Baseline High-density Lipoprotein Cholesterol Levels Research Articles

Rosuvastatin-induced high-density lipoprotein changes in patients who underwent percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome

BackgroundClinical significance of statin-induced high-density lipoprotein cholesterol (HDL-C) changes is not well known. We investigated the factors affecting rosuvastatin-induced HDL-C changes and their correlation with 12-month major adverse cardiovascular events (MACE) in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and percutaneous coronary intervention (PCI). Materials and methodsWe analyzed 556 consecutive NSTE-ACS patients who underwent PCI and received rosuvastatin 10mg before discharge. We measured serum lipids, including total cholesterol, triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and HDL-C at baseline and at 4 weeks. The relationship between on-treatment lipid levels, baseline lipid levels, and 12-month MACE was assessed. ResultsRosuvastatin treatment increased the mean HDL-C concentration by 1.1±9.8mg/dl (4.3±23.0%). HDL-C was increased in 312 patients (56.1%), but decreased in 244 patients (43.9%) after statin treatment. Changes in HDL-C during first month were inversely correlated with baseline HDL-C levels (r=−0.379, p<0.001). The patients with increased HDL-C showed higher baseline TG levels but lower on-treatment TG levels. Changes in TG were correlated with changes in HDL-C (r=−0.212, p<0.001). The incidence of 12-month MACE according to changes in HDL-C was similar between the two groups (11.9% vs. 12.3%, p=0.875). Multivariate analysis revealed that baseline HDL-C level was the only significant predictor of rosuvastatin-induced HDL-C changes. ConclusionBaseline HDL-C concentration was an independent predictor of rosuvastatin-induced HDL-C changes. Statin-induced HDL-C changes did not predict 12-month MACE in patients with NSTE-ACS.

Consistency of Extended-Release Niacin/Laropiprant Effects on Lp(a), ApoB, non-HDL-C, Apo A1, and ApoB/ApoA1 Ratio Across Patient Subgroups

According to prior analyses, extended-release niacin/laropiprant (ERN/LRPT) consistently reduces low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C) levels across a wide range of dyslipidemic patient subgroups. This analysis examined ERN/LRPT's consistency across four phase III, randomized, double-blind trials in improving other lipid/lipoprotein parameters associated with cardiovascular risk, across several key dyslipidemic patient subgroups. In three of the studies, the randomized population included patients with primary hypercholesterolemia or mixed hyperlipidemia; in the remaining study, the population included patients with type 2 diabetes mellitus. The lipid-altering consistency of ERN/LRPT's efficacy was evaluated versus the pre-defined comparator (placebo or active control) among key subgroups of sex, race (White, non-White), region (US, ex-US), baseline age (<65 years, ≥65 years), use of statin therapy (yes, no), coronary heart disease (yes, no), risk status (low, multiple, high), and type of hyperlipidemia (primary hypercholesterolemia, mixed dyslipidemia), as well as across baseline LDL-C, HDL-C, and TG levels. The consistency of the treatment effects on lipoprotein(a).[Lp(a)], apolipoprotein B (ApoB), non-HDL-C, ApoA1, and ApoB/ApoA1 ratio was evaluated by examining treatment difference estimates of the percentage change from baseline with 95% confidence intervals. Treatment with ERN/LRPT produced significantly greater improvements in Lp(a), ApoB, non-HDL-C, ApoA1, and ApoB/ApoA1 ratio compared with placebo/active comparator in each study. These effects were generally consistent across key subgroups within each study. ERN/LRPT produced lipid-altering efficacy on the parameters evaluated in four controlled studies; these effects were generally consistent across all examined subgroups. ERN/LRPT represents an effective and reliable therapeutic option for the treatment of dyslipidemia in a wide range of patient types. Registered as Clinicaltrials.gov NCT00269204, NCT00269217, NCT00479388, and NCT00485758.

High-Density Lipoprotein and Mortality Before Age 90 in Male Physicians

In cross-sectional and some cohort studies with shorter follow-up, high-density lipoprotein cholesterol (HDL-C) has been associated with longer life. We sought to examine the relationship between HDL-C and death before age 90 in the Physicians' Health Study (PHS). Of PHS enrollees who had blood collected at PHS II baseline (approximately 1997), we selected 1351 men old enough to reach age 90 by March 4, 2009, and with complete data on HDL-C and total cholesterol, lifestyle factors, and comorbidities. We used Cox proportional hazards to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cardiovascular disease (CVD), and non-CVD mortality before age 90, adjusting for potential confounders. After a mean (SD) follow-up of 6.8 (3.2) years, 44.1% of men in the lowest baseline HDL-C quartile (<32.8 mg/dL) compared with 32.9% (11.2% absolute risk reduction) in the highest HDL-C quartile (≥ 54.1 mg/dL) died before age 90. In multivariable adjusted analyses, men in the highest HDL-C quartile had a 28% lower risk (HR, 0.72; 95% CI, 0.55 to 0.94) of death before age 90 compared with men in the lowest HDL-C quartile. In age-adjusted analyses, increasing baseline HDL-C was significantly associated with a lower risk of CVD death. No association was found between HDL-C and non-CVD mortality. In male physicians, higher baseline HDL-C levels were associated with a lower risk of all-cause and CVD mortality before age 90.

Should raising high-density lipoprotein cholesterol be a matter of debate?

High-density lipoprotein cholesterol (HDL-C) has been identified as an independent inverse predictor of coronary heart disease, leading to the inclusion of HDL-C in certain risk engines. However, negative results also exist and create confusion regarding the value of interventions that increase HDL-C. The possible reasons for these conflicting findings are many, including not only patient selection (e.g. baseline HDL-C levels) but also the effect of the treatment on the quantity and quality of HDL. In the present review, the results of some HDL-C trials are discussed. They suggest that HDL-C function as well as quantity is clinically relevant. Furthermore, 'dysfunctional' HDL may be present in conditions such as diabetes or acute coronary syndromes. Efforts should focus on improving HDL particle functionality in addition to a numerical increase in HDL-C levels.

Reverse Vessel Remodeling But Not Coronary Plaque Regression Could Predict Future Cardiovascular Events in ACS Patients With Intensive Statin Therapy

The JAPAN-ACS study demonstrated that statins significantly reduced coronary plaque volume in patients with acute coronary syndrome (ACS). The clinical implications of plaque regression for clinical outcomes in ACS patients has not been established. The Extended JAPAN-ACS study was conducted to evaluate the relationship between coronary plaque regression and long-term clinical outcome, and to explore the factors associated with cardiovascular events. Patients with intravascular ultrasound (IVUS) data at both enrollment and follow-up in the JAPAN-ACS study were enrolled and observed for at least 3 years. Patients were divided into lesser and greater coronary plaque regression groups. The primary endpoint was defined as a composite of the following events: cardiovascular death, nonfatal myocardial infarction, nonfatal cerebral infarction, and unstable angina. The median value of the percent change in plaque volume, 18.0%, was used as a cutoff point. There were 4 primary events (3.4%) in the lesser regression group, and 2 events (1.7%) in the greater regression group (P=0.4). Cumulative secondary cardiovascular events did not differ between the 2 groups. Multivariate analysis identified the high-density lipoprotein cholesterol (HDL-C) at baseline and the % change of the external elastic membrane volume as independent risk factors of cardiovascular events. Coronary plaque regression induced by an intensive statin regimen did not predict future cardiovascular events in ACS patients. Rather, the baseline HDL-C level and reverse vessel remodeling might serve as predictors for cardiovascular events.

Abstract 17203: Prevalence of Low Levels of High-Density Lipoprotein Cholesterol (HDL-C) at Presentation in Acute Coronary Syndromes (ACS) and its Relation to In-Hospital Mortality: Results from the NCDR®

Background: Despite profound advances in medical and procedural therapy, significant residual risk persists for in-hospital mortality among patients admitted with ACS. Low HDL-C, a known independent risk predictor for increased cardiovascular events, may modulate risk in ACS patients. Methods: We evaluated baseline HDL-C levels among 98,276 non-ST-elevation MI patients from the NCDR ACTION-GWTG registry enrolled from 490 U.S. hospitals between January 2007 and December 2010. Clinical characteristics, treatments, and in-hospital outcomes were analyzed by quartiles of HDL-C measured during hospitalization. Using the highest quartile as referent, hazard ratios were obtained for in-hospital mortality using multivariable risk adjustment. Results: Almost half of the patients in the examined cohort had presentation HDL-C levels lower than or equal to the median (36.9 mg/dL). Patients in lower HDL-C quartiles were younger, more often male, white, smokers, obese, diabetic and had greater rates of prior MI, PCI, CABG and revascularization (P &lt;0.0001) compared to those in higher HDL-C quartiles. Use of medical therapy (aspirin, clopidogrel, beta-blockers, ACE inhibitors or ARBs, statins and other lipid-lowering agents) at home was greater among patients with lower HDL-C (P = 0.0002 for statins, &lt;0.0001 for others). Significantly greater in-hospital mortality was noted with decreasing HDL-C quartiles in the overall cohort. Among patients in the lowest HDL-C quartile, a 16% greater risk of in-hospital death was noted compared to their counterparts in the highest HDL-C quartile (P = 0.0073) (Figure 1). Conclusion: Low levels of HDL-C at presentation was common among this national contemporary “real-world” cohort of patients admitted with non-ST-elevation ACS. Very low HDL-C levels (≤ 30 mg/dL) at presentation represented an adverse prognostic factor and was associated with higher in-hospital mortality.

Cost-effectiveness of extended-release niacin/laropiprant added to a stable simvastatin dose in secondary prevention patients not at cholesterol goal in Germany

Coronary heart disease (CHD) remains the leading cause of death in Germany despite statin use to reduce low-density lipoprotein cholesterol (LDL-C) levels; improving lipids beyond LDL-C may further reduce cardiovascular risk. A fixed-dose combination of extended-release niacin (ERN) with laropiprant (LRPT) provides comprehensive lipid management. We adapted a decision-analytic model to evaluate the economic value (incremental cost-effectiveness ratio [ICER] in terms of costs per life-years gained [LYG]) of ERN/LRPT 2 g over a lifetime in secondary prevention patients in a German setting. Two scenarios were modelled: (1) ERN/LRPT 2 g added to simvastatin 40 mg in patients not at LDL-C goal with simvastatin 40 mg; (2) adding ERN/LRPT 2 g compared with titration to simvastatin 40 mg in patients not at LDL-C goal with simvastatin 20 mg. In both scenarios, adding ERN/LRPT was cost-effective relative to simvastatin monotherapy at a commonly accepted threshold of €30,000 per LYG; ICERs for ERN/LRPT were €13,331 per LYG in scenario 1 and €17,684 per LYG in scenario 2. Subgroup analyses showed that ERN/LRPT was cost-effective in patients with or without diabetes, patients aged ≤65 or >65 years and patients with low baseline high-density lipoprotein cholesterol levels; ICERs ranged from €10,342 to €15,579 in scenario 1, and from €14,081 to €20,462 in scenario 2. In conclusion, comprehensive lipid management with ERN/LRPT 2 g is cost-effective in secondary prevention patients in Germany who have not achieved LDL-C goal with simvastatin monotherapy.

Is there a future for CETP-inhibitor therapy?

Despite large improvements in cardiovascular disease mortality, coronary heart disease (CHD) and stroke remain the leading causes of death in most nations around the world [1,101]. Statins are the foundation for cardiovascular prevention, with up to 50% reductions in cardiovascular risk with the more potent statins [2]. In both statin-treated and -untreated patients, low levels of high-density lipoprotein cholesterol (HDL-C) are an important predictor of subsequent cardiovascular risk [3,4]. In epidemiologic studies, each 1 mg/dl (0.03 mmol, or ~2–3%, depending on baseline HDL-C level) increase in HDL-C is associated with a 2–4% reduction in the risk of CHD events, independent of low-density lipoprotein cholesterol (LDL-C) levels [5]. Of the drugs currently on the market, niacin is the most effective at raising HDL-C (~25% at the 2-g dose), while statins and fibrates have more modest HDL-C-raising effects (3–10%) [6]. However, it is not clear that pharmacologically raising HDL-C per se with these agents reduces cardiovascular risk. A meta-ana lysis of HDL-C-raising drugs found that after adjusting for LDL-C-lowering, raising HDL-C (or lowering triglycerides) was not associated with further cardiovascular risk reduction [6]. Several classes of HDL-C-raising agents with novel mechanisms of action are under development [7]. Farthest along are the cholesteryl ester transfer protein (CETP) inhibitors. CETP mediates the transfer of cholesteryl esters from HDL to proatherogenic apolipoprotein B-lipoproteins for transportation of cholesterol back to the cells; blocking CETP increases levels of mature HDL-C particles. The first CETP inhibitor to move into clinical trials was torcetrapib (Pfizer, Inc). Despite large increases in HDL-C, development of torcetrapib was terminated due to excess mortality in the torcetrapib group of the large outcomes trial, Investigation of Lipid Level management to Understand its Impact in Atherosclerotic Events (ILLUMINATE). Increased mortality in the torcetrapib-treated group occurred despite a 72% increase in HDL-C and a 25% decrease in LDL-C [8]. Torcetrapib also had no benefit on atherosclerotic progression in two noninvasive imaging studies, despite similar lipid changes [9,10]. The adverse mortality effect of torcetrapib has been largely attributed to accelerated hypertension due to activation of the renin–angiotensin–aldosterone system through a non-CETP-dependent effect [11]. Other mechanisms, such as lack of HDL functionality and proinflammatory effects, have also been proposed to explain torcetrapib’s adverse effects. Two CETP inhibitors are still in development, anacetrapib and dalcetrapib. Neither agent has been found to increase blood pressure or influence the renin– angiotensin–aldosterone axis in studies to date [7]. The more potent CETP inhibitor, anacetrapib, comes from the same chemical class as torcetrapib and strongly binds to the CETP molecule. Added to optimal statin therapy, anacetrapib 100 mg has been shown to increase HDL-C by 138% and reduce LDL-C an additional 40%, with modest triglyceride-lowering effects [12]. The less potent dalcetrapib is from a different chemical class, binds reversibly to and induces a different conformational “Given the excess mortality caused by torcetrapib, it is unlikely that any CETP inhibitor will receive regulatory approval prior to the completion of the long-term cardiovascular end point trials...”

Serum high‐density lipoprotein cholesterol levels, their relationship with baseline functional and cognitive status, and their utility in predicting mortality in nonagenarians

Little is known about the role of high-density lipoprotein cholesterol (HDL-C) in oldest-old subjects. The aim of this study is to evaluate the association between HDL-C levels and physical and cognitive performance indicators in nonagenarians, and also to determine the influence of HDL-C levels on the 3-year mortality risk. The data analyzed were taken from the NonaSantfeliu Study. Functional status was determined by the Lawton-Brody Index (LI) for instrumental activities of daily living (IADL) and the Barthel Index (BI) for basic activities (BADL). Cognition was assessed using the Spanish version of the Mini-Mental State Examination (MEC). The sample consisted of 49 women (79%) and 13 men, aged 94.3 ± 2.6 years. Mean HDL-C levels were 60 ± 16 mg/dL, and 16 subjects (25.8%) had low HDL-C values. HDL-C levels did correlate with BI (r = 0.28, P = 0.02) and LI (r = 0.32, P = 0.01), but not with MEC (r = 0.18, P = 0.15). Normal HDL-C levels at baseline were significantly associated with higher BI scores (P < 0.006, odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01-1.05) and a lower number of prescription drugs used (P < 0.04, OR = 0.71, 95% CI = 0.49-0.99). Baseline HDL-C levels were significantly lower among the group of nonagenarians who died within the 3 years of follow up (P = 0.02). However, after adjusting for potential confounders, the association between HDL-C and mortality lost significance. Higher levels of HDL-C correlate with better functional status and less use of prescribed drugs in nonagenarians. However, the relationship between low HDL-C levels and long-term mortality in this population remains unclear.

Comparison of Preventive Effect on Cardiovascular Events With Different Statins - The CIRCLE Study -

Although statins vary in their effectiveness in lowering low-density lipoprotein cholesterol (LDL-C) and increasing high-density lipoprotein cholesterol (HDL-C) levels, there is little evidence that the degree of these changes can explain cardiac risk reduction in Japan. Our objective was to compare the efficacy of statins on serum lipid levels and to explore the association between those changes and cardiac events in patients after percutaneous coronary intervention (PCI). The 743 consecutive patients who underwent PCI from 2001 to 2008 were retrospectively investigated. Treatment with either atorvastatin or pitavastatin significantly reduced LDL-C compared with pravastatin or no statin. In contrast, only pitavastatin treatment significantly increased HDL-C (13.4 ± 22.9%, P=0.01 vs. no statin). Each statin significantly prevented major adverse cardiac events (MACE) compared with no statin, and pitavastatin was the most effective of all. Multivariate-adjusted analysis revealed that percent changes of both LDL-C and HDL-C independently predicted the incidence of MACE (hazard ratio [HR]: 1.015; 95% confidence interval [CI]: 1.010-1.020, HR: 0.988; 95%CI: 0.981-0.996, respectively). This relationship was preserved in patients with a baseline HDL-C level ≤ 45 mg/dl, but not HDL-C level > 45 mg/ml. The extent of changes in LDL-C and HDL-C with statin treatment would independently alter the risk of cardiac events in Japanese patients for secondary prevention. Statins with varying lipid-modifying ability might provide differing prognosis in patients after PCI.

High-density lipoprotein proteome dynamics in human endotoxemia

BackgroundA large variety of proteins involved in inflammation, coagulation, lipid-oxidation and lipid metabolism have been associated with high-density lipoprotein (HDL) and it is anticipated that changes in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry (MS) was used to study the dynamic changes of HDL protein composition in a human experimental low-dose endotoxemia model. Ten healthy men with low HDL cholesterol (0.7+/-0.1 mmol/L) and 10 men with high HDL cholesterol levels (1.9+/-0.4 mmol/L) were challenged with endotoxin (LPS) intravenously (1 ng/kg bodyweight). We previously showed that subjects with low HDL cholesterol are more susceptible to an inflammatory challenge. The current study tested the hypothesis that this discrepancy may be related to differences in the HDL proteome.ResultsPlasma drawn at 7 time-points over a 24 hour time period after LPS challenge was used for direct capture of HDL using antibodies against apolipoprotein A-I followed by subsequent SELDI-TOF MS profiling. Upon LPS administration, profound changes in 21 markers (adjusted p-value < 0.05) were observed in the proteome in both study groups. These changes were observed 1 hour after LPS infusion and sustained up to 24 hours, but unexpectedly were not different between the 2 study groups. Hierarchical clustering of the protein spectra at all time points of all individuals revealed 3 distinct clusters, which were largely independent of baseline HDL cholesterol levels but correlated with paraoxonase 1 activity. The acute phase protein serum amyloid A-1/2 (SAA-1/2) was clearly upregulated after LPS infusion in both groups and comprised both native and N-terminal truncated variants that were identified by two-dimensional gel electrophoresis and mass spectrometry. Individuals of one of the clusters were distinguished by a lower SAA-1/2 response after LPS challenge and a delayed time-response of the truncated variants.ConclusionsThis study shows that the semi-quantitative differences in the HDL proteome as assessed by SELDI-TOF MS cannot explain why subjects with low HDL cholesterol are more susceptible to a challenge with LPS than those with high HDL cholesterol. Instead the results indicate that hierarchical clustering could be useful to predict HDL functionality in acute phase responses towards LPS.

Baseline and On-Treatment High-Density Lipoprotein Cholesterol and the Risk of Cancer in Randomized Controlled Trials of Lipid-Altering Therapy

We sought to examine the relationship between high-density lipoprotein cholesterol (HDL-C) levels and the risk of the development of cancer in large randomized controlled trials (RCTs) of lipid-altering interventions. Epidemiologic data demonstrate an inverse relationship between serum total cholesterol levels and incident cancer. We recently reported that lower levels of low-density lipoprotein cholesterol are associated with a significantly higher risk of incident cancer in a meta-analysis of large RCTs of statin therapy. However, little is known about the relationship between HDL-C levels and cancer risk. A systematic MEDLINE search identified lipid intervention RCTs with >or=1,000 person-years of follow-up, providing baseline HDL-C levels and rates of incident cancer. Using random-effects meta-regressions, we evaluated the relationship between baseline HDL-C and incident cancer in each RCT arm. A total of 24 eligible RCTs were identified (28 pharmacologic intervention arms and 23 control arms), with 625,477 person-years of follow-up and 8,185 incident cancers. There was a significant inverse association between baseline HDL-C levels and the rate of incident cancer (p = 0.018). The inverse association persisted after adjusting for baseline low-density lipoprotein cholesterol, age, body mass index (BMI), diabetes, sex, and smoking status, such that for every 10-mg/dl increment in HDL-C, there was a 36% (95% confidence interval: 24% to 47%) relatively lower rate of the development of cancer (p < 0.001). There is a significant inverse association between HDL-C and the risk of incident cancer that is independent of LDL-C, age, BMI, diabetes, sex, and smoking.

Quantification of the Clinical Modifiers Impacting High-Density Lipoprotein Cholesterol in the Community: Personalized Medicine Research Project

High-density lipoprotein (HDL) cholesterol levels are inversely correlated with the development of cardiovascular disease. To date, genetic association studies have explained only a small proportion of the overall variance in HDL cholesterol. Further studies are needed, within practice-based cohorts, to place genetic findings into context alongside important clinical variables (eg, age, sex, body mass index, medication use, and clinical comorbidity). The Marshfield Clinic Personalized Medicine Research Project database was designed for large-scale studies of genetic epidemiology in a clinical practice-based setting. Because of its size and its unique practice-based design, this resource will provide adequate statistical power for the assessment of genetic findings related to HDL cholesterol level within the context of covariates known to modify lipid homeostasis. The authors report construction and validation of novel electronic phenotyping algorithms that can be used to model individual baseline HDL cholesterol levels within this practice-based resource. Because these algorithms were developed in a setting that reflects routine clinical care, future genetic studies using these algorithms within practice-based DNA biobanks should facilitate the identification of markers with optimal effect size after adjustment for known clinical factors contributing to the overall variance in HDL cholesterol level within the community.

Gender differences in systemic inflammation and atheroma formation following Porphyromonas gingivalis infection in heterozygous apolipoprotein E‐deficient mice

Men are at higher risk for periodontal and cardiovascular diseases compared with women, although they have lower serum levels of risk markers, including lipids and acute phase proteins. In this study, we investigated whether infection with a major periodontal pathogen, Porphyromonas gingivalis, affected the inflammatory and atherosclerotic response of male and female mice differently. Forty-eight heterozygous apolipoprotein E-deficient mice (24 males and 24 females), maintained on normal diet, were infected twice by intrasubcutaneous chamber injections of P. gingivalis or vehicle at weeks 11 and 14 of age. Serum samples were collected before the first infection and bi-weekly thereafter, to quantify levels of high-density lipoprotein (HDL) cholesterol and the murine acute phase protein, serum amyloid A (SAA). Mice were killed at week 17 to evaluate aortic atheroma lesion score. Males had significantly higher baseline HDL cholesterol levels (p < 0.01, factorial ANOVA). Following P. gingivalis infection, HDL cholesterol levels decreased over time in infected males only [p < 0.05, generalized estimating equation (GEE)], whereas SAA levels increased and remained elevated over time in both male and female infected mice (p < 0.01, GEE). Lesion scores were significantly higher in infected mice (3-fold, p < 0.01, factorial ANOVA), and lesion scores of all mice were positively correlated with SAA levels at the time of killing (Spearman correlation coefficient = 0.40, p < 0.01). In these young mice, P. gingivalis infection induced sex-specific changes in serum lipids but no gender differences in acute phase proteins and atheroma lesion score.

Does Baseline High Density Lipoprotein Cholesterol Influence Post-exercise Change Associated With Acute Exercise?

PURPOSE: The purpose of this study was to determine if baseline levels of high density lipoprotein cholesterol (HDL) affects the change in HDL levels associated with an acute bout of exercise of varying energy expenditure. METHODS: Two groups of healthy untrained male volunteers participated in this study. Subjects were assigned to one of two groups according to their baseline HDL levels. The LOW HDL group consisted of 13 subjects with clinically low HDL (< 40mg/dl) and the NORMAL HDL group consisted of 14 subjects with normal HDL (≥ 45mg/dl). Age, diet, VO2max and anthropometric data were collected prior to initiation of the experimental protocol and were similar for both groups. Age, height, weight, BMI, VO2max and resting HDL for LOW were 21.9 ± 2.0 yrs, 1.8 ± 0.1 m, 80.9 ± 7.9 kg, 25.2 ± 2.2 kg/m2, 45.8 ± 5.1 ml/kg/min and 35.7 ± 2.7 mg/dl, respectively while characteristics of the NORMAL group were 23.4 ± 7.1yrs, 1.8 ± 0.1 m, 78.6 ± 7.6 kg, 24.3 ± 2.5 kg/m2, 47.5 ± 4.8 ml/kg/min and 53.9 ± 5.8 mg/dl. Subjects completed two nonconsecutive exercise sessions (on separate days) expending 500 and 700 kcals while running on a treadmill at 65% of VO2max. Venous blood was collected pre-exercise, immediately post-exercise (IPE), and 24 hours post-exercise (+24) and analyzed for HDL and subfractions of HDL (HDL2and HDL3) and corrected for any shift in plasma volume. RESULTS: No differences in HDL or HDL subfractions were observed between NORMAL and LOW HDL groups at any post-exercise times. With both groups pooled HDL was significantly increased (p<0.05) by 2.5mg/dl (5.6%) at IPE, but not at +24 when compared to pre-exercise values. The increase in HDL post exercise was due for the most part to increased HDL3 (3.5mg/dl, 13.6%) whereas the HDL2 subfraction remained statistically unchanged. CONCLUSIONS: Baseline HDL status does not appear to affect the magnitude of post-exercise HDL-C alterations in untrained men. Furthermore, post-exercise increases in HDL associated with acute exercise appear due to increased HDL3 and not HDL2 in the subjects of this study.

Usefulness of Serum High-Density Lipoprotein Cholesterol Level as an Independent Predictor of One-Year Mortality After Percutaneous Coronary Interventions

Low levels of high-density lipoprotein (HDL) cholesterol are a marker of coronary artery disease progression and are associated with cardiovascular events. However, whether low HDL cholesterol is a useful prognostic indicator after percutaneous coronary intervention (PCI) is not known. In a sample of 4,088 patients who underwent PCI we evaluated 1-year mortality and repeat revascularization as a function of baseline HDL levels classified into approximate quartiles of very low (<35 mg/dl), low (35 to 40 mg/dl), medium (41 to 47 mg/dl) and high (48 to 120 mg/dl) HDL cholesterol. Decreasing levels of HDL cholesterol were associated with younger age, male gender, smoking, diabetes mellitus, and a history of bypass surgery (p <0.0001 for all). One-year mortality and coronary revascularization were significantly higher in the very low HDL cholesterol group compared with the other groups (very low HDL cholesterol 6.5% and 25.4%, respectively; low HDL cholesterol 3.1% and 20.8%; medium HDL cholesterol 4.3% and 22.7%; high HDL cholesterol 3.1% and 20.6%, p = 0.0001 and p = 0.007). One-year mortality was significantly higher in men with an HDL cholesterol level <33 mg/dL and in women with an HDL cholesterol level <38 mg/dL. In multivariable analysis, very low HDL was associated with nearly twofold the risk of death after adjusting for other independent predictors of outcome. In conclusion, in patients with coronary artery disease undergoing PCI, a baseline HDL cholesterol level <35 mg/dl is an important prognostic indicator. Baseline HDL cholesterol levels <33 mg/dl for men and <38 mg/dl were associated with higher one-year mortality after PCI.

Efficacy and Safety of Coadministration of Fenofibrate and Ezetimibe Compared with Each as Monotherapy in Patients with Type IIb Dyslipidemia and Features of the Metabolic Syndrome

Patients with type IIb, or mixed, dyslipidemia have high levels of low-density lipoprotein cholesterol (LDL-C) with predominance of small dense LDL particles, high levels of triglycerides (TG), and low levels of high-density lipoprotein cholesterol (HDL-C). Fenofibrate significantly reduces TG and, more moderately, LDL-C, increases HDL-C and produces a shift from small to large LDL particle size; the main effect of ezetimibe is a reduction in LDL-C levels. Combined treatment with fenofibrate and ezetimibe may correct all the abnormalities of type IIb dyslipidemia. To assess the efficacy and safety of coadministration of fenofibrate (NanoCrystal(R)) and ezetimibe in patients with type IIb dyslipidemia and the metabolic syndrome compared with administration of fenofibrate and ezetimibe alone (ClinicalTrials.gov Identifier: NCT00349284; Study ID: CLF178P 04 01). This was a prospective, randomized, double-blind, three-parallel arm, multicenter, comparative study. Sixty ambulatory patients (mean age 56 years; 50% women, 50% men) were treated in each group. For inclusion in the study, patients were required to have LDL-C >or=4.13 mmol/L (>or=160 mg/dL), TG >or=1.71 mmol/L and <or=4.57 mmol/L (>or=150 mg/dL and <or=405 mg/dL), and at least two of the following National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome: low HDL-C or increased fasting plasma glucose, blood pressure, or waist circumference. Patients received fenofibrate 145 mg, ezetimibe 10 mg, or coadministration of both (fenofibrate/ezetimibe) daily for 12 weeks. The outcome measures were changes in lipids and related parameters, apolipoproteins, glucose metabolism parameters, and high-sensitivity C-reactive protein (hsCRP). Fenofibrate/ezetimibe was more effective than either fenofibrate or ezetimibe in reducing LDL-C (-36.2% vs -22.4% and -22.8%, respectively), non-HDL-C (-36.2% vs -24.8% and -20.9%, respectively), total cholesterol (TC) [-27.9% vs -18.9% and -17.1%, respectively], apolipoprotein B (-33.3% vs -24.5% and -18.7%, respectively), TC/HDL-C ratio (-34.2% vs -23.0% and -17.0%, respectively), and apolipoprotein B/apolipoprotein AI ratio (-37.5% vs -27.0% and -17.7%, respectively) [p < 0.001 for all comparisons between fenofibrate/ezetimibe and monotherapies]. Fenofibrate/ezetimibe was as effective as fenofibrate and more effective than ezetimibe in reducing remnant-like particle cholesterol (-36.2% and -30.7% vs -17.3%, respectively), and in increasing LDL size (+2.1% and +1.9% vs + 0.7%, respectively), apolipoprotein AI (+7.9% and +5.1% vs +0.2%, respectively) and apolipoprotein AII (+24.2% and +21.2% vs +2.7%, respectively). Fenofibrate/ezetimibe and fenofibrate were equally effective in reducing TG (both -38.3%) and in increasing HDL-C (+11.5% and + 7.9%, respectively; p = 0.282). Ezetimibe had minor effects on TG (-10.4%) and HDL-C (+2.2%). Among patients with low HDL-C at baseline (<1.29 mmol/L [<50 mg/dL] in women, <1.03 mmol/L [<40 mg/dL] in men), normalization of HDL-C was observed in 52.9% with fenofibrate/ezetimibe and in 58.8% with fenofibrate, compared with 20.0% with ezetimibe. Changes in hsCRP were -25.9% with fenofibrate/ezetimibe, -27.8% with fenofibrate, and -10.2% with ezetimibe (not statistically significant). None of the treatments altered glucose metabolism parameters. In patients with type IIb dyslipidemia and features of the metabolic syndrome, coadministration of fenofibrate 145 mg and ezetimibe 10 mg daily was more effective than either monotherapy in reducing LDL-C, non-HDL-C, apolipoprotein B, and cardiovascular risk ratios, and was as effective as fenofibrate 145 mg alone in reducing TG and in increasing HDL-C in patients with low baseline HDL-C levels.

Comparison of Treatment of Severe High-Density Lipoprotein Cholesterol Deficiency in Men With Daily Atorvastatin (20 mg) Versus Fenofibrate (200 mg) Versus Extended-Release Niacin (2 g)

To determine whether available lipid-modifying medication can increase high-density lipoprotein (HDL) cholesterol in well-defined genetic or familial HDL-deficiency states, we studied 19 men with HDL deficiency (HDL cholesterol <5th percentile for age and gender) 55 +/- 10 years of age. Concomitant risk factors included diabetes (n = 3) and hypertension (n = 7) and 8 patients had coronary artery disease. Molecular analysis revealed that 4 patients had a mutation in the ABCA1 gene. Patients were assigned to sequentially receive atorvastatin 20 mg/day, fenofibrate 200 mg/day, and extended-release niacin 2 g/day for 8 weeks, with a 4-week washout period between each treatment. Patients in whom a statin was required, according to current treatment guidelines, were kept on atorvastatin throughout the study. Baseline HDL cholesterol level was 0.63 +/- 0.12 mmol/L (24 +/- 5 mg/dl), triglycerides 2.01 +/- 0.98 mmol/L (180 +/- 86 mg/dl), and low-density lipoprotein (LDL) cholesterol 2.29 +/- 0.95 mmol/L (94 +/- 39 mg/dl). Mean percent changes in HDL cholesterol on atorvastatin, fenofibrate, and niacin were -6% (p = NS), +6% (p = NS), and +22% (p <0.05), respectively. Furthermore, niacin significantly increased the large alpha-1 apolipoprotein A-I-containing HDL subspecies (12 to 17 nm). In conclusion, niacin was the only effective drug to increase HDL cholesterol. The absolute increase in HDL cholesterol, approximately 0.10 mmol/L (3.9 mg/dl), is of uncertain clinical significance. Biomarkers of HDL-mediated cellular cholesterol efflux were not changed by niacin therapy. Atorvastatin or fenofibrate had little effect on HDL cholesterol; atorvastatin decreased the total cholesterol/HDL cholesterol ratio by 26%. Fenofibrate did not change HDL cholesterol levels and caused an increase in LDL cholesterol. Aggressive LDL cholesterol lowering may be the strategy of choice in such patients.

CETP genotypes and HDL-cholesterol phenotypes in the HERITAGE Family Study

Associations between cholesteryl ester transfer protein (CETP) polymorphisms and high-density lipoprotein cholesterol (HDL-c) levels before and after 20 wk of endurance training were investigated in the HERITAGE Family Study. Plasma HDL-c, HDL(2)-c, HDL(3)-c, and apolipoprotein (apo)A1 levels were measured, and 13 CETP single nucleotide polymorphisms (SNPs) were genotyped in 265 blacks and 486 whites. Three haplotypes defined by SNPs at the -1337, -971, and -629 sites were strongly associated with baseline HDL-c levels in whites. Both C-1337T and C-629A were associated with baseline HDL-c (P < 0.001) and apoA1 (P < 0.01) when tested separately. However, only C-629A remained significant in a combined model. G-971A was not associated with HDL phenotypes, but showed significant interactions with C-629A (P = 0.002) on baseline traits. Genotype-by-sex interactions were observed at the -629 locus for HDL(3)-c (P = 0.004) and apoA1 (P = 0.02) training responses in whites. In women, the -629 A/A homozygotes showed greater increases in HDL(3)-c (P = 0.02) and apoA1 (P = 0.02) levels than the other genotypes. Finally, apolipoprotein E (APOE) genotype and the CETP C-629A locus contributed independently and in additive fashion to the HDL traits, explaining 6.0-8.8% of the variance. The CETP -1337T and -629A alleles are associated with higher baseline HDL-c and apoA1 levels. The beneficial effects of endurance training on plasma HDL(3)-c and apoA1 levels are evident in white women homozygous for the -629A allele. The CETP and APOE genotypes account for up to 9% of the variance in HDL-c phenotypes in the HERITAGE Family Study.

Endothelial lipase is less effective at influencing HDL metabolism in vivo in mice expressing apoA-II

Endothelial lipase (EL) plays an important physiological role in modulating HDL metabolism. Data suggest that plasma contains an inhibitor of EL, and previous studies have suggested that apolipoprotein A-II (apoA-II) inhibits the activity of several enzymes involved in HDL metabolism. Therefore, we hypothesized that apoA-II may reduce the ability of EL to influence HDL metabolism. To test this hypothesis, we determined the effect of EL expression on plasma phospholipase activity and HDL metabolism in human apoA-I and human apoA-I/A-II transgenic mice. Expression of EL in vivo resulted in lower plasma phospholipase activity and significantly less reduction of HDL-cholesterol, phospholipid, and apoA-I levels in apoA-I/A-II double transgenic mice compared with apoA-I single transgenic mice. We conclude that the presence of apoA-II on HDL particles inhibits the ability of EL to influence the metabolism of HDL in vivo.