Paradoxic decreases in atherosclerotic plaque mass in insulin-treated diabetic patients

This study assessed the impact of diabetes mellitus on atherosclerotic lesion formation. Seventy insulin-treated diabetics, 150 non-insulin-treated diabetics, and 607 nondiabetics with chronic anginal syndromes and de novo native coronary stenoses were studied using (1) angiography, and (2) intravascular ultrasound (reference and lesion arterial, lumen, and plaque areas; area stenosis [reference-lesion/reference lumen area]; remodeling index [reference-lesion lumen area/lesion-reference plaque area]; and slope of the regression line relating lumen area to plaque burden [plaque/arterial area]). Despite being diabetic for longer and having similar lumen compromise, insulin-treated patients had (1) less reference plaque (8.3 +/- 3.4 vs 10.5 +/- 4.5 mm2, p = 0.0015), (2) less stenosis plaque (13.0 +/- 4.9 vs 16.9 mm2, p <0.0001), (3) smaller reference arterial areas (17.1 +/- 5.4 vs 19.7 +/- 6.2 mm2, p = 0.0063), and (4) smaller stenosis arterial areas (15.3 +/- 4.9 vs 19.5 +/- 6.5 mm2, p <0.0001) than non-insulin-treated diabetics. With use of multivariate linear regression analysis, insulin use was an independent (and negative) predictor of reference plaque and arterial areas (p = 0.0308 and p = 0.0179) and stenosis plaque and arterial areas (p = 0.0117 and p = 0.0066). This was also true when normalized for body surface area. The remodeling index showed that insulin treatment resulted in an exaggerated impact of plaque accumulation on lumen compromise. This was confirmed by the slope of the regression line relating lumen area to plaque burden. Patients with a longer duration of diabetes who were treated with insulin for > or = 1 year had (paradoxically) less reference segment and stenosis plaque accumulation. Possible explanations include impaired adaptive remodeling and/or arterial (and plaque) shrinkage.     

LDL particle size and LDL and HDL cholesterol changes with dietary fat and cholesterol in healthy subjects

We have conducted a dietary trial in 54 men and 51 women with a wide range of fasting cholesterol values to examine the use of low density lipoprotein (LDL) particle size to predict the lipoprotein response to dietary fat and cholesterol. After a 2-week low fat period, subjects were given two liquid supplements in addition to their low fat diet for 3 weeks each, one containing 31-40 g of fat and 650-845 mg of cholesterol, the other fat free. LDL particle type was determined by 3-15% gradient gel electrophoresis. On multiple regression, LDL type was independently related to plasma triglyceride (P < 0.001), waist circumference (P < 0.01), and high density lipoprotein (HDL) (P < 0.001) accounting for 56% of the variance in LDL type in the whole group. Change in LDL cholesterol with dietary fat and cholesterol was unrelated to LDL particle size in either men or women. However, change in HDL cholesterol in men was strongly related to LDL particle type (r = -0.52, P = 0.001) and change in HDL2 cholesterol in women was related to LDL particle type (r = -0.40, P < 0.01). In conclusion, we are unable to confirm the finding that LDL particle type can predict changes in LDL cholesterol following changes in dietary fat intake. However, LDL particle type can independently predict changes in HDL cholesterol in men and accounts for 27% of the variance.     

Biomechanics of atherosclerotic plaque

Atherosclerosis is the leading cause of death in the U.S. In balloon angioplasty, pressure is applied directly to atherosclerotic plaque to reopen the occluded blood vessel. The mechanical behavior of the plaque often determines the outcome of the angioplasty. Little information on the material properties of atherosclerotic plaque is available, yet the properties govern the plaque's behavior. Our discussion of the experimental testing and numerical analysis of plaque is directed toward summarizing the current knowledge of plaque material properties. Atherosclerotic plaque exhibits a wide range of behaviors consistent with the variability in the underlying composition. Overall, plaques exhibit nonlinear and inelastic mechanical behavior, although geometry and material properties are not well known. The histomorphological composition is critical in determining the plaque's mechanical response. Finite element approximations have been used to study the stresses developed in the diseased vessel; however, material properties are a critical component of a finite element analysis: the predictive capabilities depend on how accurately the material is modeled. When more information on plaque behavior is generated through careful and extensive experimental investigations, better models will be constructed to more accurately predict plaque responses. As the biomechanics community learns about plaque mechanics, we can use the knowledge to enhance the reliability of interventional procedures.     

Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization

We evaluated the proliferative activity of human atherosclerotic lesions associated with active symptoms of ischemia, by assessing the expression of the proliferating cell nuclear antigen (PCNA). We confirmed in vitro that PCNA, an essential component of the DNA synthesis machinery, is selectively expressed in proliferating human vascular smooth muscle cells. 37 atherosclerotic lesions (18 primary and 19 restenotic) retrieved by directional atherectomy from either coronary or peripheral arteries were then studied for the expression of PCNA, using in situ hybridization or immunohistochemistry. Among plaques studied by in situ hybridization, 7 out of 11 primary and 11 out of 11 restenotic lesions contained PCNA-positive cells. The mean rate of proliferation (percent of PCNA-positive cells) was 7.2 +/- 10.8% in primary lesions and 20.6 +/- 18.2% in restenotic lesions (P < 0.05). Among specimens studied by immunohistochemistry, five out of seven primary and eight out of eight restenotic lesions contained proliferating cells. The mean rate of proliferation was again higher in the restenotic (15.2 +/- 13.6%) than primary (3.6 +/- 3.5%) lesions (P < 0.05). Proliferating cells were detected as late as 1 yr after angioplasty. We conclude that cellular proliferation is a feature of atherosclerotic lesions which are associated with symptoms of ischemia, but that it is more prominent in restenosis compared to primary lesions. These findings have implications for therapies aimed at limiting lesion growth, particularly after percutaneous revascularization.     

Selection criteria for treatment of severe hyperlipoproteinemias with LDL apheresis

LDL (low density lipoprotein) - apheresis has been established as an alternative management of severe hypercholesterolaemia after failure of conventional diet and drug therapy. General indication criteria for LDL-apheresis have yet been established. Indication guidelines in USA, Europe and japan are based on whether coronary heart disease is present and on the degree of lDL cholesterol elevation after treatment with diet and maximal drug therapy. It is reasonable to consider LDL apheresis therapy for: 1. patient with coronary heart disease and LDL cholesterol 4.9 mmol/l (190 mg/dl); 2. patients without coronary heart disease, but at high risk for disease (due to an LDL cholesterol above 6.4 mmol/l (250 mg/dl), a first-degree relative with premature coronary heart disease, and the presence of one or more additional risk factor. The therapeutical goal with present coronary heart disease is lDL cholesterol less than 3.4 mmol/l (130 mg/dl), with asymptomatic coronary heart less than 5.2 mmol/l (200 mg/dl). In addition, LDL apheresis is recommended for the management of all patients with homozygous familial hypercholesterolaemia due to the very high risk of coronary heart disease and the poor response to usual lipid-lowering treatments. In the end present two typical cases, treated by LDL-apheresis.     

Effects of short-term reduction in serum cholesterol with simvastatin in patients with stable angina pectoris and mild to moderate hypercholesterolemia

To evaluate the effects of short-term cholesterol-lowering treatment on myocardial effort ischemia, 22 patients with stable effort ischemia and mild to moderate hypercholesterolemia (low density lipoprotein [LDL] cholesterol 160 to 220 mg/dl) were randomly allocated at baseline (TO) in 2 groups. Group A included 12 patients treated with simvastatin 10 mg bid; group B included 10 patients treated with placebo. All patients underwent a treadmill electrocardiography (ECG) test; total cholesterol, HDL and LDL cholesterol, triglycerides, plasma, and blood viscosity were measured. All tests were repeated after 4 and 12 weeks. For 18 of the same patients (11 taking simvastatin, 7 receiving placebo), forearm strain-gouge plethysmography was performed at baseline and after 4 weeks, both at rest and during reactive hyperemia. At 4 and 12 weeks, group A showed a significant reduction in total cholesterol (p <0.05) and LDL (p <0.05), with unchanged HDL, triglycerides, blood, and plasma viscosity. Effort was unmodified, ST-segment depression at peak effort and ischemic threshold were significantly improved after 4 and 12 weeks (all p <0.05) with unchanged heart rate x systolic blood pressure product. A significant increase in the excess flow response to reactive hyperemia was detected in group A (p <0.03); group B showed no changes in hematochemical and ergometric parameters. These data suggest that cholesterol-lowering treatment is associated with an improvement in myocardial effort ischemia; this might be explained by a more pronounced increase of coronary blood flow and capacity of vasodilation in response to effort.     

Composition- and history-dependent radial compressive behavior of human atherosclerotic plaque

Invasive procedures to revascularize occluded blood vessels rely on the mechanical response of the diseased tissue. Failure rates associated with such procedures show the need for improvement. to understand the associated mechanics, the material properties of atherosclerotic plaque should be known; yet data are scant. The purpose of this study was to investigate the different mechanical responses exhibited by plaques with different compositions, focusing specifically on radial compressive behavior. A custom-built experimental system was developed that was fully computer controlled with a broad range of loading capabilities. A temperature-controlled, physiologic specimen bath allowed testing at 37 degrees C. Monotonically loaded specimens showed that plaque behavior was nonlinear under finite deformations. A multiple cycle protocol, executed in two phases, distinguished three types of mechanical response of different plaques. The differences in behavior were associated with histologic differences in plaque composition, and mechanically characterized by different "repeatability" (the stabilization of the cyclic response) and "recoverability" (the second loading phase retracing the first loading phase behavior). Type 1 behavior was categorized by repeatability and recoverability. Type 2 behavior displayed repeatability but only partial recovery during the second loading phase. Recovery was absent in type 3 behavior. The histologic observations demonstrated that calcified tissue was present only in specimens displaying type 1 behavior. Fibrous tissue and part of a modified media (due to disease) were present in specimens displaying type 2 behavior. An atheroma, along with a relatively thin modified media, was present in specimens displaying type 3 behavior. The differences in the maximum stretches attained at the end of phase I loading, the stretch offset from the first to the 15th cycle of phase I loading, and the hysteresis in the first and 15th cycles of phase I loading distinguished the specimen behaviors with statistical significance. These compression data showed that plaques exhibit composition- and history-dependent nonlinear and inelastic responses under finite deformations.     

Correction of hypoalphalipoproteinemia in LDL receptor-deficient rabbits by lecithin:cholesterol acyltransferase

Familial hypercholesterolemia (FH), a disease caused by a variety of mutations in the low density lipoprotein receptor (LDLr) gene, leads not only to elevated LDL-cholesterol (C) concentrations but to reduced high density lipoprotein (HDL)-C and apolipoprotein (apo) A-I concentrations as well. The reductions in HDL-C and apoA-I are the consequence of the combined metabolic defects of increased apoA-I catabolism and decreased apoA-I synthesis. The present studies were designed to test the hypothesis that overexpression of human lecithin:cholesterol acyltransferase (hLCAT), a pivotal enzyme involved in HDL metabolism, in LDLr defective rabbits would increase HDL-C and apoA-I concentrations. Two groups of hLCAT transgenic rabbits were established: 1) hLCAT+/LDLr heterozygotes (LDLr+/-) and 2) hLCAT+/LDLr homozygotes (LDLr-/-). Data for hLCAT+ rabbits were compared to those of nontransgenic (hLCAT-) rabbits of the same LDLr status. In LDLr+/- rabbits, HDL-C and apoA-I concentrations (mg/dl), respectively, were significantly greater in hLCAT+ (62 +/- 8, 59 +/- 4) relative to hLCAT- rabbits (21 +/- 1, 26 +/- 2). This was, likewise, the case when hLCAT+/ LDLr-/- (27 +/- 2, 19 +/- 6) and hLCAT-/LDLr-/- (5 +/- 1, 6 +/- 2) rabbits were compared. Kinetic experiments demonstrated that the fractional catabolic rate (FCR, d(-1)) of apoA-I was substantially delayed in hLCAT+ (0.376 +/- 0.025) versus hLCAT- (0.588) LDLr+/- rabbits, as well as in hLCAT+ (0.666 +/- 0.033) versus hLCAT- (1.194 +/- 0.138) LDLr-/- rabbits. ApoA-I production rate (PR, mg x kg x d(-1)) was greater in both hLCAT+/LDLr+/- (10 +/- 2 vs. 6) and hLCAT+/LDLr-/- (9 +/- 1 vs. 4 +/- 1) rabbits. Significant correlations (P < 0.02) were observed between plasma LCAT activity and HDL-C (r = 0.857), apoA-I FCR (r = -0.774), and apoA-I PR (r = 0.771), while HDL-C correlated with both apoA-I FCR (-0.812) and PR (0.751). In summary, these data indicate that hLCAT overexpression in LDLr defective rabbits increases HDL-C and apoA-I concentrations by both decreasing apoA-I catabolism and increasing apoA-I synthesis, thus correcting the metabolic defects responsible for the hypoalphalipoproteinemia observed in LDLr deficiency.     

Psychological adjustment of children with mild and moderately severe asthma

In chronic hepatitis B virus (HBV) infection seroconversion from hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb) may be followed either by remission of the disease with low-level viraemia, or by continuing inflammation with high-level viraemia. In both situations the virus may acquire a mutation in the precore sequence which prevents it from encoding HBeAg. We now show that the number of amino acid substitutions in the HBV core is low in viral sequences from patients with HBeAg positive chronic liver disease and HBeAg negative HBeAb positive patients in remission, but the frequency of substitutions is high in HBeAg, negative HBeAb positive patients with active liver disease. Furthermore we show that these substitutions cluster in the promiscuous CD4+ T-helper-cell epitope and in HBV core/e antibody binding determinants, but are not found in regions recognized by major histocompatability complex (MHC) restricted cytotoxic T lymphocytes. Sequential viral sequences from patients before and after HBeAg/HbeAb seroconversion shows that core mutations arise either at the same time or after the precore stop mutation which prevents the virus from encoding HBeAg. These results are consistent with the hypothesis that after clearance of HBeAg, mutations in regions of the virus recognized by CD4+ helper T cells and B cells allow persistence of the HBe negative virus in HBeAb positive patients with viraemia and active hepatitis.     

Localization of lipoprotein in pre- and post-transition atherosclerotic lesions following short-term incubation with [125I]LDL

Ultrastructural autoradiography has been used to test the hypothesis that atherosclerotic regions of vessels differ with respect to lipoprotein uptake and localization. White Carneau pigeons, in which the prevalence and localization of aortic lesions are highly predictable, were fed a 0.25% cholesterol-supplemented diet to accelerate atherosclerosis. One hour prior to necropsy the birds were given a single intravenous injection of homologous [125I]LDL (low-density lipoprotein). Plasma die-away and tissue distribution of label were determined, and after the birds had been killed, the aortas, spleen and liver were processed for electron microscope autoradiography. Initial [125I]LDL uptake was rapid, with 35% of the label removed within 30 min. Predominant accumulation was in the liver, followed by the lung, kidney, the spleen and the aorta, in which the [125I]LDL level was approximately 4% that of the liver. Autoradiographic analysis documented hepatocyte (33%) and Kupffer cell (19.9%) localization in the liver and reticuloendothelial cell (57.4%) localization in the spleen. The aortic analysis involved serially sectioned lesions for direct comparison of non-lesion, lesion/non-lesion interface (edge) and deep lesion regions. Analysis of 2275 silver grains documented a ten-fold increase in LDL accumulation at the lesion edge (as compared to adjacent non-lesion) where macrophage foam cells contained more than 70% of the label. The other 30% was distributed equally among endothelium, the intimal matrix and smooth muscle cells. This distribution changed with more complex (deeper) lesions, although grain density in the complex lesions was comparable to the edge. In the complex regions, macrophage foam cell grains were reduced to 37%, whereas smooth muscle cell (22%) and the extracellular matrix (24%) label were both increased. These studies substantiate enhanced accumulation of lipoprotein specifically at lesion sites in the aorta and demonstrate a shift from macrophage localization at the developing edge to smooth muscle cell and the extracellular matrix in more complex deeper lesions.     

Psyllium-enriched cereals lower blood total cholesterol and LDL cholesterol, but not HDL cholesterol, in hypercholesterolemic adults: results of a meta-analysis

We conducted a meta-analysis to determine the effect of consumption of psyllium-enriched cereal products on blood total cholesterol (TC), LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels and to estimate the magnitude of the effect among 404 adults with mild to moderate hypercholesterolemia (TC of 5.17-7.8 mmol/L) who consumed a low fat diet. Studies of psyllium cereals were identified by a computerized search of MEDLINE and Current Contents and by contacting United States-based food companies involved in psyllium research. Published and unpublished studies were reviewed by one author and considered eligible for inclusion in the meta-analysis if they were conducted in humans, were randomized, controlled experiments, and included a control group that ate cereal providing /=50 y) on blood lipids. The meta-analysis showed that subjects who consumed a psyllium cereal had lower TC and LDL-C concentrations [differences of 0.31 mmol/L (5%) and 0.35 mmol/L (9%), respectively] than subjects who ate a control cereal; HDL-C concentrations were unaffected in subjects eating psyllium cereal. There was no effect of sex, age or menopausal status on blood lipids. Results indicate that consuming a psyllium-enriched cereal as part of a low fat diet improves the blood lipid profile of hypercholesterolemic adults over that which can be achieved with a low fat diet alone.     

Vitamin E levels in human atherosclerotic plaque: the influence of risk factors

Recent studies suggest that vitamin E may be an important preventative factor in the development and progression of atherosclerosis. In order to more clearly define the role of vitamin E in atherosclerosis, we measured vitamin E, conjugated diens, and lipid flurochromes, as well as cholesterol, triglycerides and phospholipid in arterial and venous tissue of 83 patients. Serum cholesterol and triglyceride levels were significantly higher (P < 0.05) in patients with aortic occlusive (AIOD) and aneurysmal (AAA) disease than in control organ donors (OD). Tissue cholesterol concentrations were significantly elevated in AAA tissue when compared to OD and tissue from patients with peripheral occlusive disease (POD). Tissue from patients with AIOD contained greater concentrations of phospholipid (PL) than were measured in patients with POD and in OD. Vitamin E concentrations were highest in POD tissue and approximately 3.0, 2.0, and 1.6 fold greater than OD, AIOD and AAA tissue respectively. Diene conjugates and lipid flurochromes, measures of early and intermediate products of lipid peroxidation, were markedly elevated in all diseased arterial tissue compared to controls. There were no significant differences in tissue or serum lipid levels between saphenous vein (SVBG) and diseased vein grafts (DVG). However, conjugated diene concentrations were elevated in DVG compared to SVBG. Vitamin E levels were significantly elevated in diseased arterial and venous tissue (AIOD, AAA, POD, DVG) removed from patients with diabetes (P = 0.013) and hypertension (P = 0.049) compared to those without these risk factors. Diabetes was the only risk factor associated with significantly increased (P = 0.005) levels of vitamin E when only data from atherosclerotic arterial tissue (AAA, POD, AIOD) were analyzed. These preliminary data provide additional evidence of altered vitamin E metabolism and free radical processes in the tissues of patients with various manifestations of atherosclerosis.     

Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL

In the management of major cerebral artery obstruction, cerebral perfusion reserve is key to introducing cerebral revascularization surgery. The purpose of this study was to evaluate the feasibility of assessing cerebral perfusion reserve by consecutive 99mTc-hexamethyl-propyleneamine oxime (99mTc-HMPAO) SPECT with 5% carbon dioxide (CO2) inhalation. METHODS: The CO2 inhalation and consecutive 99mTc-HMPAO SPECT study was performed on 30 chronic ischemic cerebrovascular disease patients with unilateral major cerebral artery obstruction and on 27 patients without. CO2 reactivity was expressed as the percent increase of 99mTc-HMPAO accumulation from the baseline (%Change) and as a constant k' that was the ratio of 99mTc-HMPAO accumulation per 1 mmHg change of end-tidal CO2 tension by exponential curve fitting. RESULTS: The mean %Change and k' in the middle cerebral artery (MCA) territory on the side without an obstructive lesion or in the cerebellum ranged from 10.0% to 11.1% and from 0.98% to 1.13% per mmHg, respectively. In the MCA territory, an obstructive lesion was noted in 5.9% versus 0.54% per mmHg in the contralateral MCA territory (p < 0.01). Eleven of 30 patients with major cerebral artery obstruction revealed significant asymmetry in the k' value between bilateral MCA territories. CONCLUSION: The results showed compromised cerebral perfusion reserve in the obstructed major cerebral artery territory. The present method was proven clinically useful for evaluating cerebral perfusion reserve in patients with unilateral major cerebral artery obstruction.     

Total cholesterol and high-density lipoprotein cholesterol in patients with non-insulin-dependent diabetes mellitus

Non-insulin-dependent diabetics often have quantitative changes in plasma lipid profiles characterised by higher triglycerides and lower HDL-cholesterol than the average population. This paper summarises the cross-sectional data (reported by the general practitioners participating in Medicos-Sentinela) concerning total and HDL-cholesterol in a cohort of non-insulin-dependent diabetics treated at primary care settings in Portugal. Total cholesterol and High Density Lipoprotein (HDL) associated cholesterol were significantly higher in women. Total cholesterol increased significantly with age (in women), regular alcohol intake, body mass index, systolic blood pressure and diastolic blood pressure (in males). HDL-cholesterol showed significant increase with age (both sexes and males only), gender, and alcohol intake in males. The increase in total cholesterol found in patients with regular alcohol intake is an infrequently reported finding.