Serial Changes of Aortic Vulnerable Plaques Observed via Non-Obstructive General Angioscopy.

Stabilization of aortic vulnerable plaques has not been fully elucidated. Non-obstructive general angioscopy (NOGA) is a novel method for the detailed evaluation of atheromatous plaques in the aortic intimal wall. A 57-year-old man presenting with acute myocardial infarction underwent percutaneous coronary intervention (PCI). NOGA was performed for the evaluation of aortic atherosclerosis, and vulnerable puff-chandelier plaques in the aortic arch were identified. After a strictly controlled low-density lipoprotein cholesterol lowering therapy with a strong statin for 8 months after the primary PCI, NOGA revealed stabilized aortic plaques in the same lesions. Therefore, NOGA may be helpful in evaluating the effects of lipid-lowering therapy on aortic plaque stabilization.

Impact of Physical Activity on Coronary Plaque Volume and Components in Acute Coronary Syndrome Patients After Early Phase II Cardiac Rehabilitation.

BACKGROUND: Cardiac rehabilitation (CR) is an established multidisciplinary secondary preventive program. We investigated the effects of CR involving intensive physical activity (PA) on coronary plaque volume and components in patients with acute coronary syndrome (ACS).Methods and Results:We enrolled 32 consecutive patients with ACS in early phase II CR and randomly assigned them to an intensive CR group (n=18; CR participation ≥twice/week, daily PA ≥9,000 steps) or a standard CR group (n=14; CR participation ≥once/2weeks, daily PA ≥6,000 steps). Serial integrated backscatter intravascular ultrasound was performed for non-culprit lesions at baseline and after 8 months. Baseline clinical data were identical between the 2 groups. Unexpectedly, CR participation and PA did not differ significantly between the 2 groups, and there was no significant difference in plaque volume (PV) or components between the 2 groups. Subsequently, we classified the patients into 2 groups according to median PA (7,000 steps). There were significant differences in percent change of PV and of lipid volume between these 2 groups. In addition, these changes were negatively and independently correlated with PA. CONCLUSIONS: No significant difference was observed in PV or components between the intensive CR and the standard CR groups. Intensive PA, however, may retard coronary PV and ameliorate lipid component in patients with ACS participating in late phase II CR.

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.

Icaritin Inhibits Collagen Degradation-Related Factors and Facilitates Collagen Accumulation in Atherosclerotic Lesions: A Potential Action for Plaque Stabilization.

Most acute coronary syndromes result from rupture of vulnerable atherosclerotic plaques. The collagen content of plaques may critically affect plaque stability. This study tested whether Icaritin (ICT), an intestinal metabolite of Epimedium-derived flavonoids, could alter the collagen synthesis/degradation balance in atherosclerotic lesions. Rabbits were fed with an atherogenic diet for four months. Oral administration of ICT (10 mg·kg(-1)·day(-1)) was started after two months of an atherogenic diet and lasted for two months. The collagen degradation-related parameters, including macrophages accumulation, content and activity of interstitial collagenase-1 (MMP-1), and the collagen synthesis-related parameters, including amount and distribution of smooth muscle cells (SMC) and collagen mRNA/protein levels, were evaluated in the aorta. ICT reduced plasma lipid levels, inhibited macrophage accumulation, lowered MMP-1 mRNA and protein expression, and suppressed proteolytic activity of pro-MMP-1 and MMP-1 in the aorta. ICT changed the distribution of the SMCs towards the fibrous cap of lesions without increasing the amount of SMCs. Higher collagen protein content in lesions and aorta homogenates was observed with ICT treatment compared with the atherogenic diet only, without altered collagen mRNA level. These results suggest that ICT could inhibit the collagen degradation-related factors and facilitate collagen accumulation in atherosclerotic lesions, indicating a new potential of ICT in atherosclerotic plaques.

CTRP9 enhances carotid plaque stability by reducing pro-inflammatory cytokines in macrophages.

The aim of this study was to investigate whether C1q/TNF-related protein 9 (CTRP9) could stabilize the mature plaques by targeting macrophages in the apolipoprotein E knockout (ApoE KO) mice model. In vivo, the mice were subjected to high-fat diet and constrictive collars on the right carotid artery for eight weeks, a lentiviral vectors expressing CTRP9 (LV-CTRP9) or green fluorescence protein (LV-eGFP) as a control was intravenously injected into ApoE KO mice. Delivery of LV-CTRP9 resulted in low contents of macrophages and lipids, and high contents of collagen and vascular smooth muscle cells in the carotid mature plaques. In addition, CTRP9 also decreased pro-inflammatory cytokines in mature plaques. In vitro, RAW264.7 macrophages were pretreated with or without LV-CTRP9 transfection, and then stimulated with oxLDL (50 µg/mL). We found that the expression levels of tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) in the LV-CTRP9 group were significantly lower than those in the LV-eGFP group after exposure to oxLDL. The present data indicate that CTRP9 overexpression enhances the plaque stability in ApoE KO mice by reducing pro-inflammatory cytokines in macrophages. Our study suggests that the therapeutic approaches to enhance CTRP9 production could be valuable for plaque stabilization.

Emerging Therapeutic Targets for Acute Coronary Syndromes: Novel Advancements and Future Directions.

Acute coronary syndrome (ACS) remains a major cause of morbidity and mortality worldwide, requiring ongoing efforts to identify novel therapeutic targets to improve patient outcomes. This manuscript reviews promising therapeutic targets for ACS identified through preclinical research, including novel antiplatelet agents, anti-inflammatory drugs, and agents targeting plaque stabilization. Preclinical studies have expounded these agents' efficacy and safety profiles in mitigating key pathophysiological processes underlying ACS, such as platelet activation, inflammation, and plaque instability. Furthermore, ongoing clinical trials are evaluating the efficacy and safety of these agents in ACS patients, with potential implications for optimizing ACS management. Challenges associated with translating preclinical findings into clinical practice, including patient heterogeneity and trial design considerations, are also discussed. Overall, the exploration of emerging therapeutic targets offers promising avenues for advancing ACS treatment strategies and improving patient outcomes.

S-propargyl-cysteine promotes the stability of atherosclerotic plaque via maintaining vascular muscle contractile phenotype.

Introduction: Plaque rupture in atherosclerosis contributes to various acute cardiovascular events. As a new sulfide-containing donor, S-propargyl-cysteine (SPRC) has been reported to play a beneficial role in cardioprotection, potentially through its anti-inflammatory, anti-oxidative and anti-atherogenic activities. Our previous study observed an increase in eNOS phosphorylation in endothelial cells. However, it remains unclear whether SPRC influences vascular smooth muscle cells (VSMCs) within the plaque and if this effect contributes to plaque stabilization. Methods: An atherosclerotic unstable plaque mouse model was established by subjecting ApoE-/- mice to tandem stenosis of the right carotid artery along with a Western diet. Daily SPRC administration was conducted for 13 weeks. Plaque morphology and stability were assessed using MRI scanning and histopathological staining. In our in vitro studies, we stimulated human artery vascular smooth muscle cells (HAVSMCs) with platelet-derived growth factor-BB (PDGF-BB), both with and without 100 µM SPRC treatment. Cell phenotype was assessed using both Western blot and Real-time PCR. Cell proliferation was assessed using the BrdU cell proliferation kit and immunofluorescence of Ki-67, while cell migration was measured using scratch wound healing and transwell assay. MiR-143-3p overexpression and knockdown experiments were used to investigate whether it mediates the effect of SPRC on VSMC phenotype. Results and Discussion: SPRC treatment reduced plasma lipid levels, increased collagen content and decreased cell apoptosis in atherosclerotic plaques, indicating improved plaque stability. Both in vivo and in vitro studies elucidated the role of SPRC in preserving the contractile phenotype of VSMCs through up-regulation of miR-143-3p expression. Furthermore, SPRC suppressed the pro-proliferation and pro-migration effects of PDGF-BB on HAVSMCs. Overall, these findings suggest that the inhibitory effect of SPRC on phenotype switch from contractile to synthetic VSMCs may contribute to its beneficial role in enhancing plaque stability.

Oxidized Low-density Lipoproteins and Lipopolysaccharides Augment Carotid Artery Plaque Vulnerability in Hypercholesterolemic Microswine.

Atherosclerosis is a chronic inflammatory disease and hypercholesterolemia is a risk factor. This study aims to compare the potency of lipopolysaccharide (LPS) and oxidized low-density lipoproteins (oxLDL) to induce plaque formation and increase plaque vulnerability in the carotid artery of hypercholesterolemic Yucatan microswine. Atherosclerotic lesions at the common carotid artery junction and ascending pharyngeal artery were induced in hypercholesterolemic Yucatan microswine at 5-6 months of age with balloon angioplasty. LPS or oxLDL were administered intraluminally at the site of injury after occluding the arterial flow temporarily. Pre-intervention ultrasound (US), angiography, and optical coherence tomography (OCT) were done at baseline and just before euthanasia to assess post-op parameters. The images from the US, OCT, and angiography in the LPS and the oxLDL-treated group showed increased plaque formation with features suggestive of unstable plaque, including necrotic core, thin fibrous caps, and a signal poor region more with oxLDL compared to LPS. Histomorphology of the carotid artery tissue near the injury corroborated the presence of severe lesions in both LPS and oxLDL-treated pigs but more in the oxLDL group. Vascular smooth muscle and endothelial cells treated with LPS and oxLDL showed increased folds changes in mRNA transcripts of the biomarkers of inflammation and plaque vulnerability compared to untreated cells. Collectively, the results suggest that angioplasty-mediated intimal injury of the carotid arteries in atherosclerotic swine with local administration of LPS or ox-LDL induces vulnerable plaques compared to angioplasty alone and oxLDL is relatively more potent than LPS in inducing vulnerable plaque.

Effects of Lipid Lowering Therapies on Vulnerable Plaque Features: An Updated Narrative Review of the Literature.

The clinical evidence on the efficacy of lipid lowering therapy in patients with coronary artery disease (CAD) is unequivocally established. However, the effects of these therapies on plaque composition and stability are less clear. The use of intracoronary imaging (ICI) technologies has emerged as a complement to conventional angiography to further characterize plaque morphology and detect high-risk plaque features related to cardiovascular events. Along with clinical outcomes studies, parallel imaging trials employing serial evaluations with intravascular ultrasound (IVUS) have shown that pharmacological treatment has the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved. Subsequently, the introduction of high-intensity lipid lowering therapy led to much lower levels of low-density lipoprotein cholesterol (LDL-C) levels than achieved in the past, resulting in greater clinical benefit. However, the degree of atheroma regression showed in concomitant imaging trials appeared more modest as compared to the magnitude of clinical benefit accrued from high-intensity statin therapy. Recently, new randomized trials have investigated the additional effects of achieving very low levels of LDL-C on high-risk plaque features-such as fibrous cap thickness and large lipid accumulation-beyond its size. This paper provides an overview of the currently available evidence of the effects of moderate to high-intensity lipid lowering therapy on high-risk plaque features as assessed by different ICI modalities, reviews data supporting the use of these trials, and analyse the future perspectives in this field.

Effect of aspirin on cholesterol crystallization: A potential mechanism for plaque stabilization.

Background and aims: Cholesterol crystals (CCs) have been found to be critical in the evolution and progression of atherosclerotic plaque leading up to rupture. This includes triggering inflammation and mechanically traumatizing the plaque and surrounding tissues. Thus, inhibition of crystal formation and degrading the crystals could be an important therapeutic approach in the prevention of cardiovascular events. Because of its physico-chemical properties we examined the effect of aspirin (ASA) on cholesterol crystallization. Methods: A first experiment tested three amounts of cholesterol (1, 2, 3 g) with a wide range of ASA (0-60 mg) on cholesterol crystallization and volume expansion. A second experiment tested the effect of CCs with and without ASA in perforation of fibrous membrane during crystallization. A third experiment evaluated the effect of ASA on melting CCs in human atherosclerotic plaques. Scanning electron microscopy (SEM) was used to evaluate crystal morphology. Results: Aspirin significantly inhibited cholesterol crystallization and volume expansion in a dose related fashion and even at physiologic levels (0.3 mg/ml). Moreover, ASA prevented perforation of fibrous membranes. By SEM, crystals in human atherosclerotic plaques were found melted with ASA. Conclusions: Cholesterol volume expansion during crystallization was significantly inhibited and CCs were dissolved in the presence of ASA. Fibrous membranes were not perforated with ASA because of both these effects.

Impact of early intervention with alogliptin on coronary plaque regression and stabilization in patients with acute coronary syndromes.

BACKGROUND AND AIMS: Anti-atherosclerotic effects of early intervention with dipeptidyl peptidase-4 inhibitors remain poorly defined. METHODS: In a prospective, single-center, randomized trial, 66 patients with acute coronary syndrome (ACS) and mild dysglycemia (HbA1c 6.0 (5.7, 6.3)%, 58% of impaired glucose tolerance) were randomly assigned to receive alogliptin (n = 33) or placebo (n = 33) in addition to standard treatments. Serial intravascular ultrasound (IVUS) was performed at baseline and 10 months to evaluate changes in coronary percent plaque volumes (%PV) and plaque tissue components of non-culprit lesions (NCLs). RESULTS: Baseline clinical and IVUS characteristics, as well as decreases in HbA1c and lipid variables during 10 months, did not differ significantly between the 2 groups. In contrast, with respect to vascular responses, the alogliptin group showed significantly greater decreases in plaque volumes (-0.3 ± 0.6 vs. -0.04 ± 0.7 mm3/mm, p = 0.03) and %PV (-0.9 ± 2.8 vs. 1.2 ± 3.6%, p = 0.01), with a tendency toward smaller lumen loss (-0.1 ± 0.7 vs. -0.4 ± 0.8 mm3/mm, p = 0.07) compared with the placebo group. Significantly decreased percent necrotic volumes (%NV) (-1.9 ± 3.8 vs. 0.3 ± 3.7%, p = 0.03) and increased fibrotic volumes (2.5 ± 5.0 vs. -0.3 ± 5.3%, p = 0.05) were or tended to be seen in alogliptin versus placebo groups at 10 months. In multiple regression analysis, alogliptin use was a statistically significant determinant of changes in %PV (ß = -0.33, p = 0.004) and %NV (ß = -0.28, p = 0.03) at 10 months. CONCLUSIONS: Alogliptin treatment, independently of glycemic and lipid status, resulted in significant plaque regression and stabilization in NCLs in patients with ACS and mild dysglycemia, suggesting the potential utility of early intervention with incretin-based treatments for this patients' subset.

Effects of Nicorandil on Inflammation, Apoptosis and Atherosclerotic Plaque Progression.

Nicorandil, a balanced vasodilator, is used in the second-line therapy of angina pectoris. In this study, we aimed to illuminate the effects of nicorandil on inflammation, apoptosis, and atherosclerotic plaque progression. Twenty-five LDL-R -/- mice were fed a high-fat diet for 14 weeks. After 6 weeks mice were randomly allocated to treatment with nicorandil (10 mg/kg/day) or tap water. Nicorandil treatment led to a more stable plaque phenotype, displaying an increased thickness of the fibrous cap (p = 0.014), a significant reduction in cholesterol clefts (p = 0.045), and enhanced smooth muscle cell content (p = 0.009). In endothelial cells nicorandil did not reduce the induction of adhesion molecules or proinflammatory cytokines. In H2O2 challenged endothelial cells, pretreatment with nicorandil significantly reduced the percentage of late apoptotic/necrotic cells (p = 0.016) and the ratio of apoptotic to living cells (p = 0.036). Atherosclerotic lesions of animals treated with nicorandil exhibited a significantly decreased content of cleaved caspase-3 (p = 0.034), lower numbers of apoptotic nuclei (p = 0.040), and reduced 8-oxogunanine staining (p = 0.039), demonstrating a stabilizing effect of nicorandil in established atherosclerotic lesions. We suggest that nicorandil has a positive effect on atherosclerotic plaque stabilization by reducing apoptosis.

Effects of withdrawing an atherogenic diet on the atherosclerotic plaque in rabbits.

Lifestyle interventions and pharmacotherapy are the most common of non-invasive treatments for atherosclerosis, but the individual effect of diet on plaques remains unclear. The current study aimed to investigate the effect of withdrawing the atherogenic diet on plaque in the aortas of rabbits. Experimental atheroma was induced in 33 rabbits using a 1% high cholesterol diet for 30 days (H-30 d) or 90 days (H-90 d, baseline group). After 90 days of the atherogenic diet, the remaining animals were divided into four groups: A total of 10 rabbits continued to consume the atherogenic diet for 50 days (H-90 d & H-50 d; n=5) or 140 days (H-90 d & H-140 d; n=5). Another 13 rabbits were switched to a chow diet for 50 days (H-90 d & C-50 d; n=7) or 140 days (H-90 d & C-140 d; n=6). A total of 10 age-matched rabbits in the control groups were fed a chow diet for 90 and 230 days, respectively. The en face or cross-sectional plaque areas were determined using oil red O staining and elastic van Gieson staining. Immunohistochemistry analyses were used to assess the macrophages or smooth muscle cell contents. When fed an atherogenic diet for 90 days, the rabbits' abdominal aortas exhibited severe atherosclerotic lesions (the median en face plaque area was 63.6%). After withdrawing the atherogenic diet, the plaque area did not shrink with feeding the chow diet compared with the baseline, but increased to 71.8 or 80.5% after 50 or 140 days, respectively. After removing cholesterol from the diet, the lipids content in the plaques increased during the first 50 days, and then decreased compared with the baseline group. Furthermore, withdrawing the atherogenic diet increased the total collagen content and the percentage of the smooth muscle cells, alleviated macrophage infiltration, decreased the vulnerable index and promoted the cross-linking of collagen. Feeding the rabbits an atherogenic diet followed by removal of cholesterol from the diet did not lead to the regression of established lesions but instead delayed the progression of the lesions and promoted the stabilization of the plaque.

Long-term changes after carotid stenting assessed by intravascular ultrasound and near-infrared spectroscopy.

BACKGROUND: Long-term effect of carotid stenting (CAS) on the stabilization of the plaque is almost unrecognized. Vascular healing and remodeling might seal the atherosclerotic plaque with neointimal hyperplasia decreasing the vulnerability. We aimed to assess long-term change in the lipid signal, stent and luminal dimensions and restenosis after CAS with the intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) imaging. METHODS: We performed follow-up angiography and NIRS-IVUS imaging of 58 carotid stents in 52 patients. Median time from CAS to the follow-up examination was 31 months (range, 5-56). The lipid signal of the stented segment was calculated from a NIRS-derived chemogram (a spectroscopic map) as the lipid core burden index (LCBI, a dimensionless number from 0 to 1,000). Planimetric and volumetric measurements from IVUS were performed to assess change in minimal stent area (MSA), minimal luminal area (MLA), stent and luminal volume, late stent expansion and percentage in-stent restenosis (ISR) volume. RESULTS: During the follow-up period, the mean (±SD) LCBI significantly decreased from 32±56 to 17±27 (P=0.002). The mean stent volume significantly increased from 717±302 to 1,019±429 mm3 (P<0.001) with mean stent expansion 43%±24%. The mean luminal volume increased from 717±302 to 760±359 mm3 (P=0.025) due to ISR encroaching 26%±15% of the stent volume. CONCLUSIONS: Lipid signal decreased during the follow-up period suggesting stabilization of the plaque. Late stent expansion was balanced with neointimal hyperplasia. TRIAL REGISTRATION: The trial is registered under clinicaltrials.gov NCT03141580.

Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe-/- mice.

OBJECTIVE: Interferon regulatory factor (IRF) 5 is a transcription factor known for promoting M1 type macrophage polarization in vitro. Given the central role of inflammatory macrophages in promoting atherosclerotic plaque progression, we hypothesize that myeloid cell-specific deletion of IRF5 is protective against atherosclerosis. METHODS: Female Apoe-/-LysmCre/+Irf5fl/fl and Apoe-/-Irf5fl/fl mice were fed a high-cholesterol diet for three months. Atherosclerotic plaque size and compositions as well as inflammatory gene expression were analyzed. Mechanistically, IRF5-dependent bone marrow-derived macrophage cytokine profiles were tested under M1 and M2 polarizing conditions. Mixed bone marrow chimeras were generated to determine intrinsic IRF5-dependent effects on macrophage accumulation in atherosclerotic plaques. RESULTS: Myeloid cell-specific Irf5 deficiency blunted LPS/IFNγ-induced inflammatory gene expression in vitro and in the atherosclerotic aorta in vivo. While atherosclerotic lesion size was not reduced in myeloid cell-specific Irf5-deficient Apoe-/- mice, plaque composition was favorably altered, resembling a stable plaque phenotype with reduced macrophage and lipid contents, reduced inflammatory gene expression and increased collagen deposition alongside elevated Mertk and Tgfß expression. Irf5-deficient macrophages, when directly competing with wild type macrophages in the same mouse, were less prone to accumulate in atherosclerotic lesion, independent of monocyte recruitment. Irf5-deficient monocytes, when exposed to oxidized low density lipoprotein, were less likely to differentiate into macrophage foam cells, and Irf5-deficient macrophages proliferated less in the plaque. CONCLUSION: Our study provides genetic evidence that selectively altering macrophage polarization induces a stable plaque phenotype in mice.

Melatonin inhibits macrophage infiltration and promotes plaque stabilization by upregulating anti-inflammatory HGF/c-Met system in the atherosclerotic rabbit: USPIO-enhanced MRI assessment.

Macrophage plays critical roles in the pathogenesis of atherosclerosis (AS), and is an attractive target for detecting and treating vulnerable plaque. Our previous study showed that melatonin (MLT) ameliorated AS by suppressing the pro-inflammatory Toll-like receptor 4/nuclear factor kappa B system in high-fat-fed rabbit. However, it is unknown whether the anti-atherosclerotic properties of MLT are associated with the upregulation of anti-inflammatory hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) system. In present study, we examined whether MLT could inhibit macrophage infiltration and promote plaque stabilization by upregulating HGF/c-Met system with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) assessment in AS rabbit. Rabbits in this study were randomly divided into three groups and treated with a standard diet, high-fat diet, and high-fat diet plus 10 mg/kg/day MLT for 12 weeks, respectively. MLT treatment significantly reversed spotty signal void in 3D-TOF MRI, standard signal intensity reduction in T2WI MRI and aortic luminal area reduction in 2D-TOF MRI of the atherosclerotic abdominal aorta 72 h after USPIO injection. It also decreased serum interleukin-6 (IL-6), intima/media thickness ratio of the abdominal aorta, CD68 and iron-positive areas in the aortic intima, and increased serum IL-10, HGF and c-Met protein expression and the accumulation of vascular smooth muscle cell and collagen fiber in the aortic intima of AS rabbit. Our data demonstrated that MLT significantly decreased plaque macrophage infiltration and promoted plaque stability in AS rabbit assessed by USPIO-enhanced MRI. Remarkably, it was very first revealed that upregulation of anti-inflammatory HGF/c-Met system might contribute to the atheroprotective mechanisms of MLT.

Low Levels of Plasma Osteoglycin in Patients with Complex Coronary Lesions.

AIM: Osteoglycin is one of proteoglycans that are biologically active components of vascular extracellular matrix. However, the role of osteoglycin in atherosclerosis remains unclear. METHODS: We investigated plasma osteoglycin levels and the presence, severity, and lesion morphology of coronary artery disease (CAD) in 462 patients undergoing elective coronary angiography. RESULTS: Of 462 patients, 245 had CAD. Osteoglycin levels were higher in patients with CAD than without CAD (median 29.7 vs. 25.0 ng/mL, P＜0.05). However, osteoglycin levels did not differ among patients with one-vessel, two-vessel, or three-vessel disease (30.8, 30.6, and 29.4 ng/mL, respectively) and did not correlate with the number of stenotic segments. Among 245 CAD patients, 41 had complex coronary lesions, and 70 had total occlusion, of whom 67 had good collateralization. Between 70 patients with occlusion and 175 without occlusion, osteoglycin levels did not differ (30.4 vs. 29.5 ng/mL). Notably, osteoglycin levels were lower in 41 patients with complex lesions than in 204 without such lesions (24.2 vs. 31.6 ng/mL, P＜0.02). In multivariate analysis, osteoglycin levels were an independent factor for complex lesion but not for CAD. Odds ratio for complex lesion was 0.80 (95%CI=0.67-0.96) for each 10 ng/mL increase in osteoglycin levels (P＜0.02). CONCLUSION: Although plasma osteoglycin levels were high in patients with CAD, they did not correlate with the severity of CAD and were not an independent factor for CAD. Notably, osteoglycin levels were low in patients with complex lesions and were a factor for complex lesions, suggesting that osteoglycin plays a role in coronary plaque stabilization.

Effect of Early Pitavastatin Therapy on Coronary Fibrous-Cap Thickness Assessed by Optical Coherence Tomography in Patients With Acute Coronary Syndrome: The ESCORT Study.

OBJECTIVES: The aim of the present study was to assess the effect of early statin therapy on fibrous-cap thickness in coronary plaques of patients with acute coronary syndrome (ACS) by using optical coherence tomography. BACKGROUND: Statins can contribute to the stabilization of coronary plaques. METHODS: This is a prospective, randomized, active-controlled, single-center study. Patients with ACS and untreated dyslipidemia were enrolled and randomly allocated (ratio 1:1) to either the early statin group (received pitavastatin 4 mg/day from baseline) or the late statin group (received pitavastatin 4 mg/day from 3 weeks after the baseline). Optical coherence tomography was performed at baseline, 3-week, and 36-week follow-up to assess nonculprit coronary plaques in 53 patients. RESULTS: Between baseline and 3-week follow-up, fibrous-cap thickness increased in the early statin group (140 µm [interquartile range (IQR):120 to 170 µm] to 160 µm [IQR: 130 to 190 µm]; p = 0.017), but decreased in the late statin group (135 µm [IQR: 110 to 183 µm] to 130 µm [IQR: 108 to 160 µm]; p = 0.020). The percentage of increase in fibrous-cap thickness between baseline and 3-week follow-up was significantly greater in the early statin group compared with the late statin group (8.3% [IQR: 0.0% to 21.4%] vs. -5.8% [IQR: -16.0% to 0.0%]; p < 0.001). Between baseline and 36-week follow-up, fibrous-cap thickness increased comparably in the 2 groups. CONCLUSIONS: Early therapy with pitavastatin 4 mg/day for patients with ACS provided an increase in fibrous-cap thickness in coronary plaques during the first 3 weeks of follow-up and a further increase during 36 weeks of follow-up. The study was registered with UMIN Clinical Trial Registry (Effect of PitavaStatin on Coronary Fibrous-cap Thickness-Assessment by Fourier-Domain Optical CoheRence Tomography [ESCORT]; UMIN000002678).

[Is regression of atherosclerotic plaque possible?] / ¿Es posible la regresión de la placa aterosclerótica?

As it is well-known, a thrombus evolving into a disrupted/eroded atherosclerotic plaque causes most acute coronary syndromes. Plaque stabilization via reduction of the lipid core and/or thickening of the fibrous cap is one of the possible mechanisms accounted for the clinical benefits displayed by different anti-atherosclerotic strategies. The concept of plaque stabilization was developed to explain how lipid-lowering agents could decrease adverse coronary events without substantial modifications of the atherosclerotic lesion ('angiographic paradox'). A number of imaging modalities (vascular ultrasound and virtual histology, MRI, optical coherence tomography, positron tomography, etc.) are used for non-invasive assessment of atherosclerosis; most of them can identify plaque volume and composition beyond lumen stenosis. An 'aggressive' lipid-lowering strategy is able to reduce the plaque burden and the incidence of cardiovascular events; this may be attributable, at least in part, to plaque-stabilizing effects.

Valsartan Promoting Atherosclerotic Plaque Stabilization by Upregulating Renalase: A Potential-Related Gene of Atherosclerosis.

BACKGROUND: Renalase is a protein that can regulate sympathetic nerve activity by metabolizing catecholamines, while redundant catecholamines are thought to contribute to atherosclerosis (As). Catecholamine release can be facilitated by angiotensin (Ang) II by binding to Ang II type 1 (AT1) receptors. Valsartan, a special AT1 antagonist, can dilate blood vessels and reduce blood pressure, but it remained unclear whether valsartan can promote the stability of atherosclerotic plaque by affecting renalase. OBJECTIVE: This study examined the tissue distribution of renalase in ApoE(-/-) mice fed with a high-fat diet and the effect of valsartan on expression of renalase. METHODS: ApoE(-/-) mice were fed with a high-fat diet for 13 or 26 weeks. As a control, 10 C57BL mice were fed with a standard chow diet. After 13 weeks on the high-fat diet, the ApoE(-/-) mice were randomized (10 mice/group) and treated with valsartan, simvastatin, or distilled water (control group) for an additional 13 weeks accompanied by a high-fat diet. RESULTS: Knockout of ApoE caused a dramatic increase in expression of renalase in mice adipose tissue. With the disturbance of lipid metabolism induced by a high-fat diet, renalase expression decreased in the liver. Renalase can be expressed in smooth muscle cells and M2 macrophages in atherosclerotic plaque, and its expression gradually decreases in the fibrous cap during the transition from stable to vulnerable atherosclerotic plaque. Valsartan, an AT1 receptor antagonist, promotes the stabilization of atherosclerotic plaque by increasing the levels of renalase in serum and the expression of renalase in the fibrous cap of atherosclerotic plaque. It also reduces triglyceride levels in serum and increases the expression of renalase in the liver. CONCLUSIONS: Renalase may be a potential-related gene of lipid metabolism and As, and it may be the possible molecular target of valsartan to help stabilize atherosclerotic plaque.