Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a prospective study, the role of various hemostatic factors known to be associated with thrombotic risk was investigated in 71 patients with peripheral arterial occlusive disease (PAOD, stages II through IV, Fontaine; aged 68 +/- 13 years). Laboratory investigations were done before; 1, 24, and 48 hours after; and 3 and 6 months after percutaneous transluminal angioplasty (PTA). Thirty of 71 (42.3%) patients developed restenosis (> 50% reduction of the lumen diameter) at the site of PTA within 6 months, verified by color-coded duplex sonography. Significantly increased levels of thrombin-antithrombin III complexes (P < .01), prothrombin fragments 1 + 2 (P < .01), and D-dimers (P < .01) were found 1 hour, as well as 24 to 48 hours, after PTA. Fibrinogen (P < .01) and von Willebrand factor (P < .01) were significantly higher 48 hours after PTA. Restenotic patients as a whole had higher plasma fibrinogen (3.46 +/- 1.12 versus 2.95 +/- 0.62 g/L, P < .01) and C-reactive protein (25.4 +/- 46.7 versus 7.9 +/- 6.9 mg/L, P < .05) at baseline, as well as higher fibrinogen (P < .05) and prothrombin fragments 1 + 2 (P < .01) during months 3 to 6 after PTA. There was a nonsignificant tendency for higher values of von Willebrand factor (206 +/- 98% versus 184 +/- 100%, P = .2) at baseline in patients with restenosis, whereas tissue plasminogen activator, plasminogen activator inhibitor, coagulation screening tests, blood cell counts, and serum lipids showed no significant difference between the two groups. The relative risk for developing restenosis within 6 months while having high fibrinogen (> 2.8 g/L) or C-reactive protein at baseline was 2.80 (95% CI: 1.30-6.02, P < .01) and 1.96 (95% CI: 1.07-3.58, P < .05), respectively. Patients with critical limb ischemia (stage III/IV, Fontaine) had significantly higher fibrinogen and von Willebrand factor at repeated points of time, as well as significantly higher C-reactive protein and lower creatinine clearance at entry. In the logistic regression risk factor analysis, baseline plasma fibrinogen, C-reactive protein concentration, and the severity of the arterial disease were significantly predictive of restenosis. Our results indicate that high procoagulant factors and persistent thrombin generation of the hemostatic system might promote restenosis, particularly in patients with extended atherosclerosis. This finding suggests that new treatment strategies should be taken under consideration for patients with PAOD and PTA.
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PMID:Role of hemostatic risk factors for restenosis in peripheral arterial occlusive disease after transluminal angioplasty. 940 13

Plasminogen activators (PAs) and their inhibitor, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in modulation of luminal fibrinolysis and mural proteolysis contributing to atherogenesis. Expression of PAs/PAI-1 (normalized to extracted tissue protein) was delineated by assays of conditioned media and of extracts from walls of human arterial segments in culture. Arterial specimens (n = 39 from 26 subjects) were divided into four groups: normal (n = 14), fatty streak (n = 6), moderate atherosclerosis (mural thickening with < 70% lumen obstruction, n = 5), and severe atherosclerosis (mural thickening with > 70% lumen obstruction, n = 14). Paired samples from the same individual comprising a normal arterial segment and an atherosclerotic segment were evaluated also. A fourfold molar excess in PAI-1:t-PA was seen in conditioned media from samples with any evidence of atherosclerosis compared with normal specimens (normal 21 +/- 4, diseased 82 +/- 21, P < or = .05). Compared with normal pairs, the tissue content of PAI-1 (ng) was increased in fatty streak lesions (n = 3, normal 35 +/- 12, fatty streak 50 +/- 8, P < or = .05); stable to decreased in moderate atherosclerosis (n = 3, normal 34 +/- 3, moderate 22 +/- 7, P = .16); and increased in severe atherosclerosis (n = 6, normal 48 +/- 9, severe 85 +/- 19, P < or = .05). The tissue content of PAs (ng), though not increased in fatty streak lesions, was elevated in moderately and severely atherosclerotic segments (normal 0.7 +/- 0.2, moderate 1.6 +/- 0.1; normal 0.8 +/- 0.3, severe 2.1 +/- 0.3, P < or = .05 for each comparison). Atherogenesis is associated with decreased luminal fibrinolytic capacity that may exacerbate thrombosis. Decreased mural proteolysis in early atherogenesis may exacerbate matrix accumulation. Increased mural proteolysis later is associated with, and may potentiate, smooth muscle cell migration and proliferation.
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PMID:Changes in arterial expression of fibrinolytic system proteins in atherogenesis. 940 25

Although the arterial tree is exposed to increased pressure in hypertensive patients, paradoxically, the complications of hypertension (heart attacks, stroke) are mainly thrombotic rather than hemorrhagic. Patients with left ventricular (LV) hypertrophy are at high risk of the complications of hypertension. We performed a cross-sectional study of 178 patients attending a hypertension clinic in a city center teaching hospital, and measured plasma levels of the soluble adhesion molecule P-selectin (associated with platelet activity/function and atherosclerosis), the von Willebrand factor (vWf; a marker of endothelial dysfunction), fibrin D-dimer (an index of thrombogenesis), plasminogen activator inhibitor (PAI, an index of fibrinolysis), lipoprotein(a) (Lp(a), associated with thrombogenesis and atherogenesis) and hemorheological indexes (fibrinogen, hematocrit, plasma viscosity, hemoglobin) in patients with essential hypertension, in whom the LV mass and LV mass index were determined using echocardiography. The 178 patients (86 men, mean age 54 +/- 15 years) were compared with 47 normotensive healthy controls (aged 56 +/- 20 years). Hypertensive patients had higher P-selectin, PAI, vWf, fibrin D-dimer, Lp(a), plasma fibrinogen, and plasma viscosity when compared with controls. Black hypertensive patients had higher Lp(a) levels and LV septal and posterior wall thickness on echocardiography, but lower plasma PAI levels. Patients with LV hypertrophy (defined as a LV mass index > 134 g/m2 in men or > 110 g/m2 in women) had higher plasma fibrinogen compared with those without LV hypertrophy. Systolic blood pressures were significantly correlated to age, plasma viscosity, plasma fibrinogen, and vWf. Diastolic blood pressures were significantly correlated with age and plasma fibrinogen. Fibrinogen levels were correlated with LV mass, LV mass index, left atrial size, plasma viscosity, and vWf. Fibrin D-dimer levels were significantly correlated with vWf and fibrinogen levels. Thus, hypertensive patients have high plasma fibrinogen levels, thrombogenesis, and impaired fibrinolysis (as indicated by high D-dimer and PAI levels, respectively), platelet activation (raised soluble P-selectin), and endothelial dysfunction (high vWF). The high plasma fibrinogen levels were related to blood pressures, LV mass index (and LV hypertrophy), and left atrial size. These abnormalities in hemorheologic factors and markers of thrombogenesis and endothelial function may act synergistically to increase the risk of thrombogenesis and atherosclerosis in hypertensive patients.
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PMID:Relation of endothelium, thrombogenesis, and hemorheology in systemic hypertension to ethnicity and left ventricular hypertrophy. 941 37

Our specific aim was to examine the interface between risk factors for atherosclerosis, thrombosis, and hypofibrinolysis in a previously healthy 35-year-old male who had sustained a recent myocardial infarction. By angiography, the right, left main, and left anterior descending coronary arteries were smooth-walled, widely patent, and free of significant obstruction; the circumflex exhibited total, probably thrombotic occlusion of the distal large second marginal branch. The patient was found to have prothrombotic high homocysteine (46.4 mumol/L), prothrombotic resistance to activated protein C (ratio, 1.47), and hypofibrinolytic high plasminogen activator inhibitor (PAI-Fx) activity (54 U/mL). He was homozygous for the 677C-->T; A-->V mutation in the methylenetetrahydrofolate reductase (MTHFR) gene causing homocysteinemia, heterozygous for the mutant factor V Leiden gene causing resistance to activated protein C, and heterozygous for the 4G/5G polymorphism in the PAI-1 promoter gene causing high PAI-Fx. Other major risk factors for coronary artery disease included previously undiagnosed adult-onset diabetes, high triglycerides (291 mg/dL), and low high-density lipoprotein (HDL) cholesterol (26 mg/dL). The patient's prothrombotic status (homocysteinemia and resistance to activated protein C) and hypofibrinolysis (high PAI-Fx) apparently facilitated occlusive coronary artery thrombus formation and retention. Prothrombotic factors and hypofibrinolysis appear to play important pathogenetic roles in premature myocardial infarction. In patients with severe premature coronary artery disease, we suggest that interactions between prothrombotic factors, hypofibrinolysis, and hyperlipidemia-atherosclerosis be regularly evaluated, since such interactions may have ramifications for the outcome of short- and long-term secondary prevention. Moreover, in patients with heritable prothrombotic factors or hypofibrinolysis, it should be important to optimize lipid and lipoprotein cholesterol levels with the goal of stabilizing coronary plaques to reduce the likelihood of plaque rupture and thrombosis.
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PMID:Myocardial infarction in a 35-year-old man with homocysteinemia, high plasminogen activator inhibitor activity, and resistance to activated protein C. 943 45

Sudden extreme physical stress is associated with an increased risk of myocardial infarction mainly in people with preexisting atherosclerosis. In this study we compared the effect of submaximal exercise on coagulation and fibrinolysis in patients with peripheral arterial occlusive disease (PAOD) with that in healthy control subjects. Fifteen PAOD) patients with intermittent claudication and 15 healthy control subjects, matched for age, sex, medication use, smoking habit, and conditioning, were studied. Thrombin-antithrombin III complex (TAT), D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI)-1 antigens (Ag), t-PA activity, and plasmin-alpha2-antiplasmin complex (PAP), as well as plasma catecholamines, were measured before and after a treadmill exercise test. At rest, fibrinogen (3.3+/-0.5 versus 2.9+/-0.5 g/L [mean+/-SD]; P<.05), D-dimer (392+/-128 versus 271+/-113 ng/mL; P<.05), t-PA Ag (9.1+/-5.1 versus 5.5+/-1.2 ng/mL; P<.02), and PAI-1 Ag (14.9+/-7.1 versus 7.6+/-3.8 ng/mL; P<.002) levels in plasma were markedly higher in the patient group than in the control group. In patients but not in control subjects, exercise of similar intensity elevated circulating concentrations of TAT (from 3.43+/-1.45 to 4.83+/-2.27 ng/mL; P<.05). Exercise caused a parallel increase in D-dimer, t-PA Ag, t-PA activity, PAP, and catecholamines in both groups, whereas PAI-1 Ag remained stable. Plasma lactic acid was significantly higher in patients after exercise and was associated with lower-limb ischemia. Compared with healthy control subjects, patients with PAOD showed higher t-PA Ag, PAI-1 Ag, and D-dimer levels both at rest and after exercise. Notably, submaximal exercise on a treadmill enhanced thrombin formation in patients with PAOD but not in the control subjects. Sudden catecholamine release and local ischemia during exercise may accelerate the preexisting prothrombotic potential of the atherosclerotic vessel wall.
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PMID:Physical exertion induces thrombin formation and fibrin degradation in patients with peripheral atherosclerosis. 948 89

Several studies have linked higher plasma fibrinogen and plasminogen activator inhibitor (PAI-1) concentrations with increased risk of cardiovascular disease. We studied whether members of families with increased occurrence of coronary heart disease (CHD) have increased levels of fibrinogen and PAI-1 and whether subclinical carotid atherosclerosis is associated with these two hemostatic factors. Contrary to our hypothesis, fibrinogen and PAI-1 antigen levels were not different between high CHD risk families versus random families. Adjusted for age and family type, fibrinogen and PAI-1 were both associated positively with carotid intima-media thickness assessed by B-mode ultrasound. However, adjustment for lifestyle and medical covariates essentially eliminated these associations. These data suggest 1) elevated fibrinogen and PAI-1 do not explain clustering of CHD in families and 2) fibrinogen and PAI-1 may partly mediate the effects of other risk factors on carotid atherosclerosis, though the data are also consistent with them playing no causal role.
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PMID:Fibrinogen, plasminogen activator inhibitor-1, and carotid intima-media wall thickness in the NHLBI Family Heart Study. 949 98

Increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) in blood and attenuated fibrinolytic activity, hypertriglyceridaemia, and insulin resistance are common in subjects with obesity and non-insulin-dependent diabetes mellitus who are at markedly increased risk for coronary artery disease. To clarify potentially causal relationships between these phenomena, we studied JCR:LA-cp rats, animals that are insulin resistant and prone to vasculopathy. Blood and aortas were obtained from lean and corpulent animals at 1, 2, 4, 6, and 9 months of age. The homozygous corpulent rats were hyperinsulinaemic and hypertriglyceridaemic at all ages tested. Increased activity of PAI-1 was present in blood from corpulent animals at 1, 6, and 9 months of age. Positive correlations were observed between blood PAI-1 and both insulin and triglycerides. As judged from results with aortic rings in in vitro culture, the increased PAI-1 in blood was anteceded by increased expression of PAI-1 in arterial walls. Thus, changes indicative of inhibition of the fibrinolytic system capacity precede gross atherosclerosis.
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PMID:Fibrinolysis and atherogenesis in the JCR:LA-cp rat in relation to insulin and triglyceride concentrations in blood. 949 46

The 4G allele of the plasminogen activator inhibitor (PAI-I) gene is associated with increased PAI-I levels. Increased PAI-I levels have been reported to be associated with atherothrombotic events. However, the significance of the 4G/5G polymorphism of the PAI-I gene in the pathogenesis of ischemic heart diseases has not been determined. We assessed the 4G/5G polymorphism of the PAI-I gene in 500 subjects including 148 normal controls, 23 subjects with normal coronary arteries, 28 subjects with a paradoxical acetylcholine response, 97 subjects with angina pectoris (AP) and 204 subjects with myocardial infarction (MI). We assessed the length of time between the first anginal pain and the onset of acute coronary syndromes (ACS) in the AP and MI subjects. Subjects who developed ACS within 2 months from the first anginal pain were categorized to have a rapid progression to ACS, and subjects who had had stable anginal pain more than 2 months were placed in the non-ACS group. Subjects in the ACS group were younger than those in non-ACS group (P = 0.012) The frequency of the 5G/5G genotype of the PAI-I gene was lower in the ACS (0.228) than in the non-ACS group (0.093) (P = 0.003). Multiple logistic analyses revealed that a younger age (P = 0.028, odds ratio = 1.03) and the (4G/5G + 4G/4G) genotype of the PAI-I gene (P = 0.008, odds ratio = 2.68) were associated with the ACS group. We also assessed plasma PAI-I antigen levels in 78 subjects. Plasma PAI-I antigen levels in the non-ACS group were significantly lower than those in the ACS group (P = 0.050). Multiple regression analyses revealed that plasma PAI-I levels were determined by plasma insulin (P < 0.001) and the genotype of the PAI-I gene (P = 0.019). Higher plasma insulin levels and the (4G/5G + 4G/4G) genotype of the PAI-I gene were associated with higher plasma PAI-I levels. The 4G/5G polymorphism of the PAI-I gene influenced not only plasma PAI-I antigen levels but also the time course of the progression to ACS in patients with coronary atherosclerosis.
Atherosclerosis 1998 Jan
PMID:The 4G/5G polymorphism of the plasminogen activator inhibitor gene is associated with the time course of progression to acute coronary syndromes. 954 37

Plasma von Willebrand factor antigen, soluble thrombomodulin, and tissue factor were increased in 31 patients with severe chronic renal failure (creatinine clearance <20 ml/min) under conservative treatment, whereas plasminogen activator inhibitor antigen did not differ significantly from healthy controls. No correlation among plasma levels of these proteins was found. Three patterns of relationship between endothelial cell markers and hemostatic defects were identified: 1) Plasma thrombomodulin, a marker of endothelium damage, was found an independent predictor of bleeding time and platelet aggregation, and secretion defects, and was also related to the severity of renal failure; 2) von Willebrand factor antigen, an index of endothelial cell activation and secretion, was significantly correlated with intravascular markers of thrombin and plasmin generation and with platelet adenosine triphosphate content, but not with plasma creatinine levels; and 3) tissue factor and plasminogen activator inhibitor antigen levels were not statistically correlated with the diverse hemostatic defects. Activation of coagulation and fibrinolysis, secondary to endothelial cell activation, appearing early during the evolution of chronic renal failure, is pathogenically related to the platelet dysfunction, and probably to development of atherosclerosis and thrombotic events in this disease. The progression of chronic renal failure, through endothelial cell damage, would lead to aggravation of the platelet functional defect potentiating the hemorrhagic risk.
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PMID:Endothelial cell markers in chronic uremia: relationship with hemostatic defects and severity of renal failure. 961 Sep 57

Previous studies of the pharmacodynamics of sex steroids in vivo have tended to focus on single metabolic processes, with scant attention to their integration. This paper reviews the human in vivo research evidence on the effects of diet on metabolism, the central role of insulin in metabolic control, and the interaction between lipid metabolism and hematologic factors. There is a need for more attention to events occurring within vascular tissue itself, especially at the site of atherosclerosis and thrombus formation. Insulin has been proposed as a major physiologic regulator of plasminogen activator inhibitor, and hyperinsulinemia is associated with increased blood coagulability and decreased fibrinolysis. There is a close association between insulin and triglyceride metabolism, and this may affect factor VII activity in blood. Changes in both the quantity and composition of dietary fat influence lipid metabolism as well as blood levels of a number of hematologic factors. Sex steroid-induced changes in aspects of metabolism such as blood lipid concentrations may not be as central to cardiovascular disease risk as originally believed. Changes in carbohydrate metabolism and in hematologic parameters induced by the currently used doses of sex steroids appear to be minor, although more intensive studies are recommended. Evidence suggests that genetic and early life influences are more important to the development of insulin resistance than later acquired causes.
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PMID:Metabolic interrelationships, cardiovascular disease, and sex steroids. 961 34


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