The haptoglobin 2-2 genotype is associated with carotid atherosclerosis in 64-year old women with established diabetes.

BACKGROUND: Haptoglobin polymorphism generates three common human genotypes: Hp1-1, Hp2-1 and Hp2-2. Among subjects with diabetes, Hp2-2 is associated with an elevated risk to develop cardiovascular disease. The impact of haptoglobin genotype on subclinical carotid atherosclerosis is not known. We hypothesized that Hp2-2 was associated with increased occurrence of carotid atherosclerosis in subjects with diabetes. METHODS: We studied a population-based sample of 64-year old women with diabetes (n=226), either established diabetes known before study entry (n=116) or new diabetes detected at study screening (n=110). Haptoglobin genotype was determined by PCR. Carotid atherosclerosis was assessed by ultrasound imaging. RESULTS: In the entire diabetes cohort, no differences were observed in carotid intima-media thickness (IMT) or plaque prevalence between the genotype groups. However, among those with established diabetes, Hp2-2 was associated with higher plaque prevalence and larger carotid IMT compared with the Hp2-1 and Hp1-1 genotypes. Common cardiovascular risk factors did not differ between the genotype groups. CONCLUSIONS: The Hp2-2 genotype was associated with increased occurrence of subclinical carotid atherosclerosis in 64-year old women with established diabetes. This association was not explained by traditional risk factors for cardiovascular disease. These results extend previous observations that Hp2-2 is associated with clinical cardiovascular disease in diabetes.

Soluble urokinase-type plasminogen activator receptor forms in plasma as markers of atherosclerotic plaque vulnerability.

OBJECTIVES: : To test if circulating forms of the soluble urokinase-type plasminogen activator receptor (suPAR) are potential biomarkers of plaque vulnerability. DESIGN AND METHODS: : Plasma concentrations of suPAR(I-III), suPAR(II-III) and uPAR(I) were measured by time-resolved fluorescence immunoassays in Caucasian patients operated for symptomatic carotid atherosclerosis (n=255). Local suPAR release from plaques into the circulation was assessed in plasma passing retrogradely over the plaque in the carotid artery, collected during surgery (n=7). RESULTS: : The suPAR(I-III) (P=0.03) and suPAR(II-III) (P=0.006) concentrations were higher after ischemic strokes and transient ischemic attacks, i.e., clinical subgroups associated with poorer prognosis and a less stable plaque phenotype, than after amaurosis fugax. Slightly elevated suPAR(I-III) levels were found in plasma from the carotid lesion. However, refuting the hypothesis, the concentrations of the suPAR forms were not higher in patients with short intervals between clinical event and blood sampling compared with those with long intervals. Age, inflammatory markers and diabetes were confounding factors independently associated with suPAR forms. CONCLUSION: : Circulating suPAR forms are probably not useful biomarkers of atherosclerotic plaque vulnerability.

Differences in lesion severity and cellular composition between in vivo assessed upstream and downstream sides of human symptomatic carotid atherosclerotic plaques.

BACKGROUND: The heterogeneous structure of carotid atherosclerotic plaques may be better understood if it is related to blood flow variations, influencing gene expression and cellular functions. Upstream of the maximum stenosis there is laminar blood flow and high shear stress, downstream there is turbulence and low shear stress. We studied if these variations were associated with differences in plaque morphology and composition between sites located up- and downstream of the maximum stenosis in symptomatic carotid plaques. METHODS: Patients with symptomatic carotid stenosis were examined with magnetic resonance angiography to localize the maximum stenosis in-vivo, prior to endarterectomy. In 41 endarterectomized specimens, transverse tissue sections prepared up- and downstream of the maximum stenosis were compared using histopathology and immunohistochemistry. RESULTS: The location of maximum stenosis relative the carotid bifurcation varied considerably between plaques. Compared with the downstream side, the upstream side of the stenosis had higher incidence of severe lesions with cap rupture and intraplaque hemorrhage, more macrophages, less smooth muscle cells and more collagen. CONCLUSIONS: The up- and downstream sides of symptomatic carotid plaques differed in plaque morphology and composition. This implies that the intraplaque location of sampling sites may be a confounding factor in studies of atherosclerotic plaques.

Urokinase-type plasminogen activator receptor is associated with macrophages and plaque rupture in symptomatic carotid atherosclerosis.

There is a strong correlation between macrophage infiltration and plaque instability in recently symptomatic carotid atherosclerotic plaques, and it is hypothesised that mechanisms related to macrophages may be involved in plaque vulnerability and rupture. We previously found high expression of urokinase-type plasminogen activator receptor (UPAR) in human macrophages. The aim of this study was to investigate whether UPAR co-localises with macrophages in symptomatic carotid plaques, and whether UPAR expression is associated with plaque rupture. Real-time RT-PCR assays showed that UPAR expression levels were high in monocyte-derived macrophages and in carotid endarterectomies compared with a tissue panel. Serial transverse sections were prepared from carotid endarterectomies from 12 symptomatic patients, and analyzed with immunohistochemical staining for UPAR and for CD68-positive macrophages, and with histopathological assessment. UPAR co-localised with CD68-positive macrophages, with a high correlation (r=0.90, p<0.001) between immunostained areas in 12 carotid endarterectomies from symptomatic patients. High degrees of UPAR and CD68 staining were found in sections around the bifurcation level where rupture was most common, while low degrees of staining were found in sections of the common carotid artery end of the endarterectomy (p<0.05). Higher degrees of UPAR staining were observed in ruptured plaque sections compared with non-ruptured sections. In conclusion, UPAR was highly expressed in monocyte-derived macrophages and in symptomatic carotid plaques, UPAR co-localised with macrophages in carotid symptomatic plaques and UPAR was predominantly found in ruptured plaque segments. These findings support the hypothesis that UPAR is related to plaque rupture in symptomatic atherosclerotic lesions.