[Show abstract][Hide abstract] ABSTRACT: To determine whether patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) had evidence of increased homocysteine levels compared with non-CADASIL patients with ischemic stroke or transient ischemic attack.
We compared fasting plasma homocysteine levels and levels 6 hours after oral loading with methionine, 100 mg/kg, in non-CADASIL patients with ischemic stroke or transient ischemic attack and in patients with CADASIL. Prechallenge, postchallenge, and change in homocysteine levels between the 2 groups were compared with use of the Wilcoxon rank sum test.
CADASIL and non-CADASIL groups were similar in age (mean, 48.8 vs. 46.5 years, respectively; 2-tailed t test, P=.56) and sex (men, 86% vs 59%; Fisher exact test, P=.12). The 59 patients in the CADASIL group had higher median plasma homocysteine levels compared with the 14 patients in the non-CADASIL group, both in the fasting state (12.0 vs 9.0 micromol/L; P=.03) and after methionine challenge (51.0 vs 34.0 micromol/L; P=.007). Median difference between homocysteine levels before and after methionine challenge was greater in the CADASIL group than in the non-CADASIL group (34.5 vs. 24.0 micromol/ L; P = .02).
Our findings raise the possibility that increased homocysteine levels or abnormalities of homocysteine metabolism may have a role in the pathogenesis of CADASIL.
Mayo Clinic Proceedings 01/2002; 76(12):1213-8. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the importance of classic and nonclassic risk factors in the development of coronary artery disease (CAD) or cerebrovascular disease (CVD) in patients with type 2 diabetes mellitus (DM).
In this community-based, prospective cohort study, quantitative measurements for cholesterol, triglycerides (TGs), glucose, and lipoprotein(a) detected as a sinking pre-beta-lipoprotein band on electrophoresis were obtained from 1968 through 1982 from 449 patients who were free of CAD and CVD but had type 2 DM. Demographic data and covariables obtained were age, body mass index, duration of diabetes, sex, smoking, and hypertension. The relationship of individual continuous factors to the development of CAD and CVD as well as multivariate models were evaluated with use of the Cox proportional hazards model. The primary outcome was to determine which risk factors are associated with development of CAD or CVD in patients with type 2 DM.
After a mean follow-up of 13 years, 216 CAD and 115 CVD events had developed. The hazard ratio estimates with 95% confidence intervals (CIs) for CAD after multivariate analysis were significant for age, 1.45 (95% CI, 1.27-1.67); fasting glucose levels at enrollment, 1.63 (95% CI, 1.17-2.25); smoking, 1.45 (95% CI, 1.10-1.91); and TGs, 1.49 (95% CI, 1.15-1.92). The hazard ratio estimates for CVD were significant for age, 1.95 (95% CI, 1.59-2.38); hypertension, 1.89 (95% CI, 1.30-2.74); fasting glucose levels at enrollment, 1.69 (95% CI, 1.06-2.70); and smoking, 1.57 (95% CI, 1.07-2.30).
In diabetic patients, age, fasting glucose levels, smoking, and TG levels are independent risk factors for development of CAD events. Age, hypertension, glucose, and smoking predicted development of CVD events.
Mayo Clinic Proceedings 08/2001; 76(7):707-12. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Splenomegaly with sea-blue histiocytes is not associated with dyslipidemia, except in severe cases of hypertriglyceridemia, Tangier disease, or lecithin cholesterol acyltransferase deficiency. We describe two kindreds in which the sea-blue histiocyte syndrome was associated with an apoE variant in the absence of severe dyslipidemia. Both patients presented with mild hypertriglyceridemia and splenomegaly. After splenectomy both patients developed severe hypertriglyceridemia. Pathological evaluation of the spleen revealed the presence of sea-blue histiocytes. A mutation of apoE was demonstrated, with a 3-bp deletion resulting in the loss of a leucine at position 149 in the receptor-binding region of the apoE molecule [apoE (delta149 Leu)]. Although both probands were unrelated, they were of French Canadian ancestry, suggesting the possibility of a founder effect. In summary, we describe two unrelated probands with primary sea-blue histiocytosis who had normal or mildly elevated serum triglyceride concentrations that markedly increased after splenectomy. In addition, we provide evidence linking the syndrome to an inherited dominant mutation in the apoE gene, a 3-bp deletion on the background of an apoE 3 allele that causes a derangement in lipid metabolism and leads to splenomegaly in the absence of severe hypertriglyceridemia.
[Show abstract][Hide abstract] ABSTRACT: To establish baseline data for the CardioVision 2020 program, a collaborative project in Olmsted County, Minnesota, organized to reduce cardiovascular disease rates by altering 5 health-related items: (1) eliminating tobacco use and exposure, (2) improving nutrition, (3) increasing physical activity, (4) lowering serum cholesterol level, and (5) controlling blood pressure.
Data about tobacco use, diet, and physical activity were collected by random digit dial interview and follow-up questionnaire from a sample of the population. Blood pressure data were collected from medical records at Mayo Clinic, and serum cholesterol data were derived from the Mayo Clinic laboratory database. Data were stratified into 6 age groups.
A total of 624 women and 608 men responded to the questionnaire. Population blood pressure data were available for 1,956 women and 1,084 men. Population serum cholesterol data were available for 17,042 women and 12,511 men. Except for women in the 30- to 39-year-old age group, less than 10% of the population sampled met 4 or 5 goals. Conversely, about 90% of the population met at least 1 goal, and about 80% met 1, 2, or 3 of the goals.
The data from the Olmsted County population indicate considerable opportunity to reduce this population's burden of cardiovascular disease.
Mayo Clinic Proceedings 12/2000; 75(11):1153-9. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the efficacy of stanol esters in lowering cholesterol in a US population.
After a run-in phase, 318 subjects were randomized to receive one of the following margarine-like spreads containing stanol ester or placebo for 8 weeks: EU 3 G: 1 g of stanol (ester form) per 8-g serving of a European formula 3 times a day; US 3 G: 1 g of stanol (ester form) per 8-g serving of a US reformulation 3 times a day; US 2 G: 0.67 g of stanol (ester form) per 8-g serving of a US reformulation 3 times a day; or placebo spread.
Mean +/- SD baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were 233+/-20 and 153+21 mg+/-dL, respectively. In the US 3 G group, 3 g daily of stanol esters lowered TC and LDL-C levels by 6.4% and 10.1%, respectively. There was a dose-dependent response compared with 2 g daily (US 2 G). Triglyceride and high-density lipoprotein cholesterol levels were unchanged. The incidence of adverse effects was not different from placebo. Serum vitamin A and 25-hydroxyvitamin D levels were not affected.
Stanol esters lowered TC and LDL-C levels in a mildly hypercholesterolemic US population without evidence of adverse effects. It may be a useful dietary adjunct to lower cholesterol.
Mayo Clinic Proceedings 01/2000; 74(12):1198-206. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clomiphene has been available for clinical use since 1960 and has been successfully used to aid fertility in women with certain anovulatory disorders. It is a synthetic estrogen analog, of the triphenylethylene derivative group, and its biochemical structure is similar to that of tamoxifen. Estrogen and tamoxifen lower total and low-density lipoprotein cholesterol and increase triglyceride and high-density lipoprotein cholesterol levels. In patients with baseline hypertriglyceridemia, these agents can induce severe hypertriglyceridemia and pancreatitis. The actions of clomiphene on lipid metabolism have not been studied, and to our knowledge, no cases of severe hypertriglyceridemia related to the use of clomiphene have been described. We report the case of a woman who developed 2 episodes of clomiphene-induced hypertriglyceridemia and pancreatitis while receiving this drug for treatment of infertility. Given the striking structural similarity between clomiphene and tamoxifen, it is likely that clomiphene is capable of inducing severe hypertriglyceridemia in patients with certain underlying lipid disorders by a mechanism similar to that of tamoxifen.
Mayo Clinic Proceedings 12/1999; 74(11):1125-8. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The increased risk of coronary artery disease in subjects with diabetes mellitus can be partially explained by the lipoprotein abnormalities associated with diabetes mellitus. Hypertriglyceridemia and low levels of high-density lipoprotein are the most common lipid abnormalities. In type 1 diabetes mellitus, these abnormalities can usually be reversed with glycemic control. In contrast, in type 2 diabetes mellitus, although lipid values improve, abnormalities commonly persist even after optimal glycemic control has been achieved. Screening for dyslipidemia is recommended in subjects with diabetes mellitus. A goal of low-density lipoprotein cholesterol of less than 130 mg/dL and triglycerides lower than 200 mg/dL should be sought. Several secondary prevention trials, which included subjects with diabetes, have demonstrated the effectiveness of lowering low-density lipoprotein cholesterol in preventing death from coronary artery disease. The benefit of lowering triglycerides is less clear. Initial approaches to lowering the levels of lipids in subjects with diabetes mellitus should include glycemic control, diet, weight loss, and exercise. When goals are not met, the most common drugs used are hydroxymethylglutaryl coenzyme A reductase inhibitors or fibrates.
Mayo Clinic Proceedings 11/1998; 73(10):969-76. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Elevated lipoprotein(a) [Lp(a)] levels have been associated with the presence of atherosclerotic disease. However, the results of prospective studies of Lp(a) and cardiovascular disease have been contradictory.
From 1968 through 1982, lipoprotein analysis was performed in 11,335 Olmsted County residents. Quantitative cholesterol and triglycerides were obtained along with semiquantitative Lp(a) levels based on electrophoretic pattern. Lp(a) bands were scored from 0 (absent) to 3 (increased). A cohort of 4967 men and 4968 women with no prior history of atherosclerotic disease who had baseline Lp(a) determinations were followed up for 14 years for development of coronary artery disease (CAD) and cerebrovascular disease (CVD). During 131,330 person-years of follow-up, there were 1848 CAD events and 841 CVD events. Age, diabetes, hypertension, cholesterol, and triglycerides were significantly and independently associated with an increased risk of CAD and CVD in men and women. There was a significant increase in the adjusted hazards ratio for CAD with increasing Lp(a) levels for men and women. For Lp(a) level 3, the hazard ratio was 1.9 (range, 1.3 to 2.9) in women and 1.6 (range, 1.0 to 2.5) in men. The adjusted hazard ratio for CVD showed an irregular association with Lp(a) levels in men and no association in women.
In this cohort of 9936 men and women initially free of cardiovascular disease who were followed up for 14 years, Lp(a) was a significant predictor of risk of future CAD. Lp(a) was a weak risk factor for CVD in men and was not a significant predictor of CVD risk in women.
[Show abstract][Hide abstract] ABSTRACT: Although lipid abnormalities are well described in hypothyroidism, effects on apolipoproteins are less well understood. The aim of this study was to examine the effects of thyroid dysfunction on plasma lipids and apolipoproteins.
A prospective study of lipids and apolipoproteins before and after treatment of hypothyroidism and hyperthyroidism.
Eighteen patients with hypothyroidism and 5 patients with hyperthyroidism were included.
Plasma cholesterol, triglycerides, HDL cholesterol, apo AI, apo AII, and apo E were measured before and after treatment of the thyroid abnormality.
Total and HDL cholesterol, apo AI and apo E decreased with treatment of hypothyroidism, while triglycerides and apo AII levels were unchanged. The total/HDL cholesterol and LDL/HDL cholesterol ratios also decreased with treatment of hypothyroidism. In contrast, treatment of hyperthyroidism was associated with an increase in total and HDL cholesterol, and apo AI. Triglycerides, apo AII and Apo E were unchanged by treatment of hyperthyroidism. The total/HDL cholesterol and the LDL/HDL cholesterol ratios increased with treatment of hyperthyroidism.
Hypothyroidism and hyperthyroidism have opposite effects on plasma lipids and apolipoproteins. In hypothyroidism, total and HDL cholesterol, total/HDL cholesterol ratio, apo AI and apo E are elevated. The increase in apo AI without a concomitant increase in apo AII suggests selective elevation of HDL2. In contrast, hyperthyroidism is associated with decreased total and HDL cholesterol, total/HDL cholesterol ratio, and apo AI levels. These effects are reversible with treatment of the underlying thyroid disorder.
[Show abstract][Hide abstract] ABSTRACT: Decreased HDL cholesterol levels are associated with an increased risk of coronary artery disease (CAD) in non insulin dependent diabetes mellitus (NIDDM). The aim of this study was to compare HDL subparticles with apo A-I (LpAI) and those with apo A-I and apo A-II (LpAI/AII) in subjects with and without NIDDM and to study the relationship between HDL subparticles and CAD in NIDDM. Lipids, apo A-I and HDL subparticles were measured in 240 subjects with NIDDM and in 248 age and gender matched controls. Subjects with NIDDM had higher triglyceride levels (2.5 +/- 1.8 vs. 1.4 +/- 0.8 mmol/1, P < 0.001), lower HDL cholesterol (0.9 +/- 0.3 vs. 1.2 +/- 0.3 mmol/l, P < 0.001), apo A-I (124.7 +/- 22.4 vs. 139.8 +/- 24.1 mg/dl, P < 0.001) and LpAI/AII (82.4 +/- 18.2 vs. 94.9 +/- 16.7 mg/dl, P < 0.001) in comparison to controls. LpAI levels were similar in both groups. Diabetic subjects with CAD (n = 109) had higher triglycerides (2.7 +/- 1.9 vs. 2.3 +/- 1.8 mmol/l, P = 0.02) and lower HDL cholesterol (0.8 +/- 0.2 vs. 1.0 +/- 0.3 mmol/l, P <0.001), apo A-I (115.5 +/- 20.1 vs. 132.3 +/- 21.4 mg/dl, P < 0.001), LpAI (40.2 +/- 9.1 vs. 44.4 +/- 12.4 mg/dl, P = 0.06), and LpAI/AII levels (75.4 +/- 18.0 vs. 88.3 +/- 16.2 mg/dl, P < 0.001) in comparison to diabetic subjects without CAD (n = 131). In a multivariate analysis, apo A-I was found to be the best predictor of CAD in subjects with NIDDM. In conclusion, reduced HDL cholesterol levels found in NIDDM are, principally, due to reduced concentrations of apo A-I and apo A-II-containing particles (LpAI/AII). While LpAI and LpAI/AII levels were lower in NIDDM subjects with CAD, plasma apo A-I is the best predictor of CAD in NIDDM.
[Show abstract][Hide abstract] ABSTRACT: The major classes of lipoprotein particles are chylomicrons, very-low-density lipoproteins, low-density lipoproteins, and high-density lipoproteins. Each of these particles has distinct characteristics, including a distinct apolipoprotein composition. The basic functions of these major apolipoproteins are briefly summarized for clinicians, and disorders of lipoprotein metabolism are discussed. For the effective management of lipid disorders, the therapy should be tailored to the specific defect. Compliance may be improved if the patient understands the nature of the particular lipid problem. To that end, we have developed an analogy in which the various classes of lipoprotein particles are equated to different trucking systems, and the liver is considered a warehouse for storage and distribution of fat. With use of this explanation, patients may understand the rationale for selection of various therapeutic strategies, and treatment of the hyper-lipoproteinemia is likely to be more successful.
Endocrine Practice 11/1995; 1(6):427-32. · 2.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to examine the role of HDL subparticles with apolipoprotein (apo) A-I alone (LpA-I) and with apoA-I and apoA-II (LpA-I/A-II) in predicting coronary artery disease. Concentrations of these HDL subparticles were compared in 184 subjects with angiographically confirmed significant coronary artery disease (> 50% stenosis of at least one vessel) and 191 age- and sex-matched control subjects without clinical coronary artery disease. LpA-I and LpA-I/A-II were measured with magnetic beads coated with anti-apoA-II antibodies to separate particles containing apoA-II from plasma. Total plasma cholesterol and triglyceride levels were similar in both groups. Although subjects with coronary artery disease had lower HDL cholesterol, plasma apoA-I, LpA-I, and LpA-I/A-II than age- and sex-matched control subjects without coronary artery disease, plasma apoA-I was the best predictor of coronary artery disease. In conclusion, LpA-I and LpA-I/A-II are lower in subjects with coronary artery disease but do not add to plasma apoA-I in predicting the presence of coronary artery disease.
[Show abstract][Hide abstract] ABSTRACT: P-selectin (GMP-140 or PADGEM) is translocated to the plasma membrane of platelets after platelet activation. P-selectin, therefore, may be a potential marker for evaluating platelet activation. A fluorescence-conjugated immunobinding assay (FCIBA) has been developed to detect specifically P-selectin on platelets. Platelets were isolated from fresh blood by centrifugation and stimulated with various doses of ADP before being fixed with 1% of paraformaldehyde. Fixed platelets were incubated with fluorescence-conjugated anti-P-selectin monoclonal antibody in the wells of fluoricon microtiter plates, and the fluorescence intensity was read on a fluorescence concentration analyzer. Once platelets were fixed, the procedures were completed in < 2 hours. The intra-assay coefficient of variation (CV) was 6.97% (n = 40), the time-based interassay CV was 8.11% (n = 16), and the sample-based inter-assay CV was 6.17% (n = 16). The FCIBA had an excellent correlation (r = 0.936, p < 0.001) with flow cytometry in the measurement of expressed P-selectin in platelets of 20 normal donors. Translocation of P-selectin in plasma-suspended platelets in response to increasing doses of adenosine diphosphate (ADP) occurred in a dose-dependent manner and correlated positively with ADP-induced platelet aggregation in terms of both stimulating doses of ADP (r = 0.99, p < 0.01) and time intervals (r = 0.92, p < 0.05). The findings show that FCIBA is a fast and convenient assay with good precision for the determination of P-selectin expression of human platelets.
Journal of Laboratory and Clinical Medicine 09/1994; 124(3):447-54. · 2.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Our aims were 1) to examine the effects of a high-carbohydrate low-fat diet on fasting and postprandial plasma lipids, apolipoproteins (apo), and lipoprotein composition in noninsulin-dependent diabetes mellitus, and 2) to determine whether postprandial shift of apo between triglyceride-rich lipoproteins (TRLP) and high density lipoproteins (HDL) is affected by diet. A cross-over study, of 4 weeks duration, of a high-carbohydrate (60% carbohydrate, 20% fat) and a high-fat (40% carbohydrate, 40% fat) diet was performed in seven subjects with noninsulin-dependent diabetes mellitus. TRLP, low density lipoproteins (LDL), and HDL were separated by fast protein liquid chromatography. The high-carbohydrate diet resulted in a decrease of fasting total, HDL, and LDL cholesterol and a trend toward an increase in plasma triglycerides. The apo composition of fasting TRLP and HDL was similar on both diets. TRLP apo CII, CIII, and E increased whereas HDL apo CII, CIII, and E decreased postprandially on both diets. In contrast, TRLP apo CI increased, and HDL apo CI decreased only after the high-carbohydrate diet. We conclude that 1) a high carbohydrate diet results in a decrease in total, LDL, and HDL cholesterol and a trend toward an increase in plasma triglycerides; 2) fasting TRLP and HDL apo composition was similar on a high-carbohydrate or a high-fat diet; and 3) on both diets, apo CII, CIII, and E transfer from HDL to TRLP postprandially. However, only the high-carbohydrate diet induced postprandial transfer of apo CI from HDL to TRLP. This may explain in part the changes in lipoproteins observed with this diet.
[Show abstract][Hide abstract] ABSTRACT: The aim of this paper is to describe a new methodology for the separation of human high-density lipoproteins (HDL) into apolipoprotein (apo) E-poor and apo E-rich subfractions by fast protein liquid chromatography (FPLC) using a heparin affinity column. Recoveries for apolipoproteins AI, AII, CI, CII, CIII, and E were 68.9, 74.7, 71.9, 73.5, 40.0, and 55.8%, respectively. We provide suggestive evidence that apo E-rich HDL is produced from apo E-poor HDL by the displacement of apo AI by apo E. Apo E-poor HDL was the predominant fraction. The molar ratio of apo E to apo AI in apo E-poor HDL was 0.02 and 0.01 for the subjects studied while in apo E-rich HDL it was 1.86 and 1.25. The molar ratios of the C apolipoproteins to apo AI are markedly different between the subfractions.
Journal of Chromatography A 05/1993; 613(2):239-46. · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the influence of exercise on the apolipoprotein (apo) composition of very low density lipoprotein (VLDL) subfractions, we exercised 6 sedentary men for 30 min, 1 h after a fatty meal. VLDL fractions from samples drawn 4, 6 and 8 h post-prandially were separated from pre-stained plasma by high performance liquid chromatography and fractionated to apo E-poor (heparin-unbound) and apo E-rich (heparin-bound) fractions. The postprandial peak area (volts) and apo E, C-II and C-III concentrations (mg/dl) of post-exercise VLDL fractions were compared with corresponding postprandial values obtained at rest. Plasma triglycerides (TG) levels (mg/dl) were significantly lower 4 (P < 0.05), 6 (P < 0.02) and 8 h (p < 0.05) postprandially; the apo E-poor VLDL fraction was not modified by exercise and its apo concentrations were in the low range of detection; the apo E-rich VLDL peak area significantly decreased 4 (P < 0.01), 6 (P < 0.01) and 8 h (P < 0.05) postprandially; the apo E concentration of apo E-rich VLDL was significantly lower 4 (P < 0.02) and 6 h (P < 0.05) postprandially; the apo C-III concentration of apo E-rich VLDL significantly increased, 4 and 6 h postprandially (P < 0.05). Apo E-rich VLDL is, presumably, the metabolically active fraction of the particle and may regulate plasma TG level following exercise. The metabolic role of apo E-poor VLDL remains to be defined.
[Show abstract][Hide abstract] ABSTRACT: We report the occurrence of cytopenia and hypothyroxinemia attributed to decreased levels of thyroxine-binding globulin in patients receiving nicotinic acid. We describe two patients in whom hypothyroxinemia developed while they were taking nicotinic acid; these patients also had decreased levels of thyroxine-binding globulin. Results of all thyroid function tests returned to normal when use of the nicotinic acid was discontinued. In one patient, leukopenia and thrombocytopenia developed during nicotinic acid therapy alone. These conditions were reversed after the drug regimen was discontinued. In another patient, leukopenia and thrombocytopenia developed during combination nicotinic acid and lovastatin therapy. When administration of both drugs was discontinued, the hematologic abnormalities, which could have been due to either nicotinic acid or lovastatin, diminished. We suggest that cytopenia may develop in patients receiving nicotinic acid; thus, thyroid function tests should be interpreted in light of a possible decreased level of thyroxine-binding globulin.
Mayo Clinic Proceedings 06/1992; 67(5):465-8. · 5.81 Impact Factor