bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasminogen activator inhibitor activity in diabetic and nondiabetic survivors of myocardial infarction.
Authors: Gray R P , Patterson D L , Yudkin J S
Published: June 2011

Recent studies suggest that plasminogen activator inhibitor (PAI-1) may be a risk factor for recurrent myocardial infarction. We measured PAI-1 activity and antigen and tissue-type plasminogen activator (t-PA) antigen in 35 (20 nondiabetic and 15 diabetic) subjects with no clinical or electrocardiographic evidence of ischemic heart disease and in 74 (50 nondiabetic and 24 diabetic subjects) who had survived a myocardial infarction in the preceding 6-24 months. Levels of PAI-1 activity (18.7 +/- 5.6 versus 12.0 +/- 3.8 arbitrary units [AU] per milliliter, p = 0.001) and t-PA antigen (7.0 +/- 1.9 versus 4.6 +/- 2.0 ng/mL, p = 0.001) were significantly higher in diabetic compared with nondiabetic control subjects. Survivors of myocardial infarction had higher levels of PAI-1 activity and antigen and t-PA antigen than control subjects, and the diabetic survivors had higher levels of PAI-1 activity (25.3 +/- 6.7 versus 20.1 +/- 7.1 AU/mL, p = 0.004) and t-PA antigen (10.6 +/- 4.3 versus 8.4 +/- 3.3 ng/mL, p = 0.03) than the nondiabetic survivors. No difference in PAI-1 antigen levels was found between the diabetic subjects and either the nondiabetic control subjects or survivors of myocardial infarction. After venous occlusion in control subjects, there was a significant increase in PAI-1 antigen (mean 26.7%, range 14.1-58.1% in nondiabetics and mean 25.2%, range 6.2-39.7% in diabetics) and t-PA antigen (mean 78.3%, range 13.6-186.2% for nondiabetic and mean 40.7%, range 17.5-76.2% for diabetic subjects), but in the survivors of myocardial infarction, no significant effect of venous occlusion was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Increased in vivo production of thromboxane in patients with sickle cell disease is accompanied by an impairment of platelet functions to the thromboxane A2 agonist U46619.
Authors: Foulon I , Bachir D , Galacteros F , Maclouf J
Published: June 2011

Thrombosis represents an important cause of mortality in patients with sickle cell disease, in addition to the complications caused by the primary defect of inherited abnormal hemoglobin. To study the involvement of platelets in these complications, we assessed the biosynthesis of thromboxane A2 in samples from 49 patients with sickle cell disease and in 33 control subjects. The urinary excretion of the major arachidonic acid metabolite of platelet origin (11-dehydro-thromboxane B2) and of the vascular endothelial cell (2,3-dinor-6-ketoprostaglandin F1 alpha) were very significantly increased (p < 0.0002) in the patients. In a small group of patients (n = 14), we further investigated the ex vivo response of their platelets to U46619, a stable analogue of thromboxane A2. We observed decreased aggregation and [14C]serotonin release compared with control (p < 0.05); similarly, we found impaired p47 protein phosphorylation (p < 0.05). In contrast, platelets from these patients responded normally to thrombin (0.1 unit/mL). In vivo desensitization of platelets from these patients to thromboxane may constitute a form of regulation that may prevent the propagation of aggregation by this potent inducer, as has been hypothesized in in vitro studies. Our results may also provide a rationale for using antiplatelet drugs in the prophylaxis of thrombotic complications in sickle cell patients.
Relation of hemostatic risk factors to other risk factors for coronary heart disease and to sex hormones in men.
Authors: Yang X C , Jing T Y , Resnick L M , Phillips G B
Published: June 2011

The present study was carried out to explore the possible relation of plasma plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and factor VII levels to other risk factors for coronary heart disease (CHD) and to serum sex hormone levels. The study group comprised 48 apparently healthy men. To avoid the confounding factor of obesity, correlations were determined in the 30 men in this group with a body mass index (BMI) < 26.4, after controlling for age. PAI-1 correlated with testosterone, estradiol/testosterone, and free testosterone/testosterone (FT/T), and fibrinogen correlated with FT/T. All three hemostatic factors correlated with glucose and with the ratio of cholesterol/high density lipoprotein cholesterol, while PAI-1 correlated with diastolic blood pressure. To test the effect of obesity, correlations were determined in the entire group of 48 men, which included 18 subjects with a BMI > 26.4. All three hemostatic factors correlated with BMI in this group after controlling for age; however, on controlling for testosterone, only PAI-1 correlated with BMI. Fibrinogen correlated with age in both groups after controlling for testosterone or BMI. These correlations support the hypothesis that PAI-1, fibrinogen, and factor VII are related to other risk factors for CHD and that an alteration in the sex hormone milieu may be the underlying factor linking them.
Effects of lovastatin on the levels, structure, and atherogenicity of VLDL in patients with moderate hypertriglyceridemia.
Authors: Gianturco S H , Bradley W A , Nozaki S , Vega G L , Grundy S M
Published: June 2011

The purpose of this study was to determine whether lovastatin treatment reduced very low density lipoprotein (VLDL) abnormalities in hypertriglyceridemic subjects. Lovastatin reduced plasma triglyceride levels and the levels of total VLDL, intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) cholesterol. The numbers of VLDL particles of Sf 100-400 and Sf 60-100 but not Sf 20-60 particles were reduced by lovastatin, as was the amount of cholesteryl ester per particle. All VLDL subspecies bound to the LDL receptor of cultured human fibroblasts with similar, high affinities on both placebo and lovastatin, but VLDL Sf 100-400 and VLDL Sf 60-100 caused less suppression of 3-hydroxy-3-methyl glutaryl coenzyme A reductase activity after lovastatin therapy, indicating reduced LDL receptor-mediated cholesterol delivery. The average decrease in reductase suppression by VLDL Sf 100-400 after lovastatin was 32%, similar to the 34% average decrease in cholesteryl ester content of VLDL Sf 100-400 after lovastatin. Although statistical significance was not achieved, there was a trend toward decreased VLDL Sf 100-400-induced rapid, receptor-mediated triglyceride accumulation in P388D1 macrophages after lovastatin. Taken together, these observations suggest that lovastatin may be of potential benefit in decreasing the atherosclerotic complications of hypertriglyceridemia.
Ultrasonic-pathological comparison of the human arterial wall. Verification of intima-media thickness.
Authors: Wong M , Edelstein J , Wollman J , Bond M G
Published: June 2011

Recent intravascular ultrasound experience challenges the accuracy of ultrasonic measurement of arterial wall thickness. We reevaluated the correlation between histological and sonographic measurements of intima-media thickness using standard transcutaneous vascular technology. Carotid and femoral arterial segments were imaged before and after fixation using a 7-MHz linear-array vascular transducer. Log compression and beam orientation were varied. Mean intima, media, and adventitia thicknesses were measured and compared with corresponding histological tunica. Tissue processing caused 2.5% shrinkage. Intraobserver reading error was 0.7% for histology and 5.4% for sonography. Ultrasound overestimated the thickness of the intima and adventitia and underestimated the thickness of the media. For combined intima-media thickness, the differences between histology and imaging were insignificant, averaging 4% for the carotid artery and 9% for the femoral artery in the far-wall projection. In the near-wall projection, sonographic intima-media thickness was 20% less than that determined histologically. We conclude that ultrasonography is limited mainly by axial resolution in quantifying the dimensions of individual arterial tunica but is capable of accurately measuring far-wall intima-media thickness.
The low HDL cholesterol/high triglyceride trait.
Authors: Sprecher D L , Feigelson H S , Laskarzewski P M
Published: June 2011

In 748 probands and 3,283 first-degree relatives from the Collaborative Lipid Research Clinics (LRC) Family Study, our specific aim was to examine the degree to which low (bottom decile) high density lipoprotein cholesterol (HDL-C, hypoalpha) and high (top decile) triglyceride (TG, hyperTG) levels occur conjointly (CT) and the extent to which these characteristics were shared within families. To control for family size and permit a comparison with the proband percentages, mean familial percentages of HDL-C/TG abnormalities were calculated. Concurrent low HDL-C and high TG levels were present in 2.7% of the probands, a value that was enriched to 12.7% (p = 0.003) of their associated first-degree relatives. If the proband had a low HDL-C value, 7.7% (p = 0.013) of relatives had CT. Familial (proband and at least one first-degree family member share the same lipoprotein/lipid phenotype) hypoalpha was observed in 2.4% of families while familial hyperTG was observed in 4.1%. Familial CT was seen in approximately 0.7%. If the proband had CT, 80% of their families had at least one other first-degree member with an HDL-C/TG abnormality, whereas the corresponding percentage for families associated with probands with only hypoalpha was 64% and for those with hyperTG alone, 54%. A broadly shared environmental factor cannot easily explain the familial association of hypoalpha, hyperTG, and CT. In probands with low HDL-C values alone or the conjoint low-HDL-C/high-TG trait, family screening is extremely valuable because low HDL-C/high TG is enriched in the respective family members, a conjoined trait closely associated with increased coronary heart disease risk.
Circulating lipid hydroperoxide levels in human hyperhomocysteinemia. Relevance to development of arteriosclerosis.
Authors: Dudman N P , Wilcken D E , Stocker R
Published: June 2011

Elevated circulating homocyst(e)ine is a risk factor for occlusive vascular disease. We explored whether elevated plasma homocyst(e)ine is associated with increased plasma lipid hydroperoxides that might trigger vascular disease. We obtained plasma containing high levels of homocyst(e)ine from four patients with a homozygous deficiency of cystathionine beta-synthase activity and also from four heterozygotes with a deficiency of this enzyme after an oral methionine load. The mean plasma non-protein-bound homocyst(e)ine level in all subjects was more than 11-fold higher than the mean normal fasting value. Levels of high density lipoprotein (HDL) cholesteryl ester hydroperoxides (CEOOH), normalized against the concentration of free cholesterol in HDL, were not elevated in our subjects (mean +/- SD, 0.0091 +/- 0.0061) compared with values for 14 fasting healthy donors (0.0164 +/- 0.0086). An inverse dependency was observed between plasma total homocyst(e)ine and HDL CEOOH (r = -0.78, p = 0.023). Also, the ubiquinol-10/ubiquinone-10 ratio in HDL, which is expected to fall during oxidative stress, increased with plasma homocyst(e)ine. Since HDL contains the majority of detectable plasma lipid hydroperoxides, of which CEOOHs are the most abundant, our data suggest that an elevated plasma homocyst(e)ine level does not enhance oxidative stress, increase the levels of lipid hydroperoxides in plasma, or generate vascular damage by this mechanism.
Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study.
Authors: Yarnell J W , Beswick A D , Sweetnam P M , Riad-Fahmy D
Published: June 2011

Numerous case-control studies have suggested that elevated levels of endogenous estrogen and low levels of testosterone are associated with ischemic heart disease (IHD) in men. These findings were tested in the Caerphilly study of 2,512 men from the general population who were aged 45-59 years at baseline and were followed for 5 years. Some 153 men experienced a new episode of IHD (fatal and nonfatal) during the period of follow-up. Baseline values of estradiol were marginally higher in subjects who developed IHD than in those who did not, but the difference was not statistically significant. Plasma values of testosterone were similar in the two groups. Among quintiles of the distribution of the hormone values, the incidence of IHD was similar in the case of estradiol; there was also no clear trend in the case of testosterone. These findings provide no support for the suggestion that plasma estradiol or testosterone are primary risk factors for IHD, although the associations between plasma testosterone and other probable risk markers (triglycerides, insulin, body mass index, and high density lipoprotein cholesterol) indicate the possibility that testosterone may play an indirect role in the pathogenesis of IHD.
Occlusive arterial thrombosis in cynomolgus monkeys with varying plasma concentrations of lipoprotein(a).
Authors: Williams J K , Bellinger D A , Nichols T C , Griggs T R , Bumol T F , Fouts R L , Clarkson T B
Published: June 2011

Lipoprotein(a) (Lp[a]) is a newly recognized risk factor for the development of coronary heart disease and stroke in human beings; however, the mechanisms by which Lp(a) increases the risk of coronary heart disease remain unclear. The purpose of this study was to examine the effects of Lp(a) on the occurrence of occlusive arterial thrombosis. Occlusive arterial thrombus formation was examined in 18 cynomolgus monkeys with high plasma Lp(a) concentrations (> 35 mg/dL, n = 6), intermediate Lp(a) concentrations (20-25 mg/dL, n = 6), and low Lp(a) concentrations (< 12 mg/dL, n = 6). A Goldblatt clamp was positioned around the left common carotid artery to produce a stenotic segment, and the artery was pinch-injured with needle holders. A 20-MHz Doppler velocity crystal, placed distal to the stenosis/injury site, was used to detect cyclic flow reductions (indicative of transient thrombosis) or permanent cessation of flow velocity (indicative of more stable occlusive thrombosis). All monkeys with high Lp(a) concentrations developed permanent cessation of flow, whereas only one of six arteries from low-Lp(a) monkeys developed permanent cessation of flow (p < 0.05). Arteries from monkeys with intermediate Lp(a) concentrations developed pronounced cyclic reductions of flow but did not progress to permanent cessation of flow. There were no differences in plasma von Willebrand factor activity among the three groups. Immunohistochemical analysis of the damaged arterial segments indicated incorporation of Lp(a) into the adventitia, media, and intima of arteries from monkeys with low and high plasma Lp(a) concentrations, as well as the presence of an occlusive thrombus in arteries that developed permanent cessation of flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Prevalence and risk factors of asymptomatic extracranial carotid artery atherosclerosis. A population-based study.
Authors: Willeit J , Kiechl S
Published: June 2011

To evaluate the prevalence and risk factors of asymptomatic carotid artery disease, we analyzed a sample of 909 men and women (aged 40-79 years) drawn from the community-based Bruneck Ischemic Heart Disease and Stroke Prevention Study. For the four decades of age (40-49, 50-59, 60-69, and 70-79 years), respective prevalence rates as assessed by duplex scanning were found to be 8.2%, 39.7%, 66.4%, and 82.5% in men and 3.3%, 22.3%, 48.7%, and 76.7% in women. High-grade stenosis (> 80%) classified by Doppler criteria was twice as frequent in men (2.4%) as in women (1.1%). Age and sex were found to be particularly strong and independent predictors of asymptomatic carotid artery disease. Accordingly, separate logistic regression models were developed for both men and women in the elderly (65-79 years) and middle-aged (50-64 years) groups. Systolic blood pressure turned out to be the only attribute with independent significance in all subgroups examined. Cigarette smoking, recorded as pack-years, emerged as the leading risk factor of carotid atherosclerosis in men. Serum fibrinogen levels were found to be highly indicative of carotid artery disease in elderly men and women. For apolipoprotein B predictive significance was observed in the middle-aged populations, whereas apolipoprotein A-I had a protective effect in elderly women. Diabetes mellitus completed the risk factor profile for elderly men. In summary, the relation between cardiovascular risk factors and asymptomatic carotid artery disease showed a dynamic dependence on sex and age. These findings may help to improve the efficacy of risk prediction in the general population and facilitate well-directed preventive measures.
Basic fibroblast growth factor in the extracellular matrix suppresses collagen synthesis and type III procollagen mRNA levels in arterial smooth muscle cell cultures.
Authors: Majors A , Ehrhart L A
Published: June 2011

To determine the effects of an intact extracellular matrix on collagen synthesis, arterial smooth muscle cells (SMCs) were plated sparsely on a cell-free, SMC-derived matrix and examined the following day. Collagen synthesis during a 5-hour incubation by cells on the matrix was reduced to 67% of the control values obtained from cultures on plastic. Total protein synthesis was unaffected. Treatment of the matrix with heparitinase to remove basic fibroblast growth factor (bFGF) before seeding the SMCs abolished the inhibitory effect of the matrix on collagen synthesis. The inhibitory effect was also eliminated by treating the matrix with a neutralizing polyclonal antibody directed against bFGF. Collagen synthesis by SMC cultures grown in wells coated with purified bFGF was only 61% that of control cultures, whereas total protein synthesis remained unchanged. Slot-blot analysis revealed that the relative message level for alpha 1(III) procollagen was reduced in cultures grown on the preexisting matrix or on plastic precoated with bFGF, whereas the alpha 1(I) procollagen message was unaffected. These results demonstrate the ability of the extracellular matrix to modulate the synthesis of collagen by arterial SMCs and indicate that bFGF in the matrix is responsible for these effects.
Regulation of LDL receptor expression by luminal sterol flux in CaCo-2 cells.
Authors: Field F J , Fujiwara D , Born E , Chappell D A , Mathur S N
Published: June 2011

The regulation of expression of the intestinal low density lipoprotein (LDL) receptor by luminal (apical) sterol flux was investigated in the human intestinal cell line CaCo-2. Cells were cultured on semipermeable micropore filters, which separated an upper and lower well. To the apical media were added solutions containing either taurocholate micelles alone or micelles containing sterols. Because of an efflux of cholesterol, which occurred from cells incubated with micelles alone, LDL receptor mRNA levels increased threefold. With an influx of micellar sterols, receptor mRNA levels decreased in a dose-dependent manner. Synthesis and degradation of the LDL receptor were addressed by pulse-chase experiments. In cells incubated with micelles containing 25-hydroxycholesterol, the rate of receptor synthesis was significantly decreased, whereas the rate of receptor turnover remained unchanged. As assessed by immunoblots and steady-state labeling of proteins followed by immunoprecipitation of the LDL receptor, cells incubated with micellar 25-hydroxycholesterol contained substantially less receptor protein. These cells also bound and degraded less LDL. In contrast, in cells incubated with micelles alone, the rate of receptor synthesis was increased and cells contained more LDL receptor protein, although this was not reflected in an increased in LDL binding. The results suggest that LDL receptor expression in CaCo-2 cells is regulated by luminal sterol flux and that this regulation occurs at the level of transcription.
Isolation of heparin-insensitive aortic smooth muscle cells. Growth and differentiation.
Authors: San Antonio J D , Karnovsky M J , Ottlinger M E , Schillig R , Pukac L A
Published: June 2011

Previous work has shown heparin and heparan sulfates to be potent inhibitors of vascular smooth muscle cell (VSMC) growth. This laboratory has previously isolated a VSMC line insensitive to the antiproliferative action of heparin by subjecting VSMCs that grew out from rat aortic medial explants to continuous passage in media containing heparin at 200 micrograms/mL. In the present study, we have isolated two additional heparin-resistant (HR) cell lines and have used the HR cells to investigate cellular mechanisms responsible for the potent antiproliferative activity of heparin. In contrast to normal heparin-sensitive VSMCs, the HR cells were smaller, displayed elongated processes, and possessed altered growth characteristics; however, both HR and normal cells bound and internalized comparable amounts of heparin. Immunohistochemical detection of smooth muscle cell-specific actin in growth-arrested cells showed staining of nearly all normal VSMCs and of a much smaller percentage of HR cells; heparin treatment caused a marked increase in the percentage of HR cells expressing smooth muscle cell alpha-actin, indicating that the antiproliferative and differentiation-promoting actions of heparin are independent. Proteins from control VSMCs and HR cells were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and heparin affinity chromatography. Several proteins were expressed preferentially by either HR cells or normal VSMCs, with the most significant difference being the secretion of a high-affinity, heparin-binding protein (M(r), 38,000) by control VSMCs but not by HR cells. We conclude that the aortic VSMC population may give rise to HR cells under selective conditions and that their unique characteristics, such as alterations in their ability to produce heparin-binding proteins, will prove useful in deciphering the cellular mechanisms involved in heparin's regulation of VSMC growth and differentiation.
Excretion of thromboxane metabolites in healthy women after cessation of smoking.
Authors: Rångemark C , Ciabattoni G , Wennmalm A
Published: June 2011

Cigarette smokers, but not former smokers, excrete more thromboxane A2 (TxA2) metabolites in the urine than do lifelong nonsmokers, which suggests chronic activation of their platelets. To further characterize the effect elicited by smoking on platelet function, we followed the change in urinary excretion of the 2,3-dinor (Tx-M) and 11-dehydro (dTx) metabolites of TxA2, analyzed by gas chromatography/mass spectrometry and radioimmunoassay, respectively, in eight healthy women who quit habitual smoking and compared it with the recovery of these metabolites after a single dose of acetylsalicylic acid (ASA). Tx-M and dTx before cessation of smoking were approximately 550 and 600 pg/mg creatinine, respectively. Within 3 days after quitting smoking, Tx-M and dTx had dropped to stable levels of approximately 300 and 350 pg/mg, respectively. The rates of change in excretion of Tx-M and dTx after smoking cessation were more rapid (p < 0.02 and 0.02, respectively) than those observed during the recovery of platelet function after a single dose of ASA. The excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha, a metabolite of prostacyclin, was not affected by smoking cessation. We conclude that cigarette smoking elicits an increase in platelet activity in the absence of vascular injury. This increase is reversible within the life span of the platelets.
Plasma fibrinogen and its correlates in Japanese and US population samples.
Authors: Iso H , Folsom A R , Sato S , Wu K K , Shimamoto T , Koike K , Iida M , Komachi Y
Published: June 2011

In a preliminary 1987 study, we reported that the plasma fibrinogen level was significantly higher in Caucasian American men than Japanese men. To confirm this finding, we used data from 1,020 Japanese men and women in a 1989-1991 Akita, Japan, population study and from > 15,000 men and women from the 1986-1989 Atherosclerosis Risk in Communities (ARIC) Study. To examine further the correlates of plasma fibrinogen level, subsamples of nonsmoking Akita Japanese (n = 150) and Minneapolis Caucasians (n = 150) were also studied separately in 1990. Compared with the Japanese in the Akita study, Caucasians and African Americans in ARIC had a 23-40 mg/dL higher age-adjusted fibrinogen level for men and a 25-67 mg/dL higher level for women. In the subsample, the mean plasma fibrinogen value was 288 mg/dL in Caucasian men and 248 mg/dL in Japanese men (test for difference: p < 0.001). Women showed a similar racial difference: 300 mg/dL in Caucasians and 257 mg/dL in Japanese (p < 0.001). There were weak but positive correlations of plasma fibrinogen with age and body mass index and weak inverse correlations with alcohol intake, high density lipoprotein cholesterol, and triglycerides in most of the sex-race groups. For women, plasma fibrinogen was positively associated with menopause and inversely associated with the use of hormone replacement therapy. Total fish intake was inversely associated with plasma fibrinogen in all sex-race groups, and the association was statistically significant for Caucasian men.(ABSTRACT TRUNCATED AT 250 WORDS)
Impaired chylomicron remnant clearance in familial combined hyperlipidemia.
Authors: Cabezas M C , de Bruin T W , Jansen H , Kock L A , Kortlandt W , Erkelens D W
Published: June 2011

Postprandial chylomicron remnant clearance was studied in six patients with familial combined hyperlipidemia (FCH) and seven control subjects by using an oral retinyl palmitate (RP) fat-loading test. The chylomicron remnant clearance (Sf < 1,000 fraction), expressed as the area under the RP curve (AUC-RP), was delayed in FCH subjects (65.05 +/- 12.84 hours x [mg/L]) compared with control subjects (25.1 +/- 5.4 hours x [mg/L]; p = 0.01). Postprandial lipoprotein particle size and composition in the Sf > 1,000 fraction were different between FCH and control subjects as analyzed by molecular-sieve chromatography. Fasting high density lipoprotein cholesterol was lower in FCH patients (0.54 +/- 0.09 mmol/L) than in control subjects (0.89 +/- 0.05 mmol/L; p < 0.01). Mean plasma postheparin lipoprotein lipase and hepatic lipase activities were similar between FCH patients (94 +/- 25 and 427 +/- 57 milliunits/mL, respectively) and control subjects (126 +/- 16 and 362 +/- 33 milliunits/mL, respectively). In FCH, a 54% reduction (p < 0.05) of plasma triglycerides to 2.63 +/- 0.41 mmol/L by drug treatment resulted in an enhanced, but not normalized, clearance of chylomicron remnants (39.4 +/- 6.0 hours x [mg/L]). Univariate regression analysis revealed that in FCH subjects the changes in fasting plasma apolipoprotein C-III concentrations after therapy were significantly associated with the changes in chylomicron remnant AUC-RP (r = 0.87; p = 0.02). Delayed elimination of atherogenic chylomicron remnants may contribute to the increased risk of premature atherosclerosis in FCH.
Increased production rates of LDL are common in individuals with low plasma levels of HDL cholesterol, independent of plasma triglyceride concentrations.
Authors: Ginsberg H N , Ngai C , Wang X J , Ramakrishnan R
Published: June 2011

Reduced plasma levels of high density lipoprotein (HDL) cholesterol are associated with increased risk for coronary heart disease. Although plasma HDL levels are, in general, inversely related to plasma triglyceride (TG) concentrations, a small proportion of individuals with low HDL cholesterol concentrations have normal plasma TG levels. We wished to determine whether subjects with low plasma levels of HDL cholesterol could be characterized by common abnormalities of lipoprotein metabolism independent of plasma TGs. Therefore, we studied the metabolism of low density lipoprotein (LDL) apolipoprotein B (apo B) and HDL apolipoprotein A-I (apo A-I) in subjects with low plasma HDL cholesterol concentrations with or without hypertriglyceridemia. Nine subjects with low plasma HDL cholesterol levels and normal levels of plasma TGs and LDL cholesterol were studied. Autologous 131I-LDL and 125I-HDL were injected intravenously, and blood samples were collected for 2 weeks. LDL apo B and HDL apo A-I levels were measured by specific radioimmunoassays. Fractional catabolic rates (FCRs, pools per day) and production rates (PRs, milligrams/kilogram.day) for each apolipoprotein were determined. The results were compared with those obtained previously in nine subjects with low plasma HDL cholesterol levels and hypertriglyceridemia and in seven normal subjects. The normal subjects had an HDL apo A-I FCR (mean +/- SD) of 0.21 +/- 0.04. Despite large differences in plasma TG levels, the HDL apo A-I FCRs were similar in the low-HDL, normal-TG group (0.30 +/- 0.09) and the low-HDL, high-TG group (0.33 +/- 0.10), although only the latter value was significantly increased versus control subjects (p < 0.03). Increased apo A-I FCRs were associated with reduced HDL apo A-I levels in both groups of patients. Apo A-I PRs were similar in all groups. In contrast, LDL apo B PR was increased approximately 50% in the low-HDL, normal-TG group (19.3 +/- 6.6; p < 0.01) compared with normal subjects (12.5 +/- 2.6). There was a strong trend toward a greater LDL apo B PR in the low-HDL, high-TG group (17.6 +/- 4.5; p = 0.06 versus normal subjects) as well. LDL apo B FCRs were similar in all three groups. LDL apo B concentrations were also increased in the group with low HDL cholesterol and normal TG levels. Both groups with low HDL cholesterol levels had cholesterol-depleted LDL and HDL particles.(ABSTRACT TRUNCATED AT 400 WORDS)
Physical conditioning can modulate endothelium-dependent vasorelaxation in rabbits.
Authors: Chen H I , Li H T
Published: June 2011

To investigate whether exercise training can modulate endothelium-dependent vasorelaxation, male New Zealand White rabbits were divided into either control or training groups. The training animals were trained on a treadmill with a running speed of 0.88 km/hr on a 0 degree grade for 10-60 minutes/day, 5 days/week for 8 weeks. After exercise training, the resting heart rate was lowered (p < 0.05). At the end of the experiments, three vessel segments, i.e., the thoracic aortas, the pulmonary arteries, and the common carotid arteries, were isolated and precontracted with norepinephrine. Acetylcholine-stimulated endothelium-derived relaxing factor (EDRF) release was assessed by bioassay in the presence of indomethacin (10(-5) M). Basal release of EDRF was examined by the addition of hemoglobin. In addition, the relaxing responses of the thoracic aortas and pulmonary arteries to A23187, a calcium ionophore, and to sodium nitroprusside, a direct vasodilator of vascular smooth muscle, were compared between control and trained groups to further investigate possible underlying mechanisms. The results indicated that after exercise training 1) both the thoracic aorta and pulmonary artery, but not the carotid artery, became more sensitive to acetylcholine-induced vasorelaxation; 2) no significant differences in basal release of EDRF between control and trained rabbits were observed; and 3) there were no significant differences in the vascular responses to A23187 or sodium nitroprusside between the two groups. Our data suggest that exercise training may enhance endothelium-dependent vasodilation to acetylcholine via the stimulated EDRF release and that this elevated sensitivity to acetylcholine may not be caused by the alteration of the relaxing response in vascular smooth muscle.
Coronary arteriosclerosis in dogfish (Scyliorhinus canicula). An assessment of some potential risk factors.
Authors: García-Garrido L , Muñoz-Chápuli R , de Andrés V
Published: June 2011

Coronary myointimal lesions are described in the dogfish (Scyliorhinus canicula). These lesions are similar to those previously described in salmonids and are characterized by breaks in and disappearance of the inner elastic layer and intimal thickening as a result of inclusions of fibers and smooth muscle cells. Lesions are associated with all the branching points in the main subepicardial conal coronary arteries that supply the heart. Intimal thickenings were rare in other parts of these arteries. However, we found extensive lesions unassociated with branching points in two main intramyocardial ventricular arteries that supply the ventricular spongy myocardium. We carried out a statistical study of the incidence and severity of these intramyocardial lesions in relation to several potential risk factors. Intimal thickenings were present in 90.5% of the fish specimens and 40% of the histological sections. Sex, reproductive stage, plasma triacylglycerol, and cholesterol (total and related to high-density lipoproteins) were not significantly related to either the incidence or severity of lesions. Total fish length was significantly correlated with the lesion severity index (r = 0.33, p < 0.01). We also found significant differences in incidence related to the location of lesions. The middle areas of the intramyocardial branches, very close to the atrioventricular canal, were more affected than the cranial and caudal areas. The dorsal and ventral artery walls were also more affected than the lateral ones. The preferential location of the lesions in areas presumably subjected to mechanical stress because of a bifurcating bloodstream or the pulsatile flow throughout the atrioventricular canal suggests that coronary arteriosclerosis in dogfish is an age-related process, with hemodynamic factors playing a primary or secondary pathogenetic role. This disease seems not to be related to some factors suggested for salmonids, such as reproductive cycle, anadromous migration, river pollution, or plasma lipid concentration.
Microalbuminuria is a marker of left ventricular hypertrophy but not hyperinsulinemia in nondiabetic atherosclerotic patients.
Authors: Pedrinelli R , Di Bello V , Catapano G , Talarico L , Materazzi F , Santoro G , Giusti C , Mosca F , Melillo E , Ferrari M
Published: June 2011

Microalbuminuria predicts cardiovascular events in diabetic and nondiabetic patients. For a better understanding of the physiopathological importance of microalbuminuria in atherosclerotic disease, we evaluated the relation between urinary albumin excretion and arterial blood pressure, left ventricular mass, insulin, and lipid levels. The studies were conducted in patients with atherosclerotic peripheral vascular disease. Urinary albumin excretion (studied by nephelometry; an average of triplicate collections from 8 PM to 8 AM), causal blood pressure, echocardiographic left ventricular mass index and wall thickness, plasma immunoreactive insulin and C-peptide (both basally and after a 75-g oral glucose load), blood lipids, and fibrinogen were studied in eight normal subjects and 20 nonobese, nondiabetic male patients with angiographically documented atherosclerotic peripheral vascular disease and preserved renal function, 12 of whom were either hypertensive or on antihypertensive treatment. Eight patients were microalbuminuric (urinary albumin > 20 micrograms/min) and 12 were not. Ankle-arm index and calf and foot transcutaneous oxygen tension were reduced in comparison with normal control subjects but superimposable between the two patient groups to indicate a comparable clinical progression of the vascular disease. In the microalbuminuric subjects, left ventricular mass index was greater, interventricular septum was thicker, and cardiac hypertrophy was more frequent than in nonmicroalbuminuric patients. The prevalence of hypertension tended to be greater and systolic blood pressure values were higher in the presence of microalbuminuria. Overall, a highly significant relation existed between urinary albumin excretion and left ventricular mass. Systolic blood pressure was greater and a history of arterial hypertension was more frequent among microalbuminurics, whereas diastolic blood pressure values showed a statistically significant correlation with both variables.(ABSTRACT TRUNCATED AT 250 WORDS)
Immune-complex-mediated vasculitis increases coronary artery lipid accumulation in autoimmune-prone MRL mice.
Authors: Qiao J H , Castellani L W , Fishbein M C , Lusis A J
Published: June 2011

MRL/lpr mice develop severe autoimmune disease and vasculitis by 5 months of age, whereas congenic strain MRL/n mice exhibit much milder vasculitis with a later age of onset. When maintained on a high-fat, high-cholesterol (atherogenic) diet, strain MRL/lpr mice exhibited a striking deposition of lipid in both the large and small coronary arteries, whereas strain MRL/n mice exhibited very little lipid accumulation. Neither strain exhibited lipid accumulation on a low-fat chow diet. The atherogenic diet induced hyperlipidemia in both strains, but surprisingly the levels of atherogenic apolipoprotein B-containing lipoproteins were much lower in MRL/lpr mice. Immunohistochemical studies revealed that immune complexes (immunoglobulins G and M), T and B lymphocytes, macrophages, granulocytes, apolipoprotein B, and serum amyloid A proteins were present in the walls of the coronary arteries that had vasculitis and lipid accumulation. By 6-7 months of age, MRL/lpr mice had a higher incidence of myocardial infarction in the atherogenic diet group (53%) compared with the chow group (14%), whereas MRL/n mice exhibited no myocardial infarction on either diet. These results suggest important interactions between vasculitis, hyperlipidemia, and arterial lipid accumulation. They support the concept that injury to the vessel wall in immune-complex-mediated vasculitis increases lipid deposition in the presence of hyperlipidemia.
Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia.
Authors: Venkatesan S , Cullen P , Pacy P , Halliday D , Scott J
Published: June 2011

Familial combined hyperlipidemia (FCHL) may be genetically and metabolically more heterogeneous than previously thought. A consistent feature is an increase in circulating very-low-density lipoprotein (VLDL) apolipoprotein (apo) B, which could be due to either an increase in apoB production or a decrease in its catabolism. Therefore, we directly measured VLDL apoB production in the postabsorptive state in seven FCHL subjects (four male, three female) and seven normal control subjects (three male, four female) by using L-[1-13C]leucine as an endogenous label. Mean age and body mass index did not differ significantly between the two groups. The mean total cholesterol levels were 4.7 +/- 0.8 and 8.8 +/- 1.6 mmol/L (+/- SD, P < .01) and the mean triglyceride levels were 0.84 +/- 0.14 and 3.30 +/- 1.10 mmol/L (+/- SD, P < .01) in the control and FCHL groups, respectively. Although the fractional production rate of VLDL apoB was 38% lower in the FCHL group than in the control subjects (0.11 +/- 0.03 versus 0.18 +/- 0.02 pool/h; mean +/- SD, P < .01), its absolute production rate was 2.7 times greater (534 +/- 193 micrograms/kg per hour in FCHL versus 196 +/- 71 micrograms/kg per hour in control subjects; mean +/- SD, P < .01). There was a linear relation (r = 0.8, P = .03) between triglyceride levels and the VLDL apoB production rate in FCHL, the slope of which indicated a similar VLDL triglyceride-to-apoB ratio in the FCHL and control groups. We conclude that FCHL is a metabolically coherent disorder and that the increase in circulating apoB and triglyceride levels in FCHL is due to secretion of an increased number of VLDL particles, each containing, on average, a normal amount of triglyceride and one molecule of apoB.(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma lipid, lipoprotein cholesterol, and apoprotein distributions in selected US communities. The Atherosclerosis Risk in Communities (ARIC) Study.
Authors: Brown S A , Hutchinson R , Morrisett J , Boerwinkle E , Davis C E , Gotto A M , Patsch W
Published: June 2011

The distributions of plasma lipids, lipoproteins, and apoproteins of 14,524 female and male black and white participants 45 to 64 years old in the Atherosclerosis Risk in Communities (ARIC) Study are presented. All specimens were analyzed at a central laboratory. Mean total cholesterol levels increased with increasing age across all ages from 204 to 229 mg/dL (12%) in women and from 208 to 213 mg/dL (2%) in men. Triglyceride levels increased with age in women, remained stable in men, and were higher in whites than blacks. High-density lipoprotein (HDL) cholesterol levels were higher in black and white women (range, 57 to 59 mg/dL) compared with black men (49 to 52 mg/dL) or white men (42 to 43 mg/dL). Cholesterol associated with HDL was distributed in a relatively constant proportion between HDL3 (70% to 76%) and HDL2 (24% to 30%) for all race/sex groups. Low-density lipoprotein (LDL) cholesterol levels increased with age in black (14.7%) and white (17.1%) women and in black (4.4%) and white (3.7%) men; more than 50% of all participants had LDL cholesterol levels > 130 mg/dL. Apoprotein A-I and B levels followed the same trends as HDL cholesterol and LDL cholesterol levels, respectively. Lipoprotein(a) [Lp(a)] levels were twice as high in blacks as in whites, and women's Lp(a) levels were higher than men's Lp(a) levels for each race. Menopause was associated with elevated total cholesterol, LDL cholesterol, apoprotein B, and Lp(a) levels, and hormone replacement medication use in postmenopausal subjects was associated with higher HDL cholesterol, triglyceride, and apoprotein A-I levels and lower LDL cholesterol, apoprotein B, and Lp(a) levels.
Hypercholesterolemia is associated with a reduced response of smooth muscle guanylyl cyclase to nitrovasodilators.
Authors: Schmidt K , Klatt P , Mayer B
Published: June 2011

A diminished relaxant response of atherosclerotic arteries to nitrovasodilators has been frequently observed in advanced stages of hypercholesterolemia. In the present study, we investigated whether this effect might be a result of reduced activity of smooth muscle guanylyl cyclase. Experimental atherosclerosis was induced by feeding rabbits a cholesterol-rich diet (1%) over a period of 4 months. Aortas were removed and homogenized, and guanylyl cyclase activity was measured in the 100,000 g supernatants. Sodium nitroprusside, which stimulated cyclic GMP (cGMP) formation in control tissues almost 200-fold (from 3 to 585 pmol cGMP.mg-1 x min-1), increased enzyme activities in atherosclerotic aortas only approximately 90-fold (from 3 to 257 pmol cGMP.mg-1 x min-1). Similarly, the maximal stimulatory effects of S-nitroso-glutathione were reduced from 200-fold (controls) to 114-fold in atherosclerotic tissues. Basal guanylyl cyclase activities were identical in both atherosclerotic and control vessels. Hypercholesterolemia also reduced the activity of smooth muscle adenylyl cyclase. In control aortas, basal and NaF-stimulated enzyme activities were 24 and 349 pmol cAMP.mg-1 x min-1, respectively, whereas cAMP formation was reduced in atherosclerotic aortas to 7 (basal) and 96 (NaF) pmol cAMP.mg-1.min-1. The stimulatory effect of NaF (approximately 14-fold) remained unchanged. Since adenylyl and guanylyl cyclase have important functions in regulating vascular tone, reduced activities of both enzymes may contribute to the diminished relaxant and/or enhanced vasoconstricting effects of vasoactive compounds in atherosclerotic blood vessels.
Relation of plasma triglyceride and apoB levels to insulin-mediated suppression of nonesterified fatty acids. Possible explanation for sex differences in lipoprotein pattern.
Authors: McKeigue P M , Laws A , Chen Y D , Marmot M G , Reaven G M
Published: June 2011

To test whether a sex difference in insulin-mediated suppression of nonesterified fatty acids (NEFAs) could account for sex differences in plasma triglyceride levels, we studied 632 normoglycemic men and women of European and South Asian descent aged 40 to 69 years. Mean fasting NEFA levels were 19% higher in women than in men. Between fasting and 2 hours after a 75-g oral glucose load, NEFA levels fell by 69% in women and 55% in men, so that mean NEFA levels at 2 hours after loading were 19% lower in women than in men. Plasma triglyceride and apolipoprotein B levels were correlated with 2-hour NEFA levels in each sex and ethnic group, and these associations were independent of glucose, insulin, and central obesity. These results are consistent with experimental studies of the effects of insulin and NEFAs on hepatic production of triglycerides and apolipoprotein B. Suppression of NEFA levels in response to insulin is greater in women than in men, and this may account for some of the sex differences in lipoprotein pattern and coronary heart disease risk.
Local intimal-medial uptakes of 125I-albumin, 125I-LDL, and parenteral Evans blue dye protein complex along the aortas of normocholesterolemic minipigs as predictors of subsequent hypercholesterolemic atherogenesis.
Authors: Fry D L , Herderick E E , Johnson D K
Published: June 2011

This report describes the normalized intimal-medial uptakes [uptake (M, mg.cm-2) divided serum concentration (c0, mg.cm-3)] of 125I-albumin, 125I-low-density lipoprotein (LDL), and in vivo Evans blue dye (EBD)-albumin complex as functions of pressure (P), time (t), molecular species (i), and location (z) along a ventral longitudinal z axis of the normal, intact, aortic endothelial surface in adult normocholesterolemic Sinclair Research Farm (SRF) minipigs and compares these uptake (M/c0) measurements with atherogenesis in hypercholesterolemic cohorts. Uptakes of porcine serum 125I-albumin (n = 21) and 125I-LDL (n = 10) were measured in freshly excised, metabolically supported aortas using a recently developed organ-support system. In vivo intimal-medial EBD uptake vs z data were measured photometrically on opened descending aortas from another group (n = 6) of normocholesterolemic, adult, SRF minipigs 18 hours after the intravenous administration of EBD. For comparison purposes, the corresponding incidence of atherosclerotic lesions along the aortic z axis was calculated using topographic data from hypercholesterolemic minipig cohorts (n = 39). The results showed that uptakes varied greatly with t, z, and macromolecule (i) but not with P. More specifically, the value of M/c0 at any location (z) rose with t, was insensitive to P, decreased with macromolecular (i) size, and varied with z in a pattern that "peaked" in the upstream region, decreased to a nadir in the downstream region, and then rose again as it approached the abdominal celiac orifice. The spatially z-averaged uptake rates for the three different labeled serum proteins were 0.31 x 10(-3) cm.h-1 for 125I-albumin, 0.42 x 10(-3) cm.h-1 for EBD-albumin, and 0.04 x 10(-3) cm.h-1 for 125I-LDL. Nondimensionalized analysis of the individual sets of uptake data indicated that the overall uptake relationship [M(t,P,z,i)/c(io), cm] could be characterized empirically by the simple product of two separate functions: one, a "scaling function" [m(z,i)], that described the uptake magnitude for a given i and z and appeared to be independent of t or P; the other, a "shape function" [s(t,P)], that described the shapes of the uptake vs t and P relationships and appeared to be independent of z or i. The "scaling function" [m(z,i)] vs z contour appeared to correlate well with the corresponding atherosclerotic lesion incidence vs z contour from the group of hypercholesterolemic minipig cohorts. Assuming passive transport, it was shown ("Appendix") that m(z,i) can be interpreted physically in terms of an endothelial diffusive permeability coefficient (P,cm.s-1).(ABSTRACT TRUNCATED AT 400 WORDS)