Cardiac sarcoidosis accompanied by a tumor-like blush on coronary angiography.

A 71-year-old female was diagnosed with cardiac sarcoidosis by a history of complete atrioventricular block requiring pacemaker implantation and a focal thinning of basal interventricular septum (IVS) on echocardiography. Coronary angiography showed a tumor-like blush fed by septal branch of left anterior descending artery and right coronary artery concomitant with a coronary-to-right ventricle shunt. Echocardiography showed a low echoic mass at mid-IVS with an abnormal shunt flow into right ventricle. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) showed an uptake at the corresponding site of mid-IVS. Eight months after the initiation of steroid therapy, FDG-PET showed no abnormal uptake at mid-IVS, suggesting decreased activity of cardiac sarcoidosis. We experienced a case of cardiac sarcoidosis with FDG uptake accompanied by a tumor-like blush at mid-IVS. The present case suggests the involvement of microvascular accumulation in the activity of cardiac sarcoidosis. .

Sex Differences in Culprit Plaque Characteristics Among Different Age Groups in Patients With Acute Coronary Syndromes.

BACKGROUND: Despite the significant decline in cardiovascular mortality in women over the past several decades, sex differences in the underlying pathology of acute coronary syndromes remain poorly understood. Previous postmortem studies have demonstrated sex differences in coronary plaque morphology with a higher prevalence of plaque erosion in young women and more plaque rupture in older women after menopause, whereas men showed no increase in prevalence of plaque rupture with age. However, in vivo data are limited. METHODS: This study included patients who presented with acute coronary syndrome and underwent preintervention optical coherence tomography imaging of the culprit lesion. The culprit plaque was categorized as plaque rupture, plaque erosion or culprit plaque with calcification, and stratified by age. Features of plaque vulnerability at culprit lesion were also analyzed. RESULTS: In 1368 patients (women=286), women and men had a similar distribution of culprit plaque morphology (plaque rupture versus plaque erosion). However, significant sex differences were found in the underlying mechanisms of acute coronary syndrome among different age groups: women showed a significant ascending trend with age in plaque rupture (P<0.001) and the features of plaque vulnerability such as lipid plaque (P<0.001), thin-cap fibroatheroma (P=0.005), and microstructures including macrophages, cholesterol crystals, and calcification (P=0.026). No trend was observed in men. CONCLUSIONS: Age related sex differences in culprit plaque morphology and vulnerability were identified in patients with acute coronary syndrome: prevalence of plaque rupture and vulnerability increased with age in women but not in men. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01110538 and NCT03479723.

Age and Phenotype of Patients With Plaque Erosion.

Background A recent study reported that the outcome of patients with plaque erosion treated with stenting is poor when the underlying plaque is lipid rich. However, the detailed phenotype of patients with plaque erosion, particularly as related to different age groups, has not been systematically studied. Methods and Results Patients with acute coronary syndromes caused by plaque erosion were selected from 2 data sets. Demographic, clinical, angiographic, and optical coherence tomography findings of the culprit lesion were compared between 5 age groups. Among 579 erosion patients, male sex and current smoking were less frequent, and hypertension, diabetes, and chronic kidney disease were more frequent in older patients. ST-segment-elevation myocardial infarction was more frequent in younger patients. Percentage of diameter stenosis on angiogram was greater in older patients. The prevalence of lipid-rich plaque (27.3% in age <45 years and 49.4% in age ≥75 years, P<0.001), cholesterol crystal (3.9% in age <45 years and 21.8% in age ≥75 years, P=0.027), and calcification (5.5% in age <45 years and 54.0% in age ≥75 years, P<0.001) increased with age. After adjusting risk factors, younger patients were associated with the presence of thrombus, and older patients were associated with greater percentage of diameter stenosis and the presence of lipid-rich plaque and calcification. Conclusions The demographic, clinical, angiographic, and plaque phenotypes of patients with plaque erosion distinctly vary depending on age. This may affect the clinical outcome in these patients. Registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT03479723, NCT02041650.

Optical Coherence Tomography Predictors for a Favorable Vascular Response to Statin Therapy.

Background Specific plaque phenotypes that predict a favorable response to statin therapy have not been systematically studied. This study aimed to identify optical coherence tomography predictors for a favorable vascular response to statin therapy. Methods and Results Patients who had serial optical coherence tomography imaging at baseline and at 6 months were included. Thin-cap area (defined as an area with fibrous cap thickness <200 µm) was measured using a 3-dimensional computer-aided algorithm, and changes in the thin-cap area at 6 months were calculated. A favorable vascular response was defined as the highest tertile in the degree of reduction of the thin-cap area. Macrophage index was defined as the product of the average macrophage arc and length of the lesion with macrophage infiltration. Layered plaque was defined as a plaque with 1 or more layers of different optical density. In 84 patients, 140 nonculprit lipid plaques were identified. In multivariable analysis, baseline thin-cap area (odds ratio [OR] 1.442; 95% CI, 1.024-2.031, P=0.036), macrophage index (OR, 1.031; 95% CI, 1.002-1.061, P=0.036), and layered plaque (OR, 2.767; 95% CI, 1.024-7.479, P=0.045) were identified as the significant predictors for a favorable vascular response. Favorable vascular response was associated with a decrease in the macrophage index. Conclusions Three optical coherence tomography predictors for a favorable vascular response to statin therapy have been identified: large thin-cap area, high macrophage index, and layered plaque. Favorable vascular response to statin was correlated with signs of decreased inflammation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01110538.

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.

Healed Plaques in Patients With Stable Angina Pectoris.

OBJECTIVE: Healed plaques, signs of previous plaque destabilization, are frequently found in the coronary arteries. Healed plaques can now be diagnosed in living patients. We investigated the prevalence, angiographic, and optical coherence tomography features of healed plaques in patients with stable angina pectoris. Approach and Results: Patients with stable angina pectoris who had undergone optical coherence tomography imaging were included. Healed plaques were defined as plaques with one or more signal-rich layers of different optical density. Patients were divided into 2 groups based on layered or nonlayered phenotype at the culprit lesion. Among 163 patients, 87 (53.4%) had layered culprit plaque. Patients with layered culprit plaque had more multivessel disease (62.1% versus 44.7%, P=0.027) and more angiographically complex culprit lesions (64.4% versus 35.5%, P<0.001). Layered culprit plaques had higher prevalence of lipid plaque (83.9% versus 64.5%, P=0.004), macrophage infiltration (58.6% versus 35.5%, P=0.003), calcifications (78.2% versus 63.2%, P=0.035), and thrombus (28.7% versus 14.5%, P=0.029). Lipid index (P=0.001) and percent area stenosis (P=0.015) were greater in the layered group. The number of nonculprit plaques, evaluated using coronary angiograms, tended to be greater in patients with layered culprit plaque (4.2±2.5 versus 3.5±2.1, P=0.053). Nonculprit plaques in patients with layered culprit lesion had higher prevalence of layered pattern (P=0.002) and lipid phenotype (P=0.005). Lipid index (P=0.013) and percent area stenosis (P=0.002) were also greater in this group. CONCLUSIONS: In patients with stable angina pectoris, healed culprit plaques are common and have more features of vulnerability and advanced atherosclerosis both at culprit and nonculprit lesions.

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.

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.

Lower limb ischemia due to popliteal artery compression by Baker cyst.

A Baker cyst is the most common mass around the knee joint. It is mostly asymptomatic; however, it may cause knee pain or focal swelling because of compression of vein or nerve. Herein, we report a case of Baker cyst obstructing arterial flow and causing intermittent claudication. An attached polycystic mass was found posterior to the popliteal artery. Needle aspiration was ineffective, and the patient experienced recurrent lower leg pain. Surgical resection was performed, and the patient became symptom free. Baker cyst may cause lower limb ischemia through obstruction of arterial flow, requiring surgical intervention.

Serial Optical Coherence Tomography and Intravascular Ultrasound Analysis of Gender Difference in Changes of Plaque Phenotype in Response to Lipid-Lowering Therapy.

Although the clinical benefit of statins have been demonstrated in both genders, gender differences in the response to statin therapy on plaque morphologic changes have not been reported. A total of 66 nonculprit plaques from 46 patients who had serial image acquisition at baseline, 6 months, and 12 months by both optical coherence tomography and intravascular ultrasound (IVUS) were included. Patients were treated with atorvastatin 60 mg (AT60) or 20 mg (AT20). The baseline characteristics were similar between women (n = 16) and men (n = 30) except for age (59.3 ± 6.8 vs 52.5 ± 10.6 years, p = 0.027) and smoking status (12.5% vs 70.0%, p <0.001). The change in fibrous cap thickness (FCT) at 12 months was significant in both groups (108.8 ± 87.4 µm, p <0.001, 91.3 ± 70.1 µm, p <0.001, respectively) without significant difference between the groups (p = 0.437). The percent change in mean lipid arc at 6 months was significantly greater in women than that in men (-12.8 ± 18.8% vs -1.56 ± 21.8%, p = 0.040). In women, the percent change of FCT in the AT20 group was similar to that in the AT60 group (182.5 ± 199.5% vs 192.9 ± 149.7%, p = 0.886). However, in men, the percent change of FCT in the AT20 group was significantly smaller than that in the AT60 group (92.2 ± 90.5% vs 225.9 ± 104.3%, p <0.001). No significant change in percent atheroma volume by IVUS was seen at 12 months in both women and men. In conclusion, statin therapy was effective in both genders for plaque stabilization at 12-month follow-up. High-intensity statin therapy may be particularly important in men.

Associations between the Framingham Risk Score and coronary plaque characteristics as assessed by three-vessel optical coherence tomography.

OBJECTIVES: This study sought to explore the association between the Framingham Risk Score (FRS) and coronary plaque characteristics assessed by optical coherence tomography (OCT) imaging. BACKGROUND: Clinical prediction models are useful for identifying high-risk patients. However, coronary events often occur in individuals estimated to be at low risk. METHODS: A total of 254 patients with coronary artery disease who underwent three-vessel OCT were divided into tertiles according to FRS. Nonculprit plaque characteristics were compared among the three groups. RESULTS: A total of 663 plaques were analyzed. FRS was significantly associated with calcification [37% (low FRS) vs. 46% (intermediate FRS) vs. 70% (high FRS); P<0.001] and neovascularization [39% (low FRS) vs. 41% (intermediate FRS) vs. 56% (high FRS); P<0.001], but not with lipid-rich plaques or thin-cap fibroatheroma (TCFA). On multivariate analysis, FRS was an independent predictor of the presence of both calcification and neovascularization. There were no deaths, two acute myocardial infarctions, and 15 nontarget lesion revascularizations at the 1-year follow-up. The event rate increased progressively across FRS tertiles [2.4% (low FRS) vs. 7.1% (intermediate FRS) vs. 8.6% (high FRS); P=0.186]. The c-statistic for FRS to predict future clinical events was 0.628 (95% confidence interval, 0.500-0.757). The addition of both calcification and TCFA to FRS provided incremental prognostic value [c-statistics: 0.761 (95% confidence interval, 0.631-0.890)]. CONCLUSION: The present study showed significant associations between FRS and the presence of coronary calcification and neovascularization in nonculprit plaques. The combination of FRS and OCT-detected calcifications and TCFA provides improved prognostic ability in identifying patients with known coronary artery disease who are at risk of recurrent events.

Coronary Calcification and Plaque Vulnerability: An Optical Coherence Tomographic Study.

BACKGROUND: Spotty superficial calcium deposits have been implicated in plaque vulnerability based on previous intravascular imaging studies. Biomechanical models suggest that microcalcifications between 5 and 65 µm in diameter can intensify fibrous cap stress, promoting plaque rupture. However, the 100- to 200-µm resolution of intravascular ultrasound limits its ability to discriminate single calcium deposits from clusters of smaller deposits, and a previous optical coherence tomographic investigation evaluated calcifications within a long segment of artery, which may not truly reflect the mechanics involved in potentiating focal plaque rupture. METHODS AND RESULTS: Detailed optical coherence tomographic assessment of coronary calcification at the culprit plaque (10-mm length) was performed in 53 patients with acute ST-segment-elevation myocardial infarction mediated by plaque rupture and 55 patients with stable angina pectoris. The number and longitudinal length of individual calcium deposits were recorded. Cross-sectional images were analyzed every 1 mm for calcium arc and depth, and these quantitative parameters were used to define individual deposits as spotty, large, and superficial. There was no significant difference between ST-segment-elevation myocardial infarction mediated by plaque rupture and stable angina pectoris groups in the number of total (P=0.58), spotty (P=0.87), or large calcium deposits (P=0.27). Minimum calcium depth was similar between groups (P=0.27), as was the number of superficial deposits (P=0.35 using a 65-µm depth threshold and P=0.84 using a 100-µm depth threshold). CONCLUSIONS: The number and pattern of culprit plaque calcifications did not differ between patients presenting with ST-segment-elevation myocardial infarction mediated by plaque rupture versus stable angina pectoris. The optical coherence tomographic assessment of coronary calcification may not be a useful marker of local plaque vulnerability as previously suspected. REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01110538.

Incidence and Morphological Predictors of Intrastent Coronary Thrombus After Drug-Eluting Stent Implantation (from a Multicenter Registry).

The mechanisms responsible for late and very late stent thrombosis remain incompletely understood. This study aimed to evaluate the incidence and morphologic predictors of intrastent thrombus in patients after drug-eluting stent (DES) implantation using optical coherence tomography (OCT). A total of 208 patients with 262 DES who underwent follow-up OCT examination >6 months after DES implantation were included. The detailed vascular morphology including characteristics of neointima was analyzed. Thrombus was identified in 24 patients (11.5%) 11 months after DES implantation. Minimal lumen cross-sectional area was significantly smaller in the thrombus group than in the nonthrombus group (2.9 ± 1.7 vs 4.6 ± 2.0 mm(2); p <0.001). No difference was found in the frequency of uncovered or malapposed struts between the 2 groups. Thin-cap fibroatheroma (20.6% vs 0.1%; p <0.001) and heterogeneous neointima (22.2% vs 9.0%; p = 0.001) were more frequently detected in the thrombus group compared to the nonthrombus group. Second-generation DES showed lower incidence of thrombus, uncovered struts, and extrastent lumen compared with first-generation DES. In conclusion, the present OCT study revealed that smaller lumen cross-sectional area and neointimal morphology are important factors associated with intrastent thrombus. Second-generation DES demonstrated improved arterial healing and a lower incidence of intrastent thrombus compared with first-generation DES.

Diverse contribution of bone marrow-derived late-outgrowth endothelial progenitor cells to vascular repair under pulmonary arterial hypertension and arterial neointimal formation.

AIMS: It is still controversial whether bone marrow (BM)-derived endothelial progenitor cells (EPCs) can contribute to vascular repair and prevent the progression of vascular diseases. We aimed to characterize BM-derived EPC subpopulations and to evaluate their therapeutic efficacies to repair injured vascular endothelium of systemic and pulmonary arteries. METHODS AND RESULTS: BM mononuclear cells of Fisher-344 rats were cultured under endothelial cell-conditions. Early EPCs appeared on days 3-6. Late-outgrowth and very late-outgrowth EPCs (LOCs and VLOCs) were defined as cells forming cobblestone colonies on days 9-14 and 17-21, respectively. Among EPC subpopulations, LOCs showed the highest angiogenic capability with enhanced proliferation potential and secretion of proangiogenic proteins. To investigate the therapeutic effects of these EPCs, Fisher-344 rats underwent wire-mediated endovascular injury in femoral artery (FA) and were concurrently injected intraperitoneally with 60mg/kg monocrotaline (MCT). Injured rats were then treated with six injections of one of three EPCs (1×10(6) per time). After 4weeks, transplanted LOCs, but not early EPCs or VLOCs, significantly attenuated neointimal lesion formation in injured FAs. Some of CD31(+) LOCs directly replaced the injured FA endothelium (replacement ratio: 11.7±7.0%). In contrast, any EPC treatment could neither replace MCT-injured endothelium of pulmonary arterioles nor prevent the progression of pulmonary arterial hypertension (PAH). LOCs modified protectively the expression profile of angiogenic and inflammatory genes in injured FAs, but not in MCT-injured lungs. CONCLUSION: BM-derived LOCs can contribute to vascular repair of injured systemic artery; however, even they cannot rescue injured pulmonary vasculature under MCT-induced PAH.

Comparison of Neoatherosclerosis and Neovascularization Between Patients With and Without Diabetes: An Optical Coherence Tomography Study.

OBJECTIVES: This study aimed to investigate the characteristics of neoatherosclerosis (NA) in patients with diabetes mellitus (DM) after drug-eluting stent (DES) implantation using optical coherence tomography. BACKGROUND: NA is an important substrate for stent failure. In vivo NA characteristics in DM patients have not been investigated. METHODS: A total of 397 patients with 452 DES who underwent follow-up optical coherence tomography examination after DES implantation were enrolled. Characteristics of NA were compared between DM and non-DM patients. Neovascularization was defined as signal-poor holes or tubular structures with a diameter of 50 to 300 µm. RESULTS: A total of 123 DES with NA lesions in 115 patients were identified. The incidence of NA was similar between DM and non-DM patients (29.6% vs. 28.6%; p = 0.825). Compared with the non-DM group, neovascularization was more frequently observed in the DM group (55.1% vs. 32.4%; p = 0.012). The multivariate logistic model demonstrated that DM (odds ratio: 3.00; 95% confidence interval: 1.31 to 6.81; p = 0.009) and follow-up duration (odds ratio: 1.03; 95% confidence interval: 1.02 to 1.05; p < 0.001) were the independent predictors for neovascularization in NA lesions. DM patients with glycated hemoglobin ≥7.0% had a higher prevalence of thin-cap fibroatheroma compared with those with glycated hemoglobin <7.0% (40.0% vs. 8.3%; p = 0.01). CONCLUSIONS: The incidence of NA was similar between patients with and without DM. Neovascularization in NA lesions was more frequent in those with DM. Poorly controlled DM patients had a higher incidence of thin-cap fibroatheroma, compared with those with well-controlled DM.

Angiogenic potential of early and late outgrowth endothelial progenitor cells is dependent on the time of emergence.

BACKGROUND: Recent studies have suggested that late-outgrowth endothelial progenitor cells (EPCs) derived from human peripheral blood mononuclear cells (hPBMNCs) might have higher angiogenic potential than classically-defined early-outgrowth EPCs (EOCs). However, it still remains unclear which of "so-called" EPC subpopulations defined in a variety of ways has the highest angiogenic potential. METHODS AND RESULTS: We classified hPBMNC-derived EPC subpopulations by the time of their emergence in culture. EOCs were defined as attached cells on culture days 3-7. Late-outgrowth EPCs, defined as the cell forming colonies with cobblestone appearance since day 10, were further classified as follows: "moderate"-outgrowth EPCs (MOCs) emerging on days 10-16, "late"-outgrowth EPCs (LOCs) on days 17-23, and "very late"-outgrowth EPCs (VOCs) on days 24-30. Flow cytometry analyses showed the clear differences of hematopoietic/endothelial markers between EOC (CD31(+)VE-cadherin(-)CD34(-)CD14(+)CD45(+)) and LOC (CD31(+)VE-cadherin(+)CD34(+)CD14(-)CD45(-)). We found that LOCs had the highest proliferation and tube formation capabilities in vitro along with the highest expression of angiogenic genes including KDR and eNOS. To investigate the in vivo therapeutic efficacies, each EPC subpopulation was intravenously transplanted into immunocompromised mice (total 4 × 10(5) cells) after unilateral hindlimb ischemia surgery. The LOC-treated mice exhibited significantly-enhanced blood flow recovery (flow ratios of ischemic/non-ischemic leg: 0.99±0.02 [LOC group] versus 0.67 ± 0.07 to 0.78 ± 0.09 [other groups]; P < 0.05) and augmented capillary collateral formation in ischemic leg, which were attributable to their direct engraftment into host angiogenic vessels (approximately 10%) and paracrine effects. CONCLUSION: hPBMNC-derived late-outgrowth EPCs emerging on culture days 17-23 are superior to other EPC subpopulations with regard to therapeutic angiogenic potential.

Optical coherence tomographic evaluation of the effect of cigarette smoking on vascular healing after sirolimus-eluting stent implantation.

Cigarette smoking is known to be deleterious to patients with coronary artery disease; however, the effect of smoking on vascular responses after coronary drug-eluting stent implantation is unknown. We sought to examine vascular response after sirolimus-eluting stent implantation in patients with ongoing smoking using optical coherence tomography, compared with former smokers and nonsmokers. We identified 181 sirolimus-eluting stents in 140 subjects who underwent follow-up optical coherence tomography imaging. Subjects were divided into 3 groups: current smokers (n = 28), former smokers (n = 35), and nonsmokers (n = 77). Stent strut coverage, neointimal characteristics, and strut malapposition were evaluated. The incidence of uncovered stent struts was significantly higher in nonsmokers compared with current smokers (13.3 ± 13.3% vs 6.7 ± 8.3%; p = 0.001). On qualitative evaluation of neointimal morphology, the prevalence of heterogeneous neointima was higher in current smokers (71.9%) than in former smokers (36.0%) or nonsmokers (10.1%) (p = 0.004 and p <0.001, respectively). There was no difference in the incidence of malapposition among the 3 groups. Multivariate modeling showed that current smoking was negatively associated with the presence of uncovered struts (odds ratio 0.33; 95% confidence interval 0.14 to 0.79; p = 0.013) and positively associated with the presence of heterogeneous neointima (odds ratio 9.47; 95% confidence interval 3.79 to 23.72; p <0.001). In conclusion, the incidence of strut coverage was higher in current smokers compared with nonsmokers. However, the pattern of neointima was more heterogeneous in current smokers.

Deletion of angiotensin-converting enzyme 2 promotes the development of atherosclerosis and arterial neointima formation.

AIMS: Angiotensin-converting enzyme 2 (ACE2) is known as a negative regulator of the renin-angiotensin system. We aimed to determine the roles of ACE2 on the development of vascular diseases. METHODS AND RESULTS: Using two diversely different models of vascular diseases, hyperlipidaemia-induced atherosclerosis in apolipoprotein E knockout (KO) mice and mechanical injury-induced arterial neointimal hyperplasia in C57Bl6 mice, we examined whether ACE2 deficiency could affect formation of the vascular lesions. ACE2 deficiency resulted in significantly larger vascular lesions in both aortic atherosclerotic plaques and arterial neointima formation, compared with ACE2(+) control. These ACE2-deficient vascular lesions exhibited enhanced accumulation of macrophages into the lesions and proliferation of vascular smooth muscle cells (VSMCs), accompanied with increased angiotensin-II (Ang-II) levels and enhanced expression of vascular inflammation-related genes, including vascular cell adhesion molecule (VCAM)-1, monocyte chemoattractant protein (MCP)-1, and matrix metalloproteinase (MMP)9 in aorta/artery tissues. Primary bone marrow macrophages and aortic VSMCs isolated from ACE2 KO mice also displayed enhanced pro-inflammatory responsiveness such as up-regulated gene/protein expression of VCAM-1, MCP-1, and MMP9 to stimulation with tumour necrosis factor-α and Ang-II. The similar phenotype was shown in human macrophages and aortic VSMCs that were transfected with ACE2-specific siRNA. In ACE2-deficient VSMCs, inhibition of c-Jun N-terminal kinase (JNK) by pharmacological blockade with SP600125 or genetic knockdown with JNK-specific siRNA significantly attenuated their pro-inflammatory phenotype. CONCLUSION: ACE2 deficiency promotes the development of vascular diseases associated with Ang-II-mediated vascular inflammation and activation of the JNK signalling, leading to the notion that ACE2 potentially confers protection against vascular diseases.