Atherosclerosis In Japanese Patients Research Articles

Silent Coronary Artery Disease in Japanese Patients Undergoing Carotid Artery Stenting

The aim of this retrospective study was to determine the prevalence of silent coronary artery disease (CAD) and the risk factors associated with concomitant CAD in Japanese patients undergoing carotid artery stenting (CAS). The records of 112 consecutive patients (99 men and 13 women; mean age 70 ± 8 years) who underwent elective CAS at our institution for extracranial carotid artery stenosis between January 2006 and January 2011 were reviewed retrospectively. During this period, preoperative CAD screening by coronary angiography was performed in all patients. Patients were diagnosed with CAD when ≥ 1 coronary arteries had stenosis ≥ 75% and were classified into 2 groups: (1) a group with CAD that was based on preoperative coronary angiography or a history of percutaneous coronary intervention (PCI) and/or coronary artery bypass grafting (CABG), and (2) a group without CAD that had no angiographically documented stenosis ≥ 75%. Sixteen (14.3%) patients had CAD that had already been treated by PCI and/or CABG. Silent CAD was detected in 39 (34.8%) of 112 patients. Taken together, 55 (49.1%) patients had clinically significant CAD. The patients with CAD were more likely to have diabetes mellitus (DM; P = .001), dyslipidemia (P = .013), and bilateral carotid disease (P = .033). Multivariate analysis revealed that DM (odds ratio 3.07; 95% confidence interval 1.25-7.53) and bilateral carotid stenosis (odds ratio 2.72; 95% confidence interval 1.10-6.75) were independent variables associated with concomitant CAD. Perioperative CAD screening revealed that silent CAD was frequently diagnosed in Japanese patients scheduled for CAS, particularly in those with DM and/or bilateral carotid stenosis.

Errata: Intensive Lipid-Lowering Therapy for Slowing Progression as Well as Inducing Regression of Atherosclerosis in Japanese Patients [International Heart Journal Vol. 54 (2013) No. 1 p. 33-39

Errata: Intensive Lipid-Lowering Therapy for Slowing Progression as Well as Inducing Regression of Atherosclerosis in Japanese Patients [International Heart Journal Vol. 54 (2013) No. 1 p. 33-39

Intensive Lipid-Lowering Therapy for Slowing Progression as Well as Inducing Regression of Atherosclerosis in Japanese Patients

This paper describes a subanalysis of the JART Study comparing rosuvastatin and pravastatin treatment. A total of 314 subjects were analyzed in this subanalysis, 282 of whom were eligible for evaluation of the relationship between LDL-C and carotid mean-IMT change. In the subanalysis, we evaluated the extent to which intensive lipid-lowering therapy slowed the mean-IMT progression by a correlation analysis between LDL-C and mean-IMT change after 12 months of statin treatment. Nearly half were male (49.4%) and elderly (49.7%). The majority (84.4%) were treated for primary prevention. Patients with hypertension and diabetes mellitus accounted for 65.3% and 44.0%, respectively. At the 12-month measurement point, mean-IMT change was correlated with LDL-C (R = 0.187; P = 0.0016), LDL-C/ HDL-C ratio (R = 0.152; P = 0.0105), and non-HDL-C (R = 0.132; P = 0.0259). Mean-IMT after 12 months was divided into 4 subgroups by LDL-C at 12 months; < 80, ≥ 80 to < 100, ≥ 100 to < 120, and ≥ 120 mg/dL. A trend analysis using the Jonckheere-Terpstra test showed statistical signifi cance (P = 0.0002). Even for prevention in Japanese patients who have lower risk of atherosclerotic disease than Western patients, lowering the LDL-C level to below the therapeutic target prevented mean-IMT progression after 12 months more strongly. These findings suggest that more intensive control of LDL-C to levels lower than those in current JAS guidelines should be required to achieve slowing of progression as well as induction of regression of atherosclerosis.

Higher lipoprotein-associated phospholipase A2 levels are associated with coronary atherosclerosis documented by coronary angiography

Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been proposed as an inflammatory marker of cardiovascular disease. The present study investigates associations between Lp-PLA2 and other important biomarkers in Japanese patients with coronary artery disease. We measured Lp-PLA2 levels in 141 consecutive patients (age 62.6 ± 3.8 years; men 69.2%) with angiographic evidence of coronary artery disease (acute coronary syndrome [ACS]; n = 38), stable angina pectoris (SAP; n = 72) or with angiographically normal coronary arteries (NCA; n = 31). Levels of Lp-PLA2 significantly correlated with low-density lipoprotein-cholesterol (r = 0.302), homocysteine (r = 0.528) and paraoxonase (r = 0.401) in all patients (all P < 0.01). Levels of Lp-PLA2 were significantly higher in patients with coronary atherosclerosis (ACS and SAP) than with NCA (P < 0.05). Levels of highly sensitive C-reactive protein were significantly higher in patients with ACS than with SAP and NCA (both P < 0.05). Multivariate logistic regression analyses revealed that higher Lp-PLA2 levels were independently associated with coronary atherosclerosis (odds ratio: 1.058; 95% confidence interval: 1.012-1.121; P = 0.001). Higher Lp-PLA2 levels are associated with coronary atherosclerosis independently of traditional coronary risk factors. Thus, Lp-PLA2 is a novel biomarker of coronary atherosclerosis in Japanese patients.

Pharmacodynamic assessment of a novel P2Y12 receptor antagonist in Japanese patients with coronary artery disease undergoing elective percutaneous coronary intervention

IntroductionNumerous reports have shown that prasugrel shows a rapid and consistent antiplatelet effect among European and US patients. Previous studies suggest that prasugrel might be expected to achieve an adequate antiplatelet effect in healthy Asian subjects, even at lower doses than those assessed in the TRITON-TIMI 38 study. In this study, the antiplatelet effect of prasugrel was evaluated in Japanese coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). Methods and resultsEighty-four patients were randomized into four treatment groups: prasugrel 10/2.5mg (loading dose [LD]/maintenance dose [MD]), 15/3.75mg or 20/5mg, and clopidogrel 300/75mg. The LD of each regimen was administered the day before PCI, followed by 28-day MD on aspirin background therapy (81–100mg). Antiplatelet effects were evaluated by light transmission aggregometry and VASP assay.The mean inhibition of platelet aggregation (IPA) induced by 20μM of adenosine diphosphate at 4hours after LD was higher among the prasugrel 10/2.5mg, 15/3.75mg and 20/5mg groups compared with the clopidogrel group (12.3%, 20.9%, 29.8% vs. 8.4%, respectively). The proportion of subjects with an IPA of <10% on Day 28 was lower among the prasugrel 15/3.75mg, and 20/5mg groups than in the clopidogrel group (0%, 6.3% vs. 15.8%, respectively). No “major” or “clinically relevant non-major” bleeding was observed. ConclusionsPrasugrel 15mg LD/3.75mg MD or higher doses was well tolerated and achieved a more rapid, higher and consistent antiplatelet effect than clopidogrel in Japanese CAD patients undergoing PCI.

Recurrence of angina pectoris after percutaneous coronary intervention is reduced by statins in Japanese patients

Statins have been reported to reduce cardiovascular events in patients with coronary artery disease (CAD). Percutaneous coronary intervention (PCI) is commonly used to relieve ischemic symptoms in patients with CAD. However, there is little information on the effect of statins on cardiovascular events after PCI, even in the era of coronary stent implantation. A total of 1019 patients with acute or chronic CAD and modest total cholesterol levels (180-240 mg/dl) were enrolled and randomly assigned to treatment with or without statins. We evaluated the effect of any available statin on the incidence of cardiovascular events after PCI. The primary endpoint was a composite of cardiovascular death, nonfatal acute myocardial infarction (MI), recurrent angina pectoris requiring emergency rehospitalization (rAP), heart failure, and stroke. Indications for PCI were stable angina in 54%, ST-elevation MI in 41% and non-ST-elevation MI/unstable angina pectoris in 5%. After 2 years of statin treatment, low-density lipoprotein cholesterol (LDL-C) decreased from 133 to 96 mg/dl. Stents were implanted in 84% of all cases. The primary endpoint event rate was 9.5% in the statin group and 14.7% in the non-statin group (p=0.0292). Of all primary endpoint events, only rAP was significantly suppressed by statins (p=0.0027). In rAP patients, coronary angiography revealed that statins suppressed restenosis but not new lesions. For Japanese CAD patients treated with PCI and stent implantation, statin therapy reduced the incidence of recurrent cardiovascular events, particularly rAP. Discretionary statin treatment to achieve LDL-C levels <100 mg/dl effectively reduced restenosis causing rAP.

Author's reply

We appreciate Dr Zhang's interest in our study [[1]Nakamura M. Yamashita T. Yajima J. Oikawa Y. Ogasawara K. Sagara K. Koike A. Kirigaya H. Nagashima K. Otsuka T. Uejima T. Funada R. Matsuno S. Suzuki S. Sawada H. et al.Impact of early statin initiation on secondary prevention in Japanese patients with coronary artery disease.J Cardiol. 2011; 57: 172-180Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] and the opportunity to discuss some issues. We also congratulate Dr Zhang and coworkers for their studies of the US National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry, which showed the effect of statins on reduction in mortality after percutaneous coronary intervention (PCI), consistent with our results, and the meta-analysis, which showed that statins were significantly associated with reduced repeat revascularization, but are unfortunately not associated with reduced mortality rate in patients undergoing PCI. As stated in our article, the relatively small size of the study population is one of the limitations. Propensity score analysis may be helpful for adjusting confounding factors efficiently. Moreover, the small number of events could lead to overestimation of the drug effects. We agree on these points with his comment. Therefore, a study with a larger population is now in progress and should allay his concerns. However, several previous studies using propensity score analysis have shown that the effect of early-initiated statins against death provided a similar level of risk reduction to our results in coronary artery disease (CAD) patients with or without PCI [2Lenderink T. Boersma E. Gitt A.K. Zeymer U. Wallentin L. Van de Werf F. Hasdai D. Behar S. Simoons M.L. Patients using statin treatment within 24 h after admission for ST-elevation acute coronary syndromes had lower mortality than non-users: a report from the first Euro Heart Survey on acute coronary syndromes.Eur Heart J. 2006; 27: 1799-1804Crossref PubMed Scopus (61) Google Scholar, 3Garot P. Bendaoud N. Lefèvre T. Morice M.C. Favourable effect of statin therapy on early survival benefit at the time of percutaneous coronary intervention for ST-elevation myocardial infarction and shock.EuroIntervention. 2010; 6: 350-355Crossref PubMed Scopus (13) Google Scholar]. We think the main topic in Dr Zhang's letter is, at least from the clinical perspective, whether statins, especially early-initiated statins, can reduce the repeat revascularization rate. Our study cannot reveal the effect of early statin initiation on reduction in target lesion revascularization (TLR). Here, we need to underscore the necessity to distinguish precisely between TLR and target vessel revascularization or non-target vessel revascularization (and combined repeat revascularization) when discussing the endpoint about repeat revascularization. It has not been clearly established whether statins can provide a benefit in reducing the incidence of restenosis after stent implantation. In fact, both the NHLBI Dynamic Registry and the meta-analysis performed by Dr Zhang et al. showed no effect against TLR, consistent with our result. In addition, when we consider these revascularization rates, especially TLR, the procedures during stent deployment, such as with or without intravascular ultrasound guidance, have been reported to be an indispensable factor [4Mintz G.S. Weissman N.J. Intravascular ultrasound in the drug-eluting stent era.J Am Coll Cardiol. 2006; 48: 421-429Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 5Romagnoli E. Sangiorgi G.M. Cosgrave J. Guillet E. Colombo A. Drug-eluting stenting: the case for post-dilation.JACC Cardiovasc Interv. 2008; 1: 22-31Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]. Revascularization rate could be also influenced by the follow-up method because routine angiographic follow-up increases the detection rate in restenosis and de novo stenosis. For these reasons, the conclusions drawn from Dr Zhang and coworkers’ reports of their studies may not apply to our study populations with CAD who underwent PCI because of the differences in endpoint, patient backgrounds, and follow-up method. As mentioned in our article, there are some possible explanations for the discrepancy between the effects of early initiation of statins on mortality and TLR. Although we do not have the clear answer for this discrepancy, we believe from our results and previously published reports that early-initiated statins can produce a beneficial risk reduction in mortality for Japanese CAD patients in real-world clinical practice.

Progression of carotid atherosclerosis in Japanese patients with coronary artery disease

The authors investigated the relationship between the progression of carotid atherosclerosis and the severity of coronary artery disease (CAD). The two-year follow-ups of extracranial carotid atherosclerosis in 50 patients with CAD were evaluated by B-mode high-resolution ultrasonography. The summed maximal thickness of carotid plaques increased by 3.2 to 10.1 mm (mean 1.06 mm, SD 2.42 mm). The extent of coronary atherosclerosis (p<0.02) and the serum total cholesterol level (p<0.01) were different between the progressing group (n=20) and the nonprogressing group (n=25) with carotid atherosclerosis. Carotid disease progression was significantly higher in patients with three-vessel coronary disease than in those without significant coronary disease (p<0.005). Age, serum triglyceride, high-density lipoprotein-cholesterol, pack-years of smoking, % smokers, % hypertensives, and % diabetics were not different between the two groups. It was concluded that the severity of CAD was one of the strong predictors for carotid disease progression in patients with CAD.

Association of intima-media thickening of carotid artery with genetic polymorphisms of the regulator of G-protein signaling 2 gene in patients with hypertension and in the general population

Regulator of G-protein signaling 2 (RGS2) is a key molecule in signal pathways of vasoactive peptides, such as angiotensin II and endothelin 1, and is believed to have an important role in the pathophysiology of atherosclerosis. We have previously reported that common polymorphisms of RGS2 are associated with hypertension in Japanese. In this study, we studied whether the three previously identified common polymorphisms of RGS2 (-638A>G, 1026T>A and 1891-1892delTC) could be implicated in carotid atherosclerosis in Japanese patients with hypertension (459 men and 382 woman) and in a Japanese general population (814 men and 956 woman). We assessed two criteria for carotid atherosclerosis: maximal intima-media thickness (M-IMT) and mean-IMT. When subjects with atherosclerotic lesions were defined as having mean-IMT≥1.0 mm, multivariate logistic regression analysis performed after adjusting for confounding factors showed a significant association of the three common polymorphisms, -638A>G (AA versus AG+GG: odds ratio (OR), 1.55; 95% confidence interval (CI), 1.105-2.185; P=0.0113 only for the general population), 1026T>A (TT versus TA+AA: OR, 1.42; 95% CI, 1.027-1.972; P=0.034 for hypertensive subjects and OR, 1.56; 95% CI, 1.129-2.151; P=0.0071 for the general population), and 1891-1892delTC (II versus ID+DD: OR, 1.44; 95% CI, 1.043-2.008; P=0.028 for hypertensive subjects, OR, 1.32; 95% CI 1.002-1.742; P=0.048 for the total general population and OR 1.59; 95% CI 1.155-2.207; P=0.0047 for the general population), with carotid atherosclerosis. When atherosclerosis was defined as M-IMT 1.0 mm, the values of M-IMT were also significantly different between the three genotypes in the three common polymorphisms. Taken together, these data suggest that genetic polymorphisms in RGS2 are associated with intima-media thickening of carotid artery in humans.

Intensively Lowering Both Low-Density Lipoprotein Cholesterol and Blood Pressure Does Not Reduce Cardiovascular Risk in Japanese Coronary Artery Disease Patients

Despite mounting evidence of the benefit of intensive lowering of low-density lipoprotein-cholesterol (LDL-C) in coronary artery disease (CAD) patients, it has not been shown that intensive lowering of both LDL-C and blood pressure (BP) reduces cardiovascular events in these patients. 498 patients with hypertension and hypercholesterolemia with ≥ 75% stenosis in at least one major coronary artery, were recruited from 17 cardiovascular centers in eastern Japan. Patients were randomly assigned to conventional therapy (CT) or intensive therapy (IT). CT aimed to reduce BP to < 140/90 mm Hg and LDL-C to <100mg/dl, and IT aimed for < 120/80 mm Hg and < 80 mg/dl, respectively. The primary endpoint was a composite of all deaths, non-fatal myocardial infarction, unstable angina pectoris, coronary artery bypass graft surgery, non-fatal stroke, non-fatal major vascular disease, and peripheral artery disease. The mean follow-up period was 3.2 years. The achieved systolic BP was 126.8 mm Hg for the CT group, and 121.3 mm Hg for the IT group (P < 0.001). The achieved LDL-C was 92.1mg/dl for the CT group, and 79.6 mg/dl for the IT group (P < 0.001). We detected the primary endpoint in 18 (7.1%) patients in the CT group, and 26 (10.7%) in the IT group (hazard ratio 1.53, 95% confidence interval 0.84-2.80, P = 0.164). We could not show that intensively lowering both BP and LDL-C reduced cardiovascular risks in Japanese CAD patients with hypertension and hypercholesterolemia (UMIN-CTR UMIN000000571).

Impact of early statin initiation on secondary prevention in Japanese patients with coronary artery disease

The effect of early statin initiation on secondary prevention remains uncertain in unselected Japanese populations with coronary artery disease (CAD). We investigated the mortality and morbidity in CAD patients according to presence or absence of statins within 3 months after the diagnosis of CAD in the Shinken Database cohort study. The primary endpoint was all-cause mortality. Data were available on 789 Japanese patients with CAD (male 78.8%). Among those, 351 patients (44.5%) received a statin. The mean (SD) baseline low-density lipoprotein (LDL)-cholesterol levels were 113.6 (35.7) mg/dL in the statin group and 113.6 (26.4) mg/dL in the non-statin group (p=0.992). Unadjusted 2-year survival in patients with or without statins was 98.4% and 92.1%, respectively (p<0.001). Among a prespecified subgroup of patients undergoing percutaneous coronary intervention (PCI) (n=238 with statins and n=183 without statins), a consistent effect of statins on 2-year survival was observed (98.5% and 90.9%, respectively, p<0.001). However, there was no significant difference in 2-year target lesion revascularization-free survival (77.9% in statins versus 73.7% in non-statins, respectively, p=0.298). The age- and gender-adjusted survival in the PCI subgroup was significantly higher in the statin group [hazard ratio (HR) 0.29, 95% confidence interval (CI) 0.095-0.913] compared to non-statin. Multivariate analysis showed statins significantly reduced mortality (HR 0.27, 95%CI 0.078-0.944), but not revascularization (HR 0.91, 95%CI 0.589-1.406). This study suggested that statin therapy initiated early after the diagnosis of CAD can decrease the risk of fatal events in Japanese CAD patients.

The Effect of Losartan and Amlodipine on Left Ventricular Diastolic Function and Atherosclerosis in Japanese Patients with Mild-to-Moderate Hypertension (J-ELAN) study

This study was a prospective, randomized, open, blinded endpoint study to assess the effects of angiotensin II type 1 receptor blocker, losartan, compared with calcium channel blocker, amlodipine, on left ventricular (LV) diastolic function and atherosclerosis of the carotid artery in Japanese patients with mild-to-moderate hypertension, LV hypertrophy, diastolic dysfunction and preserved systolic function. Fifty-seven patients were randomly assigned to losartan- or amlodipine-based treatment groups and were followed up for 18 months. Blood pressure was similarly reduced by both regimens. Losartan shortened the transmitral E-wave deceleration time, and amlodipine reduced LV mass index; however, there was no significant difference in the percent changes of these indices between the two groups. Mean carotid intima-media thickness (mean IMT) as well as plaque score significantly increased in the amlodipine-based regimen (pre: 1.05±0.26 mm, follow-up: 1.23±0.33 mm, P=0.0015), but not in the losartan-based regimen (pre: 1.08±0.35 mm, follow-up: 1.16±0.52 mm, P=non-significant). The percent increase in mean IMT in the amlodipine-based regimen tended to be large compared with the losartan-based regimen (amlodipine: 19.8±23.7%, losartan: 6.9±23.3%, P=0.06). Under similar reduction of blood pressure, losartan is likely effective in protecting the progression of atherosclerosis of the carotid artery compared with amlodipine. Losartan may improve LV diastolic function, and amlodipine may attenuate LV hypertrophy; however, this study cannot make consecutive remarks about the superiority of either treatment regimen in the effects on cardiac function and geometry. This study has been registered at http://www.umin.ac.jp/ctr/listj/ (identifier C000000319).

Microinflammation is a common risk factor for progression of nephropathy and atherosclerosis in Japanese patients with type 2 diabetes

Aim This study aimed to evaluate the change of serum levels of proinflammatory molecules in patients with type 2 diabetes and clarify the involvement of these molecules in diabetic nephropathy and atherosclerosis. Methods Sixty-six Japanese type 2 diabetic patients (T2DM) and 39 healthy control subjects were enrolled. We assessed clinical parameters, urinary albumin excretion rate (AER), brachial-ankle pulse wave velocity (baPWV), intima media thickness (IMT) and serum levels of proinflammatory molecules. Results Serum levels of IL-6, IP-10 and MCP-1 were significantly higher in T2DM than in control subjects. In T2DM, serum levels of high-sensitivity (hs) CRP, IP-10, hsTNF-α, VCAM-1 and E-selectin were positively correlated with AER. Serum levels of IP-10, hsTNF-α and VCAM-1 were positively correlated with baPWV. Serum levels of hsCRP, IL-6, IP-10 and hsTNF-α were positively correlated with IMT. Multiple linear regression analysis revealed that serum levels of hsTNF-α were independently associated with AER ( β = 0.235, P = 0.038) and serum levels of IP-10 were independently associated with baPWV ( β = 0.209, P = 0.047) and IMT ( β = 0.303, P = 0.032). Conclusion Our results suggest that low-grade inflammation, microinflammation, may be a common risk factor for diabetic nephropathy and atherosclerosis in Japanese type 2 diabetic patients.

Long-Term Effects of Pioglitazone on Carotid Atherosclerosis in Japanese Patients with Type 2 Diabetes without a Recent History of Macrovascular Morbidity

No previous studies have evaluated the long-term anti-atherosclerotic effects of pioglitazone in Asian patients with type 2 diabetes. Therefore, the present study investigated the protective effects of pioglitazone on the progression of carotid intima-media thickness (IMT), an established surrogate marker of cardiovascular events in Japanese type 2 diabetic patients without a recent history of cardiovascular morbidity. This 2.5-4-year, randomized, open-label, blinded endpoint study was conducted in 6 centers across Japan. Patients received pioglitazone with or without other oral glucose-lowering drugs (excluding another thiazolidinedione) (n=89) or oral glucose-lowering drugs, excluding thiazolidinediones (n=97). Treatment was adjusted to achieve HbA(1c) <6.5%. The primary endpoints of the study were the absolute changes from the baseline to final visit in max- and mean-IMT in the average of bilateral common carotid arteries. Pioglitazone induced carotid IMT regression compared to baseline measurements (from 1.060 ± 0.2368 to 0.992 ± 0.1921 mm; p=0.0042 in max-IMT and from 0.839 ± 0.1873 to 0.780 ± 0.1571 mm; p=0.0019 in mean-IMT). Although the between-group difference did not reach statistical significance, the regression of carotid IMT values was greater in the pioglitazone-treatment group than in the non-pioglitazone group, (max-IMT: -0.069 ± 0.2199 mm vs -0.031 ± 0.2327 mm, respectively; p=NS, mean-IMT: -0.058 ± 0.1718 mm vs -0.043 ± 0.1644 mm, respectively; p=NS). Pioglitazone induced and maintained the long-term regression of carotid IMT in Japanese type 2 diabetic patients. This suggests that pioglitazone may inhibit the progression of atherosclerosis in this patient group. Further studies are required to verify these findings.

Erratum:Association of C-reactive Protein with Early-stage Carotid Atherosclerosis in Japanese Patients with Early-state Type 2 Diabetes Mellitus,[Endocrine Journal Vol.53, No.5, 693-698

Erratum:Association of C-reactive Protein with Early-stage Carotid Atherosclerosis in Japanese Patients with Early-state Type 2 Diabetes Mellitus,[Endocrine Journal Vol.53, No.5, 693-698

Can Intensive Lipid-Lowering Therapy with Statins Ameliorate Atherosclerosis in Japanese Patients?

In Japan, heart disease and cerebral ischemic disease are major causes of death. A decrease in the level of low-density lipoprotein cholesterol (LDL-C) through intensive treatment with statins positively correlates with a reduction in the volume of plaques in patients with cardiovascular disease. The METEOR trial, evaluating the effect of rosuvastatin on carotid intima-media thickness (IMT), was conducted only in Europe and the US. Here we planned another trial, the Justification for Atherosclerosis Regression Treatment (JART) study, to clarify the efficacy of intensive lipid-lowering therapy with rosuvastatin in Japanese with atherosclerosis. Four hundred patients with hypercholesterolemia (LDL-C >or=140 mg/dL) and a maximum IMT of >or=1.1 mm will be treated for 24 months either with intensive lipid-lowering therapy with rosuvastatin (target LDL-C levels: 80 mg/dL for primary prevention, and 70 mg/dL for secondary prevention) or conventional lipid-lowering therapy with pravastatin (target LDL-C level: complying with JASGL2007). The primary endpoint will be the percent change of mean-IMT and the objectives of the study are to compare the two protocols. The JART trial is a prospective, randomized, open-label, blinded end-point evaluation, multi-center, parallel-group, comparative study to examine the regressive effect of intensive lipid-lowering therapy with statins on atherosclerosis by evaluating IMT in the Japanese population.

Estimated glomerular filtration rate as a predictor of secondary outcomes in Japanese patients with coronary artery disease

Coronary artery disease (CAD) is highly prevalent and strongly associated with adverse outcomes in patients with chronic kidney disease (CKD). Recent data demonstrate that estimated glomerular filtration rate (eGFR) is more useful than serum creatinine as a predictor of outcomes. We investigated the clinical significance of eGFR-defined CKD in Japanese patients with CAD. In 702 consecutive patients with suspected CAD who underwent coronary angiography, CKD (eGFR <60 ml/min/1.73 m(2)) was present in 345 patients (49%). The eGFR value was lower in patients with multi-vessel coronary artery disease compared to patients with no significant stenosis (59+/-24 ml/min/1.73 m(2) vs 66+/-21 ml/min/1.73 m(2), p<0.01). During a follow-up period of 36 months, secondary events that included all-cause death and cardiovascular events requiring hospitalization occurred in 114 (16%) patients. Multivariate analysis using a Cox proportional hazards model showed that CKD [relative risk (RR) 1.707, 95%CI, 1.170-2.489; p=0.004] along with diabetes (RR, 1.684, 95%CI, 1.262-2.386; p=0.008) were independent predictors of secondary events. eGFR-defined CKD is an important predictor of secondary outcomes in Japanese patients with CAD. Anti-atherosclerotic therapies under eGFR monitoring to consider renoprotection would be an important strategy to improve long-term prognosis in Japanese CAD patients.

Low Incidence of Cardiac Events in Statin-Administered Patients in CAG Study

The effect of statins in preventing cardiac events in Japanese coronary artery disease (CAD) patients was studied in a retrospective investigation of 148 patients diagnosed with CAD by coronary angiography (CAG). Sixty-five patients received statins within 2 weeks after CAG, and 83 patients did not receive statins after CAG. In the statin group, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were reduced significantly with statin administration (p<0.01). In the non-statin group, baseline levels of TC, LDL-C and high-density lipoprotein cholesterol were not changed significantly at the end of the follow-up period. As for the effect of statin in preventing cardiac events, the incidence of cardiac events was significantly lower (p<0.0003) in the statin group (n=5: 8%) than in the non-statin group (n=28: 34%). In subanalysis of 37 patients whose TC at the time of initial CAG was less than 200 mg/dL, none of the statin group (n=17) suffered a cardiac event. This was significantly lower than the incidence of cardiac events in the non-statin group (n=5: 25%; p<0.05). The present study demonstrated that lowering LDL-C of Japanese CAD patients by statin administration is effective to prevent cardiac events, particularly, a second percutaneous coronary intervention (PCI) for restenosis of a coronary artery following the initial PCI whether or not these patients had hypercholesterolemia.

Coronary Risk Factor Profile and Prognostic Factors for Young Japanese Patients Undergoing Coronary Revascularization

The prevalence of coronary artery disease (CAD) is increasing in young adults. Risk factor profiling will help to prevent heart attacks in young patients. This study aimed to analyze the risk factor profile and predictors of major cardiovascular events (MACE) in young CAD patients. From the Coronary REvascularization Demonstrating Outcome study in the Kyoto (CREDO-Kyoto) registry of Japanese patients undergoing their first coronary revascularization, 6,320 patients with complete data for all variables for statistical analyses were divided into younger (< or =55 years; n=898; 14.3%) and older (>55 years; n=5,422; 85.7%) patients. The risk factors that were more prevalent in the younger patients than in the older patients included: male sex, body mass index of >25 kg/m(2), current smoker, family history of CAD, dyslipidemia and metabolic syndrome-like risk factor accumulation. Multivariate analyses revealed that chronic kidney disease (CKD) was the only significant predictor of MACE, the composite of cardiovascular death, myocardial infarction and cerebrovascular accident, in the younger patients. Importance of CKD as a prognostic factor was consistently shown by a multivariate analysis in the older patients. Accumulation of multiple risk factors is prevalent and CKD is associated with MACE in young Japanese CAD patients.

Elevated Serum C-Reactive Protein Levels Predict Cardiovascular Events in the Japanese Coronary Artery Disease (JCAD) Study

Accumulating evidence indicates that C-reactive protein (CRP) is an independent predictive factor for atherosclerotic vascular disease in Caucasians. Accordingly, this study sought to investigate the relationship between the serum level of CRP and cardiovascular events of Japanese patients with coronary artery disease (CAD). The Japanese CAD (JCAD) study enrolled 15,628 patients who had significant diameter stenosis (>or=75%) in at least 1 coronary artery. Of these, 6,802 patients had their baseline serum CRP data available. Patients were followed up for a mean of 2.7 years (follow-up rate 88.3%). The primary endpoint of the JCAD study was all events. Baseline covariates possibly influencing the event rate were adjusted between the 2 groups with and without elevated serum CRP level. Kaplan-Meier analysis demonstrated a 30% higher all-events rate in patients with a serum level of CRP >or=0.1 mg/dl (P=0.0002). Cox proportional hazard analysis also showed that a serum level of CRP >or=0.1 mg/dl was an independent predictor of all events (P=0.0001), and of cardiac events and cardiac death (P=0.0005). Elevated serum level of CRP is an independent predictor of cardiovascular events in JCAD patients.