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

Differential prediction of high-sensitivity cardiac troponin-I, but not N-terminal pro-brain natriuretic peptide, in different pitavastatin doses on cardiovascular events in stable coronary artery disease.

BACKGROUND: This study aimed to examine whether high-sensitivity cardiac troponin-I (hsTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) could predict future major adverse cardiovascular events (MACE) in stable coronary artery disease (CAD) patients with high- or low-dose of pitavastatin. METHODS: This was a case-cohort analysis of the REAL-CAD study, a randomized trial of high- or low-dose (4 or 1 mg/day) pitavastatin therapy in patients with stable CAD. We examined the MACE risk according to the quartile of hsTnI and NT-proBNP at baseline. RESULTS: A total of 1336 and 1396 patients including 582 MACE cases were randomly examined into the hsTnI and NT-proBNP cohort, respectively. Both higher levels of hsTnI and NT-proBNP at baseline were significantly associated with increased risk of MACE (p < 0.001, respectively). When separately analyzed in statin dose, the higher marker levels were significantly associated with higher MACE risk in all cohorts (p < 0.001 in all cohorts). After multivariable adjustment, hsTnI levels were significantly associated with MACE risk in low-dose statin group (HR 2.54, p = 0.0001); however, in high-dose pitavastatin therapy, a significant association was diminished in MACE risk among the quartiles of baseline hsTnI levels (p = 0.154). Conversely in the NT-proBNP cohort, the association between NT-proBNP levels and MACE risk was constantly observed regardless of pitavastatin dose even after multivariable adjustment (both p < 0.0001). CONCLUSIONS: Patients with high hsTnI levels had high risk of MACE in low-dose statin group, but not in high-dose, suggesting that high-dose statin treatment might decrease MACE risk in stable CAD patients with high hsTnI levels.

High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study.

AIM: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients. METHODS: From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) ＜120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively. RESULTS: During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months. CONCLUSIONS: After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.

Effect of Rivaroxaban and Clopidogrel Combination Therapy on In-Stent Responses After Everolimus-Eluting Stent Implantation in a Porcine Coronary Model.

AIM: According to recent clinical trials, a combination of direct oral anticoagulants with antiplatelet drugs is often recommended for atrial fibrillation patients who receive drug-eluting stents (DESs). Although the optimal combination comprises direct factor Xa inhibitors and a P2Y12 receptor antagonist (or aspirin), their influence on vascular responses to DESs remains unclear. METHODS: Pigs were given either aspirin and clopidogrel (dual antiplatelet therapy [DAPT] group), aspirin and rivaroxaban (AR group), or clopidogrel and rivaroxaban (CR group), followed by everolimus-eluting stent (Promus Element) implantation into the coronary artery. Stented coronary arteries were evaluated via intravascular optical coherence tomography (OCT) and histological analysis at 1 and 3 months. RESULTS: OCT revealed lower neointimal thickness in the DAPT group and comparable thickness among all groups at 1 and 3 months, respectively. Histological analyses revealed comparable neointimal area among all groups and the smallest neointimal area in the CR group at 1 and 3 months, respectively. In the DAPT and AR groups, the neointima continued to grow from 1 to 3 months. A shortened time course for neointima growth was observed in the CR group, with rapid growth within a month (maintained for 3 months). A higher incidence of in-stent thrombi was observed in the AR group at 1 month; no thrombi were found in either group at 3 months. More smooth muscle cells with contractile features were found in the CR group at both 1 and 3 months. CONCLUSIONS: Our results proved the noninferiority of the combination of rivaroxaban with an antiplatelet drug, particularly the dual therapy using rivaroxaban and clopidogrel, compared to DAPT after DES implantation.

Three-Dimensional Fluid Dynamical Features of Coronary Plaque Rupture Provoking Acute Coronary Syndrome.

AIM: Coronary plaque rupture is the main cause of acute coronary syndrome (ACS), but the role of blood flow features around plaque rupture for ACS is still unknown. The present study aimed to assess the relationship between the geometric configuration of ruptured plaque and ACS occurrence using computational fluid dynamics (CFD) by moving particle method in patients with coronary artery disease. METHODS: In this study, 45 patients with coronary artery disease who underwent three-dimensional intravascular ultrasound (IVUS) and had a coronary ruptured plaque (24 plaques with provoked ACS, 21 without) were included. To compare the difference in blood flow profile around ruptured plaque between the patients with and without ACS, the IVUS images were analyzed via the novel CFD analysis. RESULTS: There were no significant differences in localized flow profile around ruptured plaque between the two groups when the initial particle velocity was 10.0 cm/s corresponded to a higher coronary flow velocity at ventricular diastole. However, when it was 1.0 cm/s corresponded to lower coronary flow velocity at ventricular systole, particles with lower velocity (0 ≤ V ≤ 5 cm/s) were more prevalent around ACS-PR ( p=0.035), whereas particles with higher velocity (10 ≤ V ≤ 20 cm/s) were more often detected in silent plaque ruptures (p=0.018). CONCLUSIONS: Three-dimensional IVUS revealed that coronary plaque rupture was a complex one with a wide variety of its stereoscopic configuration, leading to various patterns of the local coronary flow profile. A novel CFD analysis suggested that the local flow was more stagnant around ACS-provoked ruptures than in silent ones.

Small Dense Low-Density Lipoprotein Cholesterol and Cardiovascular Risk in Statin-Treated Patients with Coronary Artery Disease.

AIM: We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy. METHODS: This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, ＞1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population. RESULTS: High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction ＜0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04-2.68]; p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (＞34.3 mg/dL; 0.54 [0.36-0.81]; p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94-2.09]; p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002). CONCLUSIONS: These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.

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.

High Wall Shear Stress Is Related to Atherosclerotic Plaque Rupture in the Aortic Arch of Patients with Cardiovascular Disease: A Study with Computational Fluid Dynamics Model and Non-Obstructive General Angioscopy.

AIMS: Wall shear stress (WSS) has been considered a major determinant of aortic atherosclerosis. Recently, non-obstructive general angioscopy (NOGA) was developed to visualize various atherosclerotic pathologies, including in vivo ruptured plaque (RP) in the aorta. However, the relationship between aortic RP and WSS distribution within the aortic wall is unclear. This study aimed to investigate the relationship between aortic NOGA-derived RP and the stereographic distribution of WSS by computational fluid dynamics (CFD) modeling using three-dimensional computed tomography (3D-CT) angiography. METHODS: We investigated 45 consecutive patients who underwent 3D-CT before coronary angiography and NOGA during coronary angiography. WSS in the aortic arch was measured by CFD analysis based on the finite element method using uniform inlet and outlet flow conditions. Aortic RP was detected by NOGA. RESULTS: Patients with a distinct RP showed a significantly higher maximum WSS value in the aortic arch than those without aortic RP (56.2±30.6 Pa vs 36.2±19.8 Pa, p=0.017), no significant difference was noted in the mean WSS between those with and without aortic RP. In a multivariate logistic regression analysis, the presence of a maximum WSS value more than a specific value was a significant predictor of aortic RP (odds ratio 7.21, 95% confidence interval 1.78-37.1,p=0.005). CONCLUSIONS: Aortic RP detected by NOGA was strongly associated with a higher maximum WSS in the aortic arch derived by CFD using 3D-CT. The maximum WSS value may have an important role in the underlying mechanism of not only aortic atherosclerosis, but also aortic RP.

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.

Anomalous origin of the coronary artery coursing between the great vessels presenting with a cardiovascular event (J-CONOMALY Registry).

AIMS: Anomalous origin of the coronary artery (AOCA) with an inter-arterial course (IAC) between the great vessels poses a risk for a life-threatening cardiovascular event. We assessed, in a registry-based study, the clinical features, treatment strategies, and prognoses of life-threatening cardiovascular events ensuant to AOCA. METHODS AND RESULTS: Included were 65 AOCA patients (48 men/17 women, aged 41 ± 23 years) from 40 clinical centres who had experienced sudden cardiac arrest (SCA) (n = 30), acute myocardial infarction (AMI) (n = 5), angina (n = 23), or syncope (n = 7). The anomalous vessel was the right coronary artery in 72% of patients and left coronary artery in 28%; the ostium was slit-like in 42%. Coronary luminal narrowing ≥75% was absent in patients with SCA or syncope (86% and 57%, respectively), but occlusion or narrowing was seen in those with AMI (100%) or angina (52%). Age ≤40 years, male sex, sporting activity, absence of prodromal symptoms, acutely angled (≤30°) take-off from the aorta, and absence of luminal narrowing of the IAC segment were associated with SCA in this patient group. Coronary vasospasm was inducible in 12 of 17 patients without coronary narrowing. Management included surgical revascularization (n = 26) percutaneous coronary intervention (n = 9), and medical treatment (n = 26). Four SCA patients died while hospitalized; no others died during the median 5.0 (range, 1.8-7.0)-year follow-up period. CONCLUSIONS: In patients with AOCA, age ≤40 years, male sex, sporting activity, and an acute take-off angle appear to be risk factors for SCA. Appropriate management can be beneficial. Confirmation in a large-scale study is warranted.

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.

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.

Effect of Saxagliptin on Endothelial Function in Patients with Type 2 Diabetes: A Prospective Multicenter Study.

The dipeptidyl peptidase-4 inhibitor saxagliptin is a widely used antihyperglycemic agent in patients with type 2 diabetes. The purpose of this study was to evaluate the effects of saxagliptin on endothelial function in patients with type 2 diabetes. This was a prospective, multicenter, interventional study. A total of 34 patients with type 2 diabetes were enrolled at four university hospitals in Japan. Treatment of patients was initially started with saxagliptin at a dose of 5 mg daily. Assessment of endothelial function assessed by flow-mediated vasodilation (FMD) and measurement of stromal cell-derived factor-1α (SDF-1α) were conducted at baseline and at 3 months after treatment with saxagliptin. A total of 31 patients with type 2 diabetes were included in the analysis. Saxagliptin significantly increased FMD from 3.1 ± 3.1% to 4.2 ± 2.4% (P = 0.032) and significantly decreased total cholesterol from 190 ± 24 mg/dL to 181 ± 25 mg/dL (P = 0.002), glucose from 160 ± 53 mg/dL to 133 ± 25 mg/dL (P < 0.001), HbA1c from 7.5 ± 0.6% to 7.0 ± 0.6% (P < 0.001), urine albumin-to-creatinine ratio from 63.8 ± 134.2 mg/g to 40.9 ± 83.0 mg/g (P = 0.043), and total SDF-1α from 2108 ± 243 pg/mL to 1284 ± 345 pg/mL (P < 0.001). These findings suggest that saxagliptin is effective for improving endothelial function.

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.

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 epicardial fat and metabolic syndrome on reverse atrial remodeling after ablation for atrial fibrillation.

BACKGROUND: Metabolic syndrome/epicardial adipose tissue (EAT) plays an important role in atrial fibrillation (AF). Although reverse atrial remodeling (RAR) often occurs after AF ablation, the effects of EAT on RAR remain unknown. METHODS: Study subjects were 104 patients in whom transthoracic echocardiography (TTE) was performed before AF ablation and 3, 6, and 12 months afterward. EAT was assessed in terms of its thickness adjacent to the right ventricular anterior wall in the TTE parasternal view. RAR was defined as >10% reduction in the left atrial volume (LAV) index by the 3-month follow-up examination. RESULTS: Postablation RAR occurred in 57/104 (55%) patients. RAR absence was associated with a relatively thick EAT (4.92 ± 1.65 vs. 3.92 ± 1.17 mm, P = 0.0005), small LAV index (24.6 ± 7.5 vs. 28.8 ± 10.6 mL/m2, P = 0.0233), and metabolic syndrome (62% vs. 28%, P = 0.0006). Metabolic syndrome and EAT were shown to be independent predictors of RAR absence. Thick EAT was significantly associated with AF recurrence after ablation (5.05 ± 2.19 mm vs. 4.17 ± 1.16 mm for no AF recurrence group, P = 0.0116), but metabolic syndrome was not (48% vs. 42%, P = 0.6189). Despite no change in body weight, EAT thickness decreased significantly by 12 months in patients without AF recurrence (4.17 ± 1.16 vs. 3.65 ± 1.16 mm, P < 0.0001). CONCLUSIONS: EAT and metabolic syndrome appear to be strongly associated with RAR absence, but only the thick EAT was significantly associated with the postablation AF recurrence. Our findings, especially the thinning of EAT, suggest that thick EAT lead to AF vulnerability but that EAT reduction favorably affects ablation outcome.