Plasma ANGPTL8 Levels and Risk for Secondary Cardiovascular Events in Japanese Patients With Stable Coronary Artery Disease Receiving Statin Therapy.

BACKGROUND: The ability to predict secondary cardiovascular events could improve health of patients undergoing statin treatment. Circulating ANGPTL8 (angiopoietin-like protein 8) levels, which positively correlate with proatherosclerotic lipid profiles, activate the pivotal proatherosclerotic factor ANGPTL3. Here, we assessed potential association between circulating ANGPTL8 levels and risk of secondary cardiovascular events in statin-treated patients. METHODS: We conducted a biomarker study with a case-cohort design, using samples from a 2018 randomized control trial known as randomized evaluation of high-dose (4 mg/day) or low-dose (1 mg/day) lipid-lowering therapy with pitavastatin in coronary artery disease (REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease])." From that study's full analysis set (n=12 413), we selected 2250 patients with stable coronary artery disease (582 with the primary outcome, 1745 randomly chosen, and 77 overlapping subjects). A composite end point including cardiovascular-related death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergent admission was set as a primary end point. Circulating ANGPTL8 levels were measured at baseline and 6 months after randomization. RESULTS: Over a 6-month period, ANGPTL8 level changes significantly decreased in the high-dose pitavastatin group, which showed 19% risk reduction of secondary cardiovascular events compared with the low-dose group in the REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease] study. In the highest quartiles, relative increases in ANGPTL8 levels were significantly associated with increased risk for secondary cardiovascular events, after adjustment for several cardiovascular disease risk factors and pitavastatin treatment (hazard ratio in Q4, 1.67 [95% CI, 1.17-2.39). Subgroup analyses showed relatively strong relationships between relative ANGPTL8 increases and secondary cardiovascular events in the high-dose pitavastatin group (hazard ratio in Q4, 2.07 [95% CI, 1.21-3.55]) and in the low ANGPTL8 group at baseline (166

Fractal geometry of culprit coronary plaque images within optical coherence tomography in patients with acute coronary syndrome vs stable angina pectoris.

The main cause of acute coronary syndrome (ACS) is plaque rupture and thrombus formation. However, it has not been fairly successful to identify vulnerable plaque to rupture using conventional parameters of intravascular imaging modalities. Fractal analysis is one of the mathematical models to examine geometrical features of picture image using a specific parameter called as fractal dimension (FD) which suggests geometric complexity of the image. This study examined FD of the optical coherence tomography (OCT)-derived images of the culprit plaque in patients with ACS vs stable angina pectoris (SAP) to evaluate the feasibility of FD for identifying vulnerable coronary plaques prone to provoke ACS distinguished from stable plaques only provoking SAP. We examined 65 cases (34 ACS patients, 31 SAP patients) in which the culprit lesion was imaged by OCT before percutaneous coronary intervention in patients with ACS and SAP. The culprit plaque lesion in the ACS group had a significantly larger mean lipid arc (203.8 ± 39.4° vs 152.3 ± 34.5°, p < 0.001) and a larger lipid plaque length (12.6 ± 5.1 mm vs 7.7 ± 2.7 mm, p < 0.001) and a thinner fibrous cap thickness (75.3 ± 22.3 µm vs 134.8 ± 53.2 µm, p < 0.001) than those in the SAP group. The prevalence of OCT-derived macrophage infiltration (Mph) in the entire culprit coronary vessel as well as that of the OCT-derived thin-cap fibroatheroma (TCFA) at the culprit lesion were significantly greater in the ACS group than those in the SAP group, respectively (Mph: 61.8% vs 35.5%, p = 0.048; TCFA: 44.1% vs 6.4%, p < 0.001). The FD of culprit plaque in the ACS group was significantly greater than in the SAP group (2.401 ± 0.073 vs 2.341 ± 0.051, p < 0.001). In multivariate regression analysis, the presence of Mph was a significant determinant of FD (regression coefficient estimate 0.049, CI 0.018-0.079, p = 0.002). The FD of OCT-derived image of culprit coronary plaque in the ACS group was significantly greater than that in the SAP group, indicating that the culprit plaque in ACS were structurally more complex. Therefore, fractal analysis of coronary OCT images might be clinically useful for identifying coronary plaques prone to provoke ACS.

Relation of renal function to mid-term prognosis of stable angina patients with high- or low-dose pitavastatin treatment: REAL-CAD substudy.

BACKGROUND: It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction. METHODS: The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and <60 (n = 3,176); and eGFR <45 mL/Min/1.73 m2 (n = 1,164), who were randomized to pitavastatin 4mg or 1mg therapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina, and was assessed by the log-rank test and Cox proportional hazards model. RESULTS: The baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and <60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m2 (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interaction = .30). CONCLUSION: Higher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR.

Clinical significance of microvessels detected by in vivo optical coherence tomography within human atherosclerotic coronary arterial intima: a study with multimodality intravascular imagings.

The significance of microvessels within atherosclerotic plaques is not yet fully clarified. Associated with plaque vulnerability. The aim of this study is to examine tissue characteristics of plaque with microvessels detected by optical coherence tomography (OCT) by use of a commercially available color-coded intravascular ultrasound (IVUS) and coronary angioscopy (CAS). The subjects examined comprised of 44 patients with stable angina pectoris who underwent percutaneous coronary intervention. Microvessels were defined as a tiny tubule with a diameter of 50-300 µm detected over three or more frames in OCT. We compared the total volume of microvessels with tissue component such as fibrotic, lipidic, necrotic, and calcified volume and the number of yellow plaque. In IVUS analysis, % necrotic volume and % lipidic volume were significantly correlated and % fibrotic volume was inversely significantly correlated with the total volume of microvessel (r = 0.485, p = 0.0009; r = 0.401, p = 0.007; r = - 0.432, p = 0.003, respectively). The number of plaque with an angioscopic yellow grade of two or more was significantly correlated with the total volume of microvessel (r = 0.461, p = 0.002). The greater the luminal volume of microvessels, the more the percent content of necrotic/lipidic tissue volume within plaque and the more the number of yellow plaques. These data suggested that microvessels within coronary plaque might be related to plaque vulnerability.

Effect of the dipeptidyl peptidase-4 inhibitor linagliptin on atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits: iMap-IVUS and pathological analysis.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have potential as a treatment for atherosclerosis. However, it is unclear whether DPP-4 inhibitors stabilize atherosclerotic plaque or alter the composition of complex plaque. Sixteen Watanabe heritable hyperlipidemic rabbits aged 10-12 weeks with atherosclerotic plaque in the brachiocephalic artery detected by iMap™ intravascular ultrasound (IVUS) were divided into a DPP-4 inhibitor group and a control group. Linagliptin was administered to the DPP-4 inhibitor group via nasogastric tube at a dose of 10 mg/kg/day for 16 weeks, and control rabbits received the same volume of 0.5% hydroxyethylcellulose. After evaluation by IVUS at 16 weeks, the brachiocephalic arteries were harvested for pathological examination. IVUS revealed that linagliptin significantly reduced the plaque volume and vessel volume (control group vs. DPP-4 inhibitor group: ∆plaque volume, 1.02 ± 0.96 mm3 vs. - 3.59 ± 0.92 mm3, P = 0.004; ∆vessel volume, - 1.22 ± 2.36 mm3 vs. - 8.66 ± 2.33 mm3, P = 0.04; %change in plaque volume, 6.90 ± 5.62% vs. - 15.06 ± 3.29%, P = 0.005). With regard to plaque composition, linagliptin significantly reduced the volume of fibrotic, lipidic, and necrotic plaque (control group vs. DPP-4 inhibitor group: ∆fibrotic volume, 0.56 ± 1.27 mm3 vs. - 5.57 ± 1.46 mm3, P = 0.04; ∆lipidic volume, 0.24 ± 0.24 mm3 vs. - 0.42 ± 0.16 mm3 P = 0.04; ∆necrotic volume, 0.76 ± 0.54 mm3 vs. - 0.84 ± 0.25 mm3, P = 0.02). Pathological examination did not show any significant differences in the %smooth muscle cell area or %fibrotic area, but infiltration of macrophages into plaque was reduced by linagliptin treatment (%macrophage area: 12.03% ± 1.51% vs. 7.21 ± 1.65%, P < 0.05). These findings indicate that linagliptin inhibited plaque growth and stabilized plaque in Watanabe heritable hyperlipidemic rabbits.

Macrophage accumulation within coronary arterial wall in diabetic patients with acute coronary syndrome: a study with in-vivo intravascular imaging modalities.

BACKGROUND AND AIMS: Macrophage accumulation in arteriosclerotic plaque of coronary arteries is involved in plaque destabilization. Atherosclerosis has been known to be progressive in patients with type 2 diabetes mellitus (DM). This study compared the features of 3-dimensional (3D) spatial distribution of macrophage accumulation within coronary artery wall between acute coronary syndrome (ACS) patients with DM (n = 20) and those without (non-DM, n = 20) by using intravascular ultrasound (IVUS) and optical coherence tomography (OCT). METHODS: The OCT-derived macrophage accumulation was measured within the proximal left anterior-descending artery. This measurement was performed for the whole vessel segment of interest, higher shear stress region (flow divider side) and lower shear stress region (the opposite side). RESULTS: Normalized macrophage accumulation per unit length of the whole segment of interest was significantly larger in ACS patients with DM than without. In non-DM patients, macrophage density per IVUS-derived plaque volume was significantly higher in high shear stress region compared to low shear stress region, however, there was no significant difference between the two regions in DM patients. The macrophage density in the low shear stress region was significantly higher in the DM group than in the non-DM group. A multivariate analysis showed that the presence of DM was a major determinant for macrophage distribution. CONCLUSIONS: Macrophage accumulation was more abundant and homogeneous within coronary arterial wall in DM patients with ACS compared to non-DM patients, suggesting that plaque destabilization may occur more widely throughout coronary wall in DM patients.

Impact of low-dose prasugrel on platelet reactivity and cardiac dysfunction in acute coronary syndrome patients requiring primary drug-eluting stent implantation: A randomized comparative study.

OBJECTIVE: The aim of this study was to compare how prasugrel and clopidogrel affect platelet aggregation reactivity, cardiac enzyme release, cardiac remodeling, and the formation of in-stent thrombi after primary percutaneous coronary intervention (PCI). BACKGROUND: The advantages of using prasugrel over clopidogrel in cardiac injury following acute coronary syndrome (ACS) remain unclear. METHODS: A total of 78 ACS patients were randomly allocated into clopidogrel (300 mg loading/75 mg maintenance) or prasugrel (20 mg loading/3.75 mg maintenance) treatment groups, followed by undergoing primary PCI. Platelet reactivity and cardiac enzymes were measured before and after primary PCI. Moreover, cardiac function was measured by ultrasound echocardiography and coronary angioscopic observation was after primary PCI up to 8 months later. RESULTS: Antiplatelet reactivity in the prasugrel treatment group reached optimal levels (P2Y12 reaction units [PRU] less than 262) immediately after the administration and was maintained even at 8 months, independently of the CYP2C19 genotype. Prasugrel treatment significantly suppressed creatine kinase elevation compared to clopidogrel treatment (median value 404 IU/L to 726 IU/L vs. 189 IU/L to 1,736 IU/L, p = 0.018 for maximum values) and reduced left ventricular mass (217.2-168.8 g in prasugrel, p = 0.045; 196.9-176.4 g in clopidogrel, p = 0.061). There were no significant differences in the incidence of in-stent attached thrombi between the two groups. CONCLUSIONS: Compared to clopidogrel, prasugrel produced a stable platelet aggregation inhibitory effect in patients with ACS regardless of CYP2C19 genotype, reduced cardiac enzyme release, and prevented cardiac remodeling after ACS.

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

BACKGROUND: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. METHODS: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) <120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. RESULTS: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group (P<0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; P=0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73-0.93; P=0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (<95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. CONCLUSIONS: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730.

Effect of Alirocumab on Coronary Atheroma Volume in Japanese Patients With Acute Coronary Syndrome　- The ODYSSEY J-IVUS Trial.

BACKGROUND: In patients with acute coronary syndrome (ACS), alirocumab reduced the risk of recurring ischemic events. ODYSSEY J-IVUS assessed the effect of alirocumab on coronary atheroma volume in Japanese patients recently hospitalized with ACS and hypercholesterolemia, using intravascular ultrasound imaging analysis.Methods and Results:Patients (n=206) who at index ACS diagnosis either had low-density lipoprotein cholesterol (LDL-C) ≥2.59 mmol/L (≥100 mg/dL) despite stable statin therapy, or were not on statins with LDL-C levels above target after statin initiation, were randomized (1:1) to alirocumab (75 mg every 2 weeks [Q2 W]/up to 150 mg Q2 W), or standard of care (SoC; atorvastatin ≥10 mg/day or rosuvastatin ≥5 mg/day) for 36 weeks. The primary efficacy endpoint (week [W] 36 mean [standard error] percent change in normalized total atheroma volume [TAV] from baseline) was -3.1 (1.0)% with SoC vs. -4.8 (1.0)% with alirocumab (between-group difference: -1.6 [1.4]; P=0.23). W36 absolute change from baseline in percent atheroma volume was -1.3 (0.4)% (SoC) and -1.4 (0.4)% (alirocumab; nominal P=0.79). At W36, LDL-C was reduced from baseline by 13.4% (SoC) vs. 63.9% (alirocumab; nominal P<0.0001). In total, 61.8% (SoC) and 75.7% (alirocumab) of patients reported treatment-emergency adverse events. CONCLUSIONS: In Japanese patients with ACS and hypercholesterolemia inadequately controlled despite statin therapy, from baseline to W36, a numerically greater percent reduction in normalized TAV was observed with alirocumab vs. SoC, which did not reach statistical significance.

High shear stress on the coronary arterial wall is related to computed tomography-derived high-risk plaque: a three-dimensional computed tomography and color-coded tissue-characterizing intravascular ultrasonography study.

Low wall shear stress (WSS) is associated with plaque formation. However, the relationship between WSS and coronary plaque vulnerability remains unclear. Therefore, this study aimed to clarify the in vivo relationship between luminal WSS derived from three-dimensional (3D) computed tomography (CT) and plaque vulnerability within the coronary artery. Forty-three consecutive patients with ischemic heart disease and coronary stenotic lesions were enrolled and underwent coronary angiography and color-coded intravascular ultrasonography (iMap™) followed by multi-slice coronary CT angiography. CT-derived high-risk plaque was defined by specific CT characteristics, including low CT intensity (< 30 HU) and positive remodeling. The Student's t test, Mann-Whitney U test, χ2 test, repeated measures analysis of variance, and logistic and multiple regression were used for statistical analyses. CT-derived high-risk plaque (n = 15) had higher values of maximum and average shear stress than CT-derived stable plaque (474 ± 453 vs. 158 ± 138 Pa, p = 0.018; 4.2 ± 3.1 vs. 1.6 ± 1.2 Pa, p = 0.007, respectively). Compared with patients with CT-derived stable plaque, those with CT-derived high-risk plaque had a higher prevalence of necrotic and lipidic characteristics (44 ± 13 vs. 31 ± 11%, p = 0.001) based on iMap™. Multivariate logistic regression analysis showed that the average WSS and necrotic plus lipidic content were independent determinants of CT-derived high-risk plaque (average WSS: odds ratio 2.996, p = 0.014; necrotic plus lipidic content: odds ratio 1.306, p = 0.036). Our findings suggested that CT-derived high-risk plaque may coexist with high shear stress on the plaque surface.

Effect of drug-coated balloon angioplasty on in-stent restenotic coronary lesions analyzed with optical coherence tomography and serial coronary artery angioscopy.

Drug-coated balloon angioplasty (DCBA) has been recognized for its utility in preventing in-stent re-restenosis (ISR); however, imaging of the neointima immediately after treatment and during follow-up has only been described in a few case reports. This study aimed to determine the efficacy and mechanism of the DCBA using imaging studies both immediately after the DCBA and during the follow-up period. We enrolled 15 consecutive patients who underwent DCBA for in-stent restenosis (ISR). The in-stent neointimal volume was evaluated using optical coherence tomography (OCT), and the in-stent yellow grade was assessed using coronary angioscopy (CAS) immediately after DCBA and during the median follow-up period of 9 (8-15) months. The neointimal volume was significantly reduced from 77.1 ± 36.2 mm3 at baseline to 60.2 ± 23.9 mm3 immediately after DCBA (p = 0.0012 vs. baseline) and to 46.7 ± 21.9 mm3 during the follow-up (p = 0.0002 vs. post DCBA). The yellow grade of the residual plaques at the ISR lesion, which indicated plaque vulnerability, was significantly decreased in the follow-up CAG (from baseline: 1.79 ± 1.03, during the follow-up: 0.76 ± 0.82; p < 0.0001). These data suggest that DCBA may inhibit neointimal formation and provide angioscopic intimal stabilization for ISR lesions.

Balloon pin-hole rupture during percutaneous coronary intervention for recurrent, calcified in-stent restenosis: A case report.

Percutaneous coronary intervention (PCI) for patients with in-stent restenosis (ISR) is generally considered safe and effective. However, due to increased tissue hardness, PCI for calcified intra-stent ISR is technically challenging. Here, we report severe angioplasty-related complications in a patient presenting with calcified, recurrent ISR following PCI. After receiving drug-coated balloon (DCB) angioplasty for an initial ISR, the patient developed recurrent ISR during the follow-up period. Intravascular imaging revealed intra-stent calcifications and balloon angioplasty was subsequently performed. During the angioplasty, a pin-hole balloon rupture occurred, consequently causing coronary dissection as visualized by intravascular imaging. To prevent acute coronary occlusion, stent implantation was required. The present case report suggests that, following detection of intra-stent calcified stenosis, both careful balloon inflation as well as optimal ablation device selection are required to prevent potential complications and obtain successful procedural outcomes.

Effect of Aggressive lipid-lowering treatment with Rosuvastatin on vascular endoTHelium function: evaluation of vascular endothelium function (EARTH study).

Vascular endothelial dysfunction plays an important role in the process of atherosclerosis up to the final stage of plaque rupture. Vascular endothelial dysfunction is reversible, and can be recovered by medications and life-style changes. Improvement in endothelial function may reduce cardiovascular events and improve long-term prognosis. A total of 50 patients with stable angina and dyslipidemia were enrolled, including patients who had not received prior treatment with statins and had serum LDL-C levels ≥ 100 mg/dL, and patients who had previously received statin treatment. All agreed to register regardless of their LDL-C level. Rosuvastatin was initially administered at a dose of 2.5 mg and appropriately titrated up to the maximum dose of 20 mg or until LDL-C levels lower than 80 mg/dL were achieved, for 24 weeks. Endothelial function was assessed by the reactive hyperemia peripheral arterial tonometry (RH-PAT) index in the radial artery by Endo-PAT® 2000 (Endo-PAT®2000, software version 3.0.4, Itamar Medical Ltd., Caesarea, Israel). RH-PAT data were digitally analyzed online by Endo-PAT®2000 at baseline and at 24 weeks. LDL-C and MDA-LDL-C decreased from 112.6 ± 23.3 to 85.5 ± 20.2 mg/dL and from 135.1 ± 36.4 to 113.9 ± 23.5 mg/dL respectively (p < 0.0001). However, HDL-C, hs-CRP and TG did not change significantly after treatment. RH-PAT index levels significantly improved, from 1.60 ± 0.31 to 1.77 ± 0.57 (p = 0.04) after treatment, and the percent change of the RH-PAT index was 12.8 ± 36.9%. Results of multivariate analysis show that serum LDL-C levels over 24 weeks did not act as a predictor of improvement of the RH-PAT index. However, HbA1c at baseline was an independent predictor which influenced the 24-week RH-PAT index level. The RH-PAT index of patients with high HbA1c at baseline did not improve after administration of rosuvastatin but it did improve in patients with low HbA1c at baseline. Aggressive lowering of LDL-C with rosuvastatin significantly improved the RH-PAT index, suggesting that it may improve endothelial function in patients with coronary artery disease.Clinical Trial Registration No: UMIN-CTR, UMIN000010040.

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

Report of the Annual Scientific Sessions of the American College of Cardiology (ACC), Washington DC.

The 66thAnnual Scientific Sessions and Expo of the American College of Cardiology (ACC) were held at the Walter E. Washington Convention Center, Washington DC, from March 17thto 19th, 2017. This meeting offered 23 Late-Breaking Clinical Trial (LBCT) presentations, 17 Featured Clinical Research presentations with and without LBCT, and 2,572 abstracts presented in oral and poster sessions by over 2,000 experts. This report presents the highlights of this meeting, including the opening showcase, several important LBCTs and some international joint symposiums.

Effect of Ezetimibe on Stabilization and Regression of Intracoronary Plaque　- The ZIPANGU Study.

BACKGROUND: Diminishing yellow color is associated with plaque stabilization. We assessed the hypothesis that a combination of ezetimibe and statin provides more effective plaque stabilization and regression than statin alone as assessed by plaque color.Methods and Results:Stable coronary artery disease patients (n=131) who underwent elective percutaneous coronary intervention and had yellow plaques were randomized to combination therapy (atorvastatin 10-20 mg and ezetimibe 10 mg/day; Group C) or statin monotherapy (atorvastatin 10-20 mg; Group M). Changes in plaque color and plaque volume during 9 months were assessed by angioscopy and intravascular ultrasound. Low-density lipoprotein cholesterol (LDL-C) decreased from 103±28 to 63±18 mg/dL in Group C (P<0.001) and from 100±28 to 75±17 mg/dL in Group M (P<0.001). Yellow color grade decreased significantly in both Group M (2.1±1.1 vs. 1.7±1.0, P=0.005) and Group C (2.2±1.2 vs. 1.8±1.2, P=0.002), but did not differ between the groups. %plaque volume did not change in Group M (48.5±10.2% vs. 48.2±10.4%, P=0.4), but decreased significantly in Group C (50.0±9.8% vs. 49.3±9.8%, P=0.03). CONCLUSIONS: Compared with statin monotherapy, combination therapy with ezetimibe further reduced LDL-C levels. Significant plaque volume reduction was achieved by the combination therapy, but not statin monotherapy; however, plaque stabilization was similarly achieved by both therapies. Furthermore, reduction in plaque volume was dependent on reduction in LDL-C, regardless of whether it was achieved by statin alone or statin plus ezetimibe.

Serial Observations of In-Stent Restenosis Treated With Drug-Coated Balloon Angioplasty by Optical Coherence Tomography and Coronary Angioscopy.

The drug-coated balloon (DCB) is a device that is used to reduce the risk of stent re-implantation in patients with in-stent restenosis (ISR). However, imaging findings of the drug covering the neointimal plaque immediately after treatment of ISR by DCB, and during follow-up, have only been discussed in a few reports. Herein, we describe the use of optical coherence tomography (OCT) and angioscopy to evaluate ISR before and after treatment with DCB, and during the follow-up period in 3 patients. The patients developed critical ISR during the follow-up period after drug-eluting stent (DES) implantation. The patients included a 70-year-old woman, a 70-year-old man, and an 80-year-old man. These imaging modalities provided data about the various etiologies of ISR, and about the efficacy of DCB angioplasty. Based on the findings of the intracoronary images in these 3 cases, we concluded that DCB might not only inhibit neointimal proliferation, but also reduce neointimal volume and lead to changes in in-stent neointimal morphology.

A comparative study of time-specific oxidative stress after acute myocardial infarction in patients with and without diabetes mellitus.

BACKGROUND: Oxidative stress is involved in the initiation and progression of atherosclerosis, and hyperglycemia is known to increase oxidative stress, which injures the endothelium and accelerates atherosclerosis. To clarify the relation between oxidative stress, diabetes mellitus (DM), and acute myocardial infarction (AMI), we evaluated and compared time-specific oxidative stress after AMI in patients with and without DM by simple measurement of derivatives of reactive oxygen metabolites (d-ROMs) levels as indices of reactive oxygen species production. METHODS: Sixty-eight AMI patients were enrolled (34 non-DM patients and 34 DM patients). Using the FRAS4 free radical analytical system, we measured d-ROMs levels in each patient at two time points: 1 and 2 weeks after AMI onset. RESULTS: d-ROM levels decreased significantly between week 1 and week 2 (from 475.4 ± 119.4 U.CARR to 367.7 ± 87.9 U.CARR, p < 0.001) in the non-DM patients but did not change in the DM patients (from 463.1 ± 109.3 U.CARR to 461.7 ± 126.8 U.CARR, p = 0.819). Moreover, significant correlation was found in the total patient group between d-ROMs levels at 1 week and N-terminal prohormone of brain natriuretic peptide (r = 0.376, p = 0.041) and between d-ROM levels at 2 weeks and 2-hour oral glucose tolerance test glucose levels (r = 0.434, p < 0.001). CONCLUSIONS: Exposure to oxidative stress is greater in AMI patients with DM than AMI patients without DM. Our study results suggest that it is the continuous hyperglycemia that increases oxidative stress in these patients, causing endothelial dysfunction and accelerating atherosclerosis. However, long-term follow up study is needed to assess whether the increased oxidative stress affects patient outcomes.

Remodeling pattern is related to the degree of coronary plaque regression induced by pitavastatin: a sub-analysis of the TOGETHAR trial with intravascular ultrasound and coronary angioscopy.

This study aimed to clarify the relationships between arterial remodeling patterns and plaque volume regression or stabilization. The TOGETHAR trial is a prospective open-label trial designed to assess coronary plaque regression and stabilization with multiple plaque imaging modalities following 52 weeks of pitavastatin treatment (2 mg/day). Coronary plaques were observed in 46 patients with both angioscopy and intravascular ultrasound at baseline and after 52 weeks of drug treatment. We divided these patients into three groups according to their remodeling indices (RI). Group P consisted of patients with a baseline RI >1.05, Group M of patients with a baseline RI of 0.95-1.05, and Group N of patients with a baseline RI <0.95 and then evaluated differences in coronary plaque volume changes and yellow grade among the three groups. In the positive remodeling group, whose remodeling index (RI) exceeded 1.05 at baseline, RI and percent atheroma volume (PAV) were significantly reduced (RI 1.14 ± 0.07 to 1.05 ± 0.10, p = 0.010, PAV 47.3 ± 8.3 to 45.3 ± 7.3 mm(3), p = 0.048). There was no relationship between baseline RI and the change in yellow grade of plaque. RI increased without significant change of PAV or a decrease in lumen volume in group N, with RI below 0.95 at baseline. Plaques with positive remodeling were more likely to have plaque volume regression by pitavastatin than those without in patients with coronary artery disease. Moreover, plaques with positive and negative remodeling were changed into those with intermediate remodeling by pitavastatin. Pitavastatin might induce not only plaque regression or stabilization, but also conformational normalization of vessel structure.

Giant Thrombus Formation Immediately After Mitral Valvuloplasty.

Patients with atrial fibrillation (AF) are at risk of cardioembolism.(1,2)) Atrial thrombus formation associated with AF typically occurs in the left atrial appendage (LAA);(3)) therefore, transesophageal echocardiography (TEE) is important for detection of such a thrombus and measurement of LAA flow velocity.(4,5)) LAA closure is routinely performed during mitral valve surgery in patients with AF to prevent cardiogenic stroke.(6)) We report the case of a 65-year-old woman with severe mitral regurgitation (MR) and AF in whom a giant thrombus formed almost immediately after mitral and tricuspid valvuloplasty and concurrent LAA resection. No atrial thrombus or spontaneous echo contrast (SEC) was detected by TEE before the surgery. However, a giant intramural thrombus was detected in the left atrium 7 days after surgery. It was thought that the atrial dysfunction as well as the change in morphology of the left atrium resulting from the severe MR complicated by AF and congestive heart failure produced a thrombotic substrate. This case suggests that careful surveillance for thrombus formation and careful maintenance of anticoagulation therapy are needed throughout the perioperative period even if no SEC or thrombus is detected before surgery.