clinical benefit to disabled older women.     

Pulse pressure and effects of losartan or atenolol in patients with hypertension and left ventricular hypertrophy

In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, the primary composite end point of cardiovascular death, stroke, and myocardial infarction was reduced by losartan versus atenolol in patients with hypertension and left ventricular hypertrophy. The objective of this post hoc analysis was to determine the influence of pulse pressure on outcome. Patients were divided into quartiles of baseline pulse pressure. Cox regression, including baseline Framingham risk score as a covariate, was used to compare risk in the quartiles. In the atenolol group, there were significantly higher risks in the highest versus lowest quartile for the composite end point 28% (confidence interval [CI], 2% to 62%; P=0.035), stroke 84% (CI, 32% to 157%; P<0.001), and total mortality 41% (CI, 7% to 84%; P=0.013). Risk for myocardial infarction was 44% higher (CI, -5% to 120%; P=0.089). The risks in the losartan group also increased with increasing quartile, but were lower than in the atenolol group, and differences between the highest and lowest quartiles were not significant: composite end point 12% (CI, -13% to 44%; P>0.2), stroke -5% (CI, -34% to 37%; P>0.2), myocardial infarction 30% (CI, -13% to 94%; P>0.2), and total mortality 32% (CI, -1% to 76%; P=0.062). In patients with hypertension and left ventricular hypertrophy in the LIFE study, there were significantly higher risks, adjusted for the Framingham risk score, for the primary composite end point, stroke, and total mortality in the highest versus lowest quartile of pulse pressure with atenolol-based treatment. The risks in the losartan group also increased with increasing pulse pressure quartile, but were lower than those in the atenolol group, and were not significant.     

Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study.

BACKGROUND: Total homocysteine levels are associated with arteriosclerotic outcomes. OBJECTIVE: To determine whether total homocysteine levels predict incident stroke in elderly persons. DESIGN: Prospective population-based cohort study with 9.9 years of follow-up. SETTING: Framingham, Massachusetts. PATIENTS: 1947 Framingham Study participants (1158 women and 789 men; mean age +/- SD, 70 +/- 7 years). MEASUREMENTS: Baseline total homocysteine levels and 9.9-year stroke incidence. RESULTS: The quartiles of nonfasting total homocysteine levels were as follows: quartile 1, 4.13 to 9.25 micromol/L; quartile 2, 9.26 to 11.43 micromol/L; quartile 3, 11.44 to 14.23 micromol/L; quartile 4, 14.24 to 219.84 micromol/L. During follow-up, 165 incident strokes occurred. In proportional hazards models adjusted for age, sex, systolic blood pressure, diabetes, smoking, and history of atrial fibrillation and coronary heart disease, relative risk (RR) estimates comparing quartile 1 with the other three quartiles were as follows: quartile 2 compared with quartile 1--RR, 1.32 (95% CI, 0.81 to 2.14); quartile 3 compared with quartile 1--RR, 1.44 (CI, 0.89 to 2.34); quartile 4 compared with quartile 1--RR, 1.82 (CI, 1.14 to 2.91). The linear trend across the quartiles was significant (P < 0.001). CONCLUSION: Nonfasting total homocysteine levels are an independent risk factor for incident stroke in elderly persons.     

Ankle-brachial index and hemostatic markers in the Atherosclerosis Risk in Communities (ARIC) study cohort

To determine whether elevated levels of hemostatic and inflammatory markers [von Willebrand factor (vWF), fibrinogen, D-dimer, factor VII, factor VIII, PAI-1, tPA, beta-thromboglobulin (beta-TG), CRP, and WBC count] are associated with increased peripheral arterial disease (PAD) prevalence, measured by low ABI, we studied 13,778 participants from the ARIC study in a cross-sectional analysis after adjustment for major cardiovascular risk factors. PAD was positively associated with fibrinogen, vWF, factor VIII, WBC count, D-dimer, beta-TG, and CRP (p for trend <0.05) but not with the other markers. Adjusted odds ratios for the highest versus the lowest quartile of fibrinogen in men and women, respectively, were 3.49 (95% CI 1.68-7.26) and 2.44 (95% CI 1.58-3.77); for vWF 2.36 (95% CI 1.36-4.07) and 1.45 (95% CI 1.00-2.10); for factor VIII 2.31 (95% CI 1.36-3.94) and 1.68 (95% CI 1.14-2.48). In a smaller subset, the sex and risk factor adjusted odds ratio for the highest versus the lowest quartile of D-dimer was 2.70 (95% CI 1.56-4.65), for beta-TG was 1.80 (95% CI 1.12-2.88), and for CRP was 1.57 (95% CI 0.84-2.95). Plasma levels of hemostatic and inflammatory markers are elevated in PAD, suggesting these processes are involved in the pathophysiology of PAD.