Cholesterol esterification and atherogenic index of plasma correlate with lipoprotein size and findings on coronary angiography.

We examined the association between rate of cholesterol esterification in plasma depleted of apolipoprotein B-containing lipoproteins (FER(HDL)), atherogenic index of plasma (AIP) [(log (TG/HDL-C)], concentrations, and size of lipoproteins and changes in coronary artery stenosis in participants in the HDL-Atherosclerosis Treatment Study. A total of 160 patients was treated with simvastatin (S), niacin (N), antioxidants (A) and placebo (P) in four regimens. FER(HDL) was measured using a radioassay; the size and concentration of lipoprotein subclasses were determined by nuclear magnetic resonance spectroscopy. The S+N and S+N+A therapy decreased AIP and FER(HDL), reduced total VLDL (mostly the large and medium size particles), decreased total LDL particles (mostly the small size), and increased total HDL particles (mostly the large size). FER(HDL) and AIP correlated negatively with particle sizes of HDL and LDL, positively with VLDL particle size, and closely with each other (r = 0.729). Changes in the proportions of small and large lipoprotein particles, which were reflected by FER(HDL) and AIP, corresponded with findings on coronary angiography. Logistic regression analysis of the changes in the coronary stenosis showed that probability of progression was best explained by FER(HDL) (P = 0.005). FER(HDL) and AIP reflect the actual composition of the lipoprotein spectrum and thus predict both the cardiovascular risk and effectiveness of therapy. AIP is already available for use in clinical practice as it can be readily calculated from the routine lipid profile.

Nicotinic acid, alone and in combinations, for reduction of cardiovascular risk.

The current guidelines for the treatment of high risk lipid disorders do not specify a therapeutic target level of high-density lipoprotein (HDL) cholesterol for cardiovascular disease prevention in high-risk populations. However, as described in this report, there is a substantial body of evidence from basic science and epidemiologic studies and from clinical trials providing the strong, consistent message that raising HDL cholesterol by therapeutic means will effectively reduce cardiovascular risk independently of reductions in low-density lipoprotein (LDL) cholesterol. Therapeutic HDL cholesterol raising, most effectively achieved by nicotinic acid (niacin), appears to be at least as effective as comparable percentages of LDL cholesterol lowering for the reduction of atherosclerosis progression or clinical cardiovascular events, over a broad range of risk levels. The widespread adoption of this strategy awaits the results of large, ongoing controlled clinical trials of HDL cholesterol raising.

Phospholipid transfer protein activity is associated with inflammatory markers in patients with cardiovascular disease.

Plasma phospholipid lipid transfer protein (PLTP) has several known key functions in lipoprotein metabolism. Recent studies suggest that it also may play a role in the inflammatory response. Inflammatory cell activity contributes to the development of atherosclerosis. To seek further evidence for the association of PLTP with inflammation, we studied the relationship between PLTP activity and five inflammatory markers [C-reactive protein (CRP), serum amyloid A (SAA), interleukin 6 (IL-6), white blood cells (WBC), and fibrinogen] in 93 patients with low HDL and cardiovascular disease (CVD). Plasma PLTP activity had the strongest correlation with CRP (r=0.332, P<0.001) followed by SAA (r=0.239, P=0.021). PLTP, CRP, and SAA were significantly associated with body mass index (BMI), insulin or glucose, apolipoprotein (apo) B, and/or apo E level (r=0.264-0.393, P<0.01). PLTP, SAA, and IL-6 also were associated with the concentration of HDL particles without apo A-II [Lp(A-I)](r=0.373-0.472, P<0.005, n=56), but not particles with apo A-II. Smoking was associated with increased PLTP activity, CRP, and WBC, and hypertension with increased PLTP activity. In linear models, CRP remained significantly associated with PLTP after adjustment of CVD risk factors and insulin resistance. Also, much of the variability of plasma PLTP activity was explained by CRP, BMI, Lp(A-I), smoking, glucose, and blood pressure. These findings show for the first time that plasma PLTP activity is associated positively with CRP in CVD, a state of chronic inflammation.

Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study-Observational Study.

BACKGROUND: Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia. OBJECTIVES: The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study. METHODS: Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. RESULTS: UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26-0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15-0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27-1.14, P = .11). CONCLUSIONS: Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.

Coronary collateral size, flow capacity, and growth: estimates from the angiogram in patients with obstructive coronary disease.

BACKGROUND: Stimulation of coronary collateral growth has potential clinical value, yet techniques to assess such growth in patients are limited. METHODS AND RESULTS: A cineangiographic approach to classify the dominant collaterals and to quantify their lumen caliber and flow capacity was developed and validated. For measurement of 0.4- to 1.5-mm-diameter phantoms, mean error ranged from -0.01 to +0.02 mm. To illustrate the utility of such a method, 52 collateral pathways were measured in 13 patients with 17 occluded arteries before and after 10 years of intensive lipid therapy. The mean variance, final sigma, of 9 separate measurements of each collateral was +/-0.101 mm. At pretreatment, collateral diameter averaged 0.50+/-0.11 mm (SD) (range, 0.3 to 1.4 mm) without tapering or central narrowing. Over 10 years, mean increase in diameter was +16% (P=0.028); in area, +64% (P=0.015); and in estimated flow capacity, +214% (P=0.009). Certain lipoprotein characteristics tended to predict collateral growth. Patients for whom angina disappeared during 10 years had a greater increase in flow capacity than those for whom it persisted (+331% versus 4%; P=0.05). CONCLUSIONS: Coronary collateral diameter can be estimated with a precision of 0.10 mm. Flow capacity of the network is well approximated by measurement of the 2 or 3 largest connections serving an occluded artery. Initial studies with this method show that disappearance of angina is significantly associated with growth in collateral flow capacity. Collateral growth tends to associate with lipid therapy and with certain in-treatment lipid measures.

Tracking atherosclerosis regression: a clinical tool in preventive cardiology.

Progression of coronary artery disease was initially evaluated using quantitative coronary angiography with ensuing evidence indicating a strong relationship to adverse cardiovascular outcomes. Since then, several other atherosclerosis imaging techniques have emerged as new tools in cardiovascular medicine to evaluate the effectiveness of preventive therapies through serial monitoring of changes in atherosclerosis burden. Conducting large randomized trials to test new approaches for the medical management of atherosclerosis, with the goal of showing a reduction in event rates, may often be impractical in an era of cost containment and reduced societal resources. Recent evidence has unfolded that investigates alternative ways of assessing therapeutic results such as the attainment of surrogate goals with substantial outcome relevance. Atherosclerosis imaging modalities such as coronary computed tomography, carotid ultrasound, cardiovascular magnetic resonance imaging, and intravascular ultrasound each possess specific imaging abilities and inter-test characteristics that enable their serial use as intermediate endpoints in clinical trials and, increasingly, in individual patient management. The current review focuses on the application of these modalities as emerging tools in cardiovascular prevention.

Antioxidant vitamins and lipid therapy: end of a long romance?

During the past decade, the perception flourished that lipid and antioxidant therapy were 2 independent avenues for cardiovascular protection. However, studies have shown that commonly used antioxidant vitamin regimens do not prevent cardiovascular events. We found that the addition of antioxidant vitamins to simvastatin-niacin therapy substantially blunts the expected rise in the protective high density lipoprotein (HDL)2 cholesterol and lipoprotein(A-I) subfractions of HDL, with apparent adverse effects on the progression of coronary artery disease. To better understand this effect, 12 apolipoproteins, receptors, or enzymes that contribute to reverse cholesterol transport have been examined in terms of their relationship to HDL2 and lipoprotein(A-I) levels and the potential for antioxidant modulation of their gene expression. Three plausible candidate mechanisms are identified: (1) antioxidant stimulation of cholesteryl ester transfer protein expression/activity, (2) antioxidant suppression of macrophage ATP binding cassette transmembrane transporter A1 expression, and/or (3) antioxidant suppression of hepatic or intestinal apolipoprotein A-I synthesis or increase in apolipoprotein A-I catabolism. In summary, antioxidant vitamins E and C and beta-carotene, alone or in combination, do not protect against cardiovascular disease. Their use for this purpose may create a diversion away from proven therapies. Because these vitamins blunt the protective HDL2 cholesterol response to HDL cholesterol-targeted therapy, they are potentially harmful in this setting. We conclude that they should rarely, if ever, be recommended for cardiovascular protection.

Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study).

The high-density lipoprotein (HDL)-Atherosclerosis Treatment Study showed that simvastatin plus niacin (mean daily dose 13 mg and 2.4 g, respectively) halt angiographic atherosclerosis progression and reduce major clinical events by 60% in patients with coronary artery disease (CAD) who have low HDL, in comparison with placebos, over 3 years. How safe and well-tolerated is this combination? One hundred sixty patients with CAD, including 25 with diabetes mellitus, with mean low-density lipoprotein cholesterol of 128 mg/dl, HDL cholesterol of < or =35 mg/dl (mean 31), and mean triglycerides of 217 mg/dl were randomized to 4 factorial combinations of antioxidant vitamins or their placebos and simvastatin plus niacin or their placebos. Patients were examined monthly or bimonthly for 38 months; side effects (gastrointestinal upset, nausea, anorexia, vision, skin, and energy problems, or muscle aches) were directly queried and recorded. Aspartate aminotransferase, creatine phosphokinase (CPK), uric acid, homocysteine, and fasting glucose levels were regularly monitored. A safety monitor reviewed all side effects and adjusted drug dosages accordingly. Patients who received simvastatin plus niacin and those on placebo had similar frequencies of clinical or laboratory side effects: any degree of flushing (30% vs 23%, p = NS), symptoms of fatigue, nausea, and/or muscle aches (9% vs 5%, p = NS), aspartate aminotransferase (SGOT) > or =3 times upper limit of normal (3% vs 1%, p = NS), CPK > or =2 times upper limit of normal (3% vs 4%, p = NS), CPK > or =5 times upper limit of normal, new onset of uric acid > or =7.5 mg/dl (18% vs 15%, p = NS), and homocysteine > or =15 micromol/L (9% vs 4%, p = NS). Glycemic control among diabetics declined mildly in the simvastatin-niacin group but returned to pretreatment levels at 8 months and remained stable for rest of the study. This combination regimen was repeatedly described by 91% of treated patients and 86% of placebo subjects as "very easy" or "fairly easy" to take. Thus, the simvastatin plus niacin regimen is effective, safe, and well tolerated in patients with or without diabetes mellitus.

Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.

CONTEXT: Statin drugs reduce both atherogenic lipoproteins and cardiovascular morbidity and mortality. However, the optimal strategy and target level for lipid reduction remain uncertain. OBJECTIVE: To compare the effect of regimens designed to produce intensive lipid lowering or moderate lipid lowering on coronary artery atheroma burden and progression. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized active control multicenter trial (Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) performed at 34 community and tertiary care centers in the United States comparing the effects of 2 different statins administered for 18 months. Intravascular ultrasound was used to measure progression of atherosclerosis. Between June 1999 and September 2001, 654 patients were randomized and received study drug; 502 had evaluable intravascular ultrasound examinations at baseline and after 18 months of treatment. INTERVENTIONS: Patients were randomly assigned to receive a moderate lipid-lowering regimen consisting of 40 mg of pravastatin or an intensive lipid-lowering regimen consisting of 80 mg of atorvastatin. MAIN OUTCOME MEASURES: The primary efficacy parameter was the percentage change in atheroma volume (follow-up minus baseline). RESULTS: Baseline low-density lipoprotein cholesterol level (mean, 150.2 mg/dL [3.89 mmol/L] in both treatment groups) was reduced to 110 mg/dL (2.85 mmol/L) in the pravastatin group and to 79 mg/dL (2.05 mmol/L) in the atorvastatin group (P<.001). C-reactive protein decreased 5.2% with pravastatin and 36.4% with atorvastatin (P<.001). The primary end point (percentage change in atheroma volume) showed a significantly lower progression rate in the atorvastatin (intensive) group (P =.02). Similar differences between groups were observed for secondary efficacy parameters, including change in total atheroma volume (P =.02), change in percentage atheroma volume (P<.001), and change in atheroma volume in the most severely diseased 10-mm vessel subsegment (P<.01). For the primary end point, progression of coronary atherosclerosis occurred in the pravastatin group (2.7%; 95% confidence interval [CI], 0.2% to 4.7%; P =.001) compared with baseline. Progression did not occur in the atorvastatin group (-0.4%; CI -2.4% to 1.5%; P =.98) compared with baseline. CONCLUSIONS: For patients with coronary heart disease, intensive lipid-lowering treatment with atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis. These differences may be related to the greater reduction in atherogenic lipoproteins and C- reactive protein in patients treated with atorvastatin.

Effects of niacin combination therapy with statin or bile acid resin on lipoproteins and cardiovascular disease.

Two large studies in populations selected for cardiovascular disease (CVD) demonstrated that raising high-density lipoprotein (HDL) cholesterol with niacin added to statin therapy did not decrease CVD. We examine the association of lipoprotein subfractions with niacin and changes in coronary stenosis and CVD event risk. One hundred and seven patients from 2 previous studies using niacin in combination with either statin or bile acid-binding resin were selected to evaluate changes in lipoproteins separated by density-gradient ultracentrifugation to progression of coronary artery disease as assessed by quantitative coronary angiography. Improvement in coronary stenosis was significantly associated with the decrease of cholesterol in the dense low-density lipoprotein (LDL) particles and across most of the intermediate density lipoprotein (IDL) and very low density lipoprotein particle density range, but, not with any of the HDL fraction or of the more buoyant LDL fractions. Event-free survival was significantly associated with the decrease of cholesterol in the dense LDL and IDL; there was no association with changes in cholesterol in the HDL and buoyant LDL fractions. Niacin combination therapy raises HDL cholesterol and decreases dense LDL and IDL cholesterol levels. Changes in LDL and IDL are related to improvement in CVD. Lipoprotein subfraction analysis should be performed in larger studies utilizing niacin in combination with statins.

Prolonged combination lipid therapy is associated with reduced carotid intima-media thickness: a case-control study of the 20-year Familial Atherosclerosis Treatment - Observational Study (FATS-OS).

BACKGROUND: Studies have documented the short-term vascular benefits of combination lipid therapy. OBJECTIVE: Our objective was to evaluate the long-term effects of combination lipid therapy on carotid intima-media thickness (CIMT) in patients with coronary artery disease. METHODS: We performed a case-control study in patients who had finished the Familial Atherosclerosis Treatment Study (FATS) and returned to usual care with statin therapy alone or had elected to participate in the 20-year FATS-Observational Study (FATS-OS) and received combination therapy with lovastatin (40 mg/day), niacin (2-3 g/day), and colestipol (20 gm/day) for 11 years, then continued with simvastatin (10-80 mg/day) or lovastatin (40-80 mg/day) plus niacin (2-4 g/day). After 17.8 ± 0.8 years with combination therapy and 19.0 ± 0.8 years with usual care, cholesterol levels and CIMT were collected in 43 FATS-OS patients and 26 usual care patients. RESULTS: Combination therapy group had a greater decrease in total cholesterol (-42 ± 14% vs -31 ± 17%, P = .008) and low-density lipoprotein cholesterol (LDL-C) (-57 ± 13% vs -38 ± 25%, P < .001) and greater increase in high-density lipoprotein cholesterol (HDL-C) (38 ± 43% vs 15 ± 23%, P = .02) as compared with usual care. CIMT (0.902 ± 0.164 vs 1.056 ± 0.169 mm, P < .001) on intensive therapy was significantly less compared with usual care. Multivariate regression analysis (coefficient, 95% CI) showed that combination therapy (-0.13; -0.21 to -0.04, P = .003) and on-therapy LDL-C (0.15; 0.02 to 0.28, P = .03) were significant independent predictors of CIMT. CONCLUSIONS: Prolonged combination lipid therapy is associated with greater improvements in LDL-C and HDL-C levels and less atherosclerotic burden as compared with statin therapy alone.

Comparison of four methods of analysis of lipoprotein particle subfractions for their association with angiographic progression of coronary artery disease.

BACKGROUND: Compare gradient gel electrophoresis (GGE), vertical auto profile ultracentrifugation (VAP-II), nuclear magnetic resonance spectroscopy (NMR), and ion mobility for their ability to relate low- (LDL), intermediate- (IDL), very-low-density (VLDL) and high-density lipoprotein (HDL) subfraction concentrations to atherosclerotic progression. METHODS AND RESULTS: Regression analyses of 136 patients who received baseline and follow-up coronary angiographies and subfraction measurements by all four methods in the HDL Atherosclerosis Treatment Study. Prior analyses have shown that the intervention primarily affected disease progression in proximal arteries with <30% stenoses at baseline. Three-year increases in percent stenoses were consistently associated with higher on-study plasma concentrations of small, dense LDL as measured by GGE (LDLIIIb, P=10(-6); LDLIVa, P=0.006; LDLIVb, P=0.02), VAP-II (LDL4, P=0.002), NMR (small LDL, P=0.001), and ion mobility (LDL IIb, P=0.04; LDLIIIa, P=0.002; LDLIIIb, P=0.0007; LDLIVa, P=0.05). Adjustment for triglycerides, HDL-cholesterol, and LDL-cholesterol failed to eliminate the statistical significance for on-study GGE estimated LDLIIIb (P=10(-5)) and LDLIVa (P=0.04); NMR-estimated small LDL (P=0.03); or ion mobility estimated large VLDL (P=0.02), LDLIIIa (P=0.04) or LDLIIIb (P=0.02). All methods show that the effects were significantly greater for the on-study than the baseline small, dense LDL concentrations, thus establishing that the values concurrent to the progression of disease were responsible. The rate of disease progression was also related to individual VLDL, IDL, and HDL subclasses to differing extents among the various analytic methods. CONCLUSION: Four methodologies confirm the association of small, dense LDL with greater coronary atherosclerosis progression, and GGE, NMR, and ion mobility confirm that the associations were independent of standard lipid measurements. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov/ct2/show/NCT00000553.

Levels of cholesterol in small LDL particles predict atherosclerosis progression and incident CHD in the HDL-Atherosclerosis Treatment Study (HATS).

OBJECTIVE: Test whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses. METHODS: Gradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments. RESULTS: The change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2-24.6 nm) and LDL-IVa (23.3-24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values. CONCLUSIONS: Plasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000553.

Effects of niacin on glucose levels, coronary stenosis progression, and clinical events in subjects with normal baseline glucose levels (<100 mg/dl): a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), and Carotid Plaque Composition by MRI during lipid-lowering (CPC) study.

Although the effect of niacin on the glucose levels in subjects with diabetes mellitus has been investigated, niacin's effects on the glucose levels and atherosclerosis in subjects with normal glucose levels have not been well established. We examined the effect of niacin on the glucose levels, coronary stenosis progression using quantitative coronary angiography, and clinical events in 407 subjects who had a baseline glucose level <100 mg/dl and were enrolled in the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), or Carotid Plaque Composition by MRI during lipid-lowering (CPC) study testing active niacin therapy. Although the fasting glucose levels increased significantly within 3 years in both subjects treated with niacin (from 85.6 ± 9.5 to 95.5 ± 19.7 mg/dl, p <0.001) and without niacin (from 85.2 ± 9.6 to 90 ± 17.9 mg/dl, p = 0.009), those treated with niacin had a significantly larger increase in glucose levels than those not taking niacin (9.88 vs 4.05 mg/dl, p = 0.002). Overall, 29% of subjects developed impaired fasting glucose within 3 years. Incident impaired fasting glucose was significantly more likely to be observed in subjects treated with niacin than in those who were not. However, the frequency of new-onset diabetes mellitus did not differ significantly between the 2 groups (5.6% vs 4.8%, p = 0.5). Niacin-treated subjects compared to untreated subjects had significantly less change in mean coronary stenosis (0.1 ± 0.3% vs 2 ± 12%, p <0.0001) and less major cardiovascular events (8% vs 21%, p = 0.001). In conclusion, the use of niacin for 3 years in subjects with normal baseline glucose levels was associated with an increase in blood glucose levels and the risk of developing impaired fasting glucose, but not diabetes mellitus, and was associated with a significantly reduced incidence of coronary stenosis progression and major cardiovascular events.