Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

Background: Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity. Methods: Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aß42, Aß40, Aß42/Aß40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics. Results: In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) . Conclusions: Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.

Vitamin D in youth with Type 1 diabetes: prevalence of insufficiency and association with insulin resistance in the SEARCH Nutrition Ancillary Study.

AIMS: To determine the prevalence of plasma vitamin D (25-dihydroxyvitamin D) insufficiency in individuals with Type 1 diabetes and to determine the cross-sectional and longitudinal associations of plasma vitamin D with insulin resistance. METHODS: Participants from the SEARCH for Diabetes in Youth Study [n = 1426; mean age 11.2 years (sd 3.9)] had physician-diagnosed Type 1 diabetes [diabetes duration mean 10.2 months (sd 6.5)] with data available at baseline and follow-up (approximately 12 and 24 months after baseline). Insulin resistance was estimated using a validated equation. Cross-sectional and longitudinal multivariate logistic regression models were used to determine the association of plasma vitamin D with insulin resistance, adjusting for potential confounders. RESULTS: Forty-nine per cent of individuals had plasma vitamin D < 50 nmol/l and 26% were insulin resistant. In cross-sectional multivariate analyses, participants who had higher plasma vitamin D (65 nmol/l) had lower odds of prevalent insulin resistance than participants with lower plasma vitamin D (25 nmol/l) (odds ratio 0.70, 95% CI 0.57-0.85). This association was attenuated after additional adjustment for BMI z-score, which could be a confounder or a mediator (odds ratio 0.81, 95% CI 0.64-1.03). In longitudinal multivariate analyses, individuals with higher plasma vitamin D at baseline had lower odds of incident insulin resistance, but this was not significant (odds ratio 0.85, 95% CI 0.63-1.14). CONCLUSIONS: Vitamin D insufficiency is common in individuals with Type 1 diabetes and may increase risk for insulin resistance. Additional prospective studies are needed to determine the association between plasma vitamin D and insulin resistance, and to further examine the role of adiposity on this association.

SAA and PLTP activity in plasma of periodontal patients before and after full-mouth tooth extraction.

OBJECTIVE: To assess whether treatment of advanced periodontal disease affects plasma levels of serum amyloid A (SAA) and phospholipid transfer protein (PLTP) activity. DESIGN: We measured the levels of SAA and PLTP activity in plasma of 66 patients with advanced periodontal disease before and after treatment by full-mouth tooth extraction (FME). RESULTS: At baseline, median SAA levels in our study population were within the normal range (2.7 microg ml(-1)) but SAA was elevated (>5 microg ml(-1)) in 18% of periodontitis patients. Three months after FME, SAA levels were significantly reduced (P = 0.04). SAA did not correlate with any of the periodontal disease parameters. PLTP activity was elevated in patients with periodontitis, compared to the PLTP activity reference group (age-matched systemically healthy adults, n = 29; 18 micromol ml(-1) h(-1)vs 13 micromol ml(-1) h(-1), respectively, P = 0.002). PLTP activity inversely correlated with average periodontal pocket depth (PPD) per tooth (r(s) = -0.372; P = 0.002). Three months after FME, median PLTP activity did not change significantly. CONCLUSIONS: Full-mouth tooth extraction significantly reduces SAA, a marker of inflammation, while it does not affect plasma PLTP activity. However, the inverse correlation between PLTP activity and average PPD suggests that increased PLTP activity may limit periodontal tissue damage.

An analysis of the interaction between mouse apolipoprotein B100 and apolipoprotein(a).

The assembly of lipoprotein(a) (Lp(a)) involves an initial noncovalent interaction between apolipoprotein (apo) B100 and apo(a), followed by the formation of a disulfide bond between apoB100 cysteine 4326 and apo(a) cysteine 4057. The structural features of apoB100 that are required for its noncovalent interaction with apo(a) have not been fully defined. To analyze that initial interaction, we tested whether apo(a) could bind noncovalently to two apoB proteins that lack cysteine 4326: mouse apoB100 and human apoB100-C4326G. Our experiments demonstrated that both mouse apoB and the human apoB100-C4326G bind noncovalently to apo(a). We next sought to gain insights into the apoB amino acid sequences required for the interaction between apoB100 and apo(a). Previous studies of truncated human apoB proteins indicated that the carboxyl terminus of human apoB100 (amino acids 4330-4397) is important for Lp(a) assembly. To determine whether the carboxyl terminus of mouse apoB100 can interact with apo(a), transgenic mice were produced with a mutant human apoB gene construct in which human apoB100 amino acids 4279-4536 were replaced with the corresponding mouse apoB100 sequences and tyrosine 4326 was changed to a cysteine. The mutant apoB100 bound to apo(a) and formed bona fide disulfide-linked Lp(a), but Lp(a) assembly was less efficient than with wild-type human apoB100. The fact that Lp(a) assembly was less efficient with the mouse apoB sequences provides additional support for the notion that sequences in the carboxyl terminus of apoB100 are important for Lp(a) assembly.

Effect of hormone replacement therapy on the validity of the Friedewald equation in postmenopausal women: the postmenopausal estrogen/progestins interventions (PEPI) trial.

The Friedewald equation is often used to estimate low-density lipoprotein cholesterol (LDL-C). Hormone therapy is known to raise triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) and alter lipid contents of lipoproteins. We compared Friedewald estimated LDL-C to measured LDL-C in PEPI participants on placebo or four different hormone treatment groups. At baseline, the 0.2 coefficient for triglyceride (TG) was accurate for all five treatment groups. Among women who took >80% of their pills and whose TG was <4.5 mmol/l (400 mg/dl), LDL-C was underestimated for 69-82% of the participants in the active treatment groups, compared to 50% in the placebo group. After 3 years of therapy, the TG coefficient that offered a better fit of the Friedewald equation in the active treatment groups was 0.39 for the equation in mmol/l (0.17 for the equation in mg/dl). Using this coefficient is clearly warranted for greater accuracy in research studies.

Effect of cardiopulmonary bypass and heparin on plasma levels of Lp(a) and Apo(a) fragments.

Fragments of apolipoprotein(a) [apo(a)], the distinctive glycoprotein of lipoprotein(a) [Lp(a)], are present in human plasma and urine and have been implicated in the development of atherosclerosis. The mechanism responsible for the generation of apo(a) fragments in vivo is poorly understood. In this study, we examined the plasma levels of Lp(a) and apo(a) fragments [or free apo(a)] and urinary apo(a) in 15 subjects who underwent cardiac surgery necessitating cardiopulmonary bypass. We also measured the plasma concentration and activity of polymorphonuclear elastase, an Lp(a)-cleaving enzyme in vitro, and plasma levels of C-reactive protein. Despite a marked activation of polymorphonuclear cells and a pronounced inflammatory response, as documented by an 8-fold and a 35-fold increase in plasma levels of polymorphonuclear elastase and C-reactive protein, respectively, the proportion of plasma free apo(a) to Lp(a) and urinary excretion of apo(a) remained unchanged over a 7-day period after surgery, and polymorphonuclear elastase activity remained undetectable in plasma. No fragmentation of apo(a) was observed ex vivo in plasma samples collected before and after surgery. These data indicate that in this model, apo(a) is not fragmented in plasma and are consistent with the hypothesis that apo(a) fragments result from a constitutively active tissue mechanism that is not modified by cardiac surgery with cardiopulmonary bypass.

Apolipoprotein(a) enhances platelet responses to the thrombin receptor-activating peptide SFLLRN.

Elevated levels of lipoprotein(a) [Lp(a)] are correlated with an increased risk of atherosclerotic disease. We examined the effect of recombinant apolipoprotein(a) [r-apo(a)] and Lp(a) on responses of washed human platelets, prelabeled in the dense granules with [14C]serotonin and suspended in Tyrode's solution, to ADP and the thrombin receptor-activating peptide SFLLRN. No effect of the 17 kringle (K), 12K, or 6K r-apo(a) derivatives (at concentrations of 0.35 and 0.7 micromol/L) or Lp(a) (up to 0.1 micromol/L) on primary ADP-induced platelet aggregation was observed. In contrast, weak platelet responses stimulated by 7.5 micromol/L SFLLRN were significantly enhanced by the r-apo(a) derivatives; eg, 0.7 micromol/L 17K r-apo(a) increased aggregation from 15+/-4% to 58+/-6%, release of [14C]serotonin from 9+/-3% to 36+/-6%, and formation of thromboxane A2, measured as its stable metabolite thromboxane B2, from 7+/-1 to 29+/-5 ng/10(9) platelets (n=3; P<0.04 to 0.015). Significant enhancement of aggregation and release of granule contents was observed at a concentration of 17K r-apo(a) as low as 0.175 micromol/L. Purified Lp(a) (0.25 to 0.1 micromol/L) also enhanced SFLLRN-induced aggregation and release in a dose-dependent manner. Although plasminogen (0.7 and 1.5 micromol/L) and low density lipoprotein (0.025 to 0.1 micromol/L) both exhibited potentiating effects on SFLLRN-mediated platelet aggregation, the magnitude of the responses was less than that observed with either the r-apo(a) derivatives or Lp(a). The enhanced responses of platelets via the protease-activated receptor- thrombin receptor in the presence of Lp(a) may contribute to the increased risk of thromboembolic complications of atherosclerosis associated with this lipoprotein.

Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions.

BACKGROUND: Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a) in cross-sectional studies and small or short-term longitudinal studies. We report findings from a large, prospective, placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy. METHODS AND RESULT: The Postmenopausal Estrogen/Progestin Interventions study was a 3-year, placebo-controlled, randomized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age. The active regimens were conjugated equine estrogens therapy at 0.625 mg daily, alone or in combination with each of three regimens of progestational agents: medroxyprogesterone acetate (MPA) at 2.5 mg daily (ie, continuous MPA), MPA at 10 mg days 1 to 12 (ie, cyclical MPA), and micronized progesterone at 200 mg days 1 to 12. Plasma levels of Lp(a) were measured at baseline (n = 366), 12 months (n = 354), and 36 months (n = 342). Assignment to hormone therapy resulted in a 17% to 23% average drop in Lp(a) concentrations relative to placebo (P<.0001), which was maintained across 3 years of follow-up. No significant differences were observed among the four active arms. Changes in Lp(a) associated with hormone therapy were positively correlated with changes in LDL cholesterol, total cholesterol, apolipoprotein B, and fibrinogen levels and were similar across subgroups defined by age, weight, ethnicity, and prior hormone use. CONCLUSIONS: Postmenopausal estrogen therapy, with or without concomitant progestin regimens, produces consistent and sustained reductions in plasma Lp(a) concentrations.

The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1.

A cDNA clone encoding the human homolog of rat Jagged1 was isolated from normal human marrow. Analyses of human stromal cell lines indicate that this gene, designated hJagged1, is expressed by marrow stromal cells typified by the cell line HS-27a, which supports the long-term maintenance of hematopoietic progenitor cells. G-CSF-induced differentiation of 32D cells expressing Notch1 was inhibited by coculturing with HS-27a. A peptide corresponding to the Delta/Serrate/LAG-2 domain of hJagged1 and supernatants from COS cells expressing a soluble form of the extracellular portion of hJagged1 were able to mimic this effect. These observations suggest that hJagged1 may function as a ligand for Notch1 and play a role in mediating cell fate decisions during hematopoiesis.

Expression of apolipoprotein(a) kringle IV type 9 in Escherichia coli: demonstration of a specific interaction between kringle IV type 9 and apolipoproteinB-100.

A number of studies have provided evidence that lipoprotein(a) [Lp(a)] assembly is a two-step process in which initial non-covalent interactions between apolipoprotein(a) [apo(a)] and apolipoproteinB-100 (apoB-100) precede specific disulfide bond formation. We have designed a construct encoding apo(a) kringle IV type 9 (KIV9) in which the unpaired cysteine at position 67 in this kringle is replaced with a tyrosine. The single kringle was expressed in bacteria and purified to homogeneity from cell homogenates. The purified derivative (designated KIV9deltaCys) was assessed for its ability to bind to purified human LDL. This interaction was detected either by ELISA using immobilized LDL or by column chromatography in which LDL binding to KIV9deltaCys immobilized on Ni2+-Sepharose was determined. In both cases, the interaction of KIV9deltaCys and LDL was observed. Further, we demonstrated that the binding interaction was sensitive to the addition of amino acids including lysine, the lysine analogue epsilon-aminocaproic acid, arginine, phenylalanine and proline, with arginine and lysine having the greatest inhibitory effect. Binding of KIV9deltaCys to an immobilized apoB peptide spanning residues 3732-3745 of apoB was also demonstrated by ELISA. As was the case for LDL, this binding interaction was sensitive to the addition of arginine and lysine. Computer modeling of KIV9 demonstrated an excellent fit with residues 3732-3738 (PSCKLDF) of the apoB peptide. The modeling predicts the presence of overlapping lysine and phenylalanine-binding pockets in KIV9 which explains the inhibitory effects of lysine, arginine and phenylalanine which were observed in the binding assays. In summary, this study represents the first demonstration that KIV9 can interact directly with LDL through non-covalent interactions which may contribute to the first step of Lp(a) formation.

Transgenic mice expressing human ApoB95 and ApoB97. Evidence that sequences within the carboxyl-terminal portion of human apoB100 are important for the assembly of lipoprotein.

The structural features of apolipoprotein (apo) B that are important for its covalent linkage to apo(a) to form lipoprotein(a) (Lp(a)) are incompletely understood. Although apoB100 cysteine 4326 is required for the disulfide linkage with apo(a), other structural features, aside from a single free cysteine residue, must be important for apoB's initial interaction with apo(a) and for facilitating the formation of the disulfide bond. To determine if sequences carboxyl-terminal to cysteine 4326 affect the efficiency of Lp(a) formation, we used "pop-in, pop-out" gene targeting in a human apoB yeast artificial chromosome to introduce nonsense mutations into exon 29 of the apoB gene. The mutant yeast artificial chromosomes, which coded for the truncated versions of human apoB, apoB95, and apoB97, were then used to express these mutant forms of apoB in transgenic mice. As judged by in vitro assays of Lp(a) formation, apoB95 (4330 amino acids) formed a small amount of Lp(a) but did so slowly. In contrast, apoB97 (4397 amino acids) formed Lp(a) rapidly, although not quite as rapidly as the full-length apoB100 (4536 amino acids). These results were supported by an analysis of double-transgenic mice expressing both human apo(a) and either apoB95 or apoB97. In mice expressing both apoB95 and apo(a), there was only a trace amount of Lp(a) in the plasma, and most of the apo(a) was free, whereas in mice expressing both apoB97 and apo(a), virtually all of the apo(a) was bound to apoB97 in the form of Lp(a). These results show that sequences carboxyl-terminal to apoB95 (amino acids 4331-4536) are not absolutely required for Lp(a) formation, but this segment of the apoB molecule, particularly residues 4331-4397, is necessary for the efficient assembly of Lp(a).

A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants.

Lipoprotein(a) [Lp(a)] is formed by the assembly of LDL particles and a carbohydrate-rich protein, apolipoprotein(a) [apo(a)], which has a high degree of structural homology with plasminogen. While the majority of retrospective studies have found an association between Lp(a) level and cardiovascular disease (CVD), the few prospective studies to date have reported contradictory results. We conducted a nested case-control study using the participants in the Stanford Five-City Project, a long-term CVD prevention trial. Participants with an incident possible or definite myocardial infarction or coronary death were matched to a single control subject for age, sex, ethnicity, residence in a treatment or control city, and time of survey. This process yielded 134 case-control pairs, 90 male and 44 female, for whom plasma was available for analysis of Lp(a). Lp(a) values in nanomoles per liter were determined by an enzyme-linked immunoassay that measures Lp(a) independently of apo(a) size polymorphism. Apo(a) size isoforms were determined by SDS-agarose gel electrophoresis. Median Lp(a) level in male cases was almost double that in control subjects (41.8 versus 21.2 nmol/L; P < .01); in female cases, median Lp(a) was 34% higher than in control subjects (32.5 versus 21.2 nmol/L), but this difference was not statistically significant. Among the male cases, there was an increased frequency of small apo(a) isoforms, while no significant difference was found in apo(a) size between female cases and control subjects. The association between Lp(a) level and case-control status in men was independent of total, HDL, and non-HDL cholesterol levels, as well as apo(a) size isoform, cigarette smoking, blood pressure, and obesity. In men, the most efficient threshold value of Lp(a) concentration for separating cases and control subjects was 35 nmol/L; the odds ratio for being a case above this level compared with below was 2.84 (95% confidence interval: 1.53-5.27, P < .001). This study provides strong evidence that Lp(a) level is a prospective, independent risk factor for developing coronary artery disease in men and indicates that the size of apo(a) may also play a role. The lack of a significant association in women deserves further evaluation in larger studies.

Biological and lifestyle factors, and lipid and lipoprotein levels among Japanese Americans in Seattle and Japanese men in Japan.

BACKGROUND: It has been previously shown that Japanese Americans in Seattle have significantly higher cholesterol levels than native Japanese. The present study examines the association of biological and lifestyle factors with plasma lipid and lipoprotein levels among Japanese Americans (JA) and native Japanese (NJ) to determine if these associations are consistent between these high and low cholesterol populations. METHODS: Study samples consisted of 710 JA male and 728 JA female volunteers living in the Seattle area and a random sample of 3833 NJ male urban workers who participated in parallel cardiovascular disease screening and lifestyle surveys for 1989-1994. Multiple regression analysis was conducted to examine the association of lifestyle and biological factors with lipid and lipoprotein levels. RESULTS: Alcohol consumption was positively and linearly associated with high density lipoprotein cholesterol (HDL-C) levels and negatively associated with both low density lipoprotein cholesterol (LDL-C) levels and the ratio of total cholesterol (TC)/HDL-C (P < 0.05 to P < 0.001) among JA males and JA females and NJ males. Current smoking habit was observed to be negatively associated with HDL-C levels and positively with TC/HDL-C ratio and log TG levels (logarithmic transformation of triglyceride values) (P < 0.05 to P < 0.001) among all three groups. Body mass index (BMI) was negatively associated with HDL-C levels and positively associated with log TG and TC/HDL-C ratio among all three groups (P < 0.05 to P < 0.001). Moderate alcohol consumption was negatively associated with log TG levels among JA males and females (P < 0.05), whereas heavy alcohol consumption was positively associated with log TG levels in NJ males (P < 0.001). Smoking was positively associated with TC and LDL-C levels (P < 0.05) among JA males, whereas a negative association (P < 0.05) was observed in NJ males. CONCLUSION: Overall, the fitted models were consistent between JA males and females and NJ males with the exception of smoking on TC and LDL-C. The results suggest that moderate alcohol consumption favourably influences lipid profiles in both high and low cholesterol populations. The results also indicate that light alcohol consumption is associated with decreased triglyceride levels, whereas heavy alcohol consumption is associated with increased triglyceride levels.

High plasma levels of apo(a) fragments in Caucasians and African-Americans with end-stage renal disease: implications for plasma Lp(a) assay.

Apolipoprotein(a) [apo(a)] is a plasma glycoprotein that is highly polymorphic in size due to differences in the number of a tandemly arrayed cysteine-rich repeat called kringle (K)4 at its N-terminus. Most plasma apo(a) is covalently attached to apolipoprotein B-100 and circulates as part of lipoprotein(a) [Lp(a)]. A fraction of apo(a) circulates free of lipoproteins. Almost all of the free apo(a) consists of fragments containing variable numbers of K4 repeats derived from the N-terminal region. Previously we provided evidence suggesting that the apo(a) fragments present in human plasma are the source of the apo(a) fragments in human urine. If this were the case, it would be expected that plasma levels of fragments would be higher in subjects with end-stage renal disease (ESRD). In this paper we quantified the levels of apo(a) fragments and plasma Lp(a) in 26 Caucasian and 26 African-American subjects with ESRD and 52 healthy subjects matched for race, sex and the size of the apo(a) isoforms. The plasma levels of apo(a) fragments and Lp(a) were both higher in the ESRD subjects. In addition, the ratio of apo(a) fragments to total immunodetectable apo(a) was increased in ESRD. To determine how much the increase in the apo(a) fragments contributed to the increase in plasma Lp(a) in ESRD, the plasma Lp(a) levels were measured employing two different anti-apo(a) enzyme-linked immunoabsorption assays (ELISA). One assay detected both free and bound apo(a), whereas the other assay detected only bound apo(a). Although the plasma levels of apo(a) in the ESRD subjects tended to be higher using the assay that detected both fragments and full-length apo(a), the increase was modest. Thus, although a greater proportion of the apo(a) in ESRD plasma circulates as fragments, most of the elevation in plasma levels of Lp(a) associated with renal insufficiency is due to an increase in intact Lp(a).

Cholesterol levels among Japanese Americans and other populations: Seattle Nikkei Health Study.

The purpose of this study was to compare average cholesterol levels between Seattle based Japanese Americans and three other populations: U.S. population, native Japanese population and native Japanese urban workers. A total of 1,466 Japanese Americans (724 men and 742 women) participated in cardiovascular disease screening in the Seattle area during 1989 94. Data sources for comparisons are from the Third National Health and Nutrition Examination Survey for 1988-91, the results of the National Cardiovascular Disease Examination Survey in Japan for 1990, and cardiovascular disease screening conducted by the Epidemiological Arteriosclerosis Research Institute in Japan for 1989. Total cholesterol and triglyceride levels of Seattle Japanese American men and women were highest among the four populations. Among men, high density lipoprotein cholesterol (HDL-C) levels for Seattle Japanese Americans and native Japanese were similar and fell between those of urban Japanese workers and the U.S. population. In women, the average HDL C levels were highest in the Japanese urban workers, second highest in Seattle Japanese Americans, and lowest in both the U.S. population and native Japanese population. These differences in lipid levels may be caused by both genetic and environmental factors, which are now under investigation.

Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a).

OBJECTIVE: To determine if lowering elevated low-density lipoprotein cholesterol (LDL-C) levels offsets the adverse effect of raised lipoprotein(a) (Lp[a]) levels on coronary artery disease (CAC) in men. DESIGN: Randomized, double-blind, placebo-controlled trial of lipid lowering for CAD. SETTING: Post hoc analysis of the Familial Atherosclerosis Treatment Study. PARTICIPANTS: A total of 146 men aged 62 years or younger with CAD and apolipoprotein B levels of at least 125 mg/dL. INTERVENTION: Patients received a Step II Diet and lovastatin (40 mg daily) plus colestipol (30 g daily), niacin (4 g daily) plus colestipol, or placebo (plus colestipol if LDL-C > 90th percentile) for 2.5 years. They were grouped by their LDL-C responses: "minimal" if LDL-C decreased by 10% or less from baseline (mean [SD] change, +6% [13%]) and "substantial" if LDL-C decreased more than 10% (mean [SD] change, -40% [16%]). MAIN OUTCOME MEASURE: Impact of lowering elevated LDL-C on the cardiac event rate (death, myocardial infarction, and revascularization for refractory ischemia) and CAD change associated with elevated Lp(a). RESULTS: In multivariate analyses, the best correlate of baseline CAD severity was Lp(a) (r = 0.30; P < .001). For 36 patients with minimal LDL-C reduction, CAD progression correlated only with in-treatment Lp(a) levels (r = 0.45; P < .01), but for 84 patients with substantial LDL-C reduction, disease regressed and its change correlated with in-treatment LDL-C (r = 0.24; P < .05) but not with Lp(a) (r = -0.05). Lipoprotein(a) levels were not significantly altered in either group. For 40 patients with Lp(a) at the 90th percentile or higher, events were frequent (39%) if reduction of LDL-C was minimal, but were few (9%) if reduction was substantial (relative risk, 0.23; 95% confidence interval, 0.06 to 0.99). CONCLUSIONS: In men with CAD and elevated LDL-C, Lp(a) levels were dominant correlates of baseline disease severity, its progression, and event rate over 2.5 years. However, with substantial LDL-C reductions, persistent elevations of Lp(a) were no longer atherogenic or clinically threatening. This provides a possible direction for treatment in such patients with elevated Lp(a) and LDL-C.

Concentrations of Lp(a) in black and white young adults: relations to risk factors for cardiovascular disease.

The purpose of this report is to compare the distribution of total lipoprotein(a) [Lp(a)] mass in a population-based sample of blacks and whites, and to investigate the association of Lp(a) with other cardiovascular risk factors. A cross-sectional study design was used. Black and white men and women (n = 4125), aged 23-35 from the Coronary Artery Risk Development in Young Adults Study had the following data collected: Lp(a), lipids and lipoproteins, other metabolic parameters, anthropometry, physical activity, dietary intake, cigarette use, and alcohol use. Blacks had concentrations of Lp(a) approximately three-fold higher than whites. Medians were: black men 21.5 mg/dL, black women 23.9 mg/dL, white men 6.1 mg/dL, and white women 6.4 mg/dL. Lp(a) concentrations were higher in women than in men. Lp(a) was not consistently associated with smoking, alcohol consumption, physical activity, dietary fat, or obesity. In stepwise regression analyses in both blacks and whites, Lp(a) was consistently associated with low-density lipoprotein (LDL) cholesterol, fibrinogen, and apoB; regression models explained about 7% of the variance in Lp(a). In whites, Lp(a) tended to be higher in those with a positive family history of myocardial infarction. The large differences in Lp(a) between blacks and whites, and the absence of association with many other variables are consistent with previous suggestions that Lp(a) concentration is in large part genetically determined. The association of Lp(a) with LDL and fibrinogen, two strong risk factors for cardiovascular disease (CVD), could represent part of the mechanism of the CVD risk associated with Lp(a) in other studies. Longitudinal data are needed to determine the extent to which Lp(a) will independently predict disease, especially in diverse ethnic groups.

Immunohistochemical distribution of lipoprotein epitopes in xanthomata from patients with familial hypercholesterolemia.

Human xanthomas derived from four subjects with familial hypercholesterolemia (3 homozygotes and 1 heterozygote) were studied by immunohistochemical methods to determine the presence and distribution of lipoproteins, which have been implicated in the pathogenesis of atherosclerosis. Oxidatively modified low-density lipoprotein (OxLDL) epitopes detected with anti-OxLDL monoclonal antibodies, appeared to have a similar distribution in xanthomata to that of macrophages, detected by a cell-specific monoclonal antibody. Double antibody labeling with both an anti-macrophage antibody and an anti-OxLDL antibody demonstrated that OxLDL epitopes are associated with macrophages and occurred intracellularly. Low-density lipoprotein (LDL) epitopes were detected extracellularly, with a distribution that was different from that of OxLDL. In addition, apo(a) epitopes detected by an apo(a) specific monoclonal antibody, had a distribution similar to that of LDL in the dermis and subcutaneous tissues. The observed epitope distribution of LDL, OxLDL, or apo(a) was the same regardless of the method of treatment of the patients from whom the xanthomas were obtained (probucol, simvastatin, LDL apheresis). These findings suggest that OxLDL is likely to play a pathogenetic role in the lipid accumulation by macrophages in xanthomas, and suggest that Lp(a) also may play a role in their pathogenesis.

Production of monoclonal antibodies specific to theophylline-treated lymphocytes.

The T11 molecule is reported to play a key role in T lymphocytes activation. Moreover, theophylline is known to modify the functional properties of T lymphocytes probably inducing early changes in T11 molecule during T cell activation. Aim of our work was to clarify the effect on T lymphocyte surface after in vitro treatment with theophylline. In this paper, we describe the production and the functional properties of several monoclonal antibodies obtained by immunizing Balb/c mice with theophylline treated cells. Some of the monoclonal antibodies reacted only with the theophylline-treated lymphocytes and showed a promitogenic activity, enhancing the expression of T activated cell antigen. These monoclonal antibodies seem to demonstrate the existence of a membrane molecule which appears on lymphocytes surface after a trigger signal occurring in the early stages of T cell activation likely related to the T11 dependent alternative pathway.