Non-insulin-dependent diabetes mellitus and atherosclerosis: a lipoprotein perspective.
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Coronary Artery Disease↗
Biomedical subjects
A Hamsten
Publications and source records attributed to A Hamsten.
Interactions amongst insulin, lipoproteins and haemostatic function relevant to coronary heart disease.
Interest has increased considerably in the past few years in the possible interactions amongst insulin, plasma lipoproteins and several components of the haemostatic system. There is now consistent epidemiological, clinical and experimental evidence that hypertriglyceridaemia, in particular, may represent a procoagulant state involving derangements of both blood coagulation and fibrinolysis. Imbalance in the haemostatic system secondary to increased clotting activity, impaired fibrinolytic function, or a combination thereof, should influence the growth and final size of evolving thrombi and predispose to arterial occlusion. This might be of particular significance in the coronary circulation, where a hypercoagulable state is likely to promote thrombosis at the site of a suddenly ruptured atherosclerotic plaque. In addition, there is accumulating experimental evidence that the haemostatic system plays a part in plaque formation and plaque growth. Basic research on the link between haemostasis and atherosclerosis should be given high priority, because modulation of haemostatic function will probably be a potent complementary approach to the prevention of coronary heart disease.
Blood Coagulation↗
The role of beta-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden.
Beta-fibrinogen G/A-455 polymorphism genotype was determined in 123 young survivors of myocardial infarction and 86 healthy controls from Sweden. Frequency of the A-455 allele was 0.25 (95% Confidence Interval 0.21-0.29) in both patients and controls, significantly higher than that reported previously (0.19, 95% CI 0.16-0.22) in 292 men from the UK. Mean plasma fibrinogen level was significantly higher in patients (3.6 g/l) than in controls (3.1 g/l), with p < 0.001. Genotype was significantly associated with (adjusted) plasma fibrinogen level in controls (p = 0.003). This effect was confined to the smokers (n = 50) where mean fibrinogen level was significantly (p = 0.001) higher in G/A-455 and A/A-455 individuals (3.5 g/l) compared with G/G-455 homozygotes (2.9 g/l). There was a significant interaction between smoking status and genotype in determining plasma fibrinogen levels in the controls. These data provide independent confirmation of the association between beta-fibrinogen G/A-455 genotype and plasma fibrinogen levels previously observed in healthy men from the UK.
Adult↗
The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells.
We have detected a common (allele frequency 0.53/0.47) single base pair insertion/deletion polymorphism 675 base pairs upstream from the start of transcription of the plasminogen activator inhibitor-1 (PAI-1) gene, using the chemical cleavage mismatch analysis. "Band shift assays" suggest that the allele with the single base pair insertion contains an additional protein binding site which is not present in the del allele. Competition experiments confirmed that the binding was specific to the sequence of the ins allele and suggest that proteins bound to this site may be NF-kB-like proteins. Analysis of chloramphenicol acetyltransferase (CAT) mRNA produced by constructs containing the PAI-1 promoter (-805 to +83) showed that the deletion allele produced six times more mRNA than the insertion allele in response to interleukin-1 (p < 0.001). In a sample of 107 young patients with previous myocardial infarction and 95 healthy population-based subjects, the del allele was associated with increased PAI-1 levels, 21% higher than the sample mean in the del homozygotes (p < 0.05). This study also suggested that individuals homozygous for the del allele may have an altered response to the acute phase stimulus. Taken together these results suggest that the insertion/deletion polymorphism in the PAI-1 promoter is of functional importance in regulating the expression of the PAI-1 gene.
Adult↗
The hemostatic system and coronary heart disease.
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Angioplasty, Balloon, Coronary↗
A postulated phylogenetic tree for the human apolipoprotein B gene: unpredicted haplotypes are associated with elevated apo B levels.
Using published data on seven polymorphic sites in the human apolipoprotein B (apo B) gene, it is possible to postulate a model phylogenetic tree for this gene, covering the time since the divergence of human beings from other primates. This simple model assumes no obligatory recombination events or multiple occurrences of the same mutation. This model was tested in two samples of Swedish individuals consisting of 143 young, myocardial infarction patients and 90 healthy, age-matched, control individuals. All the haplotypes postulated in the simple model were observed unequivocally. However, in addition, three unpredicted haplotypes were unambiguously observed and a further nine, much rarer haplotypes were deduced to occur in these samples. The frequencies of the haplotypes postulated in the model do not differ between the patient and control samples, however most of the unpredicted haplotypes occur more frequently in the patient group than in the controls. Two of these unpredicted haplotypes, defined by the combination of the Antigen group (a) epitope and the presence of the XbaI cutting site, were associated with raised serum apo B levels in the control group and significantly elevated levels in the patient group. We propose that these observations explain in part the consistent association reported between the XbaI polymorphic site in the apo B gene and levels of plasma lipids.
Amino Acid Sequence↗
Composition of human low density lipoprotein: effects of postprandial triglyceride-rich lipoproteins, lipoprotein lipase, hepatic lipase and cholesteryl ester transfer protein.
A preponderance of small, dense low density lipoprotein (LDL) particles has been linked to increased risk of myocardial infarction, and a dense and protein-rich LDL has proved to be a characteristic of patients with manifest coronary heart disease (CHD). The present study focused on metabolic determinants of the LDL subfraction distribution with the emphasis placed on alimentary lipaemia. The relations of plasma levels and composition of light (1.019 < d < 1.040 kg/l) and dense (1.040 < d < 1.063 kg/l) LDL subfractions to postprandial triglyceride-rich lipoproteins (TGRL), postheparin plasma lipase activities and the activity of cholesteryl ester transfer protein (CETP) were studied in 32 men with angiographically ascertained premature coronary atherosclerosis (age 48.8 +/- 3.2 years) and in 10 age matched healthy control men. LDL subfractions were separated by equilibrium density gradient ultracentrifugation of fasting plasma drawn before participants were subjected to an oral fat tolerance test of a mixed meal type. The response of TGRL to the oral fat load was determined by measuring plasma triglycerides, and the apolipoprotein (apo) B-48 and apo B-100 content of Sf 60-400 and Sf 20-60 lipoprotein fractions. At a second visit plasma samples were taken for determination of postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities and for measurement of CETP activity. Hypertriglyceridaemic patients had a preponderance of dense LDL particles compared with normotriglyceridaemic patients and controls. The magnitude of the response of TGRL to the oral fat load showed a positive association with the dense LDL apo B concentration (r = 0.32-0.52, P < 0.05), whereas the LPL activity correlated positively with the free (r = 0.50, P < 0.001) and esterified cholesterol (r = 0.45, P < 0.01) and apo B (r = 0.42, P < 0.01) content of the light LDL fraction. The HL activity was found to be inversely associated with the plasma level of light LDL triglycerides (r = -0.38, P < 0.05). In contrast, no relations were noted between CETP activity and plasma concentrations of LDL constituents. Multiple stepwise linear regression analysis with the proportion of total LDL apo B contained in the dense LDL subfraction (% dense LDL apo B) used as the dependent variable indicated that the combined effect of LPL activity and postprandial plasma levels of TGRL (areas under the curve for plasma triglycerides or Sf 60-400 apo B-48) accounted for around 50% of the variability in the distribution of LDL particles between light and dense subfractions.(ABSTRACT TRUNCATED AT 400 WORDS)
Carrier Proteins↗
Relationship between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, insulin levels and insulin sensitivity: studies in randomly selected normo- and hypertriglyceridaemic men.
Impaired fibrinolytic function secondary to elevated plasma plasminogen activator inhibitor-1 activity, hypertriglyceridaemia and hyperinsulinaemia are frequent findings in patients with coronary heart disease. It has been debated whether VLDL or insulin is the major regulator of plasma plasminogen activator inhibitor-1 activity. This study examines the relationships between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, fasting and post-oral glucose load insulin levels and insulin sensitivity, as estimated by the minimal model method. Subjects studied were randomly selected hypertriglyceridaemic (n = 65) and age-matched normotriglyceridaemic (n = 61) men, aged 40-50 years, recruited in a population survey. Plasma plasminogen activator inhibitor-1 activity was higher in the hypertriglyceridaemic than in the normotriglyceridaemic group (21 +/- 14 vs 10 +/- 8 mU/l; p < 0.01). The hypertriglyceridaemic group had higher serum insulin, basal as well as 2 h after intake of the oral glucose load, and a lower insulin sensitivity index. In univariate analysis, plasma plasminogen activator inhibitor-1 activity correlated positively with VLDL triglycerides in both the hyper- and normotriglyceridaemic groups (r = 0.43 r = 0.60, respectively) and negatively with the insulin sensitivity index (r = -0.35 r = -0.44, respectively). In multivariate analysis, VLDL triglyceride levels were found to be independently related to plasma plasminogen activator inhibitor-1 activity in both groups, whereas insulin sensitivity/serum insulin levels were not. An unexpected finding was that the serum activity of the enzyme gamma glutamyl transpeptidase appeared to influence the relationships for plasma plasminogen activator inhibitor-1 in the hypertriglyceridaemic group.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Diet and exercise are equally effective in reducing risk for cardiovascular disease. Results of a randomized controlled study in men with slightly to moderately raised cardiovascular risk factors.
To study the impact of diet and exercise and the combination thereof on cardiovascular risk factors, 157 healthy men aged 35-60 years (mean +/- S.D.; 46.2 +/- 5.0) with slightly to moderately raised cardiovascular risk factors, were randomized to 4 groups, diet (D, n = 40), exercise (E, n = 39), diet plus exercise (DE, n = 39), and no active intervention (controls (C, n = 39)), and investigated at baseline and after 6 months. BMI was significantly reduced in Groups E and DE (mean difference and 95% confidence intervals (CI), -0.3 (-0.5, -0.01) and -0.6 (-0.9, -0.3) kg/m2, respectively). Waist circumference was reduced in all 3 intervention groups (D, E, and DE), -1.3 (-2.5, -0.1), -2.2 (-3.2, -1.3) and -3.0 (-3.9, -2.0) cm, but not in the control group. Blood pressure (BP) was reduced in all 3 intervention groups, systolic BP 4-7 mmHg and diastolic BP 2-6 mmHg. Serum cholesterol was reduced in Group DE, -0.45 (-0.77, -0.13) mmol/l. VLDL-cholesterol was reduced in Groups E and DE, -0.14 (-0.26, -0.03) and -0.09 (-0.18, -0.01) mmol/l, whereas LDL-cholesterol was reduced in Groups D and DE -0.30 (-0.54, -0.06) and -0.35 (-0.64, -0.05) mmol/l. In contrast, neither HDL-cholesterol nor serum triglycerides were influenced by the interventions. According to the coronary risk profile derived from the Framingham study, all 3 intervention groups (D, E, and DE) significantly reduced their estimated 10-year risk (-13, -12, and -14%, respectively). We conclude that even with rather moderate changes in diet and exercise, several important cardiovascular risk factors can be affected and that diet and exercise were about equally effective in reducing cardiovascular risk.
Adult↗
Coronary angiographic changes during 2 years after myocardial infarction largely undetected by repeated tomographic thallium-201 scintigraphy and not reflected by clinical symptoms.
Repeated coronary angiographies and single photon emission computed tomographies (SPECT) were performed at 9 and 33 months after myocardial infarction (MI) in 47 young men. Coronary lesions were classified in eight grades with respect to the reduction of the luminal diameter. The progression and regression of two steps or more in lesions of grade 2 or more, the recanalization of coronary thrombosis and an increase in collaterals were recorded. Patients were divided into three groups with regard to (A) deterioration, (B) improvement and (C) no changes in the three major coronary regions, respectively. Overall, 23 patients (49%) showed changes between the first and the second investigation. A simplified method using summarized short-axis slices for evaluation of the thallium-201 SPECT showed a significant difference in change of regional myocardial uptake of thallium-201 between groups A and B (P = 0.047) but not between the groups A and C, in lateral myocardial regions. No significant differences were found between any of the groups in respect of the anterior or inferior myocardial regions. These findings were not explained by changes in clinical status, maximum heart rate or workload, or by changes in medication. Our results suggest that substantial changes in coronary morphology can take place during the 2 years following MI without consistent changes in clinical symptoms or regional myocardial perfusion.
Adult↗
Mitogenic activity in connection with coronary angioplasty.
The aim of this study was to assess the plasma mitogenic activity in connection with percutaneous transluminal coronary angioplasty (PTCA) and the relation to restenosis. Plasma samples were taken on the morning before, 1 and 24 h after, 2 weeks after and 6 months after elective PTCA in 50 patients. Follow-up coronary angiography was carried out after 6 months or earlier if clinically warranted. Samples were also taken from 17 patients undergoing coronary angiography without PTCA. The mitogenic activity, expressed as the fraction of labelled nuclei after incubation of arterial smooth muscle cells with plasma in the presence of 3H-thymidine, was higher 1 h after PTCA than before (53.1 +/- 7.4 vs 26.8 +/- 7.3, P < 0.001). Later values were not elevated and no increase was seen after coronary angiography. The groups with (n = 19) and without (n = 31) restenosis did not differ in mitogenic activity. These results indicate that the plasma level of mitogenic activity increases immediately after PTCA. The pathophysiological significance of this increase for the development of restenosis is unclear, since the magnitude of the increase does not seem to be related to restenosis.
Aged↗
Human intestinal alkaline phosphatase--release to the blood is linked to lipid absorption, but removal from the blood is not linked to lipoprotein clearance.
To evaluate a possible quantitative relationship between the rise in intestinal alkaline phosphatase (IAP) activity and triglyceride-rich lipoproteins in the blood after an oral fat intake, a specific and sensitive immunocatalytic assay was used. First, day to day variation of the basal IAP activity in the blood of eight volunteers was evaluated. One group of subjects with high basal IAP activity and great variations from one day to the other was distinguished from a group with low basal IAP activity and small day to day variations. The subjects with high basal IAP activities were all secretors of red blood cell antigens, while those with low basal IAP activities were non-secretors. The IAP activity in the blood rose after fat rich meals but not after fat free meals. To further investigate this, IAP activities were measured in the blood of 28 men before 3, 6, 9 and 12 h after a standardized oral fat load of a mixed meal type. The activity rose in all individuals and showed a similar time course as the rise in plasma TG concentration. The elevations of the IAP activity were, however, not quantitatively correlated with the elevations in TG concentration, nor were there any relations in time to peak levels. Subjects with high basal IAP increased their IAP activity more than those with low basal IAP, but within neither group there was any correlation between the basal IAP activity and the rise in IAP activity. IAP did not float with lipoproteins on ultracentrifugation of plasma, nor did IAP bind to lipid droplets from a fat emulsion added to plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
HDLs and alimentary lipemia. Studies in men with previous myocardial infarction at a young age.
The plasma concentration, particle size, and chemical composition of high density lipoproteins (HDLs) are associated with the metabolism of triglyceride-rich lipoproteins (TGRLs). During alimentary lipemia there is active exchange of lipids and apolipoproteins between HDL and apolipoprotein B-containing lipoproteins. Whereas HDL has been assigned a protective role against the development of atherosclerosis, alimentary lipemia has been proposed to represent a potentially atherogenic state. We examined plasma HDL concentration, particle size, and composition and their relations to postprandial TGRLs in 32 postinfarction patients and 10 healthy control subjects after intake of a standardized oral fat load of a mixed-meal type. All patients had undergone coronary angiographies in connection with the myocardial infarction and around 5 years thereafter. The plasma HDL cholesterol concentration decreased significantly in response to the oral fat load, particularly in hypertriglyceridemic patients, with a concomitant increase of HDL triglycerides. A limited and reversible yet consistent increase of HDL particle size (1-2%) was seen 6 hours after intake of the oral fat load on nondenaturing gradient gel electrophoresis (GGE) in both patients and control subjects. Virtually no changes in the plasma concentration of HDL GGE subclasses, lipoproteins containing apolipoprotein A-I but no apolipoprotein A-II (LpA-I), or lipoproteins containing both apolipoproteins A-I and A-II (LpA-I:A-II) were induced in the postprandial state despite massive increases of large very low density lipoprotein (VLDL) and large chylomicron remnant levels (determined as apolipoproteins B-100 and B-48 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Strong inverse correlations with fasting plasma HDL cholesterol and the larger HDL GGE subspecies were found for large postprandial VLDL and large chylomicron remnants, whereas the corresponding relations for small VLDL and small chylomicron remnants were weaker. The relations of both large and small VLDL and chylomicron remnants to HDL cholesterol were confined to subjects in the lower fasting plasma HDL cholesterol range (< 1.2 mmol/l). None of the HDL parameters measured, either in the fasting or in the postprandial state (HDL cholesterol, HDL triglycerides, HDL GGE subclasses, LpA-I, and LpA-I:A-II), were related to the development of coronary atherosclerosis, whereas the postprandial plasma levels of small chylomicron remnants, which showed weak negative correlations with HDL, related positively to the progression of coronary atherosclerosis.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Relation of plasma levels and composition of apolipoprotein B-containing lipoproteins to angiographically defined coronary artery disease in young patients with myocardial infarction.
BACKGROUND: Hypertriglyceridemia is a common metabolic disturbance in men < 45 years old with myocardial infarction. To further investigate the relation between triglyceride-rich lipoproteins and severity of coronary atherosclerosis in this subset of postinfarction patients, apolipoprotein B-containing lipoproteins of 64 consecutive patients were subfractionated in connection with coronary angiography. METHODS AND RESULTS: Density-gradient ultracentrifugation of plasma and coronary angiography were performed 4 to 6 months after the myocardial infarction. Global coronary atherosclerosis and the number and severity of distinct stenoses were evaluated by semiquantitative analysis of 15 proximal coronary segments. The majority of the patients (60%) were hypertriglyceridemic and had higher coronary scores than normotriglyceridemic patients. Of the major plasma lipoproteins, triglycerides and cholesterol in the low-density lipoprotein (LDL) fraction were associated with global coronary atherosclerosis, whereas LDL triglycerides and high-density lipoprotein (HDL) cholesterol correlated directly and inversely, respectively, with the coronary stenosis score. Plasma apolipoprotein B correlated with both coronary scores. The plasma concentrations of lipid and protein in the very-low-density lipoprotein (VLDL) subfractions (VLDL1 through VLDL3) and intermediate-density lipoprotein (IDL) did not correlate with either of the coronary scores, whereas the concentration of triglycerides in dense LDL (density > 1.040 kg/L) was strongly associated with both coronary scores. Compositional analysis of the smallest VLDL particles (VLDL3) and IDL revealed a correlation between the number of cholesteryl ester molecules in small VLDL and global coronary atherosclerosis in hypertriglyceridemic patients. CONCLUSIONS: Global coronary atherosclerosis and distinct stenoses in young postinfarction patients are associated with the number of apolipoprotein B-containing particles in plasma and the concentration of LDL triglyceride. Specifically, dense triglyceride-rich LDL particles and, in hypertriglyceridemic patients, small cholesteryl ester-rich VLDL particles relate to coronary artery disease severity.
Adult↗
Metabolism of triglyceride-rich lipoproteins during alimentary lipemia.
The metabolism of chylomicron remnants and VLDL was studied in healthy controls and normo- (NTG) and hypertriglyceridemic (HTG) patients with coronary artery disease after intake of an oral fat load. Specific determination of apo B-48 and B-100 enabled separation of the respective contribution of the two lipoprotein species. The postprandial plasma levels of small (Sf 20-60) and large (Sf 60-400) chylomicron remnants increased in controls and NTG patients. In contrast, only large chylomicron remnants increased in the HTG patients. An increase of large VLDL was seen in response to the oral fat load in all groups, whereas small VLDL were either unchanged in the controls and the NTG patients, or decreased in the HTG patient group. The whole plasma concentration of C apolipoproteins was essentially uninfluenced by the oral fat load, whereas the content in large triglyceride-rich lipoproteins paralleled the apo B elevations in controls and NTG patients. An even more prominent increase of apo B in large triglyceride-rich lipoproteins in the HTG group was not accompanied by an increase of C apolipoproteins. These findings indicate that chylomicrons compete with VLDL for removal of triglycerides by lipoprotein lipase and that the postprandial metabolism of triglyceride-rich lipoproteins is severely defective in hypertriglyceridemia.
Apolipoproteins B↗
Lipids as a coronary risk factor: analysis of hyperlipidaemias.
Despite difficulties with epidemiological data, there is little doubt that triglyceride-rich lipoproteins are important factors in the induction of human atherogenesis, although the mechanisms remain elusive. A statistical association exists between small chylomicron remnant concentrations and fasting triglyceride levels and a stronger link is found between the larger chylomicron remnants and larger very low density lipoproteins. The link between concentrations of chylomicron remnants and disease progression is not explained by any relationship to the high density lipoprotein system but rather reflects the direct atherogenic action of the small chylomicron remnants themselves. Dense low density lipoprotein (LDL) triglyceride concentration seems to be more strongly correlated with disease severity in young post-infarction patients than LDL cholesterol concentration. There has been much recent interest in the process of LDL oxidation which re-routes LDL from normal receptors to the scavenger receptor pathway. In this regard, it was interesting to find a strong inverse correlation between low LDL vitamin E content and arterial stenosis. The relationship between dense LDL and coronary disease may depend on several different pathways all of which implicate the triglyceride-rich lipoproteins in the pathogenesis of coronary artery disease.
Chylomicrons↗
Possibilities of DNA analysis for the detection of predisposition to thrombotic disease.
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Biomarkers↗
Fibrin gel network characteristics and coronary heart disease: relations to plasma fibrinogen concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis.
The native fibrin gel structure formed in vitro from plasma samples was examined by liquid permeation of the hydrated fibrin gel networks in 18 men who had suffered a myocardial infarction before the age of 45 years and in 20 control subjects. Patients with an elevated plasma fibrinogen concentration had a considerably lower fibrin gel porosity (permeability coefficient, Ks) compared with patients with a normal plasma fibrinogen level and with controls. The calculated fiber mass-length ratio of the fibrin gel networks was decreased in both patient groups. Gel porosity differed markedly between individuals at a given plasma fibrinogen concentration. Fairly strong inverse correlations were found between plasma orosomucoid level on the one hand and Ks (r = -0.617, p less than 0.01) or fiber mass-length ratio (r = -0.499, p less than 0.05) on the other. The low density lipoprotein (LDL) cholesterol concentration also correlated inversely with Ks (r = -0.471, p less than 0.05) and fiber mass-length ratio (r = -0.522, p less than 0.05). Significant inverse relations, which were independent of plasma fibrinogen and lipoprotein concentrations, were detected between Ks (r = -0.519, p less than 0.05) and calculated fiber mass-length ratio (r = -0.723, p less than 0.001) and number and severity of coronary artery stenoses determined by angiography. A proneness to formation of tight, rigid and space-filling fibrin network structures with small pores thus appears to be associated with premature coronary artery disease.
Acute-Phase Proteins↗