Impact of Direct Measurement of Small Dense Low-Density Lipoprotein Cholesterol for Long-Term Secondary Prevention in Patients with Stable Coronary Artery Disease.

BACKGROUND: This study investigated whether directly measured small dense low-density lipoprotein cholesterol (D-sdLDL-C) can predict long-term coronary artery disease (CAD) events compared with low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB), and estimated small dense low-density lipoprotein cholesterol (E-sdLDL-C) determined by the Sampson equation in patients with stable CAD. METHODS: D-sdLDL-C measured at Showa University between 2010 and 2022, and E-sdLDL-C were evaluated in 790 male and 244 female patients with stable CAD. CAD events, defined as sudden cardiac death, onset of acute coronary syndrome, and/or need for coronary revascularization, were monitored for 12 years. Cutoff lipid levels were determined by receiver operating characteristic curves. RESULTS: CAD events were observed in 238 male and 67 female patients. The Kaplan-Meier event-free survival curves showed that patients with D-sdLDL-C ≥32.1 mg/dL (0.83 mmol/L) had an increased risk for CAD events (P = 0.007), whereas risk in patients with E-sdLDL-C ≥36.2 mg/dL (0.94 mmol/L) was not increased. In the group with high D-sdLDL-C, the multivariable-adjusted hazard ratio (HR) was 1.47 (95% CI, 1.15-1.89), and it remained significant after adjustment for LDL-C, non-HDL-C, or apoB and in patients treated with statins. HRs for high LDL-C, non-HDL-C, or apoB were not statistically significant after adjustment for high D-sdLDL-C. Higher D-sdLDL-C was associated with enhanced risk of high LDL-C, non-HDL-C, and apoB (HR 1.73; 95% CI, 1.27-2.37). CONCLUSIONS: Higher D-sdLDL-C can predict long-term recurrence of CAD in stable CAD patients independently of apoB and non-HDL-C. D-sdLDL-C is an independent risk enhancer for secondary CAD prevention, whereas E-sdLDL-C is not. UMIN-CTR Clinical Trial Number: UMIN000027504.

Comparing fluorescence-based cell-free assays for the assessment of antioxidative capacity of high-density lipoproteins.

BACKGROUND: Population studies have shown an inverse association between high-density lipoprotein (HDL) cholesterol levels and risk of coronary heart disease (CHD). HDL has different functions, including the ability to protect biological molecules from oxidation. Our aim was to evaluate the performance of two fluorescence-based assays in assessing the antioxidative capacity of HDL. METHODS: We compared the antioxidative capacity of HDL with the phospholipid 2',7'-dichlorodihydrofluorescein (DCF) assay and the dihydrorhodamine 123 (DHR) assay in controls and in subjects at increased risk of CHD, including subjects with established CHD, and subjects with elevated plasma triglycerides (TG), serum amyloid A (SAA), or myeloperoxidase (MPO) levels. RESULTS: The antioxidative capacity of HDL, as measured by the DCF assay, was significantly lower in both CHD and high-TG patients than in controls (p < 0.001 and p = 0.004, respectively). Interestingly, the mean antioxidative capacity of HDL in high-SAA subjects was significantly higher (p < 0.03), while in high-MPO subjects was similar to controls. When the DHR assay was used we did not find differences in HDL's antioxidative capacity between CHD patients and controls but we found higher antioxidative capacity in high-SAA subjects compared to controls. CONCLUSIONS: Only the DCF assay could detect significant differences in the antioxidative capacity of HDL between controls and CHD subjects. Practical use of both assays for the assessment of antioxidative capacity of HDL is limited by the large overlap in values among groups. The antioxidative activity of HDL in patients who have elevated SAA levels needs to be reassessed.

Small Dense Low-Density Lipoprotein Cholesterol: A Residual Risk for Rapid Progression of Non-Culprit Coronary Lesion in Patients with Acute Coronary Syndrome.

AIM: This study investigated whether the small dense low-density lipoprotein cholesterol (sd-LDL-c) level is associated with the rapid progression (RP) of non-culprit coronary artery lesions and cardiovascular events (CE) after acute coronary syndrome (ACS). METHODS: In 142 consecutive patients with ACS who underwent primary percutaneous coronary intervention for the culprit lesion, the sd-LDL-c level was measured using a direct homogeneous assay on admission for ACS and at the 10-month follow-up coronary angiography. RP was defined as a progression of any pre-existing coronary stenosis and/or stenosis development in the initially normal coronary artery. CEs were defined as cardiac death, myocardial infarction, stroke, or coronary revascularization. RESULTS: Patients were divided into two groups based on the presence (n=29) or absence (n=113) of RP after 10 months. The LDL-c and sd-LDL-c levels at baseline were equivalent in both the groups. However, the sd-LDL-c, triglyceride, remnant lipoprotein cholesterol (RL-c), and apoC3 levels at follow-up were significantly higher in the RP group than in the non-RP group. The optimal threshold values of sd-LDL-c, triglyceride, RL-c, and apoC3 for predicting RP according to receiver operating characteristics analysis were 20.9, 113, 5.5, and 9.7 mg/dL, respectively. Only the sd-LDL-c level (≥ 20.9 mg/dL) was significantly associated with incident CEs at 31±17 months (log-rank: 4.123, p=0.043). CONCLUSIONS: The sd-LDL-c level on treatment was significantly associated with RP of non-culprit lesions, resulting in CEs in ACS patients. On-treatment sd-LDL-c is a residual risk and aggressive reduction of sd-LDL-c might be needed to prevent CEs.

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.

Prevalence and significance of sleep disordered breathing in adolescent athletes.

Sleep disordered breathing (SDB) was more prevalent in adolescent athletes than expected, and several potential warning signs related to autonomic nerve activity appeared in SDB athletes. SDB screening may prevent associated downstream risks in the future. http://ow.ly/GQqK30nGm8r.

Comparison of plasma levels of different species of trans fatty acids in Japanese male patients with acute coronary syndrome versus healthy men.

BACKGROUND AND AIMS: It remains unclear how trans fatty acid (TFA) at low-level intake affect lipid levels and the development of acute coronary syndrome (ACS). The study aimed to investigate how plasma TFA composition differs between male patients with ACS and healthy men. METHODS: Plasma fatty acid (FA) composition (as determined by gas chromatography) was analyzed in ACS patients on hospital admission and compared to that of age-adjusted healthy men. RESULTS: Total FA and TFA levels were similar between ACS and control subjects. Palmitelaidic acid, ruminant-derived TFA (R-TFA), levels were lower in ACS patients (0.17 ±â€¯0.06 vs. 0.20 ±â€¯0.06 of total FA, in ACS and control, respectively, p<0.01), and were significantly directly associated with HDL cholesterol (HDL-C) (rho = 0.269) and n-3 polyunsaturated FA (n-3 PUFA) (rho = 0.442). Linoleic trans isomers (total C18:2 TFA), primary industrially-produced TFA (IP-TFAs), were significantly higher in ACS patients (0.68 ±â€¯0.17 vs. 0.60 ±â€¯0.20 of total FA, in ACS and control, respectively). Total trans-C18:1 isomers were comparable between ACS and control. Differences between ACS and controls in C18:1 trans varied by specific C18:1 trans species. Absolute concentrations of trans-C18:2 isomers were significantly directly associated with LDL-C and non-HDL-C in ACS men. The ACS patients showed significantly lower levels of both n-6 and n-3 PUFA (i.e., eicosapentaenoic, docosahexaenoic and arachidonic acids). CONCLUSIONS: There were several case-control differences in specific TFA that could potential affect risk for ACS. Japanese ACS patients, especially middle-aged patients, may consume less R-TFA.

Effects of Cardiac Rehabilitation on High-Density Lipoprotein-mediated Cholesterol Efflux Capacity and Paraoxonase-1 Activity in Patients with Acute Coronary Syndrome.

AIMS: We evaluated whether exercised-based cardiac rehabilitation (CR) can ameliorate the HDL function, i.e., cholesterol efflux capacity (CEC) and paraoxonase-1 activity in patients with acute coronary syndrome (ACS). METHODS: This study is a retrospective analysis of stored serum from patients with ACS following successful percutaneous coronary intervention. The CEC, measured by a cell-based ex vivo assay using apolipoprotein B-depleted serum and 3H-cholesterol labeled macrophages and arylesterase activity (AREA) at the onset or early phase of ACS, and the follow-up periods were compared between 69 patients who completed the five-month outpatient CR program (CR group) and 15 patients who did not participate and/or dropped out from CR program (non-CR group). RESULTS: Apolipoprotein A-I (apoA-I) and CEC significantly increased by 4.0% and 9.4%, respectively, in the CR group, whereas HDL-cholesterol and AREA were not changed during the follow-up periods in both groups. Among CR patients, the CEC significantly increased, irrespective of the different statin treatment, while HDL-cholesterol and apoA-I significantly increased in patients treated with rosuvastatin or pitavastatin. Although CEC and AREA were significantly correlated each other, there is a discordance between CEC and AREA for their correlations with other biomarkers. Both CEC and AREA were significantly correlated with apoA-I rather than HDL-cholesterol. Changes in CEC and those in AREA were significantly correlated with those in apoA-I (rho=0.328, p=0.002, and rho=0.428, p＜0.0001, respectively) greater than those in HDL-cholesterol (rho=0.312, p= 0.0042,and rho=0.343, p=0.003, respectively). CONCLUSIONS: CR can improve HDL function, and it is beneficial for secondary prevention.

Small dense low-density lipoprotein cholesterol is a promising biomarker for secondary prevention in older men with stable coronary artery disease.

AIM: The study objective was to investigate whether small dense low-density lipoprotein cholesterol (sdLDL-C) is superior to low-density lipoprotein cholesterol (LDL-C) and other biomarkers to predict future cardiovascular events (CE) in secondary prevention. METHODS: sdLDL-C measured by a homogeneous assay, remnant lipoprotein cholesterol, LDL particle diameter and other biomarkers were compared in 345 men aged ≥65 years with stable coronary artery disease. Baseline LDL-C was 100.5 ± 30.1 mg/dL. CE including cardiovascular death, onset of acute coronary syndrome, need for arterial revascularization, hospitalization for heart failure, surgery procedure for cardiovascular disease and hospitalization for stroke were monitored for 5 years. RESULTS: CE occurred in 96 patients during the study period. LDL-C, sdLDL-C non-high-density lipoprotein cholesterol, apolipoprotein B, remnant lipoprotein cholesterol, glucose, glycated hemoglobin and brain natriuretic peptide were significantly higher; LDL particle diameter and apolipoprotein A-1 were significantly lower in patients with than in those without CE. Age-adjusted Cox regression analysis showed that sdLDL-C per 10 mg/dL, but not LDL-C, was significantly associated with CE (HR 1.206, 95% CI 1.006-1.446). A significant association of sdLDL-C and incident CE was observed in statin users (HR 1.252, 95% CI 1.017-1.540), diabetes patients (HR 1.219, 95% CI 1.018-1.460), patients without diabetes (HR 1.257, 95% CI 1.019-1.551) and patients with hypertriglyceridemia (HR 1. 376, 95% CI 1.070-1.770). CONCLUSIONS: sdLDL-C was the most effective predictor of residual risk of future CE in stable coronary artery disease patients using statins and in high-risk coronary artery disease patients with diabetes or hypertriglyceridemia. Geriatr Gerontol Int 2018; 18: 965-972.

Significance of small dense low-density lipoprotein-cholesterol concentrations in relation to the severity of coronary heart diseases.

We have investigated the clinical significance of small dense low-density lipoprotein-cholesterol (sd-LDL-C) concentrations in coronary heart disease (CHD). We measured the LDL size by gradient gel electrophoresis and quantified sd-LDL-C concentrations by a newly developed rapid assay using heparin-magnesium precipitation in 225 consecutive CHD patients without any lipid-lowering medication and 142 healthy middle-aged subjects as controls. The LDL size was markedly smaller and sd-LDL-C levels were significantly higher in CHD patients than in controls of both sexes, whereas LDL-C levels were comparable between CHD and controls. The LDL-C levels were significantly higher in a subpopulation of 84 patients with acute coronary syndrome than in other patients groups, while LDL size and high-density lipoprotein-cholesterol (HDL-C) were not found to vary among the patients. The sd-LDL-C increased as the number of diseased vessels or Gensini atherosclerosis score increased. Among the 123 stable CHD patients, multiple logistic regression analysis revealed that sd-LDL-C levels were significantly associated with the clinically severe cases requiring coronary revascularization independently of LDL-C, HDL-C and apolipoprotein B. The sd-LDL mass plays a more important role in the progression of CHD than the LDL size, and the sd-LDL-C concentration serves as a powerful surrogate marker for the prevention of CHD.

Fenofibrate, HDL, and cardiovascular disease in Type-2 diabetes: The DAIS trial.

BACKGROUND: There are conflicting reports on the role of fibrates in CVD-risk. Several studies indicate beneficial effects of fibrates on CVD risk in type-2 diabetic patients. We tested how fenofibrate changes lipoprotein subfractions and glucose homeostasis in type-2 diabetic patients. STUDY DESIGN: Selected markers of lipid and glucose homeostasis and inflammation were measured in 204 diabetic patients who participated in the Diabetes Atherosclerosis Intervention Study (DAIS) and were randomly assigned to 200 mg fenofibrate or placebo. Percent changes from baseline until a minimum of 3 years (average 39.6 months) on therapy (end of study) were calculated for all study parameters. RESULTS: The concentrations of total LDL-C and small dense LDL-C (sdLDL-C) did not change on fenofibrate compared to placebo. Compared to placebo, fenofibrate significantly decreased concentrations of triglyceride and remnant-like particle cholesterol (RLP-C) and activity of lipoprotein-associated phospholipase A2 (Lp-PLA2), while significantly increased concentrations of HDL-C. In contrast to other lipid-modifying drugs (e.g. statins) which increase HDL-C by increasing large (α-1) HDL particles, fenofibrate increased HDL-C by increasing the smaller, less antiatherogenic HDL-C particles, α-3 and α-4. Furthermore, despite lowering TG levels by 20%, fenofibrate failed to decrease pre-ß1 levels. On fenofibrate, glycated serum-protein levels increased moderately, while insulin and adiponectin levels did not change. CONCLUSION: On fenofibrate, lipid homeostasis improved and Lp-PLA2 activity decreased while there was no improvement in glucose homeostasis. Despite increasing HDL-C and decreasing triglyceride levels, fenofibrate failed to improve the antiatherogenic properties of the HDL subpopulation profile.

Beneficial Effects of Exercise-Based Cardiac Rehabilitation on High-Density Lipoprotein-Mediated Cholesterol Efflux Capacity in Patients with Acute Coronary Syndrome.

AIM: Recent studies reported that low high-density lipoprotein (HDL)-mediated cholesterol efflux capacity rather than low HDL cholesterol (HDL-C) is strongly associated with the increased risk for coronary artery disease. It remains unclear whether exercised-based cardiac rehabilitation (CR) can increase HDL cholesterol efflux capacity. METHOD: This study is a retrospective analysis of stored serum from patients with acute coronary syndrome (ACS) who participated in outpatient CR program following successful percutaneous coronary intervention. We employed a cell-based cholesterol efflux system including the incubation of (3)H-cholesterol labeled macrophages with apolipoprotein B-depleted serum at the onset or early phase of ACS and at 6-month follow-up periods in 57 male and 11 female patients with ACS. Cardiopulmonary exercise tests were performed at the beginning and end of CR program. RESULT: Fifty-seven patients completed the CR program. Compared with patients who dropped out from CR program (non-CR group), CR participants showed marked amelioration in serum lipid levels, increased efflux capacity, and improved exercise capacity. Spearman's rank correlation coefficient analysis revealed that the percent increases of efflux capacity were significantly associated with the percent increases in HDL-C (ρ=0.598, p＜0.0001) and apolipoprotein A1 (ρ=0.508, p＜0.0001), whereas no association between increases in efflux capacity and increases in cardiopulmonary fitness was observed. Increases in cholesterol efflux capacity were not seen in patients who continued smoking and those who did not achieve all risk factor targets and higher exercise tolerance. CONCLUSION: CR can markedly increase both HDL-C and HDL cholesterol efflux capacity. These results suggest that CR is a very useful therapy for reverse cholesterol transport and secondary prevention.

Insulin resistance as a predictor for restenosis after coronary stenting.

PURPOSE: The rationale of this study was to determine whether insulin resistance is an independent risk factor for restenosis after coronary stenting. BACKGROUND: Previous studies suggested that hyperinsulinemia may be an important risk factor for ischemic heart disease. Restenosis after coronary stenting is neointimal tissue proliferation and de-novo stenosis is atherosclerosis from the point of view of histology. However, it has not been determined whether insulin resistance is independently related to restenosis after coronary stenting. METHODS: Clinical variables of unselected population of 110 patients were analyzed in multivariate logistic regression analyses for both restenosis and de-novo stenosis. Clinical, lesion-related, and procedural variables were analyzed by chi-square analysis, and relative risk. RESULTS: Multivariate logistic regression analysis showed that homeostasis model assessment insulin resistance (HOMA-IR) and HbA1c were associated with restenosis after coronary stenting (HOMA-IR; P=0.0447, HbA1c; P=0.0462), and HbA1c and low-density lipoprotein cholesterol (LDL-C) were associated with de-novo stenosis (HbA1c; P=0.0201, LDL-C; P=0.0204). Restenosis was influenced by insulin resistance [Relative Risk (RR) 2.06; 95 percent confidence interval (95%CI) 1.20 to 3.56], diabetes mellitus (DM: RR 1.92; 95%CI 1.25 to 2.95), and final minimal lumen diameter (RR 2.83; 95%CI 1.32 to 6.06). CONCLUSIONS: HOMA-IR and DM are the predictors of restenosis after coronary stenting, and HbA1c and LDL-C are the predictors of de-novo stenosis. These results may be reflected in histological differences between neointimal tissue proliferation as restenosis and atherosclerosis as de-novo stenosis.

Effects of oral eicosapentaenoic acid versus docosahexaenoic acid on human peripheral blood mononuclear cell gene expression.

OBJECTIVE: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have beneficial effects on inflammation and cardiovascular disease (CVD). Our aim was to assess the effect of a six-week supplementation with either olive oil, EPA, or DHA on gene expression in peripheral blood mononuclear cells (PBMC). METHODS: Subjects were sampled at baseline and six weeks after receiving either: olive oil 6.0 g/day (n = 16), EPA 1.8 g/day (n = 16), or DHA 1.8 g/day (n = 18). PBMC were subjected to gene expression analysis by microarray with key findings confirmed by quantitative real-time polymerase chain reaction (Q-PCR). RESULTS: Plasma phospholipid EPA increased 3 fold in the EPA group, and DHA increased 63% in the DHA group (both p < 0.01), while no effects were observed in the olive oil group. Microarray analysis indicated that EPA but not DHA or olive oil significantly affected the gene expression in the following pathways: 1) interferon signaling, 2) receptor recognition of bacteria and viruses, 3) G protein signaling, glycolysis and glycolytic shunting, 4) S-adenosyl-l-methionine biosynthesis, and 5) cAMP-mediated signaling including cAMP responsive element protein 1 (CREB1), as well as many other individual genes including hypoxia inducible factor 1, α subunit (HIF1A). The findings for CREB1 and HIF1A were confirmed by Q-PCR analysis. CONCLUSIONS: Our data indicate that EPA supplementation was associated with significant effects on gene expression involving the interferon pathway as well as down-regulation of CREB1 and HIF1A, which may relate to its beneficial effect on CVD risk reduction.

Elevated small dense low-density lipoprotein cholesterol as a predictor for future cardiovascular events in patients with stable coronary artery disease.

AIM: The aim of the present study was to investigate how small dense low-density lipoprotein cholesterol (sdLDL-C) compared with LDL-C affect the long-term prognosis in patients with stable coronary artery disease (CAD). METHODS: sdLDL-C measured by heparin magnesium precipitation and LDL particle size measured by non-denatured gradient-gel electrophoresis were compared in 190 consecutive CAD patients who underwent coronary arteriography between 2003 and 2004 who did or did not develop cardiovascular events during a seven-year follow-up period. Cardiovascular events were death caused by cardiovascular diseases(CVDs), onset of acute coronary syndrome, need for coronary and peripheral arterial revascularization, hospitalization for heart failure, surgical procedure for any CVDs, and/or hospitalization for stroke. RESULTS: First-time cardiovascular events were observed in 72 patients. Those who experienced cardiovascular events were older and had higher prevalence rates of hypertension and diabetes; significantly higher Gensini coronary atherosclerotic scores; significantly higher levels of sdLDL-C, sdLDL-C/LDL-C, and LDL-C/high-density lipoprotein cholesterol (HDL-C) ratios; and greater glycated hemoglobin(Hb)A1c and brain natriuretic peptide (BNP) levels. They also had significantly smaller LDL particle sizes, HDL-C, apolipoprotein A-1, and estimated glomerular filtration rate (GFR) compared with patients without cardiovascular events. Conversely, LDL-C, non-HDL-C, apolipoprotein B, remnantlike particle cholesterol, and high-sensitivity C-reactive protein (hs-CRP) levels were similar between the two groups. A Kaplan-Meyer event-free survival curve demonstrated that patients with sdLDL-C≥35 mg/dL (median level) had significantly poorer prognosis compared with those with lower sdLDL-C levels, while patients with LDL-C ≥100 mg/dL had a non-significantly lower survival rate. CONCLUSION: These results confirm that sdLDL-C is a very promising biomarker to predict future cardiovascular events in the secondary prevention of stable CAD.

IL-6 mobilizes bone marrow-derived cells to the vascular wall, resulting in neointima formation via inflammatory effects.

AIM: Among the many factors related to bone marrow cell mobilization, local inflammation induced by cytokines may drive bone marrow cells to the vascular wall, resulting in a thickened neointima. However, the relationship between inflammatory reactions and bone marrow cell invasion has not yet been fully clarified. METHODS: We inserted a large wire into the femoral artery in male balb/c(WT), interleukin (IL)-6-knockout (KO) and bone marrow-transplanted (BMT) mice that had received bone marrow cells from KO mice. Immunohistochemistry was performed to evaluate the degree of intimal hyperplasia and inflammation following vascular injury. RESULTS: Three days after the vascular injury, the number of CD34/Sca-1-positive cells in the blood was higher in the KO mice. The numbers of apoptotic cells in the neointima was lower in the KO and BMT mice at two hours after injury. The morphometric analysis performed at one and four weeks after injury showed that the intima/media ratio was significantly lower in the KO and BMT mice, while CD34-positive cells were much more frequent in the WT mice. Furthermore, re-endothelialization appeared earlier in the KO and BMT mice than in the WT mice. No differences in the levels of vascular endothelial growth factor or hepatocyte growth factor were observed in the mice sera between the WT, KO and BMT mice after injury. The in vitro culture of bone marrow cells showed more differentiated smooth muscle-like cells in the WT mice than in the KO mice. CONCLUSIONS: IL-6 is involved in neointimal formation following vascular injury, possibly acting through inflammatory effects inducing the production of bone marrow cells.

Small LDL-cholesterol is superior to LDL-cholesterol for determining severe coronary atherosclerosis.

AIM: Recent evidence suggests that small dense low-density lipoprotein (sd-LDL) particles are more atherogenic than large-LDL in spite of their lower cholesterol content. This study aimed to determine whether sd-LDL-cholesterol (sd-LDL-C) is superior to LDL-C as a biomarker of coronary heart disease (CHD). METHODS: LDL particle size determined by gradient gel electrophoresis and sd-LDL-C concentrations quantified by heparin-magnesium precipitation were compared between 482 stable CHD patients and 389 non-diabetic subjects without CHD who were not receiving any lipid-lowering drugs. RESULTS: Both male and female CHD patients had significantly smaller LDL particles and lower large-LDL-C concentrations (estimated by subtracting the sd-LDL-C concentration from the LDL-C concentration), and significantly higher sd-LDL-C concentrations than the control subjects. LDL-C concentrations were modestly higher and sd-LDL-C concentrations were significantly higher in 258 patients with angiographically documented severe CHD than in the patients with mild CHD irrespective of treatment by LDL-lowering drugs and history of myocardial infarction and/or coronary revascularization. Large-LDL-C concentrations, in contrast, were similar between the two groups. Multivariate logistic regression analysis revealed that sd-LDL-C levels were significantly associated with severe CHD independently of LDL-C. CONCLUSION: sd-LDL-C levels are more powerful than LDL-C levels for the determination of severe stable CHD.

High-dose granulocyte-colony stimulating factor promotes neointimal hyperplasia in the early phase and inhibits neointimal hyperplasia in the late phase after vascular injury.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) affects injured arteries through early endothelialization. Some reports, however, have cautioned that the restenosis rate may increase after G-CSF injection. In the present study, high-dose G-CSF was administered to mice with vascular injury to clarify its effect. METHODS AND RESULTS: Mice were received daily subcutaneous injections of saline or a high dose (300 microg/kg) of G-CSF for 5 days after vascular injury. In the FACS analysis, CD34-/Sca-1-positive progenitor cells were more abundant in the G-CSF group (p<0.05). Neointimal hyperplasia was more evident in the G-CSF group at 1 week (p<0.05), whereas at 4 weeks it was more evident in the control group (p<0.01). TUNEL-positive cells in the arterial wall were more numerous in the G-CSF group at day 1 (p<0.01). CD34-positive cells were observed in the G-CSF group at 1 week. Re-endothelialization appeared earlier in the G-CSF group (at 4 weeks; p<0.01). An increased number of 1A4-positive smooth muscle cells were found in bone marrow cell culture treated with G-CSF. CONCLUSION: High-dose G-CSF induced neointimal proliferation through excessive inflammation and bone marrow cell mobilization in the early phase. In the late phase, however, it induced early re-endothelialization and thereby inhibited neointimal hyperplasia.

G-CSF after myocardial infarction accelerates angiogenesis and reduces fibrosis in swine.

OBJECTIVE: Recent studies have suggested that granulocyte colony-stimulating factor (G-CSF) may improve cardiac function after acute myocardial infarction (AMI) by accelerating angiogenesis or cardiomyogenesis, but negative results and side effect of G-CSF have also been reported. However, no previous studies have used large animal models of ischemia/reperfusion to investigate the effect and side effect of G-CSF after AMI. METHODS: The diagonal branch of the left anterior descending coronary artery of swine was balloon-occluded for 1 h and then reperfused. The animals of the G-CSF group were injected with G-CSF subcutaneously (5.0 microg/kg/day) for 6 days after MI and then sacrificed after 4 weeks. The control group received the same volume of saline. RESULTS: There were no differences between the groups in the rate of thrombotic obstruction or progression of stenosis lesion in coronary angiography. The ejection fraction and end-diastolic volume in the G-CSF group were not significantly improved over the control values. The fibrotic area was significantly smaller in the G-CSF group than in the controls (P<0.05), and the numbers of vessels counted in anti-von Willebrand factor and anti-alpha-smooth muscle actin-stained sections were significantly larger (P<0.005 and P<0.05, respectively). The expression of collagen III mRNA was significantly lower in the G-CSF group than in the control in the infarct (P<0.0005) and border areas (P<0.005), and TGF-beta mRNA was significantly lower in the G-CSF group in the border area (P<0.05). CONCLUSIONS: G-CSF could modify the healing process after AMI by accelerating angiogenesis in a swine ischemia/reperfusion model. At the dose administered, however, G-CSF did not seem to improve the global cardiac function.

Predominance of small dense low-density lipoproteins and abnormal glucose regulation in patients with acute coronary syndrome.

BACKGROUND: Although small dense low-density lipoprotein (sd-LDL) has an established association with diabetic dyslipidemia, previous studies have failed to show an association between sd-LDL and diabetes among coronary heart disease patients. This study investigated the prevalence of sd-LDL and abnormal glucose regulation in acute coronary syndrome (ACS). METHODS AND RESULTS: LDL size at the onset of ACS was measured by nondenatured gradient gel electrophoresis in 314 of 429 consecutive patients. Sd-LDL was prevalent in 54% of the patients, irrespective of the presence of previously known diabetes (50% vs 60% in nondiabetes and diabetes, respectively). Diabetes was present in 122 (28%) of the patients, and 110 patients without diabetes underwent an oral glucose tolerance test. Impaired glucose tolerance (IGT) and newly detected diabetes were found in as many as 44% and 22% of the patients tested, even though their hemoglobinA1c levels were in the normal range (5.3+/-0.5%). The prevalence of sd-LDL was significantly higher in patients with glucose intolerance than in those with normal glucose tolerance (61% vs 42%). CONCLUSION: IGT and diabetes were far more common than normal glucose regulation in ACS patients, and the abnormal glycometabolism was closely associated with highly atherogenic sd-LDL.