Arterial wall MRI characteristics are associated with elevated serum markers of inflammation in humans.

Inflammation contributes to atherosclerosis, but assessment in humans is largely restricted to measurement of markers in blood. We determined whether MRI properties of large arteries were associated with markers of inflammation in serum. Double inversion recovery, fast spin-echo images of the common carotid arteries and infrarenal aorta were obtained at 1.5 T both before and after gadolinium-DTPA (0.1 mmol/kg) in 52 subjects > or =40 years of age, 17 of whom had no risk factors for atherosclerosis and thus served as controls. Twenty-two study participants had increases in wall thickness (14), T2-weighted signal intensity (11), and/or contrast enhancement values (7) that were >2 standard deviations (SDs) from control group mean values. Ten subjects in this group had evidence of focal plaques in the carotids (5) and/or aorta (6). Compared with the remaining 30 subjects, these 22 had significantly higher levels of interleukin-6 (3.53 +/- 2.46 vs. 1.97 +/- 1.37 pg/mL, P = 0.004), C-reactive protein (0.56 +/- 0.98 vs. 0.30 +/- 0.52 mg/dL, P = 0.019), vascular cell adhesion molecule-1 (572 +/- 153 vs. 471 +/- 130 ng/mL, P = 0.012), and intercellular adhesion molecule-1 (244 +/- 80 vs. 202 +/- 45 ng/mL, P = 0.015), and nonsignificant differences in levels of E-selectin (46.1 +/- 18.9 vs. 42.3 +/- 11.3 ng/mL, P = 0.369). Thus, MRI characteristics of the aorta and carotid arteries were associated with elevated serum markers of inflammation, frequently in the absence of definite atheroma. MRI of large arteries may provide a new approach to investigate the contribution of inflammation to atherogenesis.

Mechanism by which quinapril improves vascular function in coronary artery disease.

Angiotensin-converting enzyme (ACE) inhibition has been shown to improve endothelium-dependent vasodilator responsiveness, but the contribution and mechanism of enhanced nitric oxide (NO) bioactivity to this effect in patients with coronary artery disease are unknown. We investigated the effect of ACE inhibition on brachial artery dilator responsiveness to increased shear stress after forearm ischemia by ultrasonography as a bioassay for endothelial NO available to vascular smooth muscle in 9 men with coronary artery disease. Serum nitrogen oxides were measured after 3 days of nitrate-restricted diet as an index of endothelial NO release. Patients received quinapril 20 to 40 mg/day for 8 weeks. Relative to pretreatment measurements, quinapril increased flow-mediated dilation (from 2.4+/-0.4 to 10.8+/-2.2, p <0.001), with significant improvement persisting 1 week after discontinuation of therapy (6.7+/-2.5%, p <0.01). However, quinapril decreased serum nitrogen oxide levels by 19+/-17% compared with pretreatment values (from 58.2+/-19.0 to 46.0+/-13.3 micromol/L, p <0.01). Thus, ACE inhibitor therapy with quinapril selectively improves endothelium-dependent vasodilator responsiveness by increased NO bioactivity in relation to vascular smooth muscle in patients with coronary artery disease, an effect achieved at a lower rate of NO release from the endothelium. These findings suggest that ACE inhibitors may reduce angiotensin II-induced oxidant stress within the vessel wall and protect NO from oxidative inactivation. This effect may reduce endothelial NO synthesis required for vasomotor regulation.

Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic postmenopausal women.

BACKGROUND: Lipoproteins affect endothelium-dependent vasomotor responsiveness. Because lipoprotein effects of estrogen and cholesterol-lowering therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic postmenopausal women. METHODS AND RESULTS: We randomly assigned 28 women to conjugated equine estrogen (CE) 0.625 mg, simvastatin 10 mg, and their combination daily for 6 weeks. Compared with respective baseline values, simvastatin alone and combined with CE reduced LDL cholesterol to a greater extent than CE alone (both P<0.05). CE alone and combined with simvastatin raised HDL cholesterol and lowered lipoprotein(a) to a greater extent than simvastatin alone (all P<0.05). Flow-mediated dilation of the brachial artery (by ultrasonography) improved (all P<0.001 versus baseline values) on CE (4.0+/-2.6% to 10.2+/-3.9%), simvastatin (4.3+/-2.4% to 10.0+/-3.9%), and CE combined with simvastatin (4.6+/-2.0% to 9.8+/-2.6%), but similarly among therapies (P=0.507 by ANOVA). None of the therapies improved the dilator response to nitroglycerin (all P>/=0.184). Only therapies including CE lowered levels of plasminogen activator inhibitor type 1 and the cell adhesion molecule E-selectin (all P<0. 05 versus simvastatin). CONCLUSIONS: Although estrogen and statin therapies have differing effects on lipoprotein levels, specific improvement in endothelium-dependent vasodilator responsiveness is similar. However, only therapies including estrogen improved markers of fibrinolysis and vascular inflammation. Thus, estrogen therapy appears to have unique properties that may benefit the vasculature of hypercholesterolemic postmenopausal women, even if they are already on cholesterol-lowering therapy.

Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women.

To investigate the effect of estrogen with antioxidant potential on soluble markers of chronic vascular inflammation, we administered either transdermal 17beta-estradiol 0.1 mg/day (9 women) or 17beta-estradiol 0.1 mg and medroxyprogesterone acetate 2.5 mg/day (11 women) for 1-month treatment in a randomized design, with measurement of cell adhesion molecules. Hormone therapy significantly lowered intercellular adhesion molecules-1 levels by 8% (p = 0.009) and tended to lower E-selectin levels (by 6%, p = 0.096), and VCAM-1 levels (by 4%, p = 0.084).

Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women.

BACKGROUND: Plasma levels of plasminogen-activator inhibitor type 1 (PAI-1), an essential inhibitor of fibrinolysis in humans, increase in women after menopause, and this may contribute to the risk of cardiovascular disease. We studied the effects of hormone-replacement therapy on PAI-1 levels. METHODS: In a randomized, crossover study, we investigated the effects of oral conjugated estrogen (0.625 mg per day) in 30 postmenopausal women and transdermal estradiol (0.1 mg per day) in 20 postmenopausal women, either alone or in combination with medroxyprogesterone acetate (2.5 mg daily) for one month, on plasma PAI-1 antigen levels. Degradation products of cross-linked fibrin (D-dimer) were measured in serum as an index of fibrinolysis. RESULTS: PAI-1 levels were inversely associated with D-dimer levels at base line (r= -0.540, P=0.002). Conjugated estrogen, both alone and in combination with medroxyprogesterone acetate, reduced mean (+/-SD) plasma levels of PAI-1 from 32+/-34 ng per milliliter to 14+/-10 ng per milliliter (P<0.001) and from 31+/-29 ng per milliliter to 15+/-11 ng per milliliter (P=0.003), respectively; there was a significant inverse correlation between pretreatment PAI-1 levels and the degree of reduction in these levels during therapy (r= -0.631, P<0.001 for conjugated estrogen; r = -0.507, P=0.004 for combined therapy). The degree of reduction in PAI-1 levels was associated with increases in D-dimer levels both when conjugated estrogen was given alone (r= -0.572, P=0.001) and when combined hormone therapy was given (r= -0.541, P=0.002). Transdermal estradiol caused no significant changes in PAI-1 levels from base-line values. CONCLUSIONS: Conjugated estrogen, alone or combined with progestin therapy, reduced PAI-1 levels by approximately 50 percent in postmenopausal women and was associated with enhanced systemic fibrinolysis. These findings may partly explain the protective effect of hormone-replacement therapy with respect to coronary artery disease.

Gender-specific correlation of platelet ionized magnesium and serum low-density-lipoprotein cholesterol concentrations in apparently healthy subjects.

We previously found an inverse correlation between platelet ionized magnesium concentration ((Mg2+)i) and serum total cholesterol concentration in normal male but not female subjects. In the present study, we determined the platelet (Mg2+)i by using a fluorescent ionized magnesium (Mg2+) indicator, FURAPTRA, and measured the serum concentrations of the following: total cholesterol; very-low-density lipoprotein cholesterol (VLDL-C); low-density lipoprotein cholesterol (LDL-C); high-density lipoprotein cholesterol (HDL-C); antioxidized low-density lipoprotein (LDL) autoantibodies; lipoprotein(a); apolipoproteins A-I (apo A-I) and B (apo B); triglycerides; estradiol-17 (E2); ceruloplasmin (Cp); and selected electrolytes, including total and ionized magnesium and calcium and total protein and albumin. In men, but not in women, platelet (Mg2+)i significantly inversely correlated with serum total cholesterol (r = -0.52, p < 0.02), LDL-C (r = -0.54, p < 0.009 by a "direct" method; r = -0.40, p < 0.05 by an electrophoretic method), and apo B (r = -0.42, p < 0.04). We found no significant correlations between platelet (Mg2+)i and any other variables, including serum total and ionized magnesium, antioxidized LDL autoantibodies, Cp, and E2. We speculate that decreased platelet (Mg2+)i is a possible marker for platelet membrane alterations that may affect platelet involvement in thrombosis and atherogenesis.

Autoantibody titers to oxidized low-density lipoprotein in patients with coronary atherosclerosis.

Oxidation of low-density lipoprotein (LDL) is considered to be the initial step in the atherosclerotic process. Autoantibodies to oxidized LDL (ox-LDL) have been detected in human serum. We used an enzyme-linked immunosorbent assay technique to measure autoantibody titers in 63 normal subjects and patients with coronary artery disease. Thirty-five patients underwent coronary angiography for suspected coronary artery disease. Patients were divided into the following categories: group 1, 20 healthy young volunteers; group 2, 8 patients age-matched to the catheterization patients; group 3, 10 patients with normal coronary angiograms; and group 4, 25 patients with angiographic coronary artery disease. Autoantibody titers to ox-LDL were group 1, 0.142 +/- 0.023; group 2, 0.197 +/- 0.039; group 3, 0.183 +/- 0.038; and group 4, 0.340 +/- 0.026. There was no statistical difference among groups 1, 2, and 3, but the difference between these groups and group 4 was highly significant (p < 0.05). This study demonstrates that (1) autoantibodies to ox-LDL can be detected in normal subjects and in patients with abnormal coronary angiograms and (2) significantly higher titers of autoantibodies to ox-LDL were seen in patients with angiographic evidence of coronary artery disease.