Relationships of Fatty Acids,Delta-5 Desaturase Activity,and Lipid Profiles in Men with Acute Coronary Syndrome

Aims: We evaluated the relationship between the ratios of eicosapentaenoic acid and arachidonic acid (EPA/AA), docosahexaenoic acid (DHA)/AA, and delta-5 desaturase activity (D5D) and atherogenic lipid profiles (ALP) and coronary atherosclerosis.Methods: Polyunsaturated fatty acids (PUFA) and ALP were assessed in 436 men with the first episode of acute coronary syndrome (ACS) not take any lipid-lowering drugs. D5D was estimated as the ratio of AA to dihomogamma-linolenic acid (DGLA). These biomarkers were compared between the lower and higher levels of EPA/AA (0.41) or DHA/AA (0.93) according to the levels in Japanese general population. The thrombolysis in myocardial infarction flow (TIMI) grade of the culprit coronary artery was visually estimated during the initial angiography.Results: Approximately 70% of patients had low EPA/AA or DHA/AA. Serum levels of LDL-cholesterol, apolipoprotein B (apoB), and remnant lipoprotein cholesterol (RL-C) were significantly higher in the low EPA/AA or DHA/AA groups, while those of triglycerides and malondialdehyde-modified LDL (MDA-LDL) were significantly higher in the low EPA/AA group alone. The levels of EPA, EPA/AA, DHA/AA, and HbA1c increased and those of DGLA and apoA1 decreased with increasing number of stenotic vessels. Patients with three stenotic coronary vessels or TIMI grade ≥ 1 had significantly higher EPA levels compared with the others. The levels of LDL-cholesterol, non-HDL-cholesterol, triglycerides, small dense LDL-cholesterol, RL-C, MDA-LDL, apoB, and apoE decreased progressively and those of EPA, DHA, EPA/AA and HDL-cholesterol increased as D5D increased.Conclusions: The EPA/AA is a superior risk marker than DHA/AA in term of correlation with ALP in ACS patients.     

Eicosapentaenoic Acid Combined with Optimal Statin Therapy Improves Endothelial Dysfunction in Patients with Coronary Artery Disease

Purpose

Eicosapentaenoic acid (EPA) has been reported to augment endothelial function and improve clinical outcomes in patients with coronary artery disease (CAD). The purpose of this study was to determine whether EPA could improve residual endothelial dysfunction despite adequate lipid-lowering with statin in CAD patients.

Methods

Eighty patients with established CAD, who had been on statin treatment and had serum low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dl, were randomly assigned to receive either 1,800 mg of EPA daily plus statin (EPA group, n?=?40) or statin alone (Control group, n?=?40). Lipid profiles and flow-mediated dilation (FMD) were assessed just before and after more than 3 months of treatment in both groups. Only patients who had impaired FMD (<6 %) before randomization were enrolled.

Results

After treatment for 5.2?±?1.7 months, the EPA group showed a significant increase in the serum concentration of EPA and EPA to arachidonic acid (AA) (EPA/AA) ratio (62.5?±?38.1 to 159.8?±?53.8 μg/ml, 0.45?±?0.34 to 1.20?±?0.55, p?<?0.01 for both). In the EPA group, serum triglycerides significantly decreased (150.7?±?92.9 to 119.3?±?60.7 mg/dl, p?=?0.02), whereas no significant change was seen in the Control group. FMD, the primary study endpoint, showed a significant improvement in the EPA group (2.6?±?1.6 % to 3.2?±?1.6 %, p?=?0.02), whereas no significant change was observed in the Control group (2.7?±?1.6 % to 2.4?±?1.7 %, p?=?0.29).

Conclusions

EPA improved endothelial function and impaired FMD in patients with established CAD who were on optimal statin therapy.     

Plasma polyunsaturated fatty acid profile and delta-5 desaturase activity are altered in patients with type 2 diabetes

Objective

The association between imbalance of polyunsaturated fatty acids (PUFAs), especially low plasma n-3 to n-6 PUFA ratio, and risk of cardiovascular diseases is well known. A balance of plasma PUFAs is determined not only by dietary fatty acid intake, but also by the endogenous fatty acid metabolism, which could be dysregulated by diabetes. In this study, we investigated the plasma n-3 and n-6 PUFA profile and fatty acid desaturase activity in patients with type 2 diabetes (T2D).

Materials/Methods

The subjects were 396 patients with T2D and 122 healthy controls. Plasma eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-γ-linolenic acid (DGLA) levels were measured by capillary gas chromatography.

Results

Plasma DHA, AA, and DGLA levels were significantly higher, and EPA levels tended to be lower in patients with T2D than in the controls. Patients with T2D also exhibited significantly lower EPA/AA, DHA/AA, and (EPA + DHA)/AA ratios, and a higher AA/DGLA ratio than the controls. Multiple regression analyses, including age, sex, body mass index, and metabolic parameters in the total population, revealed that the presence of T2D was independently associated with elevated plasma DHA, AA, and DGLA levels and decreased EPA/AA, DHA/AA, and (EPA + DHA)/AA ratios. Furthermore, T2D was independently and positively related to the AA/DGLA ratio, which serves as an estimate of delta (Δ)-5 desaturase activity.

Conclusions

Elevated plasma AA levels and decreased n-3 PUFA/AA ratios in T2D are attributable, at least partly, to Δ5 desaturase activation.     

Lipid-lowering and anti-inflammatory effect of ezetimibe in hyperlipidemic patients with coronary artery disease

We evaluated the effects of adding ezetimibe to statin therapy in hypercholesterolemic patients with coronary artery disease (CAD) who could not achieve the target cholesterol levels recommended in the 2007 Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases on statin monotherapy. Ezetimibe (10 mg) was added to basal statin therapy for 12 weeks in 35 patients with hypercholesterolemia and a history of CAD who had not achieved their target cholesterol level with statin monotherapy. Changes in serum lipids, obesity markers, an oxidative stress marker, inflammatory markers, and laboratory values were investigated. Total cholesterol (from 200.6 ± 30.4 mg/dL in week 0 to 173.4 ± 33.3 mg/dL in week 12, P < 0.001), low-density lipoprotein cholesterol (LDL-C) (121.3 ± 29.4 vs. 94.6 ± 30.4 mg/dL, P < 0.001), and remnant lipoprotein cholesterol (6.4 ± 3.5 vs. 5.3 ± 3.0 mg/dL, P < 0.05) all decreased significantly after addition of ezetimibe. The LDL-C/high-density lipoprotein cholesterol ratio also decreased significantly (2.5 ± 0.8 in week 0 vs. 1.9 ± 0.7 in week 12, P < 0.001). The percentage of patients achieving the target LDL-C level (<100 mg/dL) increased significantly (70.8 % in week 4 and 65.4 % in week 12, P < 0.001). There were no significant changes in the obesity or oxidative stress markers and high-sensitivity C-reactive protein (an inflammatory marker). However, another inflammatory marker (tumor necrosis factor-α) was decreased significantly by ezetimibe (1.36 ± 1.06 in week 0 vs. 0.96 ± 0.24 in week 12, P = 0.042). In conclusion, when ezetimibe was added to basal statin therapy, serum lipids improved significantly and the rate of achieving the target cholesterol level increased. Thus, ezetimibe efficiently decreases LDL-C and might prevent arteriosclerosis in hypercholesterolemic patients with CAD when added to basal statin therapy.     

Impact of statin therapy on LDL and non-HDL cholesterol levels in subjects with heterozygous familial hypercholesterolaemia

Background and aimsCardiovascular risk in heterozygous familial hypercholesterolaemia (HeFH) is driven by LDL cholesterol levels. Since lipid response to statin therapy presents individual variation, this study aimed to compare mean LDL and non-HDL cholesterol reductions and their variability achieved with different types and doses of the most frequently prescribed statins.Methods and resultsAmong primary hypercholesterolaemia cases on the Spanish Arteriosclerosis Society registry, 2894 with probable/definite HeFH and complete information on drug therapy and lipid profile were included.LDL cholesterol reduction ranged from 30.2 ± 17.0% with simvastatin 10 mg to 48.2 ± 14.7% with rosuvastatin 40 mg. After the addition of ezetimibe, an additional 26, 24, 21 and 24% reduction in LDL cholesterol levels was obtained for rosuvastatin, 5, 10, 20 and 40 mg, respectively. Subjects with definite HeFH and a confirmed genetic mutation had a more discrete LDL cholesterol reduction compared to definite HeFH subjects with no genetic mutation. A suboptimal response (<15% or <30% reduction in LDL cholesterol levels, respectively with low-/moderate-intensity and high-intensity statin therapy) was observed in 13.5% and, respectively, 20.3% of the subjects.ConclusionAccording to the LDL cholesterol reduction in HeFH patients, the ranking for more to less potent statins was rosuvastatin, atorvastatin and simvastatin; however, at maximum dosage, atorvastatin and rosuvastatin were nearly equivalent. HeFH subjects with positive genetic diagnosis had a lower lipid-lowering response. Approximately 1 in 5 patients on high-intensity statin therapy presented a suboptimal response.     

Low density lipoprotein particle diameter in young,nonobese, normolipidemic Japanese men

Background: prospective studies have demonstrated that a predominance of small, dense LDL particles (pattern B) precedes the clinical onset of coronary heart disease. Prevalence and characteristics of subjects with this LDL size abnormality were studied in young, nonobese, Japanese normolipidemic men. Methods and results: LDL peak particle diameter (PPD) was measured by continuous disc polyacrylamide gel electrophoresis in 223 nonobese normolipidemic men aged 18–20 years (mean±S.D. body mass index: 21.9±3.7 kg/m², total cholesterol: 180±29 mg/dl, triglyceride: 62±34 mg/dl, HDL cholesterol: 58±12 mg/dl). Men with small LDL (PPD <25.8 nm) were found in only 5.4% (n=12) whereas 197 men (88.3%) had a preponderance of large LDL (PPD 26.3 nm). As compared with men in a top tertile (PPD 27.5 nm) those in a low tertile (PPD <26.9 nm) had higher serum levels of LDL cholesterol (120±31 vs 104±24 mg/dl), triglyceride (72±39 vs 49±16 mg/dl) and apolipoprotein (apo) B (84±21 vs 68±14 mg/dl), and lower HDL cholesterol (54±10 vs 60±12 mg/dl). They also had greater body mass index (23.2±4.6 vs 20.9 3.1 kg/m²) and percent body fat (21.5±7.7 vs 17.5±4.9%). LDL-PPD was positively correlated with HDL cholesterol (R=0.20, P=0.002) and was negatively correlated with apoB (R=0.34, P<0.001), triglyceride (R=0.32, P<0.001), percent body fat (R=0.26, P<0.001), body mass index (R=0.24, P<0.001), fat mass (R=0.23, P=0.001), total cholesterol (R=0.20, P=0.002). In multiple regression analysis, apoB, triglyceride, HDL cholesterol, apoAI and percent body fat explained 18% of LDLPPD variability. Conclusion: even in young, nonobese, normolipidemic men, LDL size appears to be associated with triglyceride-rich lipoprotein metabolism and body fat.     

Plasma triglycerides related decrease in high-density lipoprotein cholesterol and its association with myocardial infarction in heterozygous familial hypercholesterolemia

Recent studies suggest that decreased levels of high-density liopoprotein (HDL) may contribute to the risk of premature occlusive atherosclerosis in familial hypercholesterolemia (FH). To investigate further, we have analyzed the concentration as well as distribution of HDL cholesterol in relation to plasma triglycerides and their influence on ischaemic heart disease in FH subjects. The study was carried out in 71 men with heterozygous FH and 46 matched controls. FH subjects were relatively young with a mean age of 38 ± 11 years. Tendon xanthomatas were observed in 57% of the subjects, whereas ischemic heart disease was identified in 33%. Compared to normals, the mean value of HDL cholesterol is significantly reduced by 21% in FH heterozygotes (42 ± 12 v 33 ± 9 mg/dL, P < 0.001). The decrease in HDL cholesterol is highly correlated to the levels of plasma triglycerides (r = −0.50, P < 0.001) and VLDL cholesterol (r = −0.53, P < 0.001). Moreover, HDL cholesterol decrease is not associated with elevated levels of LDL cholesterol (r = −0.20, NS), which is the primary characteristic feature of FH subjects. However, HDL cholesterol decrease is weakly related to total plasma cholesterol concentration (r = −0.24, P < 0.05). The body weight is also contributory to the reduction of HDL cholesterol (r = −0.42, P < 0.01), probably due to its strong positive correlation to plasma triglycerides (r = +0.54, P < 0.001). Grouping of subjects on the basis of triglyceride levels of less than 200 mg/dL (IIa phenotype) and more than 200 mg/dL (IIb phenotype) shows that the concentration of HDL cholesterol undergoes a further significant decrease in the latter group (36 ± 9 v 30 ± 11 mg/dL, P < 0.001). Since the level of LDL cholesterol is similar in both groups (314 ± 68 v 316 ± 76 mg/dL, NS), a further reduction in HDL cholesterol concentration results in an increased LDL/HDL ratio in IIb phenotypes. Although HDL cholesterol is normally distributed in controls and type IIa phenotypes, its distribution is skewed to lower values in type IIb. In addition to similar levels of LDL cholesterol, the presence of tendon xanthomatas is equally observed in both type IIa and type IIb subjects (51.1% and 62.5%, respectively). Similarly, the incidence of angina pectoris (19.2% and 12.5% in type IIa and type IIb, respectively) is also approximately the same in both groups. However, the differences are striking in the incidence of myocardial infarction (MI), which is increased three-fold (25% v 8.5%) in type IIb subjects, as compared to type IIa. These findings indicate that in addition to LDL excess, HDL deficiency associated with elevated plasma triglycerides contributes to the severity of ischemic heart disease, as revealed from the manifestation of MI in some FH heterozygotes.     

Reduction in dietary omega-6 polyunsaturated fatty acids: eicosapentaenoic acid plus docosahexaenoic acid ratio minimizes atherosclerotic lesion formation and inflammatory response in the LDL receptor null mouse

Dietary very long chain omega (omega)-3 polyunsaturated fatty acids (PUFA) have been associated with reduced CVD risk, the mechanisms of which have yet to be fully elucidated. LDL receptor null mice (LDLr-/-) were used to assess the effect of different ratios of dietary omega-6 PUFA to eicosapentaenoic acid plus docosahexaenoic acid (omega-6:EPA+DHA) on atherogenesis and inflammatory response. Mice were fed high saturated fat diets without EPA and DHA (HSF omega-6), or with omega-6:EPA+DHA at ratios of 20:1 (HSF R=20:1), 4:1 (HSF R=4:1), and 1:1 (HSF R=1:1) for 32 weeks. Mice fed the lowest omega-6:EPA+DHA ratio diet had lower circulating concentrations of non-HDL cholesterol (25%, P<0.05) and interleukin-6 (IL-6) (44%, P<0.05) compared to mice fed the HSF omega-6 diet. Aortic and elicited peritoneal macrophage (Mphi) total cholesterol were 24% (P=0.07) and 25% (P<0.05) lower, respectively, in HSF R=1:1 compared to HSF omega-6 fed mice. MCP-1 mRNA levels and secretion were 37% (P<0.05) and 38% (P<0.05) lower, respectively, in elicited peritoneal Mphi isolated from HSF R=1:1 compared to HSF omega-6 fed mice. mRNA and protein levels of ATP-binding cassette A1, and mRNA levels of TNFalpha were significantly lower in elicited peritoneal Mphi isolated from HSF R=1:1 fed mice, whereas there was no significant effect of diets with different omega-6:EPA+DHA ratios on CD36, Mphi scavenger receptor 1, scavenger receptor B1 and IL-6 mRNA or protein levels. These data suggest that lower omega-6:EPA+DHA ratio diets lowered some measures of inflammation and Mphi cholesterol accumulation, which was associated with less aortic lesion formation in LDLr-/- mice.     

Efficacy and safety of alirocumab in insulin‐treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM‐INSULIN randomized trial

Aims

To investigate the efficacy and safety of alirocumab in participants with type 2 (T2D) or type 1 diabetes (T1D) treated with insulin who have elevated LDL cholesterol levels despite maximally tolerated statin therapy.

Methods

Participants at high cardiovascular risk with T2D (n = 441) or T1D (n = 76) and LDL cholesterol levels ≥1.8 mmol/L (≥70 mg/dL) were randomized 2:1 to alirocumab:placebo administered subcutaneously every 2 weeks, for 24 weeks' double‐blind treatment. Alirocumab‐treated participants received 75 mg every 2 weeks, with blinded dose increase to 150 mg every 2 weeks at week 12 if week 8 LDL cholesterol levels were ≥1.8 mmol/L. Primary endpoints were percentage change in calculated LDL cholesterol from baseline to week 24, and safety assessments.

Results

Alirocumab reduced LDL cholesterol from baseline to week 24 by a mean ± standard error of 49.0% ± 2.7% and 47.8% ± 6.5% vs placebo (both P < .0001) in participants with T2D and T1D, respectively. Significant reductions were observed in non‐HDL cholesterol (P < .0001), apolipoprotein B (P < .0001) and lipoprotein (a) (P ≤ .0039). At week 24, 76.4% and 70.2% of the alirocumab group achieved LDL cholesterol <1.8 mmol/L in the T2D and T1D populations (P < .0001), respectively. Glycated haemoglobin and fasting plasma glucose levels remained stable for the study duration. Treatment‐emergent adverse events were observed in 64.5% of alirocumab‐ vs 64.1% of placebo‐treated individuals (overall population).

Conclusions

Alirocumab produced significant LDL cholesterol reductions in participants with insulin‐treated diabetes regardless of diabetes type, and was generally well tolerated. Concomitant administration of alirocumab and insulin did not raise any safety concerns (NCT02585778).     

Aberrant serum polyunsaturated fatty acids profile is relevant with acute coronary syndrome

Although a robust relationship between aberrant serum polyunsaturated fatty acids (PUFAs) profile and coronary artery disease (CAD) has been reported, the details concerning the association between aberrant PUFAs profile and clinical feature of CAD are not fully discovered. Therefore, we investigated the relationship between serum PUFAs and clinical profiles in CAD patients. We classified 595 consecutive CAD patients, who underwent coronary angiography into 3 groups according to the clinical profiles of CAD (group A: early phase ACS, n = 96; group B: stable CAD with previous history of ACS, n = 259; group C: stable CAD without previous history of ACS, n = 240) and measured serum n-3 [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and n-6 [arachidonic acid (AA)] PUFAs. Serum EPA, DHA, and EPA/AA ratio were significantly low in the order of group A < B < C [EPA; 48.1 (34.1–60.3) μg/ml, 61.7 (41.2–94.5) μg/ml, and 74.4 (52.7–104.9) μg/ml, DHA; 113.1 (92.8–135.1) μg/ml, 125.8 (100.4–167.2) μg/ml, and 140.1 (114.7–177.0) μg/ml, EPA/AA ratio; 0.31 (0.22–0.45), 0.39 (0.26–0.62), and 0.44 (0.31–0.69), medians with interquartile range, p < 0.01]. Multiple regression analysis revealed that EPA (p = 0.009) and EPA/AA ratio (p = 0.023), but not DHA and DHA/AA ratio, were negatively associated with clinical profiles of ACS in CAD patients. Significant correlation was not observed between PUFAs profile and severity of coronary stenosis. Low serum EPA and EPA/AA ratio correlates with clinical profiles of ACS in patients with CAD, regardless of the extent and severity of coronary artery stenosis.     

Benefits of lipid-lowering therapy in men with elevated apolipoprotein B are not confined to those with very high low density lipoprotein cholesterol

Objectives. Do the benefits of intensive lipid-lowering therapy extend to patients with only borderline or moderately elevated levels of low density lipoprotein (LDL) cholesterol?Background. The merits of the present LDL cholesterol treatment goal of ≤100 mg/dl need to be clarified for patients without high levels of LDL cholesterol, particularly for those patients previously classified as having only borderline high (130 to 159 mg/dl) or desirable (101 to 130 mg/dl) levels.Methods. Disease change and clinical events were examined in LDL cholesterol subgroups in the Familial Atherosclerosis Treatment Study (FATS) trial, a randomized, blinded, quantitative arteriographie comparison of one conventional and two intensive lipid-lowering strategies in men with coronary artery disease, a positive family history and apolipoprotein B ≥125 mg/dl. The primary end point, disease change per patient, was measured as the mean change in severity of stenosis (Δ%S_Prox) among nine standard proximal segments.Results. Of the 120 patients completing the 30-month protocol, 60 had a baseline LDL cholesterol <90th percentile (mean LDL cholesterol 152 mg/dl) and 60 >90th percentile (mean LDL cholesterol 221 mg/dl). Thirty-one patients had levels <160 mg/dl (mean LDL cholesterol 134 mg/dl) and 89 >160 mg/dl (mean LDL cholesterol 205 mg/dl). Patients with LDL cholesterol <90th percentile benefited angiographically from therapy (Δ%S_Prox= −1.5% diameter stenosis [regression] during intensive therapy vs. 4-2.3% diameter stenosis [progression] during conventional therapy, p < 0.01), as did patients with LDL cholesterol <160 mg/dl (Δ%S_Prox= −4.2% vs. +3.3% diameter stenosis, p = 0.0001). By comparison, angiographie benefit was less pronounced among those entdring with very high LDL cholesterol (Δ%S^Prox= −0.2% vs. +1.9% diameter stenosis, p = 0.07) or with LDL cholesterol ≥160 mg/dl (Δ%S_Prox= +0.2% vs. +1.6% diameter stenosis, p = 0.13). Intensive therapy resulted in a statistically significant reduction in clinical events only in the subgroup with baseline LDL cholesterol < 90th percentile (2 of 42 vs. 8 of 29 patients initially enrolled, p = 0.01) and a trend toward fewer events in patients with LDL cholesterol < 160 mg/dl (2 of 20 vs. 6 of 15 patients, p = 0.05). No such difference was seen in the higher LDL cholesterol subgroups.Conclusions. Treatment benefit in the FATS trial was not confined to patients with very high levels of LDL cholesterol and was in fact particularly evident in those patients with levels < 160 mg/dl. Such patients should be considered more likely, not less, to benefit from intensive lipid-lowering therapy.     

Omega-3 Polyunsaturated Fatty Acids Increase Plasma Adiponectin to Leptin Ratio in Stable Coronary Artery Disease

Background

Growing evidence suggests a cardioprotective role of omega-3 polyunsaturated fatty acids (PUFA). However, the exact mechanisms underlying the effects of omega-3 PUFA in humans have not yet been fully clarified.

Purpose

We sought to evaluate omega-3 PUFA-mediated effects on adipokines in patients with stable coronary artery disease (CAD) undergoing elective percutaneous coronary intervention (PCI).

Methods

We conducted a prospective, double-blind, placebo-controlled, randomized study, in which adiponectin, leptin and resistin were determined at baseline, 3–5 days and 30 days during administration of omega-3 PUFA 1 g/day (n?=?20) or placebo (n?=?28).

Results

As compared to controls administration of omega-3 PUFA resulted in increase of adiponectin by 13.4 % (P?<?0.0001), reduction of leptin by 22 % (P?<?0.0001) and increase of adiponectin to leptin (A/L) ratio by 45.5 % (P?<?0.0001) at 30 days, but not at 3–5 days. Compared with placebo adiponectin was 12.7 % higher (P?=?0.0042), leptin was 16.7 % lower (P?<?0.0001) and A/L ratio was 33.3 % higher (P?<?0.0001) in the omega-3 PUFA group at 30 days. Resistin decreased similarly in both groups after 1 month, without intergroup differences (P?=?0.32). The multivariate model showed that the independent predictors of changes in adiponectin at 1 month (P?<?0.001) were: omega-3 PUFA treatment, baseline platelet count, total cholesterol and those in leptin (P?<?0.0001) were: omega-3 PUFA treatment and waist circumference. Independent predictors of A/L ratio changes (P?<?0.0001) were: assigned treatment, current smoking and hyperlipidemia.

Conclusions

In high risk stable coronary patients after PCI omega-3 PUFA supplementation improves adipokine profile in circulating blood. This might be a novel, favourable mechanism of omega-3 PUFA action.     

von Willebrand factor,a possible indicator of endothelial cell damage,decreases during long-term compliance with a lipid-lowering diet

Abstract. Objectives. To test whether serum von Willebrand factor (vWf) would be lower in men with atherosclerosis who had been consuming a lipid-lowering diet for 3 years than in a control group of men with atherosclerosis who had been following their normal diet. Design. A randomized, population-based case-control study. Setting. A tertiary health care referral centre at a University Hospital. Subjects. Men age less than 66 years with angiographically proven coronary atherosclerosis and a cholesterol level > 6 mmol L^?1. Sixty started the study and 50 completed it. Interventions. Subjects were randomized to a lipid-lowering diet or to taking their normal diet for approximately 3 years. Main outcome measures. The components of the subjects' diets were assessed and blood was obtained for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and for vWf. Results. Men on the lipid-lowering diet consumed less total, saturated and monounsaturated fats (all P < 0.001), cholesterol and retinol (both P < 0.002) but increased polyunsaturated fats (P < 0.001), fibre, vitamin E (both P < 0.005) and carbohydrate (P < 0.05). Those on the lipid-lowering diet also had lower serum levels of total and LDL cholesterol (P < 0.002 and P < 0.05, respectively), triglycerides (P < 0.02) and vWf (P < 0.05) than the men on their normal diet. There was no difference in HDL cholesterol. Levels of vWf correlated with both total cholesterol (P < 0.005) and inversely with dietary polyunsaturated fats (P < 0.02). Conclusion. von Willebrand factor, a possible indicator of endothelial cell damage, decreases during long-term compliance with a lipid-lowering diet.     

Comparison of Lipid-Lowering Medications and Risk for Cardiovascular Disease in Diabetes

Purpose of the Review

To summarize available evidence regarding lipid-lowering interventions for the prevention of cardiovascular disease in patients with diabetes.

Recent Findings

Statins and non-statin therapies that act through upregulation of LDL receptor expression are associated with similar cardiovascular risk reduction per decrease in LDL cholesterol.

Summary

In subjects with diabetes, with or without established cardiovascular disease, each 39 mg/dl reduction in LDL cholesterol observed with statins is associated with a 21% relative reduction in the risk of major coronary events at 5 years. Statins remain the first-line lipid-lowering agents for the management of dyslipidemia in individuals with diabetes; however, the addition of non-statin therapies to lower LDL cholesterol, such as ezetimibe and PCSK-9 inhibitors, to maximally tolerated statin therapy is recommended in patients with atherosclerotic cardiovascular disease and baseline LDL cholesterol over 70 mg/dl. Recent data support even lower LDL cholesterol targets (<?55 mg/dl) to further reduce the risk of cardiovascular events especially in subjects with diabetes and documented cardiovascular disease.

     

Acute increase in lipoprotein lipase following prolonged exercise

We investigated the acute effects of prolonged exercise on lipoprotein metabolism. Serum lipid and lipoprotein concentrations and plasma postheparin lipolytic activity were measured in ten well-trained men (ages 21 to 39) the day before and after a 42 km foot race. LDL cholesterol decreased by 10% (113 ± 31 to 103 ± 32 mg/dL, P < 0.01) and total HDL-cholesterol levels increased by 9% (65 ± 18 to 71 ± 19 mg/dL, P < 0.01) the day after the race. No changes in the concentration of apolipoprotein A-I or A-II occurred. Triglyceride levels decreased by 39% (95 ± 38 to 58 ± 23 mg/dL, P < 0.001). Two days after the race, total HDL cholesterol (74 ± 21 mg/dL, P < 0.05) and the HDL₂ subfraction (37 ± 19 mg/dL, P < 0.05) remained significantly elevated compared to pre-race values. Most dramatically, the level of lipoprotein lipase activity measured in postheparin plasma nearly doubled after the race, demonstrating that vigorous exercise acutely increases this enzyme activity. The increase in lipoprotein lipase activity probably mediated the fall in serum triglycerides after exercise and may also account for the increase in HDL cholesterol.     

Probucol selectively increases oxidation of atherogenic lipoproteins in cholesterol-fed mice and in Watanabe heritable hyperlipidemic rabbits

The anti-atherogenic and cholesterol-lowering drug probucol (0.5–1%) or quercetin (1%), a natural antioxidant, was given to cholesterol-fed (1.5%) mice for a period of 6 weeks and to Watanabe heritable hyperlipidemic (WHHL) rabbits for a period of 8 weeks to investigate the oxidative changes in plasma and lipoproteins. Oxidation was measured as the total amount of malondialdehyde (nmol MDA/g protein) by a very specific MDA-HPLC method. A large and significant increase in MDA was seen in LDL from probucol treated WHHL rabbits (1778.7±585.5 nmol/g vs. 394.4±144.5 nmol/g, P<0.001) and cholesterol-fed mice (579.7±47.3 nmol/g vs. 408.1±85.8 nmol/g, P<0.05) as compared to controls while LDL cholesterol was lowered (WHHL rabbits: P<0.05; mice: P<0.01). In WHHL rabbits VLDL oxidation was determined additionally, and also revealed a large increase in the probucol group (2102.7±1156.1 nmol/g vs. 455.0±207.8 nmol/g, P<0.01). In contrast, the oxidation of plasma and HDL from probucol treated animals was not statistically significantly increased, implying that probucol mediates a selective oxidation of atherogenic cholesterol-transporting lipoproteins. Quercetin treated animals did not show increased oxidation of LDL (and VLDL in rabbits) and cholesterol levels were not decreased. Furthermore, no protective antioxidant effect of quercetin was seen. In conclusion, the results suggest that a prooxidant mechanism rather than antioxidative effects influences lipoprotein metabolism in these animals. It is hypothesized that the oxidation of lipoproteins might be a physiological mechanism performed by macrophages or other cells for uptake and degradation (by macrophages and liver) of excessive amounts of LDL or VLDL and that probucol oxidizes atherogenic lipoproteins and thereby leads to a decrease in cholesterol levels.     

Omacor in familial combined hyperlipidemia: effects on lipids and low density lipoprotein subclasses

Elevations of plasma cholesterol and/or triglycerides, and the prevalence of small, dense LDL particles remarkably increase coronary risk in patients with familial combined hyperlipidemia (FCHL). A total of 14 FCHL patients were studied, to investigate the ability of Omacor, a drug containing the n-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA and DHA), to favorably correct plasma lipid/lipoprotein levels and LDL particle distribution. The patients received four capsules daily of Omacor (providing 3.4 g EPA+DHA per day) or placebo for 8 weeks in a randomized, double-blind, cross-over study. Omacor significantly lowered plasma triglycerides and VLDL-cholesterol levels, by 27 and 18%, respectively. Total cholesterol did not change but LDL-cholesterol and apolipoprotein B (apoB) concentrations increased by 21 and 6%. As expected, LDL particles were small (diameter=24.9+/-0.3 nm) and apoB-rich (LDL-cholesterol/apoB ratio=1.27+/-0.26) in the selected subjects. After Omacor treatment LDL became enriched in cholesterol (LDL-cholesterol/apoB ratio=1.40+/-0.17), mainly cholesteryl esters, indicating accumulation in plasma of more buoyant and core enriched LDL particles. Indeed, the separation of LDL subclasses by rate zonal ultracentrifugation showed an increase of the plasma concentration of IDL and of the more buoyant, fast floating LDL-1 and LDL-2 subclasses after Omacor, with a parallel decrease in the concentration of the denser, slow floating LDL-3 subclass. However, the average LDL size did not change after Omacor (25.0+/-0.3 nm). The resistance of the small LDL pattern to drug-induced modifications implies that a maximal lipid-lowering effect must be achieved to reduce coronary risk in FCHL patients.     

Serum n-3 to n-6 polyunsaturated fatty acids ratio correlates with coronary plaque vulnerability: an optical coherence tomography study

A low ratio of eicosapentaenoic acid to arachidonic acid (EPA/AA) has been demonstrated to be associated with a higher risk of cardiovascular events. Optical coherence tomography (OCT) is useful for the assessment of coronary plaque vulnerability. The purpose of this study was to evaluate the association between EPA/AA ratio and coronary plaque vulnerability. This study involved 58 patients with stable angina pectoris undergoing percutaneous coronary intervention. OCT image acquisition was performed before the procedure in the culprit lesions. We assessed lipid-rich plaque length and arc, fibrous cap thickness, frequency of thin-cap fibroatheroma (TCFA), thrombus, ruptured plaque, macrophage infiltration, and microvessels using OCT. Patients were divided into two groups according to the median value of serum EPA/AA ratio: a low-EPA/AA group (n = 29, EPA/AA ratio <0.36) and a high-EPA/AA group (n = 29, EPA/AA ratio ≥0.36). In qualitative analyses, TCFA (35.4 vs 6.9 %, P = 0.0095), macrophage infiltration (48.3 vs 13.8 %, P = 0.0045), and microvessels (44.8 vs 10.3 %, P = 0.0033) were more frequently observed in the low-EPA/AA group. In quantitative analyses, the low-EPA/AA group had wider maximum lipid arc (114.0 ± 94.8° vs 56.4 ± 66.0°, P = 0.0097), longer lipid length (4.8 ± 4.5 vs 1.6 ± 2.6 mm, P = 0.0037), and thinner fibrous cap (69.3 ± 28.3 vs 113.3 ± 46.6 μm, P = 0.005) compared with the high-EPA/AA group. EPA/AA ratio was positively correlated with fibrous cap thickness (r = 0.46, P = 0.007). In a multivariate model, an EPA/AA ratio <0.36 was associated with the presence of TCFA (odds ratio 6.41, 95 % confidence interval 1.11–61.91, P = 0.0371). In our detailed OCT analysis, lower EPA/AA ratio was associated with higher vulnerability of coronary plaques to rupture.     

Adipose tissue polyunsaturated fatty acids and metabolic syndrome among adult parents and their children

Background and aims

Polyunsaturated fatty acids (PUFA) may play a role in the etiology of the metabolic syndrome (MetS). The aim of the study was to examine the associations of adipose tissue PUFA biomarkers with MetS among parents and children in Mesoamerica.