High levels of very long-chain saturated fatty acid in erythrocytes correlates with atherogenic lipoprotein profiles in subjects with metabolic syndrome.

AIM: Very long chain saturated fatty acid (VLCFA) levels in erythrocytes are associated with metabolic syndrome (MS). However, the relationship between levels of the VLCFA ligonoceric acid (C24:0) in erythrocytes and the atherogenic lipoprotein profiles and inflammatory state in MS remain unclear. METHODS: Based on the International Diabetes Federation (IDF) definition of MS, 195 apparently healthy males were assigned to either an MS group (n=38) or a non-MS group (n=157). Fatty acid composition of erythrocytes was determined by gas liquid chromatography. RESULTS: Erythrocytes from the MS group had a significantly higher level of C24:0 than cells from the non-MS group (4.06±0.48% versus 3.88±0.34%; p=0.03). C24:0 levels were significantly correlated with several components of MS. The C24:0 levels showed a significant negative correlation with LDL and HDL particle size. Multivariate linear regression analysis showed that C24:0 levels were independently correlated with LDL particle size after adjusting for age and each MS criterion. C24:0 levels were also positively correlated with log-transformed high-sensitivity CRP levels (p=0.04). CONCLUSION: C24:0 levels in erythrocytes are associated with specific atherogenic lipoprotein profiles and inflammation status in subjects with MS.

Non-high-density lipoprotein cholesterol is a practical predictor of long-term cardiac death after coronary artery bypass grafting.

BACKGROUND: Recent studies have demonstrated that non-high-density lipoprotein cholesterol (non-HDL-C) can predict the risk of cardiovascular events among general population without coronary heart disease (CHD). However, few studies have investigated the predictive value of non-HDL-C for long-term prognosis in patients with CHD. The purpose of this study was to investigate whether non-HDL-C can predict long-term cardiovascular events in patients with CHD who underwent coronary artery bypass grafting (CABG). METHODS: We enrolled 1074 consecutive patients who underwent CABG at Juntendo University Hospital between 1984 and 1994, and obtained mortality data through 2000. We divided the patients into 2 groups by the median non-HDL-C level at baseline (180 mg/dL) and used Kaplan-Meier method with log-rank test for survival analyses. Cox proportional-hazard regression model was used to calculate the relative risk (RR) of cardiac death. RESULTS: The mean follow-up period was 10.6±3.5 years. The survival rate of cardiac death was significantly lower in the high non-HDL-C group than that in the low non-HDL-C group (log-rank test; p=0.006). Furthermore, in proportional regression analysis adjusted for conventional coronary risk factors, metabolic syndrome, statin treatment, and use of artery bypass graft, the increased levels of non-HDL-C were significant and independent predictor of cardiac death beyond other lipid parameters (RR1.22; by 10 mg/dL non-HDL-C increasing, 95% confidence interval 1.03-1.44; p<0.05). CONCLUSIONS: The increased levels of non-HDL-C were significantly associated with an increased risk of cardiac death. Baseline non-HDL-C levels may be a practical predictor of long-term cardiac death in patients with CHD after CABG.

Small dense LDL cholesterol is a robust therapeutic marker of statin treatment in patients with acute coronary syndrome and metabolic syndrome.

BACKGROUND: Small dense low-density lipoprotein (sd-LDL) is an atherogenic LDL subfraction and often increased in metabolic syndrome (MetS). This study aimed to determine whether sd-LDL cholesterol (sd-LDL-C) is a therapeutic marker of statin treatment in patients with acute coronary syndrome (ACS) and MetS. METHODS: We examined 71 patients with ACS and 50 non-ACS subjects with normal coronary arteries (controls). The patients with ACS were treated with life-style modifications (n=36) or those plus 20mg atorvastatin daily (n=35) for 6 months. We measured sd-LDL-C by a novel detergent-based homogenous assay and calculated buoyant LDL-C (b-LDL-C). RESULTS: The patients with ACS had higher sd-LDL-C than did the controls (30±14 vs. 22±8 mg/dl, p<0.001). Furthermore, sd-LDL-C was higher in the patients with ACS and MetS (n=31) than in those without MetS (n=40) (35±17 vs. 27±11 mg/dl, p<0.05). Atorvastatin reduced LDL-C and sd-LDL-C by 31% (102±23 to 70±28 mg/dl, p<0.0001) and 24% (29±15 to 22±13 mg/dl, p<0.01). The reduction in sd-LDL-C by atorvastatin was 5.5-fold greater in the patients with ACS and MetS than in those without MetS (p<0.001). Contrary, that in b-LDL-C was similar between the groups. CONCLUSIONS: sd-LDL-C is a superior therapeutic marker of statin treatment in patients with ACS and MetS.

Involvement of cholesterol-enriched microdomains in class A scavenger receptor-mediated responses in human macrophages.

OBJECTIVE: Lipid rafts are cholesterol-enriched microdomains on cell membranes. We hypothesized that these microdomains could involve modified low-density lipoprotein (LDL) uptake. METHODS AND RESULTS: Co-localizations of cholesterol-enriched microdomains and CD204 during the uptake of acetyl LDL (AcLDL) and oxidized LDL were observed using Alexa488-labeled polyethylene glycol cholesteryl ester, which is a sensitive probe used to analyze the dynamics of cholesterol-rich lipid microdomains in living cells. The lipid raft disruptors, methyl-ß cyclodextrin and filipin, inhibited the uptake of AcLDL. CD204 siRNA treatments significantly reduced AcLDL uptake by 80%. We also demonstrated the presence of CD204 in the detergent-resistant membrane fraction (DRM) by immunoblotting analysis. The ratio of CD204/flotillin-1 in DRM was increased 11.5-fold by modified LDL administration. The PI3 kinase inhibitor LY294002, but not the Src kinase inhibitor PP1 or the Gαi/o inhibitor pertussis toxin, inhibited modified LDL uptake. The production of interleukin (IL)-8, but not CCL2, CXCL2, CXCL3, IL-6 or tumor necrosis factor-α was increased by AcLDL administration. The AcLDL-induced IL-8 production was inhibited by LY294002 and filipin. CONCLUSIONS: These data firstly demonstrated that PI3 kinase-associated cholesterol-enriched microdomains are involved in CD204-mediated modified LDL uptake in human macrophages. Cholesterol-enriched microdomains may play a critical role in inflammatory processes.

Effects of fenofibrate on lipid profiles, cholesterol ester transfer activity, and in-stent intimal hyperplasia in patients after elective coronary stenting.

BACKGROUND: The association between modulation of detailed lipoprotein profiles and cholesterol ester transfer (CET) activity by peroxisome proliferator-activated receptor (PPAR)-a agonists in patients with coronary artery disease remains unclear. We assessed lipid profiles, plasma CET activity, and in-stent intimal hyperplasia after fenofibrate treatment in patients who underwent elective coronary stenting. METHODS: Forty-three consecutive patients who underwent elective coronary stenting were randomized to the fenofibrate group (300 mg/day for 25 weeks, n = 22) or the control group (n = 21). At baseline and follow up, CET activity and lipoprotein profiles were measured, and quantitative coronary angiography was performed. RESULTS: In the fenofibrate group, the levels of large very low-density lipoprotein cholesterol, and small low-density lipoprotein (LDL) cholesterol decreased and those of small high-density lipoprotein (HDL) cholesterol increased. Besides, CET activity decreased independent of the effect of fenofibrate on total and LDL cholesterol. The reduction of CET activity significantly correlated with the increase in LDL particle size (r = 0.47, P = 0.03) and the decrease of triglycerides in large HDL subclasses (r = 0.48, P = 0.03). Although there were no significant differences in restenosis parameters between the two groups, low CET activity significantly correlated with the inhibition of neointimal hyperplasia (r = 0.56, P = 0.01). CONCLUSIONS: Fenofibrate inhibited CET activity and thereby improved atherogenic lipoprotein profiles, and reduced intimal hyperplasia after coronary stenting.

Polyunsaturated fatty acid levels of serum and red blood cells in apparently healthy Japanese subjects living in an urban area.

AIM: We assessed levels of polyunsaturated fatty acid (PUFA) in serum and red blood cells (RBCs) among groups stratified by generation and its clinical significance in Japanese subjects living in an urban area. METHODS: We enrolled 200 apparently healthy Japanese (126 males, mean age: 50.3+/-9.2 years) living in an urban area. Levels of PUFA, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) in serum and RBCs were measured for each generation (G1 <35y, G2 35y-<45y, G3 45y-<55y, G4 55y-<65y, G5>or=65y). RESULTS: No significant differences in EPA, DHA, AA, or EPA/AA were observed between males and females. After dividing into generations, stepwise increases in EPA and DHA, but not DGLA or AA, were observed in serum (all p<0.0001). EPA/AA ratios were stepwisely increased in serum (mean: G1:0.26, G2:0.29, G3:0.43, G4:0.58, G5:0.68, p<0.0001) and RBCs (mean: G1:0.10, G2:0.09, G3:0.15, G4:0.20, G5:0.23, p<0.0001). Positive correlations of EPA (r=0.83), DHA (r=0.55), DGLA (r=0.54), AA (r=0.29), and EPA/AA (r=0.91) were demonstrated between serum and RBCs. In addition, a significant positive correlation between EPA/AA ratios and insulin sensitivity as well as a negative correlation between those ratios and insulin resistance were observed in subjects with metabolic syndrome. CONCLUSION: Low levels of EPA/AA, which were associated with insulin resistance, were demonstrated in young Japanese adults living in an urban area.

Effects of phase III cardiac rehabilitation on mortality and cardiovascular events in elderly patients with stable coronary artery disease.

BACKGROUND: Cardiac rehabilitation (CR) has numerous benefits, including reduction of mortality and cardiovascular events, in patients with coronary artery disease (CAD). However, the long-term effect of phase III CR in elderly patients with stable CAD is still unknown. METHODS AND RESULTS: The 111 elderly male CAD patients (>or=65 years), including 37 subjects participating in supervised CR for 6 months and 74 age-matched controls, were analyzed. The patients were followed for up to 3,500 days, until the occurrence of death or 1 of the following major adverse cardiovascular events (MACE): cardiovascular death, acute coronary syndrome, refractory angina requiring revascularization, admission for congestive heart failure, or stroke. All-cause mortality tended to be lower in the CR group than in the Control group (14% vs 28%, P=0.081). The MACE incidence was significantly lower in the CR group than in the Control group (30% vs 62%, P=0.001). Multivariate Cox proportional hazard analysis showed that the MACE incidence was significantly lower in the CR group than in the Control group [adjusted hazard ratio 0.43 (95% confidence interval 0.20-0.91), P=0.027]. CONCLUSIONS: Phase III CR has the beneficial effect of reducing cardiovascular events even in elderly patients with stable CAD.

Serum levels of remnant lipoprotein cholesterol and oxidized low-density lipoprotein in patients with coronary artery disease.

BACKGROUND: Oxidized low-density lipoprotein (OxLDL) and remnant lipoprotein play a crucial role in the development of atherosclerosis. Recently, a novel method for measuring remnant cholesterol levels (remnant lipoproteins cholesterol homogenous assay: RemL-C) has been established. However, the correlation between OxLDL and remnant lipoprotein, including RemL-C, has not been fully investigated. METHODS: We enrolled 25 consecutive patients with documented coronary artery disease (CAD) and 20 controls. Remnant-like particle cholesterol (RLP-C) and RemL-C were used to determine the levels of remnant lipoprotein cholesterol. Serum levels of malondialdehyde-modified LDL (MDA-LDL) and OxLDL using a monoclonal antibody DLH3 (OxPC) were used to measure the concentration of circulating OxLDL. RESULTS: The CAD group had high levels of fasting glucose and glycosylated hemoglobin (HbA1c), and low levels of high-density lipoprotein cholesterol compared with the control group. Serum levels of total cholesterol or LDL cholesterol were not significantly different between the two groups. The levels of RemL-C (p = 0.035), MDA-LDL (p = 0.018), and MDA-LDL/LDL-C (p = 0.036) in the CAD group were significantly higher than those in the control group. The levels of RLP-C tended to be higher in the CAD group than those in the control group (p = 0.096). Positive correlations were demonstrated between remnant lipoprotein cholesterol and OxLDL (RLP-C and MDA-LDL/LDL-C, r = 0.45, p = 0.0024, RLP-C and OxPC, r = 0.51, p = 0.0005, RemL-C and MDA-LDL/LDL-C, r = 0.42, p = 0.0044, RemL-C and OxPC, r = 0.43, p = 0.0043). Similar trends were observed in non-diabetic subjects and in subjects without metabolic syndrome. Positive correlations were also observed between RLP-C and RemL-C (r = 0.94, p < 0.0001) and between MDA-LDL/LDL-C and OxPC (r = 0.40, p = 0.0074). CONCLUSIONS: These results suggest that the association between high levels of remnant lipoprotein cholesterol and high OxLDL levels might be linked to atherogenesis in patients with CAD.

Deletion of the Fc receptors gamma chain preserves endothelial function affected by hypercholesterolaemia in mice fed on a high-fat diet.

AIMS: To clarify the role of Fc receptors (FcR) for immunoglobulin in endothelial dysfunction induced by hypercholesterolaemia, we evaluated the effect of deletion of the FcR gamma chain on endothelium-dependent relaxation and oxidative stress after 10 weeks on a high-fat diet in FcR gamma(-/-) mice compared with that in wild-type mice. METHODS AND RESULTS: Plasma cholesterol levels of those on the high-fat diet were significantly increased compared with those on the normal chow diet in both groups of mice. Endothelium-dependent relaxation of the aortic ring with acetylcholine in wild-type mice was significantly reduced by the high-fat diet (ED(50): 0.22 vs. 0.43 nM, P < 0.002), whereas the relaxation in FcR gamma(-/-) mice was not inhibited (ED(50): 0.22 vs. 0.23 nM, NS). Furthermore, superoxide detection by dihydroethidium-derived fluorescence and immunohistochemical staining of p22phox expression were significantly increased in wild-type mice fed on the high-fat diet, while these oxidative stresses in FcR gamma(-/-) mice were not enhanced by the high-fat diet. Oil Red O-staining showed no significant lipid accumulation at the aortic sinus in both groups of mice. CONCLUSION: This study demonstrates that the deletion of the FcR gamma chain preserves the endothelial function and attenuates oxidative stress affected by hypercholesterolaemia in FcR gamma(-/-) mice. These results indicate that FcR may play the pivotal role in endothelial dysfunction through oxidative stress induced by hypercholesterolaemia.

Effects of a phase III cardiac rehabilitation program on physical status and lipid profiles in elderly patients with coronary artery disease: Juntendo Cardiac Rehabilitation Program (J-CARP).

BACKGROUND: Limited data are available regarding the effects of phase III cardiac rehabilitation on the physical status and risk factors in elderly patients with coronary artery disease (CAD). METHODS AND RESULTS: Thirty-four male CAD patients (>65 years old) were randomly assigned to an intervention group (n=18) or a control group (n=16). The intervention group participated in a phase III cardiac rehabilitation program consisting of exercise training, diet therapy, and weekly counseling for 6 months. In the control group, usual outpatient care was provided. In the intervention group, body mass index, waist size and fat weight significantly decreased; peak VO2 and anaerobic threshold VO2 were maintained; isokinetic peak torques of knee extensor and flexor muscles significantly increased; anterior trunk flexibility was significantly improved. In the control group, all parameters were unchanged except for peak VO2, which significantly decreased. In the intervention group, serum total cholesterol levels significantly decreased after cardiac rehabilitation. However, high-density lipoprotein-cholesterol and apoA-I levels also decreased. In the control group, no significant change in lipid profile was observed. CONCLUSIONS: The results suggest that phase III cardiac rehabilitation could be beneficial for elderly patients with CAD.

Insulin response to oral glucose load is associated with coronary artery disease in subjects with normal glucose tolerance.

AIM: The critical role of hyperinsulinemia, independent of hyperglycemia, in the pathogenesis of atherosclerosis has not been fully determined. We investigated the association between secretion patterns of insulin after oral glucose load and the severity of coronary artery disease (CAD) in patients with normal glucose tolerance (NGT). METHODS: We enrolled 116 subjects with NGT from 243 patients who had undergone coronary angiography and a standard 75-g oral glucose tolerance test. The patients were divided into 0-vessel, single-vessel and multi-vessel disease groups on the basis of the severity of CAD. RESULTS: The 2-h insulin levels in the multi-vessel disease group (p=0.005) and the single-vessel disease group (p<0.05) were significantly higher than those in the 0-vessel disease group. Multivariate analysis revealed that the levels of 2-h insulin were an independent variable for the presence of CAD (p=0.02) after adjustment for gender and the presence of each criterion of metabolic syndrome using the definition of the International Diabetes Federation. CONCLUSION: A slight but significant increase in prolonged insulin secretion, which is associated with the early stage of insulin resistance, in subjects with NGT, may play an important role in the pathogenesis of atherosclerosis.

High levels of saturated very long-chain fatty acid (hexacosanoic acid; C26:0) in whole blood are associated with metabolic syndrome in Japanese men.

OBJECTIVE: Hexacosanoic acid (C26:0) is a saturated very long-chain fatty acid and high levels of C26:0 in red blood cells are reported to be closely related with risk factors of atherosclerosis. However, the relationship between absolute levels of C26:0 in whole blood and metabolic syndrome (MS) has not been determined. MATERIALS AND METHOD: We divided 218 consecutive apparently healthy male subjects into an MS group (n=78) and a non-MS group (n=140) according to the definition of the International Diabetes Federation. The levels of C26:0 in whole blood were measured by gas liquid chromatography-mass spectrometry. RESULTS: The MS group had significantly higher levels of C26:0 than the non-MS group (2.42+/-0.31mug/ml vs. 2.25+/-0.29mug/ml, P=0001). There was a significant association between the levels of C26:0 and the number of factors of MS. The levels of C26:0 positively correlated with age, blood pressure, triglyceride and fasting plasma glucose. Multivariate analysis revealed that the level of C26:0 is still an independent variable for the presence of MS after adjustment for age and each criterion of MS. CONCLUSION: The absolute levels of C26:0 in whole blood appear to be associated with MS independent of its component parts.

[Prevention and treatment for development and progression of diabetic macroangiopathy with pioglitazone and metformin].

Prevention and treatment for diabetic macroangiopathy, causing the main etiology for mortality in patients with diabetes mellitus, is crucial target point, but is still controversial. Many clinical studies improving glycemic control by insulin and oral drugs were not demonstrating enough prevention for diabetic macroangiopathy to improve life prognosis. Insulin resistance is now considered to be major pathogenesis for diabetic macroangiopathy. The agents that improve insulin resistance, such as metformin and pioglitazone, have multiple effects to improve glucose and lipid metabolism by increasing sensitivity for insulin without increasing insulin secretion and exert anti-atherogenic properties resulting in preventing development of atherosclerosis. Some clinical studies such as UKPDS 34 and PROactive demonstrated preventive effects of these agents for diabetic macroangiopathy.

Circulating malondialdehyde-modified LDL and atherogenic lipoprotein profiles measured by nuclear magnetic resonance spectroscopy in patients with coronary artery disease.

OBJECTIVE: Recent studies have suggested that circulating malondialdehyde-modified low-density lipoprotein (MDA-LDL) is a useful marker for the identification of patients with coronary artery disease (CAD). However, the role of MDA-LDL in atherogenic mechanisms has not yet been fully determined. METHOD AND RESULTS: We investigated lipoprotein profiles measured by nuclear magnetic resonance (NMR) spectroscopy and circulating MDA-LDL levels measured by ELISA in 25 male patients with CAD and 15 age-matched male controls. We selected subjects who had a serum LDL cholesterol<160 mg/dL. The MDA-LDL levels were significantly higher in the CAD group than in the control group (P=0.01) even though there was no significant difference in the LDL cholesterol levels between the two groups. NMR analysis demonstrated that the MDA-LDL levels were positively correlated with large and intermediate very low-density lipoprotein triglyceride and LDL particle concentrations, and negatively correlated with LDL diameter and large high-density lipoprotein cholesterol. The MDA-LDL levels were negatively correlated with flow-mediated dilatation of the brachial artery. CONCLUSIONS: The high concentrations of circulating MDA-LDL derived from the atherogenic lipoprotein profiles, which induce the exaggerated production of small dense LDL. The circulating MDA-LDL may impair endothelial function and play an important role in the pathogenesis of atherosclerosis.

Circulating oxidized low-density lipoprotein is an independent predictor for cardiac event in patients with coronary artery disease.

Oxidized low-density lipoprotein (oxLDL) plays a crucial role in the development of atherosclerosis, however, the predictive value of circulating oxLDL for cardiac events (CE) in patients with coronary artery disease (CAD) has remained poorly understood. We prospectively studied 238 consecutive patients with documented CAD for up to 52 months until the occurrence of one of the following cardiac events: cardiac death, nonfatal myocardial infarction (MI), and refractory angina requiring revascularization. The plasma levels of oxLDL were measured by an enzyme-linked immunosorbent assay (ELISA) using the monoclonal antibody, DLH3. The levels of circulating oxLDL were significantly higher in patients with CE than in patients without CE (median 20.3 U/ml versus 17.6 U/ml, P = 0.002). Multivariate Cox models showed that higher level of oxLDL was an independent predictor of developing CE. The adjusted hazard ratios for CE were 3.15 (95% CI 1.47-6.76, P = 0.003) times higher in patients with the highest quartile of oxLDL levels and 1.88 (95% CI 0.90-3.95, P = 0.09) times higher in patients with the third quartile than in those within the lowest quartile. Thus, measurement of circulating oxLDL may be helpful in the assessment of future CE in patients with CAD.

Promoter polymorphism in the CD14 gene and concentration of soluble CD14 in patients with in-stent restenosis after elective coronary stenting.

BACKGROUND: Activated monocytes/macrophages, neutrophils, endothelial cells and smooth muscle cells participate in the restenosis processes. Monocytes/macrophages and neutrophils are activated by lipopolysaccharide (LPS) via CD14. Endothelial cells and smooth muscle cells are also stimulated by soluble CD14 (sCD14)-LPS complexes. METHODS: We tested the hypothesis that C(-260)-->T polymorphism of the CD14 gene and sCD14 might be predictors for in-stent restenosis. We analyzed 129 consecutive patients who underwent elective coronary stenting. The restenosis was defined as > or =50% diameter stenosis at follow-up angiography. RESULTS: The prevalence of the T/T genotype and the concentration of sCD14 were significantly higher in the restenosis group than in the no-restenosis group. This CD14 polymorphism also affected the levels of sCD14, therefore, we divided the patients into four groups. The loss index was 24.8% in C/C or C/T and < or =50th percentile of sCD14, 35.9% in T/T and < or =50th percentile of sCD14, 44.2% in C/C or C/T and >50th percentile of sCD14, and 49.1% in T/T and >50th percentile of sCD14 (P=0.02). The restenosis rate was 10.0%, 26.7%, 26.2% and 50.0% in each group, respectively (P=0.003). In the multivariate analysis, T/T and >50th percentile of sCD14 was the independent predictor for in-stent restenosis. CONCLUSIONS: This study showed that the T/T genotype with a high level of sCD14 is an independent predictor of in-stent restenosis. The activation of monocytes/macrophages, endothelial cells and smooth muscle cells mediated by CD14 and/or sCD14 may play an important role in the restenosis processes.

R/R genotype of human paraoxonase (PON1) is more protective against lipoprotein oxidation and coronary artery disease in Japanese subjects.

Human paraoxonase (PON1) is an high-density lipoprotein (HDL) -associated enzyme that is proposed to protect against the oxidation of lipoproteins. Recently, the association of coronary artery disease (CAD) and PON1 activity was reported. Furthermore, the R/R genotype of PON1 has been related to the risk for CAD. In this study we investigated the PON1 genotype and susceptibility to lipoprotein oxidation to elucidate the contribution of PON1 to atherosclerosis in Japanese subjects. We studied 179 patients who underwent coronary angiography and their PON1 genotypes were determined. Lipoproteins were obtained from a patient's blood after at least 12 hours fasting and were separated with sequential ultracentrifugation. We analyzed the thiobarbituric acid reactive substances (TBARS) and continuously monitored the copper-induced oxidation three genotype groups. Genotype frequencies of Q/Q, Q/R, and R/R were 21.2%, 36.9%, and 41.9%, respectively. PON1 polymorphism clearly determined the lipid oxidation. The R/R genotype of PON1 had significantly lower levels of plasma and HDL TBARS and significantly retarded the initiation of oxidation in HDL and low-density lipoprotein (LDL). The R/R genotype was related to the lower prevalence of CAD. The PON1 genotype clearly determined the oxidative modification of lipoproteins and may play a role in the pathogenesis of atherosclerosis via its protective effect against lipoprotein oxidation in Japanese subjects.

Preventing angiographic progression of coronary atherosclerosis with pravastatin.

We conducted a prospective study to investigate the relationship between the decrease of serum lipid levels during pravastatin therapy and changes of coronary angiography parameters in Japanese patients with coronary atherosclerosis. The patients were predominantly male, aged between 18 and 75 years (mean: 58 years), had at least 25% stenosis of one or more major coronary arteries, and had a serum total cholesterol ( TC) level > or = 200 mg/dl (5.18 mM/l). Treatment with pravastatin (10 mg/day) was continued for 3 years. Coronary angiography was performed before and 3 years after the start of pravastatin therapy to assess the relationship between the mean segment diameter (MSD), the minimal lumen diameter (MLD), and the annual changes of percent stenosis and TC levels. of 265 patients who were initially registered, 129 were followed for an average of 35 months. Consequently, second angiograms were only obtained in 68 patients for various reasons, so this group was used for analysis. During pravastatin therapy, the TC level significantly decreased from 239 mg/dl (6.19 mM/l) to 210 mg/dl (5.44 mM/l) (a 12% reduction; p<0.001). In addition, HDL-cholesterol increased by 5% (p=0.007), but the triglyceride level did not show a significant change. Both MSD and MLD were significantly improved on follow-up angiography, increasing from 2.67 mm to 2.76 mm and from 2.09 mm to 2.13 mm, respectively. However, no change of percent stenosis was observed. The mean TC level during treatment did not show any significant correlation with the changes of angiography parameters. However, a significant correlation was observed between the percent reduction of TC and the annual change of MSD (r=-0.272, p=0.027). A similar relationship was also found between the change of MLD and the percent reduction of TC (r=-0.260, p=0.035). In conclusion, the percent decrease of serum cholesterol may be a better indicator of clinical efficacy than the absolute cholesterol level during pravastatin therapy.