Endothelial glycocalyx and severity and vulnerability of coronary plaque in patients with coronary artery disease.

BACKGROUND AND AIMS: Endothelial glycocalyx covers the endothelium and maintains vascular integrity. However, its association with the severity and vulnerability of coronary artery disease (CAD) remains to be elucidated. METHODS: A total of 259 consecutive patients with stable CAD requiring percutaneous coronary intervention (PCI) were prospectively enrolled. Patients were classified into 2 groups according to the median value of serum syndecan-1, which is a core component of the endothelial glycocalyx (lower syndecan-1 group [syndecan-1 <99.0 ng/mL], n = 130; higher syndecan-1 group [syndecan-1 ≥99.0 ng/mL], n = 129). Severity of CAD and focal plaque vulnerability in culprit lesion were evaluated using angiography and optical coherence tomography. RESULTS: There was no significant difference in clinical characteristics between the lower syndecan-1 group and the higher syndecan-1 group other than the prevalence of family history of CAD (19 vs. 32%, p = 0.022), prior PCI history (45 vs. 60%, p = 0.015) and estimated glomerular filtration rate (57.8 ± 17.2 vs. 50.9 ± 25.6 ml/min/1.73 m2, p = 0.011). Although disease severity on angiogram was comparable between the 2 groups, the prevalence of lipid-rich plaque (40 vs. 19%, p = 0.004) and thin-cap fibroatheroma (20 vs. 6%, p = 0.006) was significantly higher in the lower syndecan-1 group than the higher syndecan-1 group. Lower syndecan-1 level was independently associated with higher prevalence of lipid-rich plaque (odds ratio 3.626, 95% confidence interval 1.535-8.566, p = 0.003). CONCLUSIONS: Lower syndecan-1 level was associated with higher prevalence of vulnerable plaque in patients with CAD. This finding suggests the association between impaired endothelial glycocalyx and the development of vulnerable plaque.

Physical exertion as a trigger of acute coronary syndrome caused by plaque erosion.

Distinct clinical characteristics have been demonstrated in patients with plaque erosion as compared with those with plaque rupture. We reasoned that greater physical activity might influence the onset of plaque erosion. In total, 97 consecutive patients with non ST-segment elevation acute coronary syndrome (ACS) who underwent optical coherence tomography (OCT) imaging of the culprit lesion were enrolled. OCT-determined culprit plaque characteristics were plaque erosion (18.6%), calcified plaque (26.8%), plaque rupture (32.0%) and other (22.7%). The physical activity evaluated by estimated metabolic equivalents (METs) at ACS onset was significantly greater in the plaque erosion group than in the plaque rupture group (3.3 ± 1.7 vs. 2.1 ± 1.0, p = 0.011). The rate of ACS onset outdoors was the highest (61.1%) in the plaque erosion group. The combination of greater physical activity (> 3 METs), outdoor onset and higher body mass index (> 25.1 kg/m2) had a significant odds ratio for the incidence of plaque erosion (odds ratio 15.0, 95% confidence interval 3.81 to 59.0, p < 0.001). Plaque erosion was associated with greater physical activity at the onset. This finding may help to further clarify the pathogenesis of ACS Impact of physical exertion on the incidence of plaque erosion. NSTE-ACS, non ST-segment elevation acute coronary syndrome.

Age- and Gender-Related Differences in Coronary Lesion Plaque Composition on Optical Coherence Tomography.

BACKGROUND: The pathophysiology and chronological course of atherosclerosis seems to be different between men and women due to biological differences, and age and gender differences in plaque composition of coronary lesions remain to be elucidated.Methods and Results:A total of 860 consecutive patients with a median age of 69 years (IQR, 60-78 years) who underwent optical coherence tomography (OCT) of culprit lesions was included. The composition of culprit plaque on OCT was compared between female (n=171) and male (n=689) subjects in younger (<70 years old) and elderly (≥70 years old) patients. In elderly patients, the prevalence of thin-cap fibroatheroma (TCFA) was significantly higher in women than in men (30.6 vs. 15.2%, P<0.001). In younger patients, the prevalence of large calcification was significantly higher in women than in men (60.0 vs. 32.8%, P<0.001). The prevalence of other vulnerable plaque characteristics (i.e., macrophages, microchannels, and spotty calcification), was similar between women and men. Elderly women had a significantly higher prevalence of TCFA (OR, 2.13; 95% CI: 1.33-3.44, P=0.002) than other patients. CONCLUSIONS: Women had a higher prevalence of TCFA and of large calcification than men in patients ≥70 and <70 years old, respectively. This may facilitate the understanding of gender differences in the pathogenesis of coronary atherosclerosis, and the tailoring of therapy and of prevention according to age and gender.

Contrast Volume and Decline in Kidney Function in Optical Coherence Tomography-Guided Percutaneous Coronary Intervention.

Optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) may increase contrast volume. However, the impact of OCT-guided PCI on the decline in kidney function (DKF) in actual clinical practice remains unclear.Among 1,003 consecutive patients who underwent either OCT-guided or intravascular ultrasound (IVUS)-guided PCI in our institute, we identified 202 propensity score-matched pairs adjusted by baseline factors. The incidence of DKF was compared between the OCT-guided PCI group and the IVUS-guided PCI group. DKF was defined as an increase in serum creatinine level of ≥ 0.5 mg/dL or a relative increase of ≥ 25% over baseline within 48 hours (acute DKF) or 1 month (sustained DKF) after PCI.Baseline characteristics, including the prevalence of chronic kidney disease (54% versus 46%, P = 0.09), were comparable between the OCT- and IVUS-guided PCI groups except for the age. The contrast volume was comparable between the two groups (153 ± 56 versus 144 ± 60 mL, P = 0.09), although it was significantly greater in the OCT-guided PCI group in patients with acute coronary syndrome (ACS; 175 ± 55 versus 159 ± 43 mL, P = 0.04). The incidence of acute DKF (0.5% versus 2.5%, P = 0.22) and sustained DKF (5.0% versus 10.4%, P = 0.31) was comparable between the two groups. Multivariate analysis demonstrated that ACS (odds ratio 4.74, 95% confidence interval 2.72-8.25, P < 0.001) was a predictor of sustained DKF.Compared with IVUS-guided PCI, OCT-guided PCI did not increase the incidence of DKF in actual clinical practice, although the increased contrast volume was observed in ACS cases.

Lipoprotein (a) level is associated with plaque vulnerability in patients with coronary artery disease: An optical coherence tomography study.

BACKGROUND: High lipoprotein (a) [Lp(a)] levels are an independent factor for worse prognosis in patients with coronary artery disease (CAD). However, the association between serum Lp(a) level and coronary plaque vulnerability remains to be determined. METHODS: A total of 255 consecutive patients with CAD who underwent optical coherence tomography imaging of culprit lesions were included. Patients were divided into 2 groups according to their Lp(a) levels (the higher Lp(a) group [≥25 mg/dL], n = 87; or the lower Lp(a) group [<25 mg/dL], n = 168). RESULTS: The prevalence of thin-cap fibroatheroma (TCFA) was significantly higher in the higher Lp(a) group than in the lower Lp(a) group (23% [n = 20] vs. 11% [n = 19], p = 0.014). Although the prevalence of TCFA was comparable between the 2 groups among patients with a lower LDL cholesterol (LDL-C) level (<100 mg/dL), TCFA was significantly more prevalent in the higher Lp(a) group than in the lower Lp(a) group (39% [14/36] vs. 10% [5/50], p = 0.001) among patients with a higher LDL-C level (≥100 mg/dL). CONCLUSIONS: A higher Lp(a) level was associated with a higher frequency of TCFA, particularly in patients with a higher LDL-C level.

Impaired Flow-Mediated Dilation and Severity and Vulnerability of Culprit Plaque in Patients with Coronary Artery Disease.

The association between endothelial function, evaluated using flow-mediated dilatation (FMD), and the severity of coronary artery disease remains to be elucidated.A total of 245 consecutive patients with stable angina were prospectively enrolled. FMD was evaluated in the brachial artery before percutaneous coronary intervention. Patients were divided into 2 groups according to the FMD value (lower FMD group [FMD < 2.0], n = 82; higher FMD group [FMD ≥ 2.0], n = 163). The severity of coronary artery disease was evaluated using findings of angiography and optical coherence tomography, and compared between the 2 groups.The prevalence of left main (LM) disease was significantly higher in the lower FMD group than in the higher FMD group (8.5% versus 2.5%, P = 0.046), although the prevalence of multivessel disease was comparable between the groups. Lower FMD was independently associated with a higher prevalence of LM disease (odds ratio, 3.89; 95% confidence interval, 1.12-15.5; P = 0.033). A general linear model with multiple variables revealed that the minimal lumen area (MLA) in the culprit lesion was significantly smaller in patients with lower FMD than in those with higher FMD (regression coefficient b, -0.249 mm2; 95% confidence interval, -0.479--0.018 mm2; P = 0.035). The prevalence ofvulnerable plaque characteristics was comparable between the 2 groups.Patients with lower FMD had a higher incidence of LM disease and a smaller MLA in the culprit lesion. FMD may be a useful, noninvasive indicator for identifying patients with severe coronary artery disease.

Incidence, factors, and clinical significance of cholesterol crystals in coronary plaque: An optical coherence tomography study.

BACKGROUND AND AIMS: Intraplaque cholesterol crystal (CC) is recognized as a component of vulnerable plaques. However, the clinical characteristics of patients with CC and the impact of CC on clinical events remain unknown. METHODS: A total of 340 consecutive patients who underwent optical coherence tomography (OCT) imaging of culprit lesions were included in the study. CC was defined as a thin linear structure with high reflectivity and low signal attenuation on OCT images. The incidence of major adverse cardiovascular events (MACE) at 1-year was compared between patients with CC (CC group) and those without CC (non-CC group). MACE included cardiac death, non-fatal myocardial infarction, target vessel revascularization (TVR), and non-TVR (NTVR). RESULTS: CC was observed in 29% (n = 98) of the patients. There was no significant difference in baseline clinical characteristics between the CC and non-CC groups, other than in eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (0.39 ±â€¯0.29 vs. 0.47 ±â€¯0.33, p = 0.047) and hemoglobin A1c (HbA1c) levels (6.51 ±â€¯0.97 vs. 6.25 ±â€¯0.87%, p = 0.016). The incidence of MACE and NTVR at 1-year was significantly higher in the CC group than in the non-CC group (15.3 vs. 7.9%, P = 0.038; 8.1 vs. 2.5%, p = 0.017). The presence of CC was significantly associated with a higher rate of 1-year MACE (odds ratio 4.78, confidential interval 2.02-10.10, p < 0.001). CONCLUSIONS: Patients with CC in the culprit lesion had higher HbA1c and lower EPA/AA than patients without CC. The 1-year clinical outcomes in patients with CC in the culprit lesion were worse than in those without CC.

Achilles tendon thickening is associated with disease severity and plaque vulnerability in patients with coronary artery disease.

BACKGROUND: Tendon xanthomas are accumulations of collagen and macrophages, which contain cholesterol esters and a marker of high risk for coronary artery disease (CAD). OBJECTIVE: The aim of the article was to clarify whether the presence of Achilles tendon thickening (ATT) was associated with disease severity and plaque vulnerability in patients with CAD. METHODS: A total of 241 consecutive patients who underwent percutaneous coronary intervention and ATT assessment were analyzed. ATT was defined as Achilles tendon thickness of ≥9 mm on radiograph. The severity of CAD and plaque vulnerability was assessed by the findings on angiogram and optical coherence tomography, respectively. RESULTS: ATT was found in 44 patients (18.2%). The frequency of multivessel disease (79.6% vs 58.4%, P = .009) and left main lesion (13.6% vs 3.1%, P = .004) was significantly higher in patients with ATT (ATT group) than in patients without ATT (no ATT group). Multivariate logistic regression analyses demonstrated that the presence of ATT was independently associated with the presence of multivessel disease (odds ratio, 2.33; 95% confidence interval, 1.08-5.46; P = .031). The ATT group had a higher prevalence of intimal vascular channels (50.0% vs 24.7%, P = .018) and macrophage accumulation (58.3% vs 33.3%, P = .028) in culprit plaque than the no ATT group. CONCLUSIONS: Patients with the presence of ATT had a higher prevalence of multivessel coronary disease and left main coronary artery disease than with patients without ATT. The presence of ATT was also associated with vulnerable features, including intimal vascular channels and macrophage accumulation in culprit plaques.

Endothelial Dysfunction Is Associated with Cognitive Impairment of Elderly Cardiovascular Disease Patients.

Cognitive impairment is frequently represented in elderly patients with cardiovascular disease (CVD); yet, the mechanism is uncertain. Recent studies have suggested the association between the vascular endothelial dysfunction and cognitive impairment. The aim of this study was to clarify the association between endothelial dysfunction and cognitive impairment in elderly patients with CVD.A total of 80 elderly patients (> 70 years old) with CVD were included. Patients who had already pharmacologically intervened for cognitive impairment were excluded. The endothelial dysfunction was assessed by the reactive hyperemia-peripheral arterial tonometry (RH-PAT). Cognitive impairment was diagnosed by the Mini-mental state examination.The RH-PAT index was significantly lower in cognitive impairment (median 1.60 [interquartile range (IQR) 1.34 to 1.89], n = 51) as compared with non-cognitive impairment (median 1.75 [IQR 1.55 to 2.30], n = 29, P = 0.005). By a multivariate analysis, the RH-PAT index was independently associated with cognitive impairment (odds ratio: 0.89; 95% confidence interval: 0.81 to 0.97; per 0.1, P = 0.044). In the receiver-operating characteristic analysis, the best cut-off of the RH-PAT index to identify cognitive impairment was 1.65 (area under the curve 0.67; P = 0.011) with limited the sensitivity (63%) and specificity (66%).A lower RH-PAT index was significantly associated with the presence of cognitive impairment in elderly CVD patients. Further studies are required to clarify the mechanism and the causal relationship between the endothelial dysfunction and cognitive impairment in patients with CVD.

Impact of underlying plaque type on strut coverage in the early phase after drug-eluting stent implantation.

BACKGROUND: The aim of this study was to investigate whether the underlying plaque type affects the neointimal coverage after drug-eluting stent implantation. METHODS: A total of 1793 struts in 22 zotarolimus-eluting stents were assessed using optical coherence tomography imaging within 3 months of implantation. Neointimal coverage was evaluated within 5 mm from each stent edge on cross-sectional optical coherence tomography images at every 1-mm interval. The percentage of struts covered by neointima was compared among the normal segment group, the fibrous plaque group, and the lipid plaque group on the basis of the underlying plaque type. RESULTS: The percentage of covered strut was significantly lower in the normal segment group than in the fibrous plaque group (35.9±30.2 vs. 57.1±31.0%, P<0.05) and the lipid plaque group (vs. 64.7±23.5%, P<0.01). The neointima was significantly thinner in the normal segment group than in the lipid plaque group (19.0±22.3 vs. 32.0±18.8 µm, P<0.01). The percentage of struts on the normal segment was significantly higher in cross-sections with a ratio of uncovered to total struts per section more than 0.3 than in cross-sections with a ratio up to 0.3 (32.4±31.7 vs. 19.5±33.8%, P<0.01). CONCLUSION: Struts on the normal segment were less covered and had thinner neointima than struts on the lipid plaque at the stent edge within 3 months after zotarolimus-eluting stent implantation. Caution should be exercised when implanting longer drug-eluting stents to achieve uniform strut coverage in the early phase.

Lower Level of Low Density Lipoprotein Cholesterol is Associated with a Higher Increase in the Fractional Flow Reserve in Patients with Fixed-dose Rosuvastatin.

AIM: Fractional flow reserve (FFR) reflects on the diffuse atherosclerosis per coronary artery. It is unknown whether the statin therapy affects long term FFR after stenting. The aim of this study was to evaluate the long term FFR after stent implantation in patients who are intaking fixed-dose rosuvastatin. METHODS: A total of 22 patients with stable angina pectoris were enrolled. The values of FFR were measured before, immediately after, and 18 months after (follow-up day) the implantation of everolimus eluting stent (EES; Promus ElementTM or Promus Element PlusTM). A fixed dose of rosuvastatin at 5 mg/day was administrated to all patients. RESULTS: Of the 22 patients, 2 were excluded because of adverse effect of rosuvastatin and in-stent total occlusion after EES implantation. Overall, the values of FFR immediately after and 18 months after EES implantation did not show significant change (from 0.90±0.05 to 0.88±0.06, p=0.16). However, there was a significant negative correlation between low density lipoprotein (LDL) cholesterol level at follow-up day and changes in the value of FFR (p=0.01, r =－0.74). There was an increase in the FFR value after stenting in 8 out of 9 patients with LDL cholesterol level below 75 mg/dl (area under the curve 0.92, p=0.0005). CONCLUSIONS: LDL cholesterol level was associated with the change in the FFR value in patients following stent implantation. Lower LDL cholesterol tended to improve in the long-term FFR, underscoring the importance of lowering LDL cholesterol to prevent the progression of coronary atherosclerosis.

Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation.

In recent years, direct oral anticoagulants (DOACs) of dabigatran, rivaroxaban, apixaban, edoxaban, which are all alternatives to warfarin, have been released. The use of DOACs is becoming more widespread in the clinical management of thrombotic stroke risk in patients with atrial fibrillation (AF). In large-scale clinical trials of each drug, DOACs were reported to inhibit intracranial hemorrhage, stroke, and death compared to warfarin. Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). OC is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification in the vessel wall. GAS6 prevents the apoptosis of vascular smooth muscle cells. Therefore, decrease of blood vitamin K levels may cause osteoporosis, vascular calcification, and the inhibition of vessels angiogenesis. This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. We studied 21 consecutive patients with persistent or chronic AF, who were treated with warfarin at least for 12 months. Warfarin administration was changed to rivaroxaban (10 or 15 mg/day) in all patients. Osteopontin (OPN), bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were measured. Pulse wave velocity (PWV) and augmentation index (AI) were also measured as atherosclerosis assessments. All measurements were done before and six months after the rivaroxaban treatment. There was a significant increase in serum level of BAP compared to baseline (12.5 ± 4.6 to 13.4 ± 4.1 U/L, P < 0.01). In contrast, there was a significant decrease in the serum level of ucOC (9.5 ± 5.0 to 2.7 ± 1.3 ng/ml, P < 0.01). Also, in the ucOC levels, there was a significant negative correlation between baseline values and baseline to 6-months changes in high ucOC group (r = -0.97, P < 0.01). The atherosclerosis- and osteoporosis-related biomarker, serum level of OPN were significantly decreased compared to baseline (268.3 ± 46.8 to 253.4 ± 47.1 ng/ml, P < 0.01). AI and PWV were significantly decreased after 6 months of treatment with rivaroxaban (33.9 ± 18.4 to 24.7 ± 18.4%, P = 0.04; 1638.8 ± 223.0 to 1613.0 ± 250.1 m/s, P = 0.03, respectively). Switching to rivaroxaban from warfarin in patients with atrial fibrillation was associated with an increase of bone formation markers and a decrease of bone resorption markers, and also improvements of PWV and AI.

Ezetimibe enhances and stabilizes anticoagulant effect of warfarin.

Ezetimibe reduces plasma levels of low-density lipoprotein cholesterol by inhibiting Niemann-Pick C1-like protein 1 (NPC1L1). A recent study demonstrated that NPC1L1 plays an important role in absorption of fat-soluble vitamins including vitamin K. We evaluated whether the add-on treatment of ezetimibe affects anticoagulation in patients taking warfarin. Between October 2007 and March 2015, the administration of ezetimibe was started to a total of 101 outpatients who were already on oral anticoagulation with warfarin. We retrospectively analyzed blood lipid levels, prothrombin time international normalized ratio (PT-INR) and time in therapeutic INR range (TTR). Seventy-one patients (70 %) showed increase in PT-INR after ezetimibe treatment (1.96 ± 0.45 to 2.20 ± 0.61, p < 0.001). It was necessary to reduce the warfarin dose in 9 of 101 patients for clinical indication. There was a significant positive correlation between change in PT-INR and statin usage at baseline (p = 0.03). The mean value of changes in PT-INR of patients with taking statin was significantly larger than that of patients without taking statin (0.34 ± 0.54 vs. 0.06 ± 0.36, p = 0.03). There was an increase in the TTR (52 ± 26 to 61 ± 23 %, p < 0.0001) and a decrease in the frequency to change the dose of warfarin after the ezetimibe treatment [45 times of 735 examination days (6 %) to 20 times of 695 examination days (3 %), p = 0.02]. Our data suggest possible drug interaction between warfarin and ezetimibe. Ezetimibe may increase and stabilize the anticoagulant effect of warfarin, especially in patients taking statins.

Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes.

Incretin hormones have been reported to have cytoprotective actions in addition to their glucose-lowering effects. We evaluated whether teneligliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, affects left ventricular (LV) function in patients with type 2 diabetes mellitus (T2DM). Twenty-nine T2DM patients not receiving any incretin-based drugs were enrolled and prescribed with teneligliptin for 3 months. Compared to baseline levels, hemoglobin A1c levels decreased (7.6 ± 1.0 % to 6.9 ± 0.7 %, p < 0.01) and 1,5-anhydro-D-glucitol levels increased (9.6 ± 7.2 µg/mL to 13.5 ± 8.7 µg/mL, p < 0.01) after treatment. Clinical parameters, including body mass index and blood pressure, did not show any difference before and after treatment. Three months after treatment, there were improvements in LV systolic and diastolic function [LV ejection fraction, 62.0 ± 6.5 % to 64.5 ± 5.0 %, p = 0.01; peak early diastolic velocity/basal septal diastolic velocity (E/e') ratio, 13.3 ± 4.1 to 11.9 ± 3.3, p = 0.01]. Moreover, there was an improvement in endothelial function (reactive hyperemia peripheral arterial tonometry [RH-PAT] index; 1.58 ± 0.47 to 2.01 ± 0.72, p < 0.01). There was a significant negative correlation between changes in the E/e' ratio and RH-PAT values. Furthermore, circulating adiponectin levels increased (27.0 ± 38.5 pg/mL to 42.7 ± 33.2 pg/mL, p < 0.01) without changes in patient body weight. Teneligliptin treatment was associated with improvements in LV function and endothelial functions, and an increase in serum adiponectin levels. These results support the cardio-protective effects of teneligliptin in T2DM patients and increase in serum adiponectin levels.