Compositional Features of HDL Particles Interact with Albuminuria to Modulate Cardiovascular Disease Risk.

Lipoproteins containing apolipoprotein B modify associations of elevated urinary albumin excretion (UAE) with cardiovascular disease (CVD). Additionally, it is known that elevated UAE alters high-density lipoprotein functionality. Accordingly, we examined whether HDL features might also modify UAE-associated CVD. Multivariable Cox proportional-hazards modeling was performed on participants of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study at the baseline screening with standard lipid/lipoprotein analyses and, three-to-four years later (second screen), with nuclear magnetic resonance lipoprotein analyses focusing on HDL parameters including HDL particle (HDL-P) and apolipoprotein A-I concentrations. These were used with UAE and derived measures of HDL apoA-I content (apoA-I/HDL-C and apoA-I/HDL-P) in risk models adjusted for gender, age, apoB, diabetes, past CVD history, CRP and GFR. Interaction analysis was also performed. Baseline screening revealed significant associations inverse for HDL-C and apoA-I and direct for apoA-I/HDL-C. The second screening demonstrated associations inverse for HDL-P, large HDL-P, medium HDL-P, HDL size, and apoA-I/HDL-P. Significant interactions with UAE included apoA-I/HDL-C at the baseline screening, and apoA-I/HDL-P and medium HDL-P but not apoA-I/HDL-C at the second screening. We conclude that features of HDL particles including apoA-I/HDL-P, indicative of HDL apoA-I content, and medium HDL-P modify associations of elevated UAE with CVD risk.

Simultaneous interferometric measurement of linear coefficient of thermal expansion and temperature-dependent refractive index coefficient of optical materials.

Characterizing the thermal properties of optical materials is necessary for understanding how to design an optical system for changing environmental conditions. A method is presented for simultaneously measuring both the linear coefficient of thermal expansion and the temperature-dependent refractive index coefficient of a sample interferometrically in air. Both the design and fabrication of the interferometer is presented as well as a discussion of the results of measuring both a steel and a CaF2 sample.

Apolipoprotein B attenuates albuminuria-associated cardiovascular disease in prevention of renal and vascular endstage disease (PREVEND) participants.

Whether urinary albumin excretion relates to higher levels of atherogenic apolipoprotein B fractions in the nondiabetic population is uncertain. Such a relationship could explain, in part, the association of elevated urinary albumin excretion with cardiovascular disease risk. We assessed the relationship of urinary albumin excretion with apolipoprotein B fractions and determined whether the association of elevated urinary albumin excretion with incident cardiovascular events is modified by high apolipoprotein B fraction levels. We performed a prospective study on 8286 nondiabetic participants (580 participants with cardiovascular disease; 4.9 years median follow-up time) with fasting lipids, apolipoprotein B, and urinary albumin excretion determined at baseline. With adjustment for sex and age, micro- and macroalbuminuria were associated with increased apolipoprotein B fractions (non-HDL cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B). All four apolipoprotein B fractions modified associations of urinary albumin excretion with incident cardiovascular disease (hazard ratios for interaction terms ranged from 0.89 to 0.94 with 95% confidence intervals ranging from 0.84 to 0.99 and P values ranging from 0.001 to 0.02 by Cox proportional hazards modeling). These interactions remained present after additional adjustment for conventional risk factors, eGFR, cardiovascular history, and lipid-lowering and antihypertensive drug treatments. Such modification was also observed when urinary albumin excretion was stratified into normo-, micro-, and macroalbuminuria. We conclude that there is an association between elevated urinary albumin excretion and apolipoprotein B fraction levels and a negative interaction between these variables in their associations with incident cardiovascular events. Elevated urinary albumin excretion may share common causal pathways with high apolipoprotein B fractions in the pathogenesis of cardiovascular disease.

PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry.

BACKGROUND: Higher lipoprotein-associated phospholipase A(2)(Lp-PLA2) activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal. METHODS AND RESULTS: A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only, and 2 cross-sectional studies; n=26 118) was undertaken to examine the association of the following: (1) Lp-PLA2 activity versus cardiovascular biomarkers and risk factors and CHD events (2 prospective studies; n=4884); (2) PLA2G7 single-nucleotide polymorphisms and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and (3) PLA2G7 single-nucleotide polymorphisms and angiographic coronary artery disease (2 case-control, 1 case-only study; n=4971 cases) and CHD events (5 prospective, 2 case-control studies; n=5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratios for CHD events for the top versus bottom quartile of Lp-PLA2 activity were 1.61 (95% confidence interval, 1.31 to 1.99) and 1.17 (95% confidence interval, 0.91 to 1.51) after adjustment for baseline traits. Of 7 single-nucleotide polymorphisms, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, with VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (odds ratio, 1.03; 95% confidence interval, 0.80 to 1.32), or CHD events (odds ratio, 0.98; 95% confidence interval, 0.82 to 1.17). CONCLUSIONS: Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma, or CHD. Larger association studies, identification of single-nucleotide polymorphisms with larger effects, or randomized trials of specific Lp-PLA2 inhibitors are needed to confirm or refute a contributory role for Lp-PLA2 in CHD.

An association of ABO non-identical platelet and cryoprecipitate transfusions with altered red cell transfusion needs in surgical patients.

BACKGROUND: Transfusion of ABO non-identical plasma, platelets and cryoprecipitate is routine practice even though adverse effects can occur. METHODS AND MATERIALS: Our hospital changed transfusion practice in 2005 and adopted a policy of providing ABO-identical blood components to all patients when feasible. We retrospectively compared the transfusion requirements, length of stay and in-hospital mortality in relation to ABO blood group in surgical patients who received platelet transfusions before and after this change to determine whether it resulted in any benefit. RESULTS: Prior to the change in practice, both group B and AB patients received more ABO non-identical platelet transfusion (P=0·0004), required significantly greater numbers of red cell transfusions (P=0·04) and had 50% longer hospital stays (P=0·039) than group O and A patients. Following the policy change, there was a trend for fewer red cell transfusions (P=0·17) and length of stay in group B and AB patients than group O or A patients. Overall, the mortality rate per red cell transfusion decreased from 15·2 per 1000 to 11·0 per 1000 (P=0·013). CONCLUSIONS: These results, in the context of previous findings, suggest that providing ABO-identical platelets and cryoprecipitate might be associated with reduction in transfusion requirements and improve outcomes in surgical patients.

Cholesteryl ester transfer protein polymorphism (TaqIB) associates with risk in postinfarction patients with high C-reactive protein and high-density lipoprotein cholesterol levels.

OBJECTIVE: To investigate the roles of inflammation and a cholesteryl ester transfer protein (CETP) polymorphism potentially related to recent findings demonstrating coronary risk with increasing high-density lipoprotein cholesterol (HDL-C) level. METHODS AND RESULTS: A novel graphical exploratory data analysis tool allowed the examination of coronary risk in postinfarction patients relating to HDL-C and C-reactive protein levels. Results demonstrated a high-risk subgroup, defined by high HDL-C and C-reactive protein levels, exhibiting larger HDL particles and lower lipoprotein-associated phospholipaseA(2) levels than lower-risk patients. Subgroup CETP-associated risk was probed using a functional CETP polymorphism (TaqIB, rs708272). In the high-risk subgroup, multivariable modeling revealed greater risk for B2 allele carriers (less CETP activity) versus B1 homozygotes (hazard ratio, 2.41; 95% CI, 1.04 to 5.60; P=0.04). Within the high-risk subgroup, B2 allele carriers had higher serum amyloid A levels than B1 homozygotes. Evidence also demonstrates that CETP genotypic differences in HDL subfraction distributions regarding non-HDL-C and lipoprotein-associated phospholipaseA(2) may potentially relate to impaired HDL remodeling. CONCLUSIONS: Postinfarction patients with high HDL-C and C-reactive protein levels demonstrate increased risk for recurrent events. Future studies should aim at characterizing altered HDL particles from such patients and at elucidating the mechanistic details related to inflammation and HDL particle remodeling. Such patients should be considered in drug trials involving an increase in HDL-C level.

Inflammation reduces HDL protection against primary cardiac risk.

BACKGROUND: We recently reported high high-density lipoprotein (HDL) cholesterol as a predictor of recurrent risk in a subgroup of postinfarction patients defined by hypercholesterolemia and high C-reactive protein (CRP) levels. We investigated whether a similar high-risk subgroup might exist for incident cardiovascular disease. MATERIAL AND METHODS: A graphical exploratory data analysis tool was used to identify high-risk subgroups in a male population-based cohort (n = 3405) from the prevention of renal and vascular end-stage disease study by generating 3-dimensional mappings of risk over the HDL-cholesterol/CRP domain with subsequent use of Kaplan-Meier analysis to verify high-risk. Within-subgroup risk was assessed using Cox proportional hazards regression and Kaplan-Meier analysis. RESULTS: Mappings revealed two high-risk subgroups: a low HDL-cholesterol/high CRP subgroup and a high HDL-cholesterol/high CRP subgroup. The low HDL-cholesterol subgroup demonstrated a pattern of metabolic syndrome dyslipidemia contrasted with a predominantly unremarkable biomarker pattern for the high HDL-cholesterol subgroup. However, in the high HDL-cholesterol subgroup, CRP levels were higher than the low HDL-cholesterol subgroup; and within the high HDL-cholesterol subgroup, CRP predicted risk. Moreover, in the high HDL-cholesterol subgroup, risk was associated with lower triglyceride levels in conjunction with presumptively larger HDL particles. CONCLUSIONS: High HDL-cholesterol and high CRP levels define a subgroup of men at high-risk for incident cardiovascular disease. High HDL cholesterol-associated risk likely relates to impaired HDL particle remodelling in the setting of inflammation. This approach may facilitate identification of additional inflammation-related mechanisms underlying high HDL cholesterol-associated risk; and potentially influence management of such patients.

Center-related Bias in MELD Scores Within a Liver Transplant UNOS Region: A Call for Standardization.

BACKGROUND: Model for End-Stage Liver Disease (MELD) score-based liver transplant allocation was implemented as a fair and objective measure to prioritize patients based upon disease severity. Accuracy and reproducibility of MELD is an essential assumption to ensure fairness in organ access. We hypothesized that variability in laboratory methodology between centers could impact allocation scores for individuals on the transplant waiting list. METHODS: Aliquots of 30 patient serum samples were analyzed for creatinine, bilirubin, and sodium in all transplant centers within United Network for Organ Sharing (UNOS) region 9. Descriptive statistics, intraclass correlation coefficients (ICCs), and linear mixed-effects regression were used to determine the relationship between center, bilirubin, and calculated MELD-sodium (MELD-Na) score. RESULTS: The mean MELD-Na score per sample ranged from 14 to 38. The mean range in MELD-Na per sample was 3 points, but 30% of samples had a range of 4-6 points. Correlation plots and intraclass correlation coefficient analysis confirmed bilirubin interfered with creatinine, with worsening agreement in creatinine at high bilirubin levels. Center and bilirubin were independently associated with creatinine reported in mixed-effects models. Unbiased hierarchical clustering suggested that samples from specific centers have consistently higher creatinine and MELD-Na values. CONCLUSIONS: Despite implementation of creatinine standardization, centers within a single UNOS region report clinically significant differences in MELD-Na on an identical sample, with differences of up to 6 points in high MELD-Na patients. The bias in MELD-Na scores based upon center choice within a region should be addressed in the current efforts to eliminate disparities in liver transplant access.

Plasminogen activator inhibitor-1 polymorphism (4G/5G) predicts recurrence in nonhyperlipidemic postinfarction patients.

OBJECTIVE: Nonhyperlipidemic postinfarction patients are at high risk for recurrent coronary events by virtue of incident myocardial infarction (MI); however, few studies assess risk beyond incident MI. The aim of this study was to assess such risk as a function of 37 atherosclerosis-associated genetic polymorphisms and 17 blood marker variables. METHODS AND RESULTS: Screening of polymorphisms in nonhyperlipidemic postinfarction patients revealed significant risk only for the 4G/5G insertion/deletion polymorphism in the promoter of the plasminogen-activator inhibitor-1 (PAI-1) gene. Outcome event mapping, an exploratory data analysis tool, was then applied to define a subgroup (182 patients from total study population of 846 nondiabetic patients) exhibiting maximal functional dependence of risk on the PAI-1 polymorphism. Cox multivariable regression analyses within the subgroup adjusted for significant clinical covariates and medication use as a function of the PAI-1 polymorphism and 17 atherosclerosis-associated blood markers revealed significant risk for patients homozygous for the 4G allele (hazard ratio 4.30, 95% CI 1.98 to 9.33, P=0.00023), and lack of significant risk-association with any blood marker. CONCLUSIONS: In a subgroup of normolipidemic postinfarction patients, only the PAI-1 4G/5G polymorphism was associated with recurrent risk from a set of atherosclerosis-associated genetic polymorphisms and blood markers.

Plasma ApoE elevations are associated with NAFLD: The PREVEND Study.

Non-alcoholic fatty liver disease (NAFLD) is featured by increased plasma very low density lipoproteins (VLDL). The extent to which plasma apolipoprotein E (ApoE) levels are elevated in NAFLD is unclear. We determined whether plasma ApoE is elevated in subjects with suspected NAFLD. Plasma ApoE and genotypes were determined in 6,762 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. A Fatty Liver Index (FLI) ≥ 60 was used as a proxy of NAFLD. A total of 1,834 participants had a FLI ≥ 60, which coincided with increased triglycerides, non-HDL cholesterol, ApoB and ApoE (all P<0.001). In multivariable linear regression analysis, plasma ApoE levels were positively associated with an elevated FLI when taking account of ApoE genotypes and other clinical and laboratory covariates (fully adjusted model: ß = 0.201, P<0.001). Stratified analysis for ApoE genotypes (ApoE ε3ε3 homozygotes, ApoE ε2 carriers, and ApoE ε3ε4 and ε4ε4 carriers combined), also showed positive associations of plasma ApoE levels with an elevated FLI in each group (all P<0.001). In conclusion, it is suggested that NAFLD is characterized by increased plasma ApoE levels, even when taking account of the various ApoE genotypes. Increased plasma ApoE may contribute to altered VLDL metabolism and to increased atherosclerosis susceptibility in NAFLD.

Low Serum Paraoxonase-1 Activity Associates with Incident Cardiovascular Disease Risk in Subjects with Concurrently High Levels of High-Density Lipoprotein Cholesterol and C-Reactive Protein.

Paroxonase-1 (PON1) is a key enzyme that inhibits low-density lipoprotein oxidation and consequently atherogenesis. Here, we assessed whether low serum PON1 activity associates with incident cardiovascular disease (CVD) in subjects with high levels of high-density cholesterol (HDL-C) and C-reactive protein (CRP), a marker of low-grade systemic inflammation. Cox proportional-hazards modeling of incident CVD risk (11 years mean follow-up) adjusted for relevant clinical and biomarker covariates was performed on a population-based study (N = 7766) stratified into three groups: low CRP-(LR; event rate 4.9%); low HDL-C/high CRP-(HR1; event rate 14.4%); and high HDL-C/high CRP-(HR2; event rate 7.6%). Modeling results for PON1 activity in HR2 were significant and robust (hazard ratio/SD unit-0.68, 95% CI 0.55-0.83, p = 0.0003), but not so for LR and HR1. Analyses in HR2 of the interaction of PON1 with HDL-C, apoA-I, apoA-II, and apoE levels were significant only for PON1 with apoE (hazard ratio-1.77, 95% CI 1.29-2.41, p = 0.0003). Subsequent subgroup analysis revealed inverse risk dependence for apoE at low PON1 levels. In conclusion, in a population-based study of subjects with concurrently high HDL-C and CRP levels, low serum PON1 activity associates with incident CVD risk with risk accentuated at low apoE levels.

Roles of high apolipoprotein E blood levels and HDL in development of familial dysbetalipoproteinemia in ε2ε2 subjects.

OBJECTIVE: Familial dysbetalipoproteinemia (FD) or Type III hyperlipoproteinemia is a mixed hyperlipidemia closely associated with the ε2ε2 genotype of the common APOE polymorphism although not all homozygotes progress to FD. Unlike the polymorphism, few studies explore effects of apolipoprotein E (apoE) blood levels on FD development. Likewise, despite the known apoE2 lipoprotein binding preference for high-density lipoprotein (HDL); little work exists exploring HDL in FD. Accordingly, this study was undertaken to investigate potential roles in FD development for apoE and HDL. Additionally, insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were investigated in view of reports linking insulin resistance to FD. METHODS: APOE genotyping and levels of apoE, apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II), insulin, HOMA-IR, lipids, and NMR lipoprotein analysis were determined in a cohort of healthy individuals (N=7169). A lipid-based algorithm identified FD in 24 of 52 e2e2 subjects. Logistic regression modeling assessed associations of FD development with measured variables. RESULTS: Univariate models revealed associations with FD significant and positive for apoE, apoA-II/apoA-I, apoA-I/HDL-C, apoA-II/HDL-C, and HOMA-IR. For HDL-C, association was significant but inverse. Results of multivariable models containing apoE with single parameters added revealed statistical significance only for the apoA-II/HDL-C ratio (OR 10.52, 95%CI 1.17-94.79, p=0.036) concurrent with significance for apoE (OR 2.21, 95%CI 1.06-4.65, p=0.035). Interaction was not demonstrated (p=0.36). NMR results revealed for FD versus nonFD subjects generally higher levels of VLDL and small HDL and for IDL few differences. CONCLUSION: High apoE and high apoA-II/HDL-C independently associate with FD development in ε2ε2 individuals.

Insulin resistance involvement in prevalence of familial dysbetalipoproteinemia in ε2ε2 subjects by Bayesian network modeling.

OBJECTIVE: Familial dysbetalipoproteinemia (FD) or Type III hyperlipoproteinemia is closely associated with the ε2ε2 genotype of the common APOE polymorphism although not all ε2 homozygotes develop FD indicating that additional factors play a role including insulin resistance (IR). The current study was undertaken to explore relationships and influences among factors, especially IR, that might elucidate FD progression pathways. METHODS: Bayesian network (BN) modeling, a probabilistic graphical exploratory data analysis tool that portrays relationships and influences among variables as simple diagrams, was applied to 52 e2e2 subjects. An algorithm based on apolipoprotein and lipid values identified 24 subjects having FD. BN modeling parameters included plasma apoE, HDL cholesterol (HDL-C), apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II), apoA-I/HDL-C ratio, apoA-II/HDL-C ratio, insulin, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). RESULTS: Modeling resulted in twenty network graphs. Each graph revealed apoE and the apoA-II/HDL-C ratio as sole determinants of FD prevalence. BN results did not demonstrate a direct role for insulin and HOMA-IR. However, multiple graphs in the set did reveal indirect influence of IR on FD prevalence as conveyed through the apoA-II/HDL-C ratio; while all remaining graphs in the set demonstrated the apoA-II/HDL-C ratio as directly influencing insulin levels and HOMA-IR. For apoE, the other determinant of FD prevalence, results revealed no relationship with IR parameters. CONCLUSIONS: In so far as insulin levels and HOMA-IR are associated with IR in e2e2 subjects, IR may act indirectly in FD progression via the apoA-II/HDL-C ratio; and/or the apoA-II/HDL-C ratio acts directly to promote IR.

Inflammatory markers modify the risk of recurrent coronary events associated with apolipoprotein A-I in postinfarction patients.

BACKGROUND: Laboratory findings have suggested that systemic and vascular inflammation can impair the antiatherogenic function of high-density lipoproteins (HDLs). However, evidence from population studies is sparse. OBJECTIVE: The objective of the study was to assess if blood inflammatory markers modify the risk of recurrent coronary events associated with apolipoprotein A-I (apoA-I) and HDL cholesterol (HDL-C) among postinfarction patients. METHODS: ApoA-I, HDL-C, and inflammatory markers (C-reactive protein [CRP], serum amyloid A (SAA), fibrinogen, von Willebrand factor [vWF], and D-dimer) were measured from blood samples of 1028 patients drawn 2 months after an index myocardial infarction (MI). Patients were followed up for the composite coronary endpoint (nonfatal MI, coronary death, or unstable angina) for an average of 26 months. Cox proportional hazard models were used to assess effect modifications for the association of apoA-I and HDL-C with coronary risk by each inflammatory marker. RESULTS: CRP significantly modified the risk of recurrent coronary events associated with apoA-I. Among the entire population, multivariable-adjusted hazard ratios associated with each standard deviation increase in apoA-I for those with low and high CRP levels were 0.89 and 1.35, respectively (P value for interaction = .008). vWF was a significant effect modifier of the apoA-I/coronary risk association only among diabetic patients (hazard ratios were 0.56 and 1.43, for diabetic patients with low and high vWF levels, respectively; P value for interaction = .002). No effect modification was observed for the HDL-C/coronary risk association. CONCLUSION: Among stable post-MI patients, CRP modified the risk of recurrent coronary events associated with apoA-I. VWF modified this association only among the diabetic subgroup.

Elevated HDL is a risk factor for recurrent coronary events in a subgroup of non-diabetic postinfarction patients with hypercholesterolemia and inflammation.

Recent studies demonstrate important roles for inflammation in development of atherosclerosis with current attention focusing on interactions of inflammation with traditional lipoprotein risk factors. Since the nature of such relationships is largely unknown, we sought to investigate interactions of inflammation with hyperlipidemia in generating cardiovascular risk in a way that would allow recognition of such interactions whether anticipated or not. Thus, we searched for subgroups at high risk for recurrent coronary events in 767 non-diabetic postinfarction patients using an exploratory three-dimensional graphical screening technique with previously established factor analysis-derived inflammatory and lipoprotein-related factors. Results indicated a high-risk patient subgroup defined by factor interaction that was best characterized clinically by high levels of C-reactive protein (CRP) and total cholesterol. Kaplan-Meier and Cox multivariate analysis confirmed high-risk. Additionally, within-subgroup risk related to metabolic, inflammatory, and thrombogenic blood markers was assessed using Cox analysis with results showing only elevated HDL as a significant and independent predictor of risk with hazard ratio, 2.24 (95% CI; 1.12, 4.49; p = 0.023). We conclude that in non-diabetic postinfarction patients, elevated HDL is predictive of risk of recurrent coronary events within a subgroup of patients characterized by simultaneous elevations in serum CRP and total cholesterol.

Data in support of a central role of plasminogen activator inhibitor-2 polymorphism in recurrent cardiovascular disease risk in the setting of high HDL cholesterol and C-reactive protein using Bayesian network modeling.

Data is presented that was utilized as the basis for Bayesian network modeling of influence pathways focusing on the central role of a polymorphism of plasminogen activator inhibitor-2 (PAI-2) on recurrent cardiovascular disease risk in patients with high levels of HDL cholesterol and C-reactive protein (CRP) as a marker of inflammation, "Influences on Plasminogen Activator Inhibitor-2 Polymorphism-Associated Recurrent Cardiovascular Disease Risk in Patients with High HDL Cholesterol and Inflammation" (Corsetti et al., 2016; [1]). The data consist of occurrence of recurrent coronary events in 166 post myocardial infarction patients along with 1. clinical data on gender, race, age, and body mass index; 2. blood level data on 17 biomarkers; and 3. genotype data on 53 presumptive CVD-related single nucleotide polymorphisms. Additionally, a flow diagram of the Bayesian modeling procedure is presented along with Bayesian network subgraphs (root nodes to outcome events) utilized as the data from which PAI-2 associated influence pathways were derived (Corsetti et al., 2016; [1]).

Apolipoprotein E levels and apolipoprotein E genotypes in incident cardiovascular disease risk in subjects of the Prevention of Renal and Vascular End-stage disease study.

BACKGROUND: Apolipoprotein E (apoE) is a component of all major lipoprotein classes with multiple functions including clearance of circulating triglyceride-rich lipoprotein particles and hepatic production of triglyceride-rich lipoprotein, thus affording several avenues for apoE involvement in atherosclerosis development. ApoE has 3 isoforms (E2, E3, and E4) based on a common genetic polymorphism. Numerous studies have been performed assessing cardiovascular disease (CVD) risk relative to the 6 resulting genotypes; however, surprisingly, few studies have been performed assessing risk attributable to apoE plasma levels either alone or in addition also taking into account apoE genotypes. OBJECTIVE: To examine the role of apoE levels together with apoE genotypes on incident CVD risk in a large population-based cohort and also to afford preliminary characterization of atherogenic apoE-containing lipoprotein particles. METHODS: Cox multivariable proportional hazards modeling was performed on a cohort of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study as a function of apoE levels and apoE genotypes adjusted for age, gender, and past history of CVD. Further modeling was performed with single addition of clinical and biomarker parameters to elucidate the nature of apoE-associated risk. RESULTS: High apoE levels were demonstrated to be associated with CVD risk (hazard ratio per apoE standard deviation, 1.20; 95% confidence interval, 1.11-1.31; P < .0001) both overall and within the high-frequency apoE genotype groups (ε2ε3, ε3ε3, and ε3ε4). Only on addition of apoB-containing lipoprotein parameters to models, did apoE levels lose association with risk. CONCLUSIONS: ApoE levels positively associate with incident CVD risk with apoE-associated risk likely residing in apoB-containing lipoproteins.

Influences on plasminogen activator inhibitor-2 polymorphism-associated recurrent cardiovascular disease risk in patients with high HDL cholesterol and inflammation.

BACKGROUND AND AIMS: Evidence continues to accumulate that athero-protective effects of high-density lipoprotein (HDL) depend to some degree on effective HDL functionality and that such functionality can become degraded in the setting of chronic inflammation. To investigate this issue, we have studied a group of post-myocardial infarction patients with high levels of C-reactive protein as an indicator of chronic inflammation and with concurrently high levels of HDL cholesterol. For these patients we have demonstrated high-risk for recurrent cardiac events as well as a strong association of risk with a polymorphism of the gene (SERPINB2) for plasminogen activator inhibitor-2 (PAI-2) presumptively reflective of an important role for fibrinolysis in risk. However, additional processes might be involved. The current work sought to characterize processes underlying how PAI-2 might be involved in the generation of risk. METHODS: Multivariate population data were leveraged using Bayesian network modeling, a graphical probabilistic approach for knowledge discovery, to generate networks reflective of influences on PAI-2 polymorphism-associated risk. RESULTS: Modeling results revealed three individual networks centering on the PAI-2 polymorphism with specific features providing information relating to how the polymorphism might associate with risk. These included racial dependency, platelet clot initiation and propagation, oxidative stress, inflammation effects on HDL metabolism and coagulation, and induction and termination of fibrinolysis. CONCLUSIONS: Beyond direct association of a PAI-2 polymorphism with recurrent risk in post-myocardial infarction patients, results suggest that PAI-2 likely plays a key role leading to risk through multiple pathophysiologic processes. Such knowledge could potentially be valuable with individualization of patient care.

Serum glucose and triglyceride determine high-risk subgroups in non-diabetic postinfarction patients.

A strategy was developed to identify subgroups at high risk for recurrent coronary events in non-diabetic postinfarction patients as a function of metabolic, inflammatory, and thrombogenic blood markers. A graphical screening technique for presumptively identifying high-risk subgroups from outcome prevalence maps was devised that was equally sensitive for all values of risk factors in contrast to traditional approaches where risk is presumed for the highest or the lowest values. Traditional statistical analysis confirms high risk in identified subgroups. Serum glucose and triglyceride served as bivariate search domain. Results demonstrated three high-risk subgroups. One was characterized as pre-diabetic; another as metabolic syndrome-enriched; and the third, with unexpectedly high risk, as normoglycemic and modestly hypertriglyceridemic. Within-subgroup risk as determined by Cox proportional hazards model gave for odds ratios and 95 percentile confidence intervals: glucose, 2.49 (1.17-5.33) in pre-diabetic; PAI-1, 3.95 (1.81-8.61) in metabolic syndrome-enriched; and BMI, 2.79 (1.17-6.63) and fibrinogen, 2.79 (1.29-6.04) in normoglycemic, modestly hypertriglyceridemic patients. We conclude that the graphical approach holds promise in screening for high-risk patient subgroups. Finding different within-subgroup predictors of risk underscores the notion of context-dependent risk, an observation that may be relevant for determining optimal use of emerging risk factors.