Effects of 6-month eicosapentaenoic acid treatment on postprandial hyperglycemia, hyperlipidemia, insulin secretion ability, and concomitant endothelial dysfunction among newly-diagnosed impaired glucose metabolism patients with coronary artery disease. An open label, single blinded, prospective randomized controlled trial.

BACKGROUND: Recent experimental studies have revealed that n-3 fatty acids, such as eicosapentaenoic acid (EPA) regulate postprandial insulin secretion, and correct postprandial glucose and lipid abnormalities. However, the effects of 6-month EPA treatment on postprandial hyperglycemia and hyperlipidemia, insulin secretion, and concomitant endothelial dysfunction remain unknown in patients with impaired glucose metabolism (IGM) and coronary artery disease (CAD). METHODS AND RESULTS: We randomized 107 newly diagnosed IGM patients with CAD to receive either 1800 mg/day of EPA (EPA group, n = 53) or no EPA (n = 54). Cookie meal testing (carbohydrates: 75 g, fat: 28.5 g) and endothelial function testing using fasting-state flow-mediated dilatation (FMD) were performed before and after 6 months of treatment. The primary outcome of this study was changes in postprandial glycemic and triglyceridemic control and secondary outcomes were improvement of insulin secretion and endothelial dysfunction. After 6 months, the EPA group exhibited significant improvements in EPA/arachidonic acid, fasting triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). The EPA group also exhibited significant decreases in the incremental TG peak, area under the curve (AUC) for postprandial TG, incremental glucose peak, AUC for postprandial glucose, and improvements in glycometabolism categorization. No significant changes were observed for hemoglobin A1c and fasting plasma glucose levels. The EPA group exhibited a significant increase in AUC-immune reactive insulin/AUC-plasma glucose ratio (which indicates postprandial insulin secretory ability) and significant improvements in FMD. Multiple regression analysis revealed that decreases in the TG/HDL-C ratio and incremental TG peak were independent predictors of FMD improvement in the EPA group. CONCLUSIONS: EPA corrected postprandial hypertriglyceridemia, hyperglycemia and insulin secretion ability. This amelioration of several metabolic abnormalities was accompanied by recovery of concomitant endothelial dysfunction in newly diagnosed IGM patients with CAD. Clinical Trial Registration UMIN Registry number: UMIN000011265 ( https://www.upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000013200&language=E ).

Myocardial blood volume reserve by intravenous contrast echocardiography predicts improvement in left ventricular function in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Impaired myocardial perfusion has been shown in nonischemic dilated cardiomyopathy (DCM). Intravenous myocardial contrast echocardiography (MCE) has been introduced to examine myocardial blood volume (MBV) noninvasively. This study was designed to evaluate if MBV reserve assessed by intravenous MCE with adenosine triphosphate (ATP) can predict efficacy of optimal medical therapy in patients with DCM. METHODS AND RESULTS: Fifteen DCM patients and 8 control subjects underwent conventional echocardiography and intravenous MCE. We obtained the change in peak contrast integrated backscatter intensity (∆PI) by ATP on the left ventricular (LV) anteroseptal myocardium. After 3 months of optimal medical therapy in DCM patients, we reperformed conventional echocardiography. A good responder to therapy was defined as a decrease in LVDd >5 mm to final LVDd <55 mm and increase in LVEF >20 % to final LVEF >45 %. In DCM patients, ∆PI was lower compared to controls (p < 0.001). Good responders to therapy (n = 6) had higher ∆PI than poor responders (n = 9) (p < 0.05). CONCLUSIONS: The present study demonstrates that the response to the medical therapy in DCM is predicted by the assessment of dilator reserve in MBV. Intravenous MCE with ATP may provide useful information to evaluate MBV reserve.

Effects of human atrial natriuretic peptide on myocardial performance and energetics in heart failure due to previous myocardial infarction.

BACKGROUND: Human atrial natriuretic peptide (hANP) and spontaneous nitric oxide (NO) donor share cyclic guanosine monophosphate (cGMP) as a second messenger, but their effect on myocardium may differ. We compared the effect of hANP and sodium nitroprusside (SNP) on left ventricular (LV) mechano-energetics in heart failure (HF). METHODS: Ten patients with HF due to previous myocardial infarction (LV ejection fraction: 45±3%) were instrumented with conductance and coronary sinus thermodilution catheters. LV contractility (Ees: slope of end-systolic pressure-volume relation) and the ratio of LV stroke work (SW) to myocardial oxygen consumption (SW/MVO2=mechanical efficiency) were measured in response to intravenous infusion of ANP (0.05 µg/kg/min) or SNP (0.3 µg/kg/min) to lower blood pressure by at least 10 mmHg, and changes in plasma cGMP. RESULTS: SNP had no effect on Ees, SW, or MVO2, thus SW/MVO2 remained unchanged (40.54±5.84% to 36.59±5.72%, p=0.25). ANP increased Ees, and decreased MVO2 with preserved SW, resulting in improved SW/MVO2 (40.49±6.35% to 50.30±7.96%, p=0.0073). Infusion of ANP (10.42-34.95 pmol/ml, p=0.0003) increased cGMP levels, whereas infusion of SNP had no effect (10.42-12.23 pmol/ml, p=0.75). CONCLUSIONS: Compared to SNP, the ANP-dependent increase in cGMP may ameliorate myocardial inotropy and energetics in HF.

Easy-to-use comprehensive speckle-tracking approach for cardiac resynchronization therapy.

BACKGROUND: Left ventricular (LV) dyssynchrony has emerged as an important mechanism contributing to the patient's response to cardiac resynchronization therapy (CRT), but other potential factors, especially LV myocardial viability, are also influential. METHODS AND RESULTS: We studied 132 patients undergoing CRT. LV dyssynchrony was determined by anteroseptal-to-posterior wall delay on the mid-LV short-axis view using 2-dimensional speckle-tracking radial strain (≥130 ms as significant). Global circumferential strain (GCS), considered as a parameter of LV intrinsic myocardial function, was also determined as the peak GCS from the same view. Long-term follow-up was tracked over 40 months. Kaplan-Meier analysis indicated that patients with GCS >3.9% experienced fewer cardiovascular events overall (log-rank P=0.034). Similarly, patients with GCS >3.9% and ≥6.6% experienced fewer cardiovascular events than those with GCS ≤3.9% and <6.6% among patients with and without LV dyssynchrony (log-rank P=0.025 and P=0.029, respectively). An important finding from multivariate Cox proportional hazards analysis was that LV dyssynchrony and GCS were independently associated with cardiovascular events. Of note, only 2±1 min per patient were needed to analyze both LV dyssynchrony and GCS from the same routine mid-LV short-axis view. CONCLUSIONS: This easy-to-use combined assessment of LV dyssynchrony and myocardial function using speckle-tracking strain from the same mid-LV short-axis view may well have clinical implications for CRT.

Comparison of effects of α-Glucosidase inhibitors and glinide drugs on endothelial dysfunction in diabetic patients with coronary artery disease.

BACKGROUND: Studies have shown that repeated post-prandial hyperglycemia may play an important role in the development of atherosclerosis by suppressing endothelial function. α-Glucosidase inhibitors (α-GIs), which reduce post-prandial hyperglycemia without stimulating insulin secretion, significantly reduce the risk of coronary artery disease (CAD), whereas glinides, which improve post-prandial hyperglycemia through post-prandial insulin secretion, do not appear to affect CAD. METHODS AND RESULTS: A total of 104 diabetic patients with CAD were randomly divided into 2 groups: those treated with miglitol (M-group; n=52) and those treated with nateglinide (N-group; n=52). After 4 months' treatment, although hemoglobin A1c and 1,5-anhydroglucitol were significantly improved in both groups, only the M-group had significant reductions in insulin resistance index and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C; a beneficial index for assessing the presence of small dense low-density lipoprotein, and a marker of atherogenic dyslipidemia). Furthermore, only the M-group had improvement in percentage flow-mediated dilatation (%FMD) and reactive oxygen metabolites. In the M-group, multiple regression analysis showed that improvement in TG/HDL-C, in addition to 1,5-anhydroglucitol, was an independent predictor of improvement in %FMD. CONCLUSIONS: The ameliorating effect of α-GI on post-prandial hyperglycemia without stimulating insulin secretion may improve atherogenic dyslipidemia by reducing insulin resistance. These effects are associated with its beneficial impact on oxidative stress, consequently leading to an improvement in endothelial dysfunction.

The apolipoprotein B/A1 ratio is associated with reactive oxygen metabolites and endothelial dysfunction in statin-treated patients with coronary artery disease.

AIM: The prognostic significance of the apolipoprotein B/A1 (ApoB/A1) ratio in statintreated patients with coronary artery disease (CAD) is unknown. We aimed to evaluate the association of the ApoB/A1 ratio with oxidative stress and endothelial dysfunction in these patients. METHODS: We enrolled 62 consecutive statin-treated patients who underwent percutaneous coronary intervention (PCI). Their lipid profiles, diacron-reactive oxygen metabolites (d-ROMs), as a marker of oxidative stress, flow-mediated dilatation (FMD), as a marker of vascular endothelial function, and C-reactive protein (CRP) levels, as a marker of inflammation, were measured. RESULTS: Our study population comprised 44 men and 18 women (mean age, 70.5 ± 2.5 years). The ApoB/A1 ratio was positively correlated with the results of the d-ROMs test (p=0.004, r=0.36) and CRP level (p=0.02, r=0.30) and negatively correlated with the %FMD (p=0.005, r=-0.40). A multivariate logistic regression analysis showed that the most powerful predictive factor for the d-ROMs was the ApoB/A1 ratio (p=0.026). We therefore divided patients into two groups according to the cutoff point reported by the INTERHEART study: a low ApoB/A1 ratio (<0.641, n=26) and a high ApoB/A1 ratio (>0.641, n=36). The patients with a high ApoB/A1 ratio had higher levels of d-ROMs and CRP, and tended to have a lower %FMD. CONCLUSION: The ApoB/A1 ratio was associated with the d-ROMs, a marker of oxidative stress, endothelial dysfunction and inflammation, and could be useful as a residual atherosclerotic risk marker to help prevent CAD in statin-treated patients.

Comparisons of detailed arterial healing response at seven months following implantation of an everolimus- or sirolimus-eluting stent in patients with ST-segment elevation myocardial infarction.

BACKGROUND: The difference of arterial healing response following everolimus-eluting stent (EES) or sirolimus-eluting stent (SES) implantation in patients with ST-segment elevated myocardial infarction (STEMI) has not been compared in detail. METHODS: Thirty-five patients with STEMI were randomly implanted with an EES or SES (23 EES, 12 SES). At seven months, neointimal thickness (NIT) and strut malapposition were evaluated by optical coherence tomography (OCT) and the grade and heterogeneity of neointimal coverage (NIC) and development of intra-stent thrombi were evaluated by angioscopy. RESULTS: No significant differences were noted in clinical events experienced by the two groups, although one patient with an EES died following a papillary muscle rupture and one patient with a SES experienced sub-acute stent thrombosis. On OCT, although the EES implants showed a greater NIT than the SES implants (94.8 ± 88.8 µm vs 65.6 ± 63.3 µm, P<0.0001), both the EES and SES showed an excellent suppression of neointimal proliferation in the culprit lesion of STEMI. The frequency of uncovered and malapposed struts of EES was significantly lower than that of SES (2.7% vs. 15.7%, P<0.0001, 0.7% vs. 2.3%, P<0.0001, respectively). The ratio of stents fully covered with neointima of EES group was significantly higher than that of SES group (P=0.04). Angioscopic analysis also showed greater dominant NIC grade with homogenous NIC in EES than in SES (P=0.03, P=0.0002, respectively). The incidence of massive intra-stent thrombus of EES was lower than that of SES (P=0.05). CONCLUSION: For patients with STEMI, EES may promote better arterial healing response than SES.

Qualitative and quantitative assessment of stent restenosis by optical coherence tomography: comparison between drug-eluting and bare-metal stents.

BACKGROUND: We hypothesized that the tissue components of in-stent restenosis (ISR) might differ between drug-eluting stents (DES) and bare-metal stents (BMS) and that these differences could be distinguished by qualitative and quantitative optical coherence tomography (OCT) analyses. METHODS AND RESULTS: One-hundred and twenty-two initial ISR lesions (sirolimus-eluting stents: n=28; paclitaxel-eluting stents: n=51; BMS: n=43) were evaluated with OCT. Based on their OCT appearance, the lesions were classified as homogeneous, layered or heterogeneous. The optical properties of backscatter, attenuation and signal intensity of the neointimal tissue (NIT) were quantified. To evaluate the vascular response after balloon angioplasty (BA), the rate of reduction of the NIT area (NITA) was calculated (NITA before - after BA/NITA before BA at the minimum lumen cross-sectional area). Among the morphologic OCT patterns, the layered type was predominant with DES, whereas lesions were homogeneous with BMS (P<0.001). Backscatter and signal intensity were significantly higher with BMS (P<0.05 and P<0.001 respectively). The NITA reduction rate was significantly greater in the layered and heterogeneous groups than in the homogeneous group (P<0.01). CONCLUSIONS: The morphologic OCT patterns of the NIT in ISR differed significantly between DES and BMS, probably reflecting pathologic differences. Layered and heterogeneous tissues might respond better than homogeneous tissue to simple balloon dilatation, suggesting a possible direction for OCT-based ISR treatment strategies.

Possible association between non-invasive parameter of flow-mediated dilatation in brachial artery and whole coronary plaque vulnerability in patients with coronary artery disease.

BACKGROUND: Despite being a relatively widely-used non-invasive parameter of endothelial dysfunction, little is known regarding the relationship between flow-mediated dilatation (FMD) and coronary plaque vulnerability in patients with coronary artery disease (CAD). METHODS: 111 CAD patients (age; 68.9 ± 9.3) who underwent both coronary intervention and FMD were enrolled. Spectral analyses of intravascular ultrasound radiofrequency data for both culprit and non-culprit lesions were performed using Virtual Histology software. Plaque burden was described based on fibrotic, fibro-fatty, dense calcium, and necrotic core (NC) components, and thin-cap fibroatheroma (TCFA) was defined as focal NC rich (> 10%) plaques touching the lumen with a percent-plaque volume exceeding 40%. RESULTS: Averaged %FMD was 2.86 ± 2.03% (median 2.27%, 25th 1.40%, 75th 4.20%). NC volumes were negatively correlated with log%FMD for both culprit and non-culprit lesions (P = 0.001, r = 0.31 and P = 0.03, r = 0.21, respectively). We divided the patients into three tertiles according to %FMD; 38 were lower (≤ 1.75%), 41 were middle (> 1.75%, but ≤ 3.5%), and 32 were upper tertile (> 3.5%). The prevalence rate of TCFA increased with decreasing %FMD tertile and the incidence of major adverse cardiac events was significantly higher in lower %FMD tertile. Multivariate logistic regression analyses showed that the most powerful predictive factor for TCFA was log%FMD (P < 0.0001), and ROC curve analysis identified %FMD of < 2.81% (AUC = 0.82, sensitivity: 91.2%, specificity: 66.7%) as the optimal cut-off point for predicting the presence of TCFA. CONCLUSIONS: Impaired endothelial function in brachial arteries may be associated with whole coronary plaque vulnerability and poor clinical outcome in patients with CAD.

Utility of combined assessment of baseline dyssynchrony and its acute improvement to predict long-term outcomes after cardiac resynchronization therapy.

Although left ventricular (LV) mechanical dyssynchrony can predict the response to cardiac resynchronization therapy (CRT), the presence of baseline LV dyssynchrony might not be the only determinant of the response to CRT. The objectives of the present study were to test the hypothesis that a combined assessment of baseline LV dyssynchrony and its acute improvement can produce a more accurate prediction of the long-term outcomes after CRT. We studied 121 patients with heart failure undergoing CRT. LV dyssynchrony was determined by measuring the anteroseptal-to-posterior wall time delay using the speckle-tracking radial strain (≥130 ms was predefined as significant) and was assessed at baseline and 7 ± 3 days after CRT. Long-term unfavorable outcome events were tracked for 5 years. Acute improvement in LV dyssynchrony of ≥33% was predictive of the long-term outcome with an area under the curve of 0.67 (p = 0.0024). Using this cutoff value, the Kaplan-Meier curve showed that patients with acute improvement in LV dyssynchrony experienced fewer cardiovascular events than those without (log-rank p = 0.0002). The event-free survival of patients whose baseline LV dyssynchrony was ≥130 ms and whose acute improvement in LV dyssynchrony was ≥33% was greater than that of the patients with baseline LV dyssynchrony of ≥130 ms but with acute improvement in LV dyssynchrony of <33% (88% vs 65%, p = 0.012). In conclusion, the combined assessment of baseline LV dyssynchrony and its acute improvement after CRT produced a more accurate prediction of long-term outcomes after CRT.

The change in low-density lipoprotein cholesterol concentration is positively related to plasma docosahexaenoic acid but not eicosapentaenoic acid.

AIM: The Japan EPA Lipid Intervention Study (JELIS) reported a 19% reduction of the risk for coronary artery disease after long-term use of pure eicosapentaenoic acid (EPA) in Japanese patients with hypercholesterolemia. The variation in plasma fatty acid composition influenced the risk of coronary events. The aim of this study was to examine in JELIS participants the possible correlation of changes in plasma fatty acids with those of serum lipids. METHODS: The coefficient for the correlation between the absolute change in plasma fatty acid concentrations and the changes in serum lipids was calculated in 13,901 JELIS participants. RESULTS: Low-density lipoprotein (LDL) cholesterol exhibited a positive correlation with docosahexaenoic acid (DHA; r=0.117 in control group, r=0.155 in EPA group) and linoleic acid (r=0.139 in control group, r=0.177 in EPA group), but the correlation coefficients with EPA (r=0.097 in control group, r=-0.032 in EPA group) were less than 0.1. We distributed the patients into 9 groups according to tertiles of the change in EPA and DHA. The average absolute decrease of LDL cholesterol and L/H ratio in each group was significantly smaller (p<0.001) in the DHA-high tertile, but not in any EPA tertile. CONCLUSION: The changes in DHA, but not in EPA, showed a positive correlation with the changes in LDL-cholesterol.

Effect of 3-month repeated administration of miglitol on vascular endothelial function in patients with diabetes mellitus and coronary artery disease.

Repeated postprandial hyperglycemia may play an important role in the development of atherosclerosis by suppressing vascular endothelial function. Although miglitol suppresses the elevation of blood glucose levels shortly after a meal more than other α-glucosidase inhibitors, the effect of 3-month repeated administration of miglitol on endothelial dysfunction is unknown. Fifty patients with type 2 diabetes and coronary artery disease were enrolled in the present study. The patients were randomly divided into 2 groups, the first treated with miglitol and the second with voglibose for 3 months. Blood chemistry (lipid and blood glucose profiles, glycosylated hemoglobin, 1,5-anhydroglucitol, serum insulin levels, and C-reactive protein) and flow-mediated dilatation were measured at the beginning and end of the trial period. Patient characteristics and blood chemistry of the 2 groups were similar at the beginning of the trial. At the end of the trial, glycosylated hemoglobin decreased in the 2 groups, but the improvements in 1,5-anhydroglucitol in the miglitol group were significantly higher than in the voglibose group. Insulin resistance index, C-reactive protein, and percentage flow-mediated dilatation were also improved in the miglitol group but not in the voglibose group. In conclusion, 3-month repeated administration of miglitol improved vascular endothelial dysfunction by strongly suppressing postprandial hyperglycemia. Miglitol may have antiatherogenic effects in patients with type 2 diabetes and coronary artery disease.

Relationship between coronary artery disease and non-HDL-C, and effect of highly purified EPA on the risk of coronary artery disease in hypercholesterolemic patients treated with statins: sub-analysis of the Japan EPA Lipid Intervention Study (JELIS).

AIM: The present study examined the importance of reducing non-high-density lipoprotein cholesterol (non-HDL-C) for the primary prevention of the occurrence of coronary artery disease (CAD) in the JELIS, and the effects of EPA. METHODS: The patients were distributed into 4 subgroups using the lipid management goal for LDL-C recommended by the Japan Atherosclerosis Society guideline (2007) and the goal for non-HDL-C defined as 30 mg/dL higher than LDL-C: A) achieved both goals; B) achieved the LDL-C but not non-HDL-C goal; C) achieved the non-HDL-C but not LDL-C goal; and D) did not attain either goal. The incidences of CAD in the 4 subgroups were compared, and the effects of eicosapentaenoic acid (EPA) on the risk of CAD in these subgroups were examined. RESULTS: In the non-EPA group, the incidence of CAD in patients who did not achieve the goals for LDL-C or non-HDL-C was higher than in patients who achieved those goals. Patients in subgroups B, C, and D were at higher risk for CAD than those in subgroup A (B, HR 2.31; C, HR 1.90; D, HR 2.47). EPA reduced the risk of CAD by 38% in subgroups B, C, and D (p= 0.007). CONCLUSION: We reconfirmed non-HDL-C as a predictor of the risk for CAD and a residual risk marker of CAD after LDL-C-lowering therapy. EPA was useful to reduce the occurrence of CAD in patients who did not achieve the goals for LDL-C and/or non-HDL-C.

Orally administered eicosapentaenoic acid induces rapid regression of atherosclerosis via modulating the phenotype of dendritic cells in LDL receptor-deficient mice.

OBJECTIVE: Eicosapentaenoic acid (EPA) has been shown to have beneficial effects on cardiovascular diseases, although the precise mechanism is unknown. We investigated the effect of EPA on the regression of atherosclerosis. METHODS AND RESULTS: LDL-receptor-deficient mice were fed a high-cholesterol diet for 8 weeks to build up aortic sinus atherosclerotic lesions and then were fed a normal diet with or without 5% EPA for 4 weeks. Atherosclerotic lesions were histologically assessed, and immunologic assays were performed. EPA treatment significantly regressed atherosclerosis (-22.7%, P<0.05) and decreased the content of macrophages, CD4(+) T cells, and dendritic cells (DCs) in atherosclerotic lesions, though only changing the chow never induced the regression. Flow cytometric analysis revealed that EPA increased immature DCs (CD11c(+) CD80(-) CD86(-)), increased the indoleamine 2,3-dioxygenase (IDO) in DCs, and decreased the number of CD4(+) T cells. In the presence of the IDO inhibitor, the beneficial effects of EPA on regression were inhibited, suggesting that the effect of EPA was mainly mediated through IDO. CONCLUSIONS: In addition to lowering plasma cholesterol, EPA regressed atherosclerosis probably due to modulation of DC phenotype and reduction in T cell numbers. The present findings might partly explain the beneficial effects of EPA in clinics and support clinical evidence.

Predictive importance of left ventricular myocardial stiffness for the prognosis of patients with congestive heart failure.

OBJECTIVES: This study was designed to determine the prognostic importance of left ventricular (LV) myocardial stiffness, a hemodynamic index which is closely related to B-type natriuretic peptide (BNP) concentration in patients with congestive heart failure (CHF). BACKGROUND: While elevated BNP, an abnormality of cardiac neurohormones, is known to be an independent marker of death or re-admission, it remains to be clarified whether there is also a strong predictor directly related to cardiac dysfunction. METHODS: LV performance variables and stress-strain analyses including diastolic myocardial stiffness constant (K(m)) were obtained from 37 patients with initial CHF by the combined simultaneous measurement of echocardiographic and hemodynamic data. Survivors were monitored for a mean of 23 months, with the main endpoint being combined death or first re-admission for CHF. RESULTS: Ten patients (27%) were primary endpoint cases. Both K(m) and plasma BNP levels were higher in the event than in the event-free group. By Cox proportional hazards analysis, K(m)≥4.0 was identified as the only variable with significant and independently incremental predictive power to affect the primary endpoint (adjusted hazard ratio=7.354, 95% confidence interval 1.379-39.232, p=0.02). CONCLUSIONS: In patients with CHF, increased myocardial stiffness may have greater prognostic significance compared to other conventional predictors. Increased myocardial stiffness may be considered to be an important prognostic factor independent of the loading conditions.

Serum levels of thiobarbituric acid-reactive substances are associated with risk of coronary heart disease.

AIM: Evidence of relationships between lipid peroxidation and the incidence of coronary heart disease is limited. We therefore investigated this association in a Japanese general population. METHODS: We prospectively studied 1945 individuals who were apparently healthy at the baseline. Cox proportional-hazards models were used to investigate the relationship between serum levels of thiobarbituric acid-reactive substances (TBARS) as a marker of lipid peroxidation and the incidence of coronary heart disease, adjusted for established risk factors including age, sex, current smoking, body mass index, systolic blood pressure, glycohemoglobin A1c, serum total cholesterol, and serum high-density lipoprotein cholesterol levels. RESULTS: During 20,226 person-years of follow-up (median follow-up, 10.9 years), 44 coronary events were documented. The risk of coronary heart disease increased in consecutive tertiles of the TBARS level. On age-and sex-adjusted analysis, the level of TBARS was significantly associated with the incidence of coronary heart disease. The hazard ratio in the highest tertile compared with the lowest tertile was 3.22 (95% confidence interval, 1.38 to 7.53; p= 0.007). On multivariate analysis adjusted for age, sex, and other established risk factors, this association remained significant (hazard ratio, 3.23; 95% confidence interval, 1.28 to 8.16; p= 0.01). CONCLUSIONS: Serum levels of TBARS are a strong and independent predictor of coronary heart disease. These findings support the hypothesis that lipid peroxidation is an important risk factor for coronary heart disease.

Relationships between plasma fatty acid composition and coronary artery disease.

AIM: The Japan EPA Lipid Intervention Study (JELIS) was the first prospective randomized clinical trial to demonstrate prevention of coronary events by pure eicosapentaenoic acid (EPA). The aim of this study was to examine the relationships between various plasma fatty acid concentrations and the risk of coronary events in JELIS participants. METHODS: In 15,534 participants, we calculated the hazard ratio for major coronary events (sudden cardiac death, fatal or nonfatal myocardial infarction, unstable angina pectoris, and angioplasty/stenting or coronary artery bypass grafting) relative to the on-treatment average level of plasma fatty acids with the Cox proportional hazard model. RESULTS: As a result of EPA intervention, the plasma EPA concentration increased, but the docosahexaenoic acid (DHA) concentration did not. The other fatty acids measured decreased slightly. The higher plasma level of EPA (hazard ratio=0.83, p=0.049, in all participants and hazard ratio=0.71, p=0.018, in the EPA intervention group), but not of DHA, was inversely associated with the risk of major coronary events. The associations between other fatty acids and the risk of major coronary events were not significant. In all JELIS participants, the risk of major coronary events was significantly decreased (20%) in the group with high (150 µg/mL or more) on-treatment plasma EPA concentration compared with that in the low (less than 87 µg/mL) group. CONCLUSION: The risk of coronary artery disease is influenced by variations in plasma fatty acid composition. Among n-3 polyunsaturated fatty acids, EPA and DHA exhibited differences in the correlation with the risk of major coronary events.

Repeated intra-stent thrombus formation in a patient with acute coronary syndrome due to poor responsiveness to clopidogrel may be associated with cytochrome P-450 2C19*2 polymorphism.

A drug-eluting stent was implanted at the culprit lesion in a 65-year-old man with acute coronary syndrome. Nine days after the procedure, he suffered stent thrombosis, and a bare-metal stent was subsequently implanted. Twelve days after this second procedure, a follow-up angiogram showed a newly emerged thrombus at the site of stent implantation. Although the patient had continued dual anti-platelet therapy with aspirin and clopidogrel since the first procedure, platelet optical aggregation test showed no inhibition of aggregation. Further, genetic analysis revealed him to be homozygous for the CYP2C19*2 polymorphism. This case suggests that the mechanism of stent thrombosis, while multi-factorial, is affected greatly by crossover of poor responsiveness to clopidogrel due to the CYP2C19*2 polymorphism.

Preventive effects of eicosapentaenoic acid on coronary artery disease in patients with peripheral artery disease.

BACKGROUND: The JELIS trial examined the preventive effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemia. Previous investigators have reported that patients with peripheral artery disease (PAD) have a poor prognosis due to the potential risk for CAD. We conducted a subanalysis to examine whether the incidence of CAD was high in patients with PAD and whether EPA prevented the occurrence of CAD. METHODS AND RESULTS: Of 18,645 the Japan EPA lipid intervention study (JELIS) patients, 223 had PAD (control group; complicated (n=77), newly diagnosed (n=29), EPA group; complicated (n=96), newly diagnosed (n=21)). We analyzed the incidence of major coronary events (MCE) in the 2 groups. Cox proportional hazard ratio adjusted for baseline risk factor levels was used to test differences between the 2 groups. The incidence of MCE in the control group was significantly higher in patients complicated with PAD and in those newly diagnosed with PAD than in patients without PAD (complicated: hazard ratio 1.97, P=0.039; newly diagnosed: hazard ratio 2.88, P=0.030). As for patients with PAD, the EPA group had a significantly lower MCE hazard ratio than the control group (hazard ratio 0.44, 95% confidence interval 0.19-0.97, P=0.041). CONCLUSIONS: Subanalysis of the JELIS trial demonstrated that in patients with PAD the incidence of CAD was higher than in controls, and that EPA markedly reduced the occurrence of CAD in those patients.