Hemostatic factors as predictors of coronary events and total mortality: The FINRISK '92 Hemostasis Study

The role of hemostatic factors as predictors of coronary heart disease (CHD) and total mortality is poorly understood. Therefore, we carried out a prospective cohort study in Finland. In 1992, a random population sample of 2378 men and women aged 45 to 64 years was investigated and then followed up until December 31, 1998. During the follow-up, 133 CHD events were observed; 73 were among participants free of CHD at baseline. The total number of deaths was 124. After adjustment for traditional risk factors and prevalent CHD at baseline and correction for regression dilution bias, a 1-SD increase in plasminogen was associated with a 1.41-fold (95% CI 1.09 to 1.81) increase in CHD risk. The predictive power of plasminogen depended significantly on the level of total cholesterol being stronger for persons with high cholesterol. A 1-SD increase in fibrinogen was associated with a 1.23-fold (95% CI 1.05 to 1.44) increase in all-cause mortality, but its association with CHD events did not reach statistical significance. Factor VII antigen or coagulant activity or lipoprotein(a) were not independent predictors of CHD risk. These findings support the role of plasminogen as a risk factor for CHD events.     

Prognostic value of T‐wave morphology parameters in coronary artery disease in current treatment era

Background

The prognostic value of T‐wave morphology parameters in coronary artery disease in the current treatment era is not well established.

Methods

The Innovation to reduce Cardiovascular Complications of Diabetes at the Intersection (ARTEMIS) study included 1,946 patients with angiographically verified coronary artery disease (CAD). The study patients underwent thorough examinations including 12‐lead digital electrocardiogram (ECG) at baseline.

Results

During a follow‐up period of 73 ± 22 months, a total of 201 (10.3%) patients died. Of the study patients, 95 (4.9%) experienced cardiac death (CD) consisting of 44 (2.3%) sudden cardiac deaths (SCD) and 51 (2.6%) nonsudden cardiac deaths (NSCD), and 106 (5.4%) patients experienced noncardiac death (NCD). T‐wave morphology dispersion (TMD), T‐wave area dispersion (TWAD), and total cosine R‐to‐T (TCRT) had a significant association with CD even after adjustment with relevant clinical risk markers in the Cox regression analysis (multivariate HRs: 1.015, 95% CI 1.007–1.023, p = .0003; 0.474, 95% CI 0.305–0.737, p = .0009; 0.598, 95% CI 0.412–0.866, p = .006, respectively). When including these parameters to the clinical risk model for CD, the C‐index increased from 0.810 to 0.823 improving the discrimination significantly (integrated discrimination index [IDI] = 0.0118, 95% CI 0.0028–0.0208, p = .01). These parameters were more closely associated with NSCD (multivariate p‐values from .016 to .001) than with SCD (univariate/multivariate p‐values for TMD .015/.197 and for TCRT .012/.43).

Conclusion

T‐wave morphology parameters describing repolarization heterogeneity improve the predictive power of the clinical risk model for CD in patients with CAD in the current treatment era.

     

Increased carotid atherosclerosis in andropausal middle-aged men

OBJECTIVES: This study examined the association between carotid artery intima-media thickness (IMT), serum sex hormone levels, and andropausal symptoms in middle-aged men. BACKGROUND: Male sex hormones may play a dual role in the pathogenesis of atherosclerosis in men by carrying both proatherogenic and atheroprotective effects. METHODS: We studied 239 40- to 70-year-old men (mean +/- SD: 57 +/- 8 years) who participated in the Turku Aging Male Study and underwent serum lipid and sex hormone measurements. Ninety-nine men (age 58 +/- 7 years) were considered andropausal (i.e., serum testosterone <9.8 nmol/l or luteinizing hormone [LH] >6.0 U/l and testosterone in the normal range), and in both situations, they had subjective symptoms of andropause (a high symptom score in questionnaire). Three were excluded because of diabetes. The rest of the men (age 57 +/- 8 years) served as controls. Carotid IMT was determined using high-resolution B-mode ultrasound, and serum testosterone, estradiol (E2), LH, and sex hormone-binding globulin were measured using standard immunoassays. RESULTS: Andropausal men had a higher maximal IMT compared with controls in the common carotid (1.08 +/- 0.34 vs. 1.00 +/- 0.23, p < 0.05) and in the carotid bulb (1.44 +/- 0.48 vs. 1.27 +/- 0.35, p = 0.003). Common carotid IMT correlated inversely with serum testosterone (p = 0.003) and directly with LH (p = 0.006) in multivariate models adjusted for age, total cholesterol, body mass index, blood pressure, and smoking. CONCLUSIONS: Middle-aged men with symptoms of andropause, together with absolute or compensated (as reflected by high normal to elevated LH) testosterone deficiency, show increased carotid IMT. These data suggest that normal testosterone levels may offer protection against the development of atherosclerosis in middle-aged men.     

Plasma asymmetric dimethylarginine and hyperemic myocardial blood flow in young subjects with borderline hypertension or familial hypercholesterolemia

OBJECTIVE: The goal of this study was to examine the relationship between plasma asymmetric dimethylarginine (ADMA) level and hyperemic myocardial blood flow (MBF) in subjects with borderline hypertension (BHT) and familial hypercholesterolemia (FH). METHODS: Asymmetric dimethylarginine is an endogenous competitive inhibitor of nitric oxide synthase that may modulate vascular function.We measured plasma ADMA levels and myocardial flow in 77 young men (mean age 35 +/- 5 years), including 47 healthy controls, 16 men with BHT, and 14 men with FH. Basal and dipyridamole-induced myocardial flow was measured using positron emission tomography. Plasma ADMA levels were measured using high-pressure liquid chromatography. RESULTS: Asymmetric dimethylarginine levels were significantly elevated in the BHT group compared with controls (0.59 +/- 0.13 micromol/l vs. 0.43 +/- 0.12 micromol/l, p < 0.001), and they had significantly lower dipyridamole flow (2.85 +/- 1.20 ml/min/g vs. 3.69 +/- 1.68 ml/min/g, p < 0.05). In a multivariate regression model adjusted for the study group, dipyridamole flow was inversely associated with ADMA (p < 0.05), age (p < 0.05), and apolipoprotein B concentration (p < 0.05). CONCLUSIONS: We conclude that plasma ADMA concentration is related to dipyridamole-induced vasodilatory function in young men, independently of blood pressure elevation and hypercholesterolemia. Subjects with BHT have significantly increased plasma ADMA levels, which may partly explain the impaired hyperemic MBF in this condition.     

The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

Aims

Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).

Methods

In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20 mg day⁻¹ (n = 15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α-epoxycholesterol ratios were used as negative controls.

Results

Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference –0.069, –0.0067). The ratios of 25-hydroxycholesterol and 5α,6α-epoxycholesterol to cholesterol did not change.

Conclusions

The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations.     

Effects of dietary sodium on reactive oxygen species formation and endothelial dysfunction in low-density lipoprotein receptor-deficient mice on high-fat diet

Hypertension and high serum cholesterol level are important risk factors for atherosclerosis and coronary heart disease. In the present study we tested the hypothesis whether high sodium intake, when given in combination with Western type high-fat diet, induces endothelial dysfunction and promotes atherosclerosis. Furthermore, the role and enzyme sources of increased oxidative stress were examined. Low-density lipoprotein receptor-deficient mice (LDLR^−/−) and control C57Bl/6 mice received either high-fat, normal-sodium diet (fat 18% and cholesterol 0.5%; NaCl 0.7%; w/w) or high-fat, high-sodium diet (7% NaCl w/w) for 12 weeks. Superoxide formation was assessed by lucigenin enhanced chemiluminescence, endothelial functions were examined ex vivo, and atherosclerotic lesions from the aorta were assessed by light microscopy. High-fat, high-sodium diet increased systolic blood pressure in LDLR^−/− mice but not in C57Bl/6 mice, whereas it induced cardiac hypertrophy in both mouse strains. Dietary combination of fat and sodium induced endothelial dysfunction in LDLR^−/− mice. Preincubation with a superoxide scavenger Tiron normalized endothelial dysfunction, whereas the hydrogen peroxide scavenger catalase did not alter endothelial function. High sodium intake induced superoxide formation in LDLR^−/− mice on high-fat diet. Stimulation of muscarinic receptors in the endothelial cells by acetylcholine increased superoxide generation, whereas preincubation with the nitric oxide synthase (NOS) inhibitor L-arginine methyl ester or endothelium removal reduced superoxide production. Inhibition of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase by apocynin decreased vascular superoxide formation whereas the xanthine oxidase inhibitor oxypurinol did not significantly affect oxidative stress in LDLR^−/− mice. In conclusion, the detrimental effects of dietary sodium on endothelial function and progression of atherosclerosis in LDLR^−/− mice on high-fat diet are mediated by increased ROS formation mainly through uncoupled NOS and NADPH oxidase. The present study also underscores the importance of superoxide and endothelial NOS uncoupling in the pathogenesis of endothelial dysfunction.     

Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer's parents

This study examines the relationship between fibrillar beta-amyloid (Aβ) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40–80-year-old NL received positron emission tomography (PET) with ¹¹C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ −0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aβ deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9–5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aβ increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.