Metabolism and proteomics of large and small dense LDL in combined hyperlipidemia: effects of rosuvastatin.

Small dense LDL (sdLDL) has been reported to be more atherogenic than large buoyant LDL (lbLDL). We examined the metabolism and protein composition of sdLDL and lbLDL in six subjects with combined hyperlipidemia on placebo and rosuvastatin 40 mg/day. ApoB-100 kinetics in triglyceride-rich lipoproteins (TRLs), lbLDL (density [d] = 1.019-1.044 g/ml), and sdLDL (d = 1.044-1.063 g/ml) were determined in the fed state by using stable isotope tracers, mass spectrometry, and compartmental modeling. Compared with placebo, rosuvastatin decreased LDL cholesterol and apoB-100 levels in TRL, lbLDL, and sdLDL by significantly increasing the fractional catabolic rate of apoB-100 (TRL, +45%; lbLDL, +131%; and sdLDL, +97%), without a change in production. On placebo, 25% of TRL apoB-100 was catabolized directly, 37% was converted to lbLDL, and 38% went directly to sdLDL; rosuvastatin did not alter these distributions. During both phases, sdLDL apoB-100 was catabolized more slowly than lbLDL apoB-100 (P < 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL (P < 0.05). In our view, sdLDL is more atherogenic than lbLDL because of its longer plasma residence time, potentially resulting in more particle oxidation, modification, and reduction in size, with increased arterial wall uptake. Rosuvastatin enhances the catabolism of apoB-100 in both lbLDL and sdLDL.

Comparing remnant lipoprotein cholesterol measurement methods to evaluate efficacy of ezetimibe/statin vs statin therapy.

BACKGROUND: Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies. OBJECTIVE: To evaluate the effect of ezetimibe (Eze) + statins vs statin monotherapy on RLP-C using immunoseparation (IM), vertical auto profile (VAP) ultracentrifugation, and calculated RLP-C measurement methods. METHODS: This post hoc analysis evaluated data pooled from 3 first-line (all-statin [simvastatin 10/20/40/80 mg] vs Eze + statin [Eze 10 mg + simvastatin]) and 2 second-line (statin [atorvastatin uptitrated to 40/80 mg] vs statin + Eze [atorvastatin 20/40 mg + Eze 10 mg]) studies. Similarity of RLP-C methods was evaluated using Pearson correlation coefficients and Bland-Altman plots. RLP-C changes and percent changes from baseline were measured by all 3 methods in first-line and VAP and calculated methods in second-line studies. RESULTS: Correlations between methods were generally moderate to strong for RLP-C levels, changes, and percent changes across treatment groups (r = 0.29-0.79) but with little evidence of agreement by Bland-Altman plots. Baseline RLP-C levels for Eze + statin vs all-statin groups were lower by IM (14.0 vs 14.0) compared with VAP (36.9 vs 35.9) and calculated (32.8 vs 33.3) methods. RLP-C changes (mg/dL) and percent changes from baseline were significantly greater (P < .01) with Eze + statins vs statins by VAP, calculated, and IM methods (between-treatment differences: -5.0 and -12.0, -2.0 and -5.4, and -1.5 and -12.1, respectively) in first-line, and VAP and calculated methods (between-treatment differences: -5.0 and -19.9 and -2.0 and -7.3) in second-line studies. CONCLUSION: Although the 3 methods showed little agreement, each supported Eze + statins for achieving greater RLP-C reductions vs statin monotherapy; variability of results reinforces urgent need to standardize RLP-C measurements.

Enhanced hype.

The recently published Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients With Heterozygous Familial Hypercholesterolemia (ENHANCE) trial seems to raise questions regarding the notion that lipid lowering is of benefit in the prevention and treatment of vascular disease. Before one can make this conclusion, a careful analysis of the trial, including the subjects included and the surrogate end point studied, is required. The results of this study should be taken in context with those of many other studies showing that lipid lowering by many approaches is beneficial. In conclusion, the public fury over this study, with physicians making unsupported statements to the press and on the Web, is unfortunate and should be discouraged in the future.

The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient.

Despite current standards of care aimed at achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure and glycaemia, dyslipidaemic patients remain at high residual risk of vascular events. Atherogenic dyslipidaemia, specifically elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease, type 2 diabetes, obesity or metabolic syndrome and is associated with macrovascular and microvascular residual risk. The Residual Risk Reduction Initiative (R3I) was established to address this important issue. This position paper aims to highlight evidence that atherogenic dyslipidaemia contributes to residual macrovascular risk and microvascular complications despite current standards of care for dyslipidaemia and diabetes, and to recommend therapeutic intervention for reducing this, supported by evidence and expert consensus. Lifestyle modification is an important first step. Additionally, pharmacotherapy is often required. Adding niacin, a fibrate or omega-3 fatty acids to statin therapy improves achievement of all lipid risk factors. Outcomes studies are evaluating whether these strategies translate to greater clinical benefit than statin therapy alone. In conclusion, the R3I highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual vascular risk among dyslipidaemic patients who are treated in accordance with current standards of care.

Expert commentary: the safety of fibrates in lipid-lowering therapy.

The use of fibrates in the management of lipoprotein disorders has a history dating back to the mid-1960s. This group of drugs has now been tested in several large long-term trials with cardiovascular end points. Overall, there is good evidence for the reduction of cardiovascular disease in primary prevention studies and in those of subjects with manifest disease. More recent trials have suffered from high interference due to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) introduction, particularly in their placebo control groups. However, there is very good evidence for overall safety from a combined study of >20,000 patients in these controlled clinical trials lasting approximately 5 years. Abdominal pain has been observed more frequently in the statin vs placebo group. Myopathy, liver enzyme elevations, and cholecystitis have been potential adverse reactions of interest. However, these have occurred at a very low rate and are rarely found to be statistically more frequent in the active-treatment group compared with the subjects taking placebo. The recent Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study found a slightly higher incidence of pancreatitis, deep venous thrombosis, and pulmonary embolism. Small creatinine and homocysteine elevations are observed in many patients taking fibrates, and the effect of this on long-term outcomes is under study. The FIELD study also described a significant reduction in the rates of progression of proteinuria and vascular retinopathy with fibrate therapy. To date, there has been no study exclusive to patients with elevated triglycerides, raising the question of the potential benefit of these drugs in patients with the lipid abnormalities most effectively treated with fibrates.

JCL roundtable: Managing lipid disorders in patients with HIV.

The HIV-AIDS epidemic has provided one of the more challenging problems in treatment of infectious diseases. As antiretroviral drugs made a very marked improvement in controlling the immunodeficiency state and patients gained in their longevity, the concern with lipid abnormalities came to the fore. The initial drugs produced a form of metabolic syndrome accompanied by very elevated plasma triglyceride concentrations. Furthermore, the drugs used to control the virus were often metabolized in a manner that interfered with lipid lowering drug therapy. The antiviral agents have improved in many respects and the experience in managing the lipid disorders has added greatly to our ability to control these problems as well. This roundtable discussion has been conducted with 4 physicians who have been involved in management of large cohorts of patients with HIV infection and who have had a special interest in reduction of vascular disease risk.

JCL roundtable: PCSK9 inhibitors in clinical practice.

The roundtable this month will involve a discussion of two new drugs that have been approved by the Food and Drug Administration for the reduction of low-density lipoprotein cholesterol (LDL-C). The Food and Drug Administration approved the first of these, alirocumab as an "adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL [low-density lipoprotein]-cholesterol." Evolucumab has similar indications plus an indication specifically for treatment of homozygous familial hypercholesterolemia. This sets the stage for their clinical use and in this roundtable, we will discuss with two experts, the implications of these indications for the practicing physician. Dr McKenney and Dr Moriarty have had extensive experience in the conduct of clinical trials that provided the evidence of safety and efficacy of these so called PCSK9 inhibitors.

JCL Roundtable: Should we treat elevations in Lp(a)?

The focus of this Roundtable discussion is the mysterious lipoprotein Lp(a). There is growing evidence that it confers significant risk of vascular disease at high plasma concentrations. The concentration in plasma is highly variable from person to person but relatively stable in any given individual. The issue of defining this as a target of treatment has many facets, which have stymied clinicians in their management of this risk factor. The pertinent questions are many such as: "How does one obtain the most meaningful measure as there are so many components?" "What agents are truly effective in lowering this lipoprotein particle?" "Does direct treatment with reduction affect risk?" "How does low-density lipoprotein-cholesterol relate to the risk?" "If low-density lipoprotein-cholesterol is reduced, is there residual risk related directly to Lp(a)?" and "Are there effective therapies under development?" For this Roundtable, I am fortunate to have three experts that have studied these questions in various settings and have agreed to answer my questions relevant to these clinical issues. These include Dr Moriarty from the University of Kansas, Dr Remaley from the National Institutes of Health, and Dr Tsimikas from the University of California San Diego.

JCL roundtable: Risk evaluation and mitigation strategy.

Many factors enter into the decision by the Food and Drug Administration (FDA) to approve a new drug for use by physicians and other health care providers in treating diseases. Initially, the FDA authority was restricted to issues of safety and only later did the documentation of efficacy become part of the review process required for approval. However, all drugs have the potential for causing harm at some dose level to all and at lower doses in certain patients with vulnerability to the particular pharmacology of the agent. As new drugs have been designed to manage disorders that are uncommon, but of significant consequence, they may have adverse effects that are acceptable only because they are so uniquely beneficial to these specific conditions. The risk of these adverse effects may be acceptable since the benefit can outweigh the harm in most patients and the adversity can be predicted and managed. The approval of this category of drugs has grown rapidly since definition of a mechanism of action to manage and modify the risk has been provided by a process known as known as Risk Evaluation and Mitigation Strategy or "REMS." In 2007, the Food and Drug Administration Amendments Act (FDAAA) allowed the FDA to require postmarketing studies and the authority to mandate the implementation of a REMS for drugs with efficacy but documented potential for harm. Two relatively new drugs useful in the management of severe elevations of low-density lipoprotein cholesterol have been approved under a requirement for a REMS. These are lomitapide, an inhibitor of microsomal triglyceride transfer protein and mipomersen, an antisense oligonucleotide which reduces the synthesis of apolipoprotein B.

National Lipid Association Annual Summary of Clinical Lipidology 2016.

The National Lipid Association (NLA) Annual Summary of Clinical Lipidology is a yearly updated summary of principles important to the patient-centered evaluation, management, and care of patients with dyslipidemia. This summary is intended to be a "living document," with future annual updates based on emerging science, clinical considerations, and new NLA Position, Consensus, and Scientific Statements, thus providing an ongoing resource that applies the latest in medical science towards the clinical management of patients with dyslipidemia. Topics include the NLA Recommendations for Patient-Centered Management of Dyslipidemia, genetics, Familial Hypercholesterolemia, secondary causes of dyslipidemia, biomarkers and advanced lipid testing, nutrition, physical activity, obesity, adiposopathy, metabolic syndrome, diabetes mellitus, lipid pharmacotherapy, lipid-altering drug interactions, lipoprotein apheresis, dyslipidemia management and treatment based upon age (children, adolescents, and older individuals), dyslipidemia considerations based upon race, ethnicity and gender, dyslipidemia and human immune virus infection, dyslipidemia and immune disorders, adherence strategies and collaborative care, and lipid-altering drugs in development. Hyperlinks direct the reader to sentinel online tables, charts, and figures relevant to lipidology, access to online atherosclerotic cardiovascular disease risk calculators, worldwide lipid guidelines, recommendations, and position/scientific statements, as well as links to online audio files, websites, slide shows, applications, continuing medical education opportunities, and patient information.

Inverse relationship between high-density lipoprotein cholesterol raising and high-sensitivity C-reactive protein reduction in older patients treated with lipid-lowering therapy.

BACKGROUND: Little is known regarding relationships between high-sensitivity C-reactive protein (hsCRP) and lipoproteins other than low-density lipoprotein cholesterol (LDL-C). High-density lipoprotein (HDL), with both anti-inflammatory and cholesterol-mediating effects, is of particular interest. This exploratory analysis assessed associations between hsCRP and lipids in older (>65 years) patients with moderate and/or high cardiovascular disease risk, before and after treatment with ezetimibe/simvastatin (E/S) or atorvastatin (ATV). METHODS: An analysis of a multicenter, randomized, double-blind, 12-week study. Correlations were assessed in 1054 patients with both baseline and 12-week hsCRP ≤ 10 mg/L, pooled across doses of E/S (10/20 and 10/40 mg) and ATV (10, 20, and 40 mg), and combined E/S + ATV treatments. Because of multiple comparisons, observed relationships were considered significant only if P values were < .01. RESULTS: Correlations between baseline levels of hsCRP and either LDL-C, non-HDL-C, or apolipoprotein B were weak and nonsignificant in the E/S, ATV, and E/S + ATV groups. After 12 weeks of treatment, these correlations increased slightly and significantly in all groups, except for LDL-C in the ATV group. HDL-C was significantly but inversely correlated with hsCRP in the ATV and E/S + ATV groups at baseline, and in all groups at 12 weeks. Only with HDL-C did change correlate with change in hsCRP in both the E/S and combined groups. CONCLUSIONS: Relationships between hsCRP and lipid factors in older patients were weak at baseline and somewhat stronger after treatment. HDL-C was inversely and consistently correlated with baseline and 12-week on-treatment hsCRP and with therapy-induced changes in HDL-C and hsCRP.

Predictors of Calf Arterial Compliance in Male Veterans With Psychiatric Diagnoses.

BACKGROUND: Peripheral arterial compliance (PAC) is a measure of the ability of the vascular tree to dilate in response to a pressure wave. Reduced PAC is seen in patients with psychiatric diagnoses and has been associated with increased risk for stroke, myocardial infarction, and mortality. The objective of this pilot study was to identify predictors of reduced PAC in subjects with psychiatric diagnoses. METHODS: Male psychiatric subjects (N = 77) were studied in a cross-sectional study of medication effects on PAC conducted from August 2005 to February 2010. Calf and thigh compliance were modeled in separate linear regressions. The models were adjusted for age, race, smoking status, presence or absence of the metabolic syndrome, current treatment with a statin, diagnosis of schizophrenia or schizoaffective disorder, current antipsychotic treatment, and body mass index (BMI). RESULTS: Of the 77 subjects (mean ± SD age of 53.7 ± 8.8 years), 41 were white, 36 were black, and 27 were diagnosed with schizophrenia or schizoaffective disorder (DSM-IV criteria). Fifty participants were being treated with an antipsychotic medication, while the remaining 27 were off of antipsychotics for at least 2 months. Our model explained 27% of the variance in calf compliance. Black subjects had reduced calf compliance compared to white subjects (P = .02). Having metabolic syndrome was associated with reduced PAC at a trend level (P < .08), and BMI (P = .004) and BMI2 (P = .011) were significant predictors of calf compliance. Schizophrenia versus other psychiatric diagnoses and antipsychotic treatment were not significantly associated with calf compliance. CONCLUSIONS: In this pilot study, significant predictors of calf compliance were race (black vs white) and BMI. PAC is a noninvasive measure that may be a predictor of cardiovascular risk in psychiatric patients. The reduced PAC seen in patients with psychiatric diagnoses does not appear to be directly related to their diagnosis or antipsychotic treatment but rather to other characteristics inherent to the subject. Future studies are warranted to better understand the pathophysiology of PAC including but not limited to inflammation in psychiatric patients.

Relationship between arterial stiffness and subclinical aortic atherosclerosis.

BACKGROUND: Noninvasive measures of arterial compliance may be useful for the detection of subclinical atherosclerosis. METHODS AND RESULTS: Measures of calf and thigh arterial compliance (MaxV50) were recorded in 267 subjects who also underwent MRI of the distal aorta to quantify distal aorta atherosclerosis. The average of calf and thigh MaxV50 was strongly predictive of extent of aortic atherosclerosis and risk of being in the top quartile of aortic atherosclerosis after adjustment for the Framingham Coronary Risk Score (FCRS) or the combination of the FCRS and C-reactive protein (P<0.0001). The areas under the receiver operating curves predicting the top quartile of gender-specific aortic atherosclerosis were 0.57, 0.60, and 0.75 for models containing the FCRS, the FCRS and C-reactive protein, and the FCRS, C-reactive protein, and the average of calf and thigh MaxV50. CONCLUSIONS: Lower-extremity arterial compliance may identify subjects with extensive subclinical atherosclerosis. Further studies examining the potential value of arterial stiffness as a screening tool to guide initiation of more aggressive preventive interventions are warranted.

Usefulness of arterial compliance in the thigh in predicting exercise capacity in individuals without coronary heart disease.

This study examined the relation between arterial compliance of the lower extremities and aerobic capacity in patients with a broad spectrum of cardiovascular risk but without overt coronary heart disease (CHD). Local arterial compliance was noninvasively measured in the thigh and calf in 104 men and 99 women using air plethysmography. Subjects also underwent maximal exercise treadmill testing as a measure of aerobic capacity. In univariate analysis, age (r = -0.49, p <0.001), systolic blood pressure at rest (r = -0.27, p <0.001), pulse pressure (r = -0.39, p <0.001), total cholesterol (r = -0.25, p <0.001), triglycerides (r = -0.025, p <0.001), non-high-density lipoprotein cholesterol (r = -0.23, p <0.001), high-sensitivity C-reactive protein (r = -0.21, p = 0.002), and low-density lipoprotein cholesterol (r = -0.15, p = 0.03) all demonstrated a significant inverse association with treadmill time. Thigh and calf compliance demonstrated a significant positive association with treadmill time (r = 0.48, p <0.001; r = 0.46, p <0.001). In multivariate analysis, thigh compliance (p = 0.003), age (p <0.001), gender (p = 0.005), and triglycerides (p = 0.017) were independent predictors of treadmill time. In conclusion, thigh compliance measured with a simple-to-use, fully automated device independently predicts aerobic fitness in patients with a wide range of cardiovascular risk but without CHD.

Comparison of the relation of triglyceride-rich lipoproteins and muscular artery compliance in healthy women versus healthy men.

To determine whether structural features or concentrations of plasma lipoproteins are predictive of arterial compliance in healthy women versus healthy men, cohorts of 111 men and 112 women with a wide range of 10-year risks for coronary artery disease were selected using assessments based on the Framingham Heart Study. Age ranges were restricted to 35 to 69 years for men and 45 to 79 years for women. Lipid-lowering drugs or any evidence of vascular disease was cause for exclusion. Fasting lipoprotein analysis and arterial compliance measurements in thigh and calf were completed in all patients. Plasma triglyceride levels were the most powerful predictor of compliance in women. Weaker but significant relations were observed between plasma non-high-density lipoprotein cholesterol, apolipoprotein-B, and apolipoprotein-CIII. In contrast, the only significant predictor of compliance in men was body weight. Thus, the major lipid predictors of arterial stiffness in women are concentrations of triglyceride-rich lipoproteins. These results are consistent with previous findings that triglyceride measurements are more strongly related to clinical vascular events in women than in men.

Apolipoprotein C-III protein concentrations and gene polymorphisms in Type 1 diabetes: associations with microvascular disease complications in the DCCT/EDIC cohort.

AIM: We investigated the associations of apolipoprotein C-III (apoCIII) protein and apoCIII gene variation with microvascular disease complications in Type 1 diabetes. METHODS: The serum apoCIII concentration, and both a T(-455)-->C and a SacI gene polymorphisms were determined in 409 patients in the DCCT/EDIC cohort of patients with Type 1 diabetes. Correlations with albumin excretion rate (AER) and the severity of retinopathy were investigated. RESULTS: Higher apoCIII concentrations were associated (P<.0001) with increased triglycerides (r=.78), total (r=.61) and LDL (r=.40) cholesterol, apoAI (r=.26), and apoB (r=.50), AER (r=.08), and the severity of retinopathy (ETDRS score, r=.11), and these relationships persisted after controlling for age, gender, body mass index (BMI), and HbA1c level. The apoCIII concentration was significantly higher in the group of patients with macroalbuminuria (AERs 300 mg/24 h) compared to the groups with microalbuminuria (AER 40-299 mg/24 h; P<.0001) or normoalbuminuria (AER <40 mg/24 h) (P<.0001). The apoCIII concentration also was significantly higher in the group of patients with severe retinopathy (ETDRS 10-23) compared to those with moderate (ETDRS 4-9; P<.02) or mild retinopathy (ETDRS 1-3; P<.0001). Neither the T(-455)-->C polymorphism nor a SacI polymorphism in the 3' UTR were associated with circulating apoCIII concentrations, nor the severity of nephropathy or retinopathy. CONCLUSIONS: Elevated apoCIII levels have been associated with increased macrovascular disease risk. In the DCCT/EDIC cohort of patients, there was an independent positive association of apoCIII level with microvascular complications of Type 1 diabetes.

JCL roundtable: Apolipoproteins as causative elements in vascular disease.

In clinical lipidology, we have focused our major efforts in defining risk status and specifying the targets of therapy by using the cholesterol content of the lipoproteins. However, we now know that these measures are variable and that they may not reveal all the valuable information that can be used to treat our patients. The amount of cholesterol in each lipoprotein can be quite different in different patients. The number of particles containing apolipoprotein B (apoB) can be abnormally high with a value for low-density lipoprotein cholesterol, which is within our guidelines. Furthermore, the content of apoC3 in apoB-containing lipoproteins can predict risk without a close association with triglycerides or cholesterol. The genome-wide association studies and studies in special families with known genetic polymorphisms have been particularly revealing relationships between these vascular risk.

JCL Roundtable: Gender differences in risk reduction with lifestyle changes.

The first efforts to uncover the causes of cardiovascular disease focused on the behavioral, now called lifestyle habits of populations. Diet, exercise, and smoking were recognized as important issues with strong relationships in community-based observational studies such as the Seven Countries study, the Framingham Heart Study, and the Western Electric Study in Chicago. The first meaningful intervention in the United States was the dietary recommendations made by the American Heart Association in 1963 and the Surgeon General's Report on Smoking and Health in 1964. The American public listened and a very large change occurred in food consumption data and cigarette smoking over the next decade. These changes were mainly focused on men because the incidence of myocardial infarction was much higher in middle aged and older men than women. As smoking prevalence has decreased in men and increased in women and the population has aged, the differences in major vascular events have virtually disappeared. Women still enjoy a longer period of low rates but eventually the incidence rates approach those of men. As we constantly attempt to demonstrate ways of reducing risk by improved lifestyle it behooves us to re-evaluate the potential differences in gender response and adjust our expectations accordingly as clinicians.

JCL Roundtable: is inflammation a future target in preventing arteriosclerotic cardiovascular disease.

It has been a long developing concept that inflammatory infiltration by white blood cells from the blood plasma is an important part of the atherosclerotic process. However, we have thought of this as a secondary phenomenon resulting from the causative insults of high concentrations of apolipoprotein B (apoB)-containing lipoproteins, toxins such as those from cigarette smoke, high blood pressure, and high blood glucose. Much research has provided evidence as to how the invading cells interact with the basic components of the arterial structure to produce the damage observed throughout the vessel wall. We have focused our preventive efforts on the clinical risk factors with significant but partial success in patients with active disease. It is a relatively new concept that suppressing the inflammation itself, as an adjunct to risk factor modification, could help reduce the clinical manifestations of atherosclerosis. This concept is now being tested in randomized clinical trials. Our discussants in this Roundtable are Dr Alan Remaley, a Senior Investigator in the Lipoprotein Metabolism Section of the National Heart Lung and Blood Institute and Dr Paul Ridker, a cardiologist at the Brigham and Women's Hospital and a Professor at the Harvard Medical School. Both have made very significant contributions to our understanding of the signaling process that drives this inflammatory aspect of the disease.