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Mor-Li Hartman,1 J Max Goodson,1 Roula Barake,2 Osama Alsmadi,3 Sabiha Al-Mutawa,4 Jitendra Ariga,4 Pramod Soparkar,1 Jawad Behbehani,5 Kazem Behbehani,6 Francine Welty7 1Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA; 2Department of Nutrition, The Dasman Diabetes Institute, Dasman, Kuwait; 3Genome Center, The Dasman Diabetes Institute, Dasman, Kuwait; 4Ministry of Health, Kuwait City, Kuwait; 5Faculty of Dentistry, Kuwait University, Kuwait City, Kuwait; 6The Dasman Diabetes Institute, Dasman, Kuwait; 7Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA Background: Metabolic syndrome in childhood predicts the development of cardiovascular disease and type 2 diabetes (T2D) in adulthood. Testing for features of metabolic syndrome, such as fasting plasma glucose concentration, requires blood sampling which can be difficult in children. Here we evaluated salivary glucose concentration as a surrogate measurement for plasma glucose concentration in 11-year-old US children. Methods: Children from Portland, Maine, and Cambridge, Massachusetts, with a mean age of 10.6±0.2 years provided 6-hour fasting samples of both blood and whole saliva. Salivary glucose levels were measured with a high-sensitivity assay (sensitivity =0.002 mg/dL). Plasma glucose levels were determined by a commercial clinical laboratory. Blood pressure, salivary flow rate, height, and weight were also measured. Results: Of the 65 children enrolled, there were two underweight children (3.1%), 30 normal-weight children (46.2%), 12 overweight children (18.4%), and 21 obese children (32.3%). The mean overall glucose concentrations were 0.11±0.02 mg/dL in saliva and 86.3±0.8 mg/dL in plasma, and these did not differ significantly by body–weight groups. By regression analysis, the plasma concentration equaled 13.5 times the saliva concentration, with a threshold level of 84.8 mg/dL. Salivary glucose values less than threshold plasma concentration were essentially zero. Diagnostic analysis indicated a positive predictive value of 50%, a negative predictive value of 90%, and a sensitivity and specificity both of approximately 75%. The salivary glucose concentration did not vary with saliva flow rate. Conclusion: Taking into account the threshold response characteristics of the salivary glucose concentration response, these results suggest that testing salivary glucose levels may be useful as a screening assay for high fasting plasma glucose levels. The low false positive value is important to assure a low fraction of missed diagnoses. Keywords: saliva, salivary glucose, plasma glucose, children

Cardiovascular disease mortality rates have decreased in men during the past 20 years, but have steadily increased in women. In the United States, >500,000 women die of coronary artery disease (CAD) every year. Although many factors can influence an individual's risk for CAD, some factors are unique to women, including reproductive status. Menopause is associated with significant elevations in serum cholesterol levels and a 3-fold increase in the risk of CAD. It has been suggested that these changes result from a reduction in the level of estrogen. However, recent data from prospective clinical trials have not found any evidence that hormone replacement therapy protects against cardiovascular disease. On the other hand, several studies have shown that, in women, lipid lowering with statin therapy can reduce coronary events. On the strength of these findings, the Beyond Endorsed Lipid Lowering with Electron-Beam Computed Tomography Scanning (BELLES) trial-a 1-year, multicenter, randomized, double-blind, parallel-group study-has been specifically designed to determine the benefits of aggressive statin therapy on the progression of atherosclerosis in postmenopausal women. [ABSTRACT FROM AUTHOR]

Women have a higher in-hospital mortality rate than men after percutaneous transluminal coronary angioplasty (PTCA). To determine reasons for this, we analyzed the outcome of PTCA at our institution from 1989 to 1995 for 5,989 patients (2,101 women). Women were older than men (66.8 +/- 10.9 vs 61.0 +/- 11.2 years, respectively; p <0.0001) and more likely to have diabetes mellitus, hypertension, or a history of congestive heart failure than men. In-laboratory complications at the time of PTCA were similar for women and men. During the first 24 hours after PTCA, women were more likely than men to become hypotensive (0.33% vs 0.08%, p = 0.04) and had a higher rate of vascular injury than men (1.6% vs 0.6%, p <0.001). More than 24 hours after the procedure, women had a significantly higher mortality rate (1.2% vs 0.52%, p = 0.017), which was no longer significantly different after adjustment for age (odds ratio 0.72, 95% confidence interval 0.39 to 1.32). Multivariate correlates of death >24 hours after PTCA were age, a prior history of congestive heart failure, vascular injury, and use of thrombolytic agents. Of those dying >24 hours after the procedure, 67% of women suffered a noncardiac-related death compared with only 10% of men (p <0.001). The noncardiac death rate was 0.8% for women and 0.05% for men. These deaths were related to renal failure, vascular complications, bleeding, hypotension, and stroke, especially hemorrhagic stroke. In conclusion, immediate procedural complications at PTCA were similar for women and men; however, mortality was higher for women >24 hours after PTCA and before discharge due to a higher rate of noncardiac death. [ABSTRACT FROM AUTHOR]

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been gaining major attention recently after the emergence of data showing the promising role of these proteins in lipid homeostasis and atherosclerosis process, glucose and blood pressure regulation., Materials and Methods: PubMed, EMBASE, Scholar and Scopus databases were searched to identify randomized controlled trials, observational studies, in-vitro trials and reviews about the role of PCSK9 in cardiovascular homeostasis., Results: PCSK9 was found to have major impact on lipid homeostasis and inflammatory process through regulation of low-density lipoprotein receptors. Furthermore, inflammation was found to stimulate the expression of PCSK9 in various cells. As for glomerular proteinuria, a positive correlation was determined between PCSK9 levels and the degree of proteinuria. Hypertension, a major cardiovascular risk factor, is likely affected by PCSK9 levels through their role on epithelial sodium channel (ENaC) surface expression. Likewise, some studies show that PCSK9 is associated with higher fasting blood glucose and plasma insulin, demonstrating a potential role of PCSK9 in glucose homeostasis. The role of PCSK9 in cardiovascular homeostasis is one that is still not completely unraveled., Conclusion: Studies have clearly shown the implication of PCSK9 in the cardiovascular risk factors: the higher the PCSK9 levels, the higher the risk of atherosclerosis, fasting plasma glucose and insulin resistance. Inhibiting PCSK9 may therefore theoretically prove to present great benefits in diabetic patients with high cardiovascular risk., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Importance: Inflammation may contribute to pathological associations among obesity, diabetes mellitus, and cardiovascular disease., Objective: To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque., Design, Setting, and Participants: In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial participants were randomly assigned between September 23, 2008, and July 5, 2012, to 30 months of salsalate or placebo in addition to standard, guideline-based therapies. Randomization was computerized and centrally allocated, with patients, health care professionals, and researchers masked to treatment assignment. Participants were overweight and obese statin-using patients with established, stable coronary heart disease., Interventions: Salsalate (3.5 g/d) or placebo orally over 30 months., Main Outcomes and Measures: The primary outcome was progression of noncalcified coronary artery plaque assessed by multidetector computed tomographic angiography. Secondary outcomes were other measures of safety and efficacy., Results: Two hundred fifty-seven participants were randomized to salsalate (n = 129) or placebo (n = 128). Their mean (SD) age was 60.8 (7.0) years, and 94.0% (236 of 251) were male. One hundred ninety participants (89 in the salsalate group and 101 in the placebo group) completed the study. Compared with baseline, there was no increase in noncalcified plaque volume in the placebo-treated patients and no difference in change between the salsalate and placebo groups (mean difference, -1 mm3; 95% CI, -11 to 9 mm3; P = .87). Salsalate treatment decreased total white blood cell, lymphocyte, monocyte, and neutrophil counts and increased adiponectin levels without change in C-reactive protein levels. Fasting glucose, triglycerides, uric acid, and bilirubin levels were decreased in the salsalate group compared with the placebo group, while hemoglobin levels were increased. Urinary albumin levels increased, with tinnitus and atrial arrhythmias more common, in the salsalate group compared with the placebo group., Conclusions and Relevance: Salsalate when added to current therapies that include a statin does not reduce progression of noncalcified coronary plaque volume assessed by multidetector computed tomographic angiography in statin-using patients with established, stable coronary heart disease. The absence of progression of noncalcified plaque volume in the placebo group may limit interpretation of the trial results., Trial Registration: clinicaltrials.gov Identifier: NCT00624923.

Objective: Here, we investigated the relationships between obesity and the salivary concentrations of insulin, glucose, and 20 metabolic biomarkers in Kuwaiti adolescents. Previously, we have shown that certain salivary metabolic markers can act as surrogates for blood concentrations., Methods: Salivary samples of whole saliva were collected from 8,317 adolescents. Salivary glucose concentration was measured by a high-sensitivity glucose oxidase method implemented on a robotic chemical analyzer. The concentration of salivary insulin and 20 other metabolic biomarkers was assayed in 744 randomly selected saliva samples by multiplexed bead-based immunoassay., Results: Obesity was seen in 26.5% of the adolescents. Salivary insulin predicting hyperinsulinemia occurred in 4.3% of normal-weight adolescents, 8.3% of overweight adolescents, and 25.7% of obese adolescents (p < 0.0001). Salivary glucose predicting hyperglycemia was found in only 3% of obese children and was not predictive (p = 0.89). Elevated salivary glucose and insulin occurring together was associated with elevated vascular endothelial growth factor and reduced salivary interleukin-12., Conclusion: Considering the surrogate nature of salivary insulin and glucose, this study suggests that elevated insulin may be a dominant sign of metabolic disease in adolescent populations. It also appears that a proangiogenic environment may accompany elevated glucose in obese adolescents.

Background: Binary definitions of the metabolic syndrome based on the presence of a particular number of individual risk factors are limited, particularly in the pediatric population. To address this limitation, we aimed at constructing composite and continuous metabolic syndrome scores (cmetS) to represent an overall measure of metabolic syndrome (MetS) in a large cohort of metabolically at-risk children, focusing on the use of the usual clinical parameters (waist circumference (WC) and systolic blood pressure (SBP), supplemented with two salivary surrogate variables (glucose and high density lipoprotein cholesterol (HDLC). Two different approaches used to create the scores were evaluated in comparison., Methods: Data from 8,112 Kuwaiti children (10.00 ± 0.67 years) were used to construct two cmetS for each subject. The first cmetS (cmetS-Z) was created by summing standardized residuals of each variable regressed on age and gender; and the second cmetS (cmetS-PCA) was defined as the first principal component from gender-specific principal component analysis based on the four variables., Results: There was a graded relationship between both scores and the number of adverse risk factors. The areas under the curve using cmetS-Z and cmetS-PCA as predictors for severe metabolic syndrome (defined as the presence of ≥3 metabolic risk factors) were 0.935 and 0.912, respectively. cmetS-Z was positively associated with WC, SBP, and glucose, but inversely associated with HDLC. Except for the lack of association with glucose, cmetS-PCA was similar to cmetS-Z in boys, but had minimum loading on HDLC in girls. Analysis using quantile regression showed an inverse association of fitness level with cmetS-PCA (p = 0.001 for boys; p = 0.002 for girls), and comparison of cmetS-Z and cmetS-PCA suggested that WC and SBP were main contributory components. Significant alterations in the relationship between cmetS and salivary adipocytokines were demonstrated in overweight and obese children as compared to underweight and normal-weight children., Conclusion: We have derived continuous summary scores for MetS from a large-scale pediatric study using two different approaches, incorporating salivary measures as surrogate for plasma measures. The derived scores were viable expressions of metabolic risk, and can be utilized to study the relationships of MetS with various aspects of the metabolic disease process.

Objective: The study of obesity-related metabolic syndrome or Type 2 diabetes (T2D) in children is particularly difficult because of fear of needles. We tested a non-invasive approach to study inflammatory parameters in an at-risk population of children to provide proof-of-principle for future investigations of vulnerable subjects., Design and Methods: We evaluated metabolic differences in 744, 11-year old children selected from underweight, normal healthy weight, overweight and obese categories by analyzing fasting saliva samples for 20 biomarkers. Saliva supernatants were obtained following centrifugation and used for analyses., Results: Salivary C-reactive protein (CRP) was 6 times higher, salivary insulin and leptin were 3 times higher, and adiponectin was 30% lower in obese children compared to healthy normal weight children (all P<0.0001). Categorical analysis suggested that there might be three types of obesity in children. Distinctly inflammatory characteristics appeared in 76% of obese children while in 13%, salivary insulin was high but not associated with inflammatory mediators. The remaining 11% of obese children had high insulin and reduced adiponectin. Forty percent of the non-obese children were found in groups which, based on biomarker characteristics, may be at risk for becoming obese., Conclusions: Significantly altered levels of salivary biomarkers in obese children from a high-risk population, suggest the potential for developing non-invasive screening procedures to identify T2D-vulnerable individuals and a means to test preventative strategies.

Objective: The purpose of our study was to evaluate a new method using voxel analysis for quantifying noncalcified plaque in coronary arteries using MDCT angiography (MDCTA) compared with luminal stenosis by catheter coronary arteriography., Materials and Methods: Forty-one normal and eight abnormal arterial cross sections with noncalcified plaque selected from 40 patients undergoing MDCTA were analyzed for percentage of stenosis and plaque volume using a voxel analysis technique., Results: Using voxel analysis, the normal arterial wall thickness was determined to be 0.8 +/- 0.4 mm. Attenuation values (in Hounsfield units) for normal segments ranged between 30 and 175 H and for abnormal (plaque-containing) segments ranged from -49 to 139 H (p < 0.05). Plaque volume measurements varied from 0.90 to 156 mm(3) with good interobserver correlation (R(2) = 0.9671). Percentage of stenosis correlated with quantitative coronary arteriography measurement (R(2) = 0.55). Voxel analysis underestimated the percentage of stenosis (Pearson's correlation coefficient, 1.2; p = 0.03)., Conclusion: The study shows that the voxel analysis technique appears to be an accurate and reproducible method to measure arterial wall thickness, noncalcified plaque, and degree of arterial stenosis using density values measured in Hounsfield units. The technique may be useful on further correlative studies.

Tangier disease (TD), caused by mutations in the gene encoding ATP-binding cassette 1 (ABCA1), is a rare genetic disorder in which homozygotes have a marked deficiency of high density lipoproteins (HDL), as well as concentrations of low density lipoproteins (LDL) that are typically 40% of normal. Although it is well known that the reduced levels of HDL in TD are due to hypercatabolism, the mechanism responsible for the low LDL levels has not been defined. Recently, it has been reported that intestinal cholesterol absorption is altered in ABCA1 deficient mice, suggesting that aberrant cholesterol metabolism may contribute to the LDL reductions in TD. In order to explore this possibility, as well as to define the role that ABCA1 plays in the metabolism of apolipoprotein (apoB)-containing lipoproteins, we determined the kinetics of apoB-100 within lipoproteins, and cholesterol absorption, biosynthesis, and turnover, in a compound heterozygote for TD. The levels of HDL cholesterol, LDL cholesterol and LDL apoB-100 in this subject were 7, 27 and 69% of normal, respectively, the latter of which was due to a two-fold increase in LDL catabolism (0.54 vs. 0.26+/-0.07 poolsday(-1)) relative to controls (n=11). NMR analysis of plasma lipoproteins revealed that 91% of the LDL cholesterol in the TD subject was contained within small, dense LDL, as compared with only 20% for controls (n=70). Cholesterol absorption was 97% of the value for controls (n=15) in the TD subject, at 45%, with cholesterol synthesis and turnover increased modestly by 17 and 25%, respectively. Our data are consistent with the concept that the reductions of LDL observed in TD are due to enhanced catabolism, secondary to changes in LDL composition and size, with neither cholesterol absorption nor metabolism significantly influenced by mutations in ABCA1.

Cardiovascular disease mortality rates have decreased in men during the past 20 years, but have steadily increased in women. In the United States, >500,000 women die of coronary artery disease (CAD) every year. Although many factors can influence an individual's risk for CAD, some factors are unique to women, including reproductive status. Menopause is associated with significant elevations in serum cholesterol levels and a 3-fold increase in the risk of CAD. It has been suggested that these changes result from a reduction in the level of estrogen. However, recent data from prospective clinical trials have not found any evidence that hormone replacement therapy protects against cardiovascular disease. On the other hand, several studies have shown that, in women, lipid lowering with statin therapy can reduce coronary events. On the strength of these findings, the Beyond Endorsed Lipid Lowering with Electron-Beam Computed Tomography Scanning (BELLES) trial-a 1-year, multicenter, randomized, double-blind, parallel-group study-has been specifically designed to determine the benefits of aggressive statin therapy on the progression of atherosclerosis in postmenopausal women.

Background: Apolipoprotein (apo) A-IV is a major component of triacylglycerol-rich lipoprotein (TRL) apolipoproteins., Objective: We investigated the effects of dietary saturated fat and cholesterol restriction on the metabolism of TRL and plasma apo A-IV., Design: We assessed TRL and plasma apo A-IV kinetics in 16 and 4 subjects, respectively, consuming an average US (baseline) diet for 6 wk and a National Cholesterol Education Program Step II diet for 24 wk, respectively. At the end of each diet period, all subjects received a primed, constant infusion of deuterated leucine for 15 h with hourly feeding. Ratios of stable-isotope tracer to tracee were measured by using gas chromatography-mass spectrometry, and kinetic data were modeled by using SAAM II., Results: Mean apo A-IV concentrations during the isotope infusion period were 6.9 +/- 2.6 mg/L in TRL and 2.2 +/- 3.2 mg/L in plasma with the baseline diet; these values were 37.7% (P < 0.001) and 19.4% (P < 0.01) lower with the Step II diet. Similar changes were observed in the fasting state between the 2 diets. The mean apo A-IV secretion rate decreased significantly from baseline by 59.6% in TRLs and by 40.2% in plasma. Significant correlations were observed between TRL apo A-IV concentrations and the secretion rate (r = 0.94, P < 0.001) and between TRL apo A-IV pool size and TRL-cholesterol concentrations (r = 0.48, P < 0.01)., Conclusions: Our data indicate that the National Cholesterol Education Program Step II diet significantly decreases TRL and plasma apo A-IV concentrations compared with the average US diet and that this decrease is due to a decreased secretion rate.

In order to investigate the metabolism of apo A-IV within TRL and plasma, we assessed TRL and plasma apo A-IV kinetics in 19 and 4 subjects, respectively, consuming an average US diet for a 6-week period. At the end of this diet study, each subject received a primed-constant infusion of deuterated leucine over a 15 h time period with hourly feeding, and blood samples were drawn at 10 time points. TRL was separated by ultracentrifugation. Apo A-IV was isolated by immunoprecipitation and/or SDS-PAGE. Apo A-IV concentrations were determined by immunoelectrophoresis. Stable isotope tracer/tracee ratios were measured by gas chromatography/mass spectrometry, and the data were analyzed by multicompartmental modeling. The mean concentrations of plasma and TRL apo A-IV during the isotope infusion period were 21.0+/-3.2 and 0.66+/-0.25 mg/dl, respectively, and these values were 11.5 and 30.5% higher than those of fasting samples. The mean TRL and plasma apo A-IV residence times (RT) were 1.97+/-0.57 and 2.71+/-0.65 days, and transport rates (TR) were 0.17+/-0.19 and 3.90+/-1.24 mg/kg per day, respectively. There were significant correlations between TRL apo A-IV concentrations and TR (r(2)=0.79, P<0.001), and between TRL apo A-IV pool size and TRL cholesterol levels (r(2)=0.29, P=0.02). Our data indicated that; (1) TRL apo A-IV has a RT of 1.97 days which is similar to that earlier reported for HDL apo A-IV; (2) Apo A-IV recirculates between TRL and other slowly turning over pools; (3) the primary determinant of TRL apo A-IV levels is its TR; and (4) there is no correlation between TRL apo A-IV and apo B48 fractional catabolism in TRL.

Background: Electron beam tomography (EBT) is a noninvasive technique that allows the study of the entire coronary artery tree during a brief imaging session without the injection of any contrast media. Atherosclerosis is identified vicariously through the visualization of coronary calcific deposits. Quantitative assessments of calcium burden, such as calcium volume scores, have been shown to be a useful means to assess treatment-related changes in the extent of atherosclerotic plaques. Historically, the elderly female population has received less medical recognition regarding the risk and severity of coronary heart disease (CHD)., Methods: In the BELLES (Beyond Endorsed Lipid Lowering with EBT Scanning) trial, the presence of asymptomatic CHD in 600 postmenopausal women will be assessed by EBT. In this 1-year, multicenter, randomized, double-blind, parallel-group study, aggressive lipid-lowering treatment will be compared with moderate lipid-lowering treatment in postmenopausal women with hypercholesterolemia. The hypothesis we will test is that aggressive lipid-lowering therapy with 80 mg/d atorvastatin can produce greater reductions in atherosclerotic plaque burden as assessed by volumetric calcium scores than a moderate treatment with 40 mg/d pravastatin. The primary outcome measure will be the percent change from baseline in total CVS determined by EBT at 12 months., Conclusions: The results of the BELLES trial will help assess the actual incidence of CHD in postmenopausal women and the relative ability of two different lipid-lowering therapies to halt its progression.

Cardiovascular disease, primarily coronary heart disease (CHD), outnumbers the next 16 causes of death in women combined. However, the long-held belief that heart disease in women has a more benign prognosis than in men has resulted in less aggressive diagnosis and management patterns. Appreciation of the differences between men and women in CHD risk factors and presentation can assist in treatment decisions. Although estrogen replacement offers substantial beneficial effects on lipid levels in postmenopausal women, the first 2 randomized trials of estrogen alone and estrogen plus progestin, the Heart and Estrogen/Progestin Replacement Study and Estrogen Replacement and Atherosclerosis Study, observed no benefit in reducing risk of CHD death and nonfatal myocardial infarction and angiographic progression of CHD, respectively, in women with CHD. Available data show that lipid-lowering therapy reduces women's CHD risk and mortality but also indicate that a considerable proportion of women remains untreated or undertreated. Randomized trials of statins for primary and secondary prevention of coronary heart disease suggest that these agents are at least as effective for lowering coronary disease risk in women as in men. Therefore, statin drugs should be the drug of first choice for women with established CHD. Hypercholesterolemic postmenopausal women who require estrogen for menopausal symptoms may derive further reductions in low-density lipoprotein cholesterol and reductions in trigyceride levels with the addition of a statin drug.

Subjects with the apolipoprotein (apo) E4 allele have been shown to have higher low density lipoprotein (LDL) cholesterol and apoB levels than do subjects with the other alleles. To elucidate the metabolic mechanisms responsible for this finding, we examined the kinetics of apoB-48 within triglyceride-rich lipoproteins (TRLs) and of apoB-100 within very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and LDL by using a primed constant infusion of [5,5,5-(2)H(3)]leucine in the fed state (hourly feeding) during consumption of an average American diet in 18 normolipidemic subjects, 12 of whom had the apoE3/E3 genotype and 6, the apoE3/E4 genotype. Lipoproteins were isolated by ultracentrifugation and apolipoproteins, by sodium dodecyl sulfate gels; isotope enrichment was assessed by gas chromatography-mass spectrometry. Kinetic parameters were calculated by multicompartmental modeling of the data with SAAM II software. Compared with the apoE3/E3 subjects, the apoE3/E4 subjects had significantly higher levels of total apoB, 100. 1+/-17.8 versus 135.4+/-34.0 mg/dL (P=0.009), and significantly higher levels of LDL apoB-100, 88.1+/-19.2 versus 127.5+/-32.7 mg/dL (P=0.005), respectively. The pool size of TRL apoB-48 was 17.4% lower for apoE3/E4 subjects compared with apoE3/E3 subjects due to a 33.3% lower production rate (P=0.28). There was no significant difference in the TRL apoB-48 fractional catabolic rate (5.1+/-2.2 versus 5.0+/-2.1 pools per day). The pool size for VLDL apoB-100 was 36% lower for apoE3/E4 subjects compared with apoE3/E3 subjects due entirely to a 30% lower production rate (P=0.04). The LDL apoB-100 pool size was 57.8% higher (P=0.003) for apoE3/E4 subjects compared with apoE3/E3 subjects due to a 35.5% lower fractional catabolic rate of LDL apoB-100 (P=0.003), with no significant difference in production rate. In addition, 77% of VLDL apoB-100 was converted to LDL apoB-100 in apoE3/E4 subjects compared with 58% in apoE3/E3 subjects (P=0.05). In conclusion, the presence of 1 E4 allele was associated with higher LDL apoB-100 levels owing to lower fractional catabolism of LDL apoB-100 and a 33% increase in the conversion of VLDL apoB-100 to LDL apoB-100.

Amino acid precursors labelled with stable isotopes have been successfully used to explore the metabolism of the apolipoproteins of HDL. Some methodological and mathematical modelling problems remain, mainly related to amino acid recycling in a plasma protein such as apolipoprotein A-I with a long residence time (the reciprocal of the fractional catabolic rate) of 4-5 days. Apolipoprotein A-I, apolipoprotein E, and apolipoprotein A-IV in triglyceride-rich lipoproteins (containing chylomicrons, VLDL, and remnants) exhibit more complex kinetics. The small amounts of apolipoprotein A-I and of apolipoprotein A-IV in the triglyceride-rich lipoproteins have a residence time similar to that of the apolipoprotein A-I of HDL. In contrast, the apolipoprotein E in triglyceride-rich lipoproteins has been found to have an average residence time of 0.11 days. Diets low in saturated fat and cholesterol, which lower HDL levels, do so by decreasing the secretion of apolipoprotein A-I, with apolipoprotein A-II kinetics unaffected. Individuals with impaired glucose tolerance have a decreased residence time of apolipoprotein A-I but no change in secretion rate or in apolipoprotein A-II kinetics. This suggests a link between insulin resistance and the risk of atherosclerosis. In heterozygous familial hypercholesterolemia, both the fractional catabolic rate and the secretion rate of apolipoprotein A-I are increased, resulting in no change in the plasma level. Stable isotope studies have strengthened the evidence that triglyceride enrichment of HDL increases its catabolism Laboratory.

The purpose of our study was to investigate high density lipoprotein (HDL) apolipoprotein (apo) A-I and apoA-II kinetics in a state of constant feeding after a primed-constant infusion of [5,5, 5-(2)H(3)]L-leucine in 32 normolipidemic older men and postmenopausal women (aged 41 to 79 years). ApoA-I and apoA-II were isolated from plasma HDL, and enrichment was determined by gas chromatography/mass spectrometry. The fractional secretion rate was obtained by using a monoexponential equation calculated with the SAAM II program (Department of Bioengineering, University of Washington, Seattle). Mean HDL cholesterol (HDL-C) and total triglyceride levels were 23% higher and 27% lower, respectively, in women than in men. Mean plasma apoA-I levels were 10% greater in women than in men, whereas mean apoA-II levels were similar. HDL size, estimated by gradient-sizing gels and by the HDL-C/apoA-I+apoA-II ratio, was significantly higher in women than in men. Mean apoA-I secretion rates (SRs) were similar in men and women (12.28+/-3.64 versus 11.96+/-2.92 mg/kg per day), whereas there was a trend toward a lower (-13%) apoA-I fractional catabolic rate (FCR) in women compared with men (0.199+/-0.037 versus 0. 225+/-0.062 pools per day, P=0.11). Mean apoA-II SRs (2.21+/-0.57 versus 2.27+/-0.91 mg/kg per day) and FCRs (0.179+/-0.034 versus 0. 181+/-0.068 pools per day) were similar in men and women. For the group as a whole, there was an inverse association between the HDL-C/apoA-I+apoA-II ratio and apoA-I FCR and between the ratio and triglyceride levels. Plasma levels of apoA-I and apoA-II were correlated with their respective SRs but not FCRs. These data suggest a major role for apoA-I and apoA-II SRs in regulating the plasma levels of these proteins, whereas apoA-I FCR might be an important factor contributing to the differences in apoA-I levels between men and postmenopausal women. Moreover, plasma triglyceride levels are important determinants of HDL size and apoA-I catabolism.

The kinetics of apolipoprotein (apo) B-100 and apoB-48 within triglyceride-rich lipoproteins (TRLs) and of apoB-100 within IDL and LDL were examined with a primed-constant infusion of (5,5,5-(2)H(3)) leucine in the fed state (hourly feeding) in 19 subjects after consumption of an average American diet (36% fat). Lipoproteins were isolated by ultracentrifugation and apolipoproteins by SDS gels, and isotope enrichment was assessed by gas chromatography/mass spectrometry. Kinetic parameters were calculated by multicompartmental modeling of the data with SAAM II. The pool sizes (PS) of TRL apoB-48, VLDL apoB-100, and LDL apoB-100 were 17+/-10, 273+/-167, and 3325+/-1146 mg, respectively. There was a trend toward a faster fractional catabolic rate (FCR) for VLDL apoB-100 than for TRL apoB-48 (6.73+/-3.48 versus 5.02+/-2.07 pools/d, respectively, P=0.06). The mean FCRs for IDL and LDL apoB-100 were 10.07+/-7.28 and 0.27+/-0.08 pools/d, respectively. The mean production rate (PR) of TRL apoB-48 was 6.5% of VLDL apoB-100 (1. 3+/-0.90 versus 20.06+/-6.53 mg. kg(-1). d(-1), P<0.0001). TRL apoB-48 PS was correlated with apoB-48 PR (r=0.780, P<0.0001) but not FCR (r=-0.1810, P=0.458). VLDL apoB-100 PS was correlated with both PR (r=0.713, P=0.0006) and FCR (r=-0.692, P=0.001) of VLDL apoB-100 and by apoB-48 PR (r=0.728, P=0.0004). LDL apoB-100 PS was correlated with FCR (r=-0.549, P=0.015). These data indicate that (1) the FCRs of TRL apoB-48 and VLDL apoB-100 are similar in the fed state, (2) TRL apoB-48 PS is correlated with TRL apoB-48 PR, (3) VLDL apoB-100 PS is correlated with both PR and FCR of VLDL apoB-100 and PR of TRL apoB-48, and (4) LDL apoB-100 PS is correlated with LDL FCR.

Stable isotope methodology was used to determine the kinetic behavior of apolipoprotein (apo) A-I within the triglyceride-rich lipoprotein (TRL) fraction and to compare TRL apoA-I kinetics with that of apoA-I in high density lipoprotein (HDL) and TRL apoB-48. Eight subjects (5 males and 3 females) over the age of 40 were placed on a baseline average American diet and after 6 weeks received a primed-constant infusion of [5,5,5-(2)H(3)]-l-leucine for 15 h while consuming small hourly meals of identical composition. HDL and TRL apoA-I and TRL apoB-48 tracer/tracee enrichment curves were obtained by gas chromatography;-mass spectrometry. Data were fitted to a compartmental model to determine the fractional secretion rates of apoA-I and apoB-48 within each lipoprotein fraction. Mean plasma apoA-I levels in TRL and HDL fractions were 0. 204 +/- 0.057 and 134 +/- 15 mg/dl, respectively. The mean fractional catabolic rate (FCR) of TRL apoA-I was 0.250 +/- 0.069 and HDL apoA-I was 0.239 +/- 0.054 pools/day, with mean estimated residence times (RT) of 4.27 and 4.37 days, respectively. The mean TRL apoB-48 FCR was 5.2 +/- 2.0 pools/day and the estimated mean RT was 5.1 +/- 1.8 h. Our results indicate that apoA-I is catabolized at a slower rate than apoB-48 within TRL, and that apoA-I within TRL and HDL fractions are catabolized at similar rates.

We examined the mechanisms responsible for the decrease in HDL cholesterol (HDL-C) levels after the consumption of a diet low in total fat, saturated fat, and cholesterol. Twenty-one subjects with a mean age of 58+/-12 years were placed on a baseline isocaloric diet (15% protein, 49% carbohydrate, 36% fat, and 150 mg/1000 kcals of cholesterol) and then switched to an NCEP Step 2 diet (15% protein, 60% carbohydrate, 25% fat, and 45 mg/1000 kcals of cholesterol). After 6 or 24 weeks on each diet, subjects received a 15-hour primed-constant infusion of [5,5,5-2H3]-L-leucine. HDL apoA-I and apoA-II tracer curves were determined by gas chromatography-mass spectrometry and fitted to a monoexponential equation. Compared with the baseline diet, consumption of the Step 2 diet lowered HDL-C mean levels by 15% (1.03+/-0.23 to 0.88+/-0.16 mmol/L, P<0.001), apoA-I by 12% (1.25+/-0.15 to 1.10+/-0.13 g/L, P<0. 001) and the TC/HDL-C ratio by 5% (0.145+/-0.04 to 0.137+/-0.03). No significant changes were observed in apoA-II levels and HDL particle size with diet. HDL apoA-I fractional catabolic rate did not change (0.219+/-0.052 to 0.220+/-0.043 pools/day, P=0.91) but HDL apoA-I secretion rate decreased by 8% (12.26+/-3.07 to 10.84+/-2.11 mg. kg-1. day-1, P=0.03) during consumption of the Step 2 diet. There was no effect of diet on apoA-II fractional catabolic rate or secretion rate. Our results indicate that the decrease in HDL-C and apoA-I levels during the isocaloric consumption of a Step 2 diet paralleled the reductions in apoA-I secretion rate.

Hypobetalipoproteinemia (HBLP) is characterized by plasma concentrations of apolipoprotein B (apoB) and low density lipoprotein cholesterol (LDL-C) below the fifth percentile. Some forms of HBLP have been shown to be due to truncated forms of apoB-100. A total of 3873 subjects participating in the Framingham Offspring Study had LDL-C levels measured every 4 to 5 years throughout a 25-year period. Seventy-five subjects were identified with persistent HBLP, defined as an LDL-C <70 mg/dL on at least 2 observations, for a prevalence of 1.9% in this population. Compared with subjects with LDL- C >/=70 mg/dL, subjects with HBLP had significantly lower mean levels of total cholesterol, LDL-C, triglyceride, and apoB; higher levels of high density lipoprotein cholesterol; and a higher prevalence of the E2/E3 genotype: 38.7% versus 10.9% (P<0.001). Men with HBLP had a larger mean LDL particle size than did men with an LDL- C >/=70 mg/dL. One individual had a truncated apoB as a cause of HBLP, for a prevalence of 0.03%. Medical causes of HBLP included 2 cases of Crohn's disease, 1 of hemochromatosis, and 1 of hepatitis. Three subjects with HBLP developed coronary heart disease, for an incidence of 4% compared with 5% in those with an LDL- C >/=70 mg/dL (P=NS). The incidence of cancer was 8% in those with HBLP compared with 4% in those with an LDL-C >/=70 mg/dL (P=0.21). In conclusion, a truncated apoB was a rare cause of HBLP, whereas the E2/E3 genotype was a much more common cause. A large prospective study is needed to evaluate the incidence of cancer and atherosclerosis in subjects with HBLP.

In vivo kinetics of apoB were performed in three apoB-67/apoB-100 heterozygotes using a primed-constant infusion of (5,5,5-(2)H3)-leucine. Mean plasma VLDL and LDL apoB-67 concentrations were 0.05 +/- 0.01 mg/dl and 0.62 +/- 0.17 mg/dl, respectively, which were 0.2% and 2.8% of total plasma apoB concentrations. When cation exchange chromatography was used to separate plasma amino acids from fragments of polyacrylamide gels, the tracer/tracee ratio at plateau for VLDL apoB-67 was less than 50% of that observed when centrifugation was used. Mean fractional catabolic rate for LDL apoB-67 was 2-fold higher when the lower plateau was used in multicompartmental analysis compared to the higher plateau (0.70 +/- 0.21 versus 0.37 +/- 0.06 pools per day, P = 0.06). The lower plateau resulted from introduction of unlabeled leucine during cation exchange chromatography; therefore, all samples were processed with centrifugation. Mean fractional catabolic rates for VLDL and LDL apoB-67 were not significantly different from VLDL and LDL apoB-100 (VLDL: 9.7 +/- 3.4 versus 18.1 +/- 8.6 pools per day, respectively, P = 0.19; LDL: 0.37 +/- 0.06 versus 0.34 +/- 0.11 pools per day, respectively, P = 0.66). Mean secretion rate of VLDL apoB-67 was 5.6% of VLDL apoB-100 (0.20 +/- 0.04 versus 3.6 +/- 1.3 mg/kg/day, P = 0.01). Fifty-three % of apoB-67 was directly removed from VLDL compared to only 3.5% of apoB-100 (P = 0.003), thus accounting for the lower proportion of apoB-67 in LDL (3.3 +/- 1.8%) as compared to VLDL (11.2 +/- 2.5%). Mean LDL production rate for apoB-67 was 2.6% of LDL apoB-100 (0.09 +/- 0.02 versus 3.50 +/- 1.39 mg/kg/day, P = 0.05). Thus, decreased secretion of apoB-67 is responsible for low levels of apoB-67.

Apolipoprotein (apo) B-67 is a truncated form of apoB-100 due to deletion of an adenine at cDNA 9327. Heterozygotes have one allele making apoB-100; therefore, plasma apoB levels would be predicted to be at least 50% of normal. However, apoB-67 heterozygotes have total plasma apoB levels that are 24% of normal. To determine the mechanisms responsible for the lower-than-expected levels of apoB, in vivo kinetics of apoB-100 were performed in three apoB-67/apoB-100 heterozygotes and compared with those of six control subjects by using a primed-constant infusion of [5,5,5-2H3]leucine in the fed state. Kinetic parameters were calculated by multicompartmental modeling of the data. The mean total apoB plasma concentration of the apoB-67 subjects was 21.8+/-6.1 mg/dL, or 24% of that of control subjects (89.6+/-24.1 mg/dL, P=.002). ApoB-67 subjects had lower mean VLDL apoB-100 production rates (3.6+/-1.2 versus 13.9+/-3.5 mg x kg(-1) x d(-1), P=.002) and lower mean transport rates of apoB-100 into LDL (3.5+/-1.4 versus 12.6+/-4.1 mg x kg(-1) x d(-1), P=.008) compared with control subjects. The transport rate into IDL was not significantly different (1.2+/-0.5 versus 6.2+/-4.0 mg x kg(-1) x d(-1), P=.07). The fractional catabolic rate of VLDL apoB-100 was significantly higher in apoB-67 subjects than in control subjects (18.1+/-8.6 versus 7.6+/-1.6 mg x kg(-1) x d(-1), P=.017). ApoB-100 IDL and LDL fractional catabolic rates were not significantly different. VLDL apoB-100 pool size in apoB-67 subjects was 11% of that of control subjects (15.8+/-7.7 versus 141.6+/-33.7 mg, P=.0004) due to a 74% lower production rate (26% of control values) and a 2.4-fold higher fractional catabolic rate. LDL apoB-100 pool size in apoB-67 subjects was 22% of that of control subjects (665.3+/-192.4 versus 2968.3+/-765.2 mg, P=.002) due primarily to a lower production rate (27% of control values). Thus, both decreased production of VLDL and LDL apoB-100 and increased catabolism of VLDL apoB-100 are responsible for the low levels of apoB-100 in apoB-67 subjects.

Background: Given the importance of thrombosis in causation of acute coronary syndromes, it is possible that the beneficial effect of low lipid levels on the risk of coronary events is achieved by lowering thrombotic potential of the blood. Hypobetalipoproteinemia is characterized by plasma concentrations of apolipoprotein B and LDL cholesterol that are one third of those observed in the general population. The aim of this study was to utilize subjects with hypobetalipoproteinemia to examine the relation between thrombotic potential and low levels of LDL cholesterol., Methods and Results: Hemostatic risk factors were measured in 1878 individuals (1003 women and 875 men) participating in cycle 5 of the Framingham Offspring Study. The subjects were divided into five groups on the basis of LDL cholesterol level. Subjects with hypobetalipoproteinemia (LDL cholesterol < 70 mg/dL) had the lowest levels of fibrinogen, plasminogen activator inhibitor-1 antigen, and tissue plasminogen activator antigen. As LDL cholesterol increased, there was a significant increase in the levels of the hemostatic risk factors, with the exception of von Willebrand factor antigen. Adjustment with multivariate regression analyses for the covariates age, sex, body mass index, diabetes mellitus, smoking, alcohol intake, triglyceride level, and use of antihypertensive medication did not materially alter the results., Conclusions: Decreasing levels of LDL cholesterol are associated with decreasing levels of hemostatic risk factors. Subjects with hypobetalipoproteinemia have the lowest levels of hemostatic risk factors and may be protected against thrombotic complications of atherosclerotic cardiovascular disease because of reduced thrombotic potential. One mechanism by which lipid-lowering therapy may decrease clinical cardiac events is through a reduction in thrombotic tendency.

Background: Prognosis after myocardial infarction (MI) is influenced by the presence of post-MI ischemia and possibly the patency of the infarct-related artery. The purpose of this study was to compare long-term outcome (reinfarction and death) in patients with open versus closed coronary arteries after percutaneous transluminal coronary angioplasty performed for MI complicated by persistent ischemia., Methods and Results: Between 1981 and 1989, 505 patients underwent percutaneous transluminal coronary angioplasty for post-MI ischemia at the Deaconess Hospital. Long-term incidence (mean follow-up, 34 months) of death, nonfatal reinfarction, repeated coronary angioplasty, and coronary bypass surgery was determined for 479 patients and then compared on the basis of the status of the artery, open versus closed, at the end of angioplasty. The 5-year Kaplan-Meier actuarial mortality rate was 4.9% for 456 patients with open infarct-related arteries and 19.4% for 23 patients with closed infarct-related arteries (P=.0008). Multivariate Cox proportional hazards analyses controlling for age, sex, number of diseased vessels, type and location of MI, and year of coronary angioplasty revealed a hazard ratio for death for closed compared with open arteries of 6.1 (95% CI, 1.8 to 20.0). Among patients with ejection fractions <50%, a closed artery was associated with a higher mortality (p=.0014) compared with patients with open arteries. The status of the artery was not associated with a difference in mortality in patients with ejection fractions > or = 50%., Conclusions: As open artery after coronary angioplasty for post-MI ischemia is associated with significantly lower long-term mortality, particularly in patients with ejection fractions <50%.

Naturally occurring mutant forms of apolipoprotein B (apoB)-100 may be able to provide valuable information on the structure-function relationships of apoB with the low density lipoprotein (LDL) receptor. ApoB-67, recently identified in a kindred displaying apoB levels 25% of normal (Welty et al. J. Clin. Invest. 1991. 87: 1748-1754), is predicted to contain 3040 amino acids and therefore, contains part of the epitope for antibody 4G3, which blocks binding of LDL to the LDL-receptor. To determine whether the amino terminal 67% of apoB-100 is important for binding to the LDL receptor, the apoB-67-containing lipoprotein particle was purified from plasma by gradient ultracentrifugation. The fractions containing apoB-67 were in the density range 1.049-1.070 g/ml. These fractions were pooled and adsorbed onto an affinity chromatography column containing the monoclonal antibody, MB-47. The epitope for MB-47 is two nonlinear domains between amino acids 3429 to 3453 and 3507 to 3523; therefore, apoB-100 will bind to the MB-47 column but apoB-67 will not. The resulting apoB-67-containing particles were completely devoid of apoB-100. In competitive binding studies, the apoB-67 lipoprotein particle did not compete with 125I-labeled apoB-100-containing LDL particles for binding, uptake, or degradation by normal human fibroblast monolayers. We conclude that the amino terminal 67% of apoB-100 in the naturally occurring lipoprotein particle does not appear to contain a functionally relevant epitope of the LDL-receptor binding domain.

Background: Familial hypobetalipoproteinemia (FHB) is an autosomal codominant disorder characterized by abnormally low plasma levels of apoB and LDL cholesterol. Heterozygotes for FHB almost always have plasma LDL cholesterol levels < 70 mg/dL and are asymptomatic. Because the low cholesterol levels may protect FHB heterozygotes from coronary heart disease, the mechanisms for FHB are of considerable interest., Methods and Results: The plasma lipoproteins of 29 subjects with LDL cholesterol levels < 70 mg/dL were examined by SDS-PAGE. One subject who had virtually undetectable levels of LDL cholesterol had a truncated apoB, apoB-44.4, in his lipoproteins; a second subject with an LDL cholesterol level of 44 mg/dL had apoB-55 in his lipoproteins. The apoB-44.4 (2014 amino acids in length) resulted from a frameshift caused by an 11-bp insertion in exon 26 of the apoB gene; the apoB-55 (2494 amino acids) was caused by a nonsense mutation in exon 26 of the apoB gene. The apoB-55 mutation occurred at a CpG dinucleotide pair, a mutational hot spot, and was identical to a mutation described previously in a subject with hypobetalipoproteinemia. Our subject with apoB-55, however, had a different haplotype than the subject described previously, suggesting that the two apoB-55 mutations may have arisen independently. Of note, the apoB-55 proband's father, who had very low cholesterol levels and who probably carried the apoB-55 mutation, had significant coronary and aortic atherosclerosis at autopsy., Conclusions: In a study of adults with low LDL cholesterol levels, we discovered two subjects with truncated apoB proteins and identified the responsible mutations. ApoB gene mutations causing truncated apoB are not particularly rare in subjects with low cholesterol levels. The role of these mutations in preventing atherosclerosis deserves further study.

Predictors of increased risk for recurrent cardiac events and death after acute myocardial infarction include postinfarction myocardial ischemia, anterior location of the infarct, and non-Q-wave versus Q-wave infarction. Although coronary angioplasty is performed in patients with postinfarction ischemia to alleviate symptoms, the outcome according to location and type of infarction and the effect on prevention of subsequent myocardial infarction and death are not known. To determine if location and type of myocardial infarction provide prognostic information in patients with postinfarction ischemia, we analyzed morbidity and mortality during and after coronary angioplasty according to the location (anterior vs inferior) and type (Q-wave vs non-Q-wave) of myocardial infarction in 505 consecutive patients. The incidence of recurrent angina, repeat coronary angioplasty, coronary bypass surgery, reinfarction, and death during long-term follow-up after hospital discharge (mean 34 +/- 19 months) for the 440 patients with an initial successful angioplasty was also compared. During the procedure, there was no difference in the primary success rate or mortality among the different groups; however, more patients with anterior non-Q-wave myocardial infarction underwent emergent bypass grafting after unsuccessful coronary angioplasty (p = 0.001). Multivariate Cox proportional-hazards analyses controlling for age, gender, number of diseased vessels, location, type of infarction, and year of coronary angioplasty revealed that more patients with anterior infarction had > or = 1 cardiac event (repeat angioplasty, coronary artery bypass grafting, reinfarction, or death) than did those with inferior infarction (RR 1.80, 95% confidence interval [Ci] 1.22 to 2.65, p = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Although extensive evidence indicates that estrogen is responsible for the markedly decreased cardiovascular risk of premenopausal women, the mechanism through which estrogen might exert its protective effect has not been adequately explained. Since thrombosis is now recognized to play an important role in the onset of cardiovascular disease, we investigated the relation between estrogen status and fibrinolytic potential, a determinant of thrombotic risk., Methods and Results: We determined levels of plasminogen activator inhibitor (PAI-1) antigen and tissue plasminogen activator (TPA) antigen in 1431 subjects from the Framingham Offspring Study. Fibrinolytic potential was compared between subjects with high estrogen status (premenopausal women and postmenopausal women receiving hormone replacement therapy) and low estrogen status (men and postmenopausal women not receiving hormone replacement therapy). In all comparisons, subjects with high estrogen status had greater fibrinolytic potential (lower PAI-1 levels) than subjects with low estrogen status. First, postmenopausal women receiving estrogen replacement therapy had lower levels of PAI-1 than those not receiving therapy (13.0 +/- 0.5 versus 19.5 +/- 1.0 ng/mL, P < .001). Second, premenopausal women had lower levels of PAI-1 than men of a similar age (14.8 +/- 0.6 versus 20.3 +/- 0.8 ng/mL, P < .001); this sex difference diminished when postmenopausal women not receiving hormone replacement therapy were compared with men of a similar age (19.6 +/- 0.7 versus 21.1 +/- 0.7 ng/mL, P = .089). Third, premenopausal women had markedly lower levels of PAI-1 antigen than postmenopausal women not receiving estrogen therapy (14.8 +/- 0.6 versus 19.5 +/- 1.0 ng/mL, P < .001). The between-group differences observed for TPA antigen were similar to those for PAI-1 antigen., Conclusions: Each of these comparisons indicates that the cardioprotective effect of estrogen may be mediated, in part, by an increase in fibrinolytic potential. These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.

Objectives: The purpose of this study was to determine whether there are gender differences in the outcome of percutaneous transluminal coronary angioplasty performed for postmyocardial infarction ischemia., Background: Although women have a higher mortality rate after myocardial infarction than that of men, they are less frequently referred for coronary angioplasty (and coronary artery bypass graft surgery) than are men, possibly because of expectations of a worse procedural outcome., Methods: We analyzed the morbidity and mortality at coronary angioplasty and during a mean follow-up period of 34.4 months for women and 34.2 months for men in 505 consecutive patients (164 women and 341 men) with postmyocardial infarction ischemia between 1981 and 1989., Results: Compared with men, women had similar procedural success rates (89.6% and 91.2%, respectively), need for coronary artery bypass surgery (3.7% and 2.6%) and mortality rates at coronary angioplasty (0.6% and 0.9%). During the follow-up period, there were no significant gender differences in the requirement for coronary artery bypass surgery (3.6% and 4%), repeat angioplasty (18.7% and 17.3%), reinfarction (5.8% and 6%) and death (3.6% and 3.7%) or the combined end points of all four events (26.6% and 26.6%). Women had significantly more recurrent angina than did men (54% vs. 42.5%, p < 0.01), even though the extent of coronary artery disease and frequency of incomplete revascularization were similar in men and women., Conclusions: The procedural outcome of coronary angioplasty for postmyocardial infarction ischemia is similar in women and men. Long-term follow-up is also similar except that women experience an increased incidence of recurrent angina, an outcome also reported after bypass surgery. Therefore, concerns over the safety of coronary angioplasty in women should not adversely influence decisions concerning referral of women for coronary angioplasty after myocardial infarction complicated by ischemia.

We describe a case of Pseudallescheria boydii endocarditis involving the pulmonic valve in an orthotopic liver transplant recipient. The patient required transplantation because of hepatic failure secondary to chronic active hepatitis B. His postoperative course was complicated by surgery for gastric and duodenal ulcers, persistent fever, and, ultimately, sepsis leading to oliguric renal failure. Two days before death, the patient experienced complete heart block, and an echocardiogram revealed pulmonic valve thickening and an endocardial mass along the left side of the septum. At autopsy the patient was found to have a vegetation on the pulmonic valve and a septal abscess. There were multiple fungal emboli found throughout other organs, and P. boydii was obtained on culture. This unique association between pulmonic valve endocarditis and myocardial septal abscess is discussed. In addition, review of the five previous cases of P. boydii endocarditis reveals that this rare infection is associated with immunosuppression and prosthetic devices.

Objective: To assess the impact on renal transplant patients and graft survival of clinical, laboratory, and echocardiographic parameters commonly measured prior to surgery., Patients: Forty-seven consecutive diabetics with preoperative echocardiograms at the time of transplantation., Methods: Clinical history, standard chest roentgenogram, electrocardiogram, blood tests, echocardiograms, and HLA testing at baseline; follow-up from 2 to 7 years with periodic reassessment of graft function., Results: Patient survival did not appear to be influenced by age, sex, or type of allograft. A history of either myocardial infarction, congestive heart failure, or angina was present in 15 patients with 3-year survival of 50% (72% if not present, p less than 0.05). Histocompatibility testing did not impact on survival. Serum sodium, potassium, calcium, phosphate, and calcium-phosphate product did not discern different survival groups. A hematocrit greater than 30% was present in 15 patients with 3-year survival of 43% (73% if not present, p less than 0.05). Greater than 10% antibody sensitization of the recipient resulted in a 3-year survival of 38% in eight patients (68% if not present, p less than 0.05). Radiologic evidence of cardiomegaly or congestive heart failure and standard electrocardiographic evidence for left ventricular hypertrophy or strain did not impact on survival. Echocardiographic measurements of left ventricular end-diastolic diameter, posterior wall thickness, or ejection fraction were also not predictive. Increased end-systolic diameter (10 patients, 30% 3-year survival versus 69%, p less than 0.05) and decreased velocity of circumferential fiber shortening (11 patients, 45% 3-year survival versus 71%, p less than 0.05) both appeared to be related to survival. Increased accuracy of prediction could be obtained by adding risk factors so that a history of coronary artery disease and increased end-systolic diameter predicted 3-year survival of 42% versus 82% if neither was present. In terms of graft survival, no clinical, radiographic, or electrocardiographic result yielded predictive information. Among the laboratory tests, only highly antibody-sensitized patients (eight patients, 0% 3-year survival versus 66% 3-year survival, p less than 0.001) showed different survival patterns. Echocardiographic elevated end-systolic diameter predicted a significantly (p less than 0.001) decreased graft survival (3-year survival 33% versus 63%)., Conclusion: Preoperative prediction of patient and graft survival in diabetic renal transplantation may be enhanced by echocardiographic assessment of systolic load and function. For patients with normal systolic function, whose hematocrit is below 30%, with preformed antibodies less than 10%, renal transplantation has an excellent prognosis; invasive cardiac procedures are not likely required. Since these risk factors are likely additive, a high-risk group may be identified. These latter patients should undergo coronary angiography.

Patients with a recent myocardial infarction, congestive heart failure, sever angina, or uncorrected multivessel coronary artery disease are at increased risk of cardiac complications after major noncardiac surgery. Although invasive hemodynamic monitoring and preoperative optimization of cardiac status may lead to some reduction in the rate of perioperative cardiac events, the mortality from such events remains high. We report our experience with the use of perioperative intra-aortic balloon counterpulsation in eight patients with unstable coronary syndromes or severe coronary artery disease who underwent urgent noncardiac surgery. There were no perioperative cardiac events while the intra-aortic balloon pump (IABP) was in place. There were two postoperative cardiac events (non-fatal myocardial infarction, congestive heart failure) in the first postoperative week after the IABP was removed. One patient required emergent femoral thrombectomy as a result of intra-aortic balloon counterpulsation and subsequently died of a gastrointestinal hemorrhage. Intra-aortic balloon counterpulsation should be considered as an adjunct to maintain hemodynamic stability for the high-risk cardiac patient about to undergo urgent or emergent noncardiac surgery.

We describe a kindred in which the proband and 6 of his 12 children have hypobetalipoproteinemia. The plasma lipoproteins of the affected subjects contained a unique species of apolipoprotein (apo) B, apo B67, in addition to the normal species, apo B100 and apo B48. The size of apo B67 and immunochemical studies with a panel of apo B-specific antibodies indicated that apo B67 was a truncated species of apo B that contained approximately the amino-terminal 3,000-3,100 amino acids of apo B100. Sequencing of genomic apo B clones revealed that affected family members were heterozygous for a mutant apo B allele containing a single nucleotide deletion in exon 26 (cDNA nucleotide 9327). This frameshift mutation is predicted to result in the synthesis of a truncated apo B containing 3,040 amino acids. Apo B67 is present in low levels in the plasma but is easily detectable within the very low density lipoprotein and low density lipoprotein fractions. Examination of the proband's immediate family revealed seven normolipidemic subjects and seven subjects with hypobetalipoproteinemia. In the affected subjects, the mean total and low density lipoprotein cholesterol levels were 120 and 42 mg/dl, respectively. A significantly higher mean high density lipoprotein cholesterol level was found in the affected subjects (75 vs. 55 mg/dl). We hypothesize that the elevated high density lipoprotein cholesterol levels in subjects heterozygous for the apo B67 mutation may be metabolically linked to the low levels of apo B-containing lipoproteins in their plasma.

Electroimmunodiffusion assay was used to quantitate changes in lactoferrin concentration in mammary secretions during involution of the bovine mammary gland. Concentration of lactoferrin began to increase 2 to 4 days after cessation of regular milking and continued to increase linearly at a rate of 1.15 mg/ml per day as a result of increased net synthesis of lactoferrin during the first 14 to 21 days of involution. Maximum lactoferrin concentration (approximately 20 mg/ml) was attained after 3 to 4 wk of involution. These changes represent a 100-fold increase in lactoferrin concentration over that in normal milk. Maximum lactoferrin concentration was variable between cows. In some cows, the concentration of lactoferrin plateaued at less than 10 mg/ml after 10 days of involution. In others, much higher lactoferrin concentrations of 75 to 100 mg/ml were measured. Lactoferrin concentration decreased markedly prior to parturition and onset of lactation. The increase in lactoferrin concentration during mammary gland involution appeared to be related closely to the process of involution.

A corrinoid enzyme has been purified to approximately 80% homogeneity from Clostridium thermoaceticum. It catalyzes the formation of acetate from N5-methyltetrahydrofolate and pyruvate in combination with the required supplementary enzymes which are supplied by an extract that has been treated with propyl iodide. The enzyme was purified by chromatography on a folate affinity column and a DEAE-Bio-Gel column and by ultrafiltration. The molecular weight as determined by sedimentation equilibrium is 158,000 and the sedimentation coefficient is 10.5 S. By gel electrophoresis in sodium dodecyl sulfate, the subunit molecular weight was found to be 40,000, thus, the enzyme may be a tetramer of four similar subunits. The results of electron microscopy confirmed the tetrameric structure. In the absence of sodium dodecyl sulfate, two bands of similar intensity were observed by electrophoresis, but both yielded the 40,000 molecular weight subunit in the presence of sodium dodecyl sulfate. These results indicate the two bands represent either two different molecular weight forms of the enzyme or two differently charged isoenzymes. The enzyme is quite labile being sensitive to dilution, aerobic conditions, and light. Dithiothreitol and glycerol were found to stabilize the enzyme. The cofactor requirements for acetate synthesis have been determined. ATP, thiamin pyrophosphate, S-adenosylmethionine, and Fe2+ were found to be required for maximum activity and the Km values were determined. High concentrations of methyltetrahydrofolate, pyruvate, and S-adenosylmethionine were found to inhibit the synthesis of acetate.