Estrogen deficiency accelerates postmenopausal atherosclerosis by inducing endothelial cell ferroptosis through inhibiting NRF2/GPX4 pathway.

Oxidative stress and lipid metabolism disorder caused by estrogen deficiency are regarded as the main causes of postmenopausal atherosclerosis, but the underlying mechanisms remain still unclear. In this study, ovariectomized (OVX) female ApoE-/- mice fed with high-fat diet were used to imitate postmenopausal atherosclerosis. The atherosclerosis progression was significantly accelerated in OVX mice, accompanied by the upregulation of ferroptosis indicators, including increased lipid peroxidation and iron deposition in the plaque and the plasma. While both estradiol (E2) and ferroptosis inhibitor ferrostatin-1 alleviated atherosclerosis in OVX mice, with the inhibition of lipid peroxidation and iron deposition, as well as the upregulation of xCT and GPX4, especially in endothelial cells. We further investigated the effects of E2 on ferroptosis in endothelial cells induced by oxidized-low-density lipoprotein or ferroptosis inducer Erastin. It was found that E2 exhibited anti-ferroptosis effect through antioxidative functions, including improving mitochondrial dysfunction and upregulating GPX4 expression. Mechanistically, NRF2 inhibition attenuated the effect of E2 against ferroptosis as well as the upregulation of GPX4. Our findings revealed that endothelial cell ferroptosis played a pivotal role in postmenopausal atherosclerosis progression, and the NRF2/GPX4 pathway activation contributed to the protection of E2 against endothelial cell ferroptosis.

Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells.

BACKGROUND: Tar is the main toxic of cigarettes, and its effect on atherosclerosis progression and the underlying mechanisms remain largely unknown. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and plaque vulnerability. The present study sought to investigate the mechanism of atherosclerosis progression through tar-induced VSMC necroptosis, a recently described form of necrosis. METHODS: The effect of tar on atherosclerosis progression and VSMC necroptosis was examined in ApoE-/- mice and cultured VSMCs. The role of necroptosis in tar-induced plaque development was evaluated in RIPK3-deletion mice (ApoE-/-RIPK3-/-). The key proteins of necroptosis in carotid plaques of smokers and non-smokers were also examined. Quantitative proteomics of mice aortas was conducted to further investigate the underlying mechanism. Pharmacological approaches were then applied to modulate the expression of targets to verify the regulatory process of tar-induced necroptosis. RESULTS: Tar administration led to increased atherosclerotic plaque area and reduced collagen and VSMCs in ApoE-/- mice. The expression of RIPK1、RIPK3、and MLKL in VSMCs of plaques were all increased in tar-exposed mice and smokers. RIPK3 deletion protected against VSMC loss and plaque progression stimulated by tar. In mechanistic studies, quantitative proteomics analysis of ApoE-/- mice aortas suggested that tar triggered endoplasmic reticulum (ER) stress. PERK-eIF2α-CHOP axis was activated in tar-treated VSMCs and atherosclerotic plaque. Inhibition of ER stress using 4PBA significantly reduced plaque progression and VSMC necroptosis. Further study revealed that ER stress resulted in calcium (Ca2+) release into mitochondria and cytoplasm. Elevated Ca2+ levels lead to mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, which consequently promote RIPK3-dependent necroptosis. In addition, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activated by cytosolic Ca2+ overload binds to RIPK3, accounting for necroptosis. CONCLUSION: The findings revealed that cigarette tar promoted atherosclerosis progression by inducing RIPK3-dependent VSMC necroptosis and identified novel avenues of ER stress and Ca2+ overload.

VEGFC ameliorates salt-sensitive hypertension and hypertensive nephropathy by inhibiting NLRP3 inflammasome via activating VEGFR3-AMPK dependent autophagy pathway.

Salt-sensitivity hypertension (SSHTN) is an independent predictor for cardiovascular mortality. VEGFC has been reported to be a protective role in SSHTN and hypertensive kidney injury. However, the underlying mechanisms remain largely unclear. The current study aimed to explore the protective effects and mechanisms of VEGFC against SSHTN and hypertensive nephropathy. Here, we reported that VEGFC attenuated high blood pressure as well as protected against renal inflammation and fibrosis in SSHTN mice. Moreover, VEGFC suppressed the activation of renal NLRP3 inflammasome in SSHTN mice. In vitro, we found VEGFC inhibited NLRP3 inflammasome activation, meanwhile, upregulated autophagy in high-salt-induced macrophages, while these effects were reversed by an autophagy inhibitor 3MA. Furthermore, in vivo, 3MA pretreatment weakened the protective effects of VEGFC on SSHTN and hypertensive nephropathy. Mechanistically, VEGF receptor 3 (VEGFR3) kinase domain activated AMPK by promoting the phosphorylation at Thr183 via binding to AMPK, thus enhancing autophagy activity in the context of high-salt-induced macrophages. These findings indicated that VEGFC inhibited NLRP3 inflammasome activation by promoting VEGFR3-AMPK-dependent autophagy pathway in high-salt-induced macrophages, which provided a mechanistic basis for the therapeutic target in SSHTN and hypertensive kidney injury.

Homocysteine promotes atherosclerosis through macrophage pyroptosis via endoplasmic reticulum stress and calcium disorder.

BACKGROUND: Elevated plasma homocysteine levels, known as hyperhomocysteinemia, have been identified as an independent risk factor for atherosclerosis and related cardiovascular diseases. Macrophage pyroptosis-mediated inflammation is crucial in the development of atherosclerosis, but the underlying mechanisms remain unclear. METHODS: A hyperhomocysteinemia atherosclerotic model with ApoE-/- mice fed with a high-methionine diet was constructed to investigate the role of plasma homocysteine in atherosclerosis. THP-1-derived macrophages were used to investigate the mechanisms by which Hcy regulates pyroptosis. RESULTS: We found that hyperhomocysteinemia resulted in larger atherosclerotic plaques and more secretion of inflammatory cytokines, while these effects were attenuated in Caspase-1 knockdown mice. Likewise, in vitro experiments demonstrated that treatment of macrophages with homocysteine resulted in NLRP3 inflammasome activation and pyroptosis, as evidenced by cleavage of Caspase-1, production of downstream IL-1ß, elevation of lactate dehydrogenase activity, and extensive propidium iodide-positive staining of cells. These were all inhibited by Caspase-1 inhibitor. In addition, excessive generation of reactive oxygen species was associated with mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential and ATP synthesis. Moreover, further experiments revealed that homocysteine induced endoplasmic reticulum stress, enhanced communication between the endoplasmic reticulum and mitochondria, and consequently contributed to calcium disorder. Furthermore, the endoplasmic reticulum stress inhibitor, 4PBA, the calcium chelator, BAPTA, and calcium channel inhibitor, 2-APB significantly improved macrophage pyroptosis. CONCLUSION: Homocysteine accelerates atherosclerosis progression by enhancing macrophages pyroptosis via promoting endoplasmic reticulum stress, endoplasmic reticulum-mitochondria coupling, and disturbing of calcium disorder.

Peripheral atherosclerosis in acute coronary syndrome patients with plaque rupture vs plaque erosion: A prospective coronary optical coherence tomography and peripheral ultrasound study.

BACKGROUND: Plaque rupture (PR) and plaque erosion (PE) are 2 distinct, different, and most common culprit lesion morphologies responsible for acute coronary syndrome (ACS). However, the prevalence, distribution, and characteristics of peripheral atherosclerosis in ACS patients with PR vs PE has never been studied. The aim of this study was to assess peripheral atherosclerosis burden and vulnerability evaluated by vascular ultrasound in ACS patients with coronary PR vs PE identified by optical coherence tomography (OCT). METHODS: Between October 2018 and December 2019, 297 ACS patients who underwent preintervention OCT examination of the culprit coronary artery were enrolled. Peripheral ultrasound examinations of carotid, femoral, and popliteal arteries were performed before discharge. RESULTS: Overall, 265 of 297 (89.2%) patients had at least one atherosclerotic plaque in a peripheral arterial bed. Compared with coronary PE, patients with coronary PR had a higher prevalence of peripheral atherosclerotic plaques (93.4% vs 79.1%, P < .001), regardless of location: carotid, femoral, or popliteal arteries. The number of peripheral plaques per patient was significantly larger in the coronary PR group than coronary PE (4 [2-7] vs 2 [1-5], P < .001). Additionally, there was a greater prevalence of peripheral vulnerable characteristics including plaque surface irregularity, heterogeneous plaque, and calcification in patients with coronary PR vs PE. CONCLUSIONS: Peripheral atherosclerosis exists commonly in patients presenting with ACS. Patients with coronary PR had greater peripheral atherosclerosis burden and more peripheral vulnerability compared to those with coronary PE, suggesting that comprehensive evaluation of peripheral atherosclerosis and multidisciplinary cooperative management maybe necessary, especially in patients with PR. TRIAL REGISTRATION: clinicaltrials.gov (NCT03971864).

Apigenin inhibits macrophage pyroptosis through regulation of oxidative stress and the NF-κB pathway and ameliorates atherosclerosis.

Pyroptosis plays an important role in inflammatory diseases such as viral hepatitis and atherosclerosis. Apigenin exhibits various bioactivities, particularly anti-inflammation, but its effect on pyroptosis remains unclear. The aim of this study is to investigate the effect of apigenin on pyroptosis and explore its potential against inflammatory diseases. THP-1 macrophages treated by lipopolysaccharides/adenosine 5'-triphosphate were used as the in vitro pyroptosis model. Western blot was used to detect the expression of NLRP3 inflammasome components and key regulators. Immunofluorescence was used to observe ROS production and intracellular location of p65. The potential of apigenin against inflammatory diseases was evaluated using atherosclerotic mice. Plaque progression was observed by pathological staining. Immunofluorescence was used to observe the expression of NLRP3 inflammasome components in plaques. The results showed that apigenin inhibited NLRP3 inflammasome activation. Apigenin reduced ROS overproduction and inhibited p65 nuclear translocation. Additionally, apigenin decreased the expression of NLRP3 inflammasome components in the plaque. Plaque progression was inhibited by apigenin. In conclusion, apigenin exhibited a preventive effect on macrophage pyroptosis by reducing oxidative stress and inhibiting the NF-κB pathway. Apigenin may alleviate atherosclerosis at least partially by inhibiting macrophage pyroptosis. These findings suggest apigenin to be a promising therapeutic agent for inflammatory diseases.

Impact of nodular calcification in patients with acute coronary syndrome (ACS) treated with primary percutaneous coronary intervention (PCI).

BACKGROUND: Calcified plaque is thought to adversely impact outcomes after percutaneous coronary intervention (PCI). This study sought to evaluate the impact of nodular calcification in patients with acute coronary syndrome treated with primary percutaneous coronary intervention. METHODS: Using optical coherence tomography (OCT), 500 culprit plaques with calcification were analyzed from 495 acute coronary syndrome (ACS) patients on whom PCI was performed. Based on morphology, we classified calcification into two subtypes: nodular calcification and non-nodular calcification. Nodular calcification was defined as protruding mass with an irregular surface, high backscattering, and signal attenuation while non-nodular calcification was defined as an area with low backscattering heterogeneous region with a well-delineated border without protrusion into the lumen on OCT. RESULTS: Calcified culprit plaques were divided into nodular calcification group (n = 238) and non-nodular calcification group (n = 262). Patients with nodular calcification were older (p < 0.001) and had lower left ventricular ejection fraction (p = 0.006) compared to patients with non-nodular calcification. Minimum stent area (5.0 (3.9, 6.3) mm2 vs. 5.4 (4.2, 6.7) mm2, p = 0.011) and stent expansion (70 (62.7, 81.8) % vs. 75 (65.2, 86.6) %, p = 0.004) were significantly smaller in the nodular calcification group than in the non-nodular calcification group. Stent under-expansion was most frequent (p = 0.003) in the nodular calcification group. CONCLUSION: This study demonstrate that the presence of nodular calcification is associated with a smaller minimum stent area and a higher incidence of stent under-expansion. Lesions with nodular calcification may be at risk of stent under-expansion.

Is the effect of atorvastatin 60 mg on stabilization of lipid-rich plaque equivalent to that of rosuvastatin 10 mg? A serial optical coherence tomography combined with intravascular ultrasound imaging.

OBJECTIVES: This study aimed to compare the effect of atorvastatin 60 (AT60) mg to that of rosuvastatin 10 (RT10) mg on the morphological changes in lipid-rich plaques (LRPs) and plaque volume, using serial optical coherence tomography (OCT) and intravascular ultrasound imaging (IVUS). BACKGROUND: Intensive lipid lowering therapy by statin provides more clinical benefit compared to that of moderate lipid lowering therapy. METHODS: Fifty patients who underwent OCT and IVUS at baseline, 6, and 12 months were grouped by statin therapy into the AT60 mg (n = 27) and RT10 mg (n = 23) groups. The relationships between absolute and percentage changes in biomarkers and fibrous cap thickness (FCT) during follow-up were investigated using a simple regression analysis. RESULTS: At 6 months, the mean low-density lipoprotein cholesterol level reduced from 113.5 to 65.5 mg/dl (AT60 mg group) and 100.2 to 72.2 mg/dl (RT10 mg groups). A continuous increase in FCT from baseline to 12 months was observed in both groups (p < .001, p < .001, respectively). Mean lipid arc significantly decreased in both AT60 mg (189.0 ± 55.9°, 170.9 ± 60.2°, 155.6 ± 50.6°, p < .001) and RT10 mg (160.0 ± 45.6°, 151.2 ± 48.5°, 141.1 ± 52.9°, p = .010) groups. Plaque burden did not change significantly in both groups. CONCLUSIONS: Lipid-lowering therapy effect with AT60 mg was equivalent to that of RT10 mg in terms of change in plaque morphology. AT60 mg showed more intensive low-density lipid cholesterol level reduction compared to RT10 mg while RT10 mg was effective in increasing the high-density lipid cholesterol level. Both statin therapies could effectively stabilize LRPs.

In vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction: a clinical, angiographical, and intravascular optical coherence tomography study.

Aims: Plaque erosion is a significant substrate of acute coronary thrombosis. This study sought to determine in vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction (STEMI). Methods and results: A prospective series of 822 STEMI patients underwent pre-intervention optical coherence tomography. Using established diagnostic criteria, 209 had plaque erosion (25.4%) and 564 had plaque rupture (68.6%). Plaque erosion was more frequent in women <50 years when compared with those ≥50 years of age (P = 0.009). There was a similar, but less striking, trend in men (P = 0.011). Patients with plaque erosion were more frequently current smokers but had fewer other coronary risk factors (dyslipidaemia, hypertension, chronic kidney disease, and diabetes mellitus) than those with plaque rupture. There was a preponderance of plaque erosion in the left anterior descending artery (LAD; 61.2%), whereas plaque rupture was more equally distributed in both the LAD (47.0%) and right coronary artery (43.3%). Despite the similar spatial distribution of erosions and ruptures over the lengths of the coronary arteries, plaque erosion occurred more frequently near a bifurcation (P < 0.001). In the multivariable analysis, age <50 years, current smoking, absence of other coronary risk factors, lack of multi-vessel disease, reduced lesion severity, larger vessel size, and nearby bifurcation were significantly associated with plaque erosion. Nearby bifurcation and current smoking were especially notable in men, while age <50 years was most predictive in women. Conclusions: Plaque erosion was a predictable clinical entity distinct from plaque rupture in STEMI patients, and gender-specific role of risk factors in plaque erosion should be considered.

High Levels of Circulating MicroRNA-3667-3p Are Associated with Coronary Plaque Erosion in Patients with ST-Segment Elevation Myocardial Infarction.

Plaque erosion (PE) is a significant substrate of acute coronary thrombosis. An improved ability to distinguish plaque phenotype in vivo among patients with ST-segment elevation myocardial infarction (STEMI) is of considerable interest because of the potential to formulate tailored treatment. This study assessed the plaque features and screened the circulating microRNAs (miRNAs) characteristically expressed in patients with PE compared with those with plaque rupture (PR). An miRNA microarray profile was generated in an initial cohort of eight STEMI patients with PE and eight clinically matched subjects with PR to select the circulating miRNAs with significant differences. miRNAs of interest were validated in a prospective cohort, and the plaque characteristics of enrolled patients were assessed by optical coherence tomography (OCT). Thirty culprit lesions were classified as PE (32.6%) and 46 as PR (50%). The main component of PE was fibrotic tissue, whereas the chief component of PR was lipids (P < 0.001). Thirty-four miRNAs were differentially expressed between the two groups; we validated five candidates and found that only the level of circulating miR-3667-3p exhibited significant discriminatory power in predicting the presence of PE (AUC = 0.767; P < 0.001). Our results show that high levels of circulating miR-3667-3p are closely related to PE in STEMI patients, which provides further evidence for PE pathophysiology and potential tailor treatment strategies.

Non-culprit plaque characteristics in acute coronary syndrome patients with raised hemoglobinA1c: an intravascular optical coherence tomography study.

BACKGROUND: Raised hemoglobinA1c (HbA1c) is an indicator of pre-diabetes, which is associated with increased risk of coronary artery disease. However, the detailed morphological characteristics of non-culprit plaques in acute coronary syndrome (ACS) patients remain largely unknown. METHODS: A total of 305 non-culprit plaques from 216 ACS patients were analyzed by intravascular optical coherence tomography. These patients were divided into three groups according to the serum glycosylated hemoglobin level: normal HbA1c (< 5.7%), pre-diabetes with raised HbA1c (5.7-6.4%) and diabetes mellitus (DM). RESULTS: Plaques in patients with raised HbA1c had a longer lipid length (17.0 ± 8.3 mm vs. 13.9 ± 7.2 mm, P = 0.004) and greater lipid index (2775.0 ± 1694.0 mm° vs. 1592.1 ± 981.2 mm°, P = 0.001) than those with normal HbA1c but were similar to DM. The prevalence of calcification in patients with raised HbA1c was significantly higher (38.7% vs. 26.3%, P = 0.048) than normal HbA1c but was similar to DM. The percentage of macrophage infiltration in the DM group was higher than that in the normal HbA1c group (20.5% vs. 7.4%, P = 0.005). CONCLUSIONS: Compared to patients with normal HbA1c, the non-culprit plaques in ACS patients with raised HbA1c had more typical vulnerable features but were similar to DM.

Does spotty calcification attenuate the response of nonculprit plaque to statin therapy?: A serial optical coherence tomography study.

OBJECTIVES: The aim of this study was to determine if spotty calcification decreases the response of plaque progression to statin therapy. BACKGROUND: Previous studies showed that the presence of spotty calcification is a marker of vulnerable plaque. However, the relationship between spotty calcification and plaque progression is not clear. METHODS: Ninety-six nonculprit lipid-rich plaques in 69 patients who received serial optical coherence tomography (OCT) imaging were included. Plaques were divided into three groups: spotty calcification (n = 38), calcified (n = 12) and noncalcified (n = 46) plaques. Spotty calcification was identified by the presence of a lesion <4 mm in length with an arc of calcification <90°. Changes in plaque characteristics and fibrous cap thickness (FCT) at 6 and 12 months under statin therapy were analyzed by OCT. RESULTS: The increase of FCT was sustained from baseline to 6 and 12 months in three groups: spotty calcification (62.8 ± 20.9, 126.4 ± 84.9, and 169.2 ± 81.6 µm, respectively; P < .001), calcified (59.8 ± 17.0, 93.4 ± 51.4, and 155.2 ± 61.7 µm, respectively; P < .001) and noncalcified (60.0 ± 17.2, 125.5 ± 62.1, and 161.0 ± 80.5 µm, respectively; P < .001). Intensive statin induced a greater change in FCT at 12 months than moderate statin in the spotty calcification group (P = 0.034). The mean lipid arc decreased significantly at 12 months from baseline in the three groups (P = 0.004, P = 0.023, and P < .001, respectively). CONCLUSIONS: Statin therapy was effective for plaque stabilization in plaques with and without spotty calcification. Patients with spotty calcification benefitted more from intensive statin than from moderate statin therapy.

Effective anti-thrombotic therapy without stenting: intravascular optical coherence tomography-based management in plaque erosion (the EROSION study).

AIMS: Plaque erosion, compared with plaque rupture, has distinctly different underlying pathology and therefore may merit tailored therapy. In this study, we aimed to assess whether patients with acute coronary syndrome (ACS) caused by plaque erosion might be stabilized by anti-thrombotic therapy without stent implantation. METHODS AND RESULTS: This was a single-centre, uncontrolled, prospective, proof-of concept study. Patients with ACS including ST-segment elevation myocardial infarction were prospectively enrolled. If needed, aspiration thrombectomy was performed. Patients diagnosed with plaque erosion by optical coherence tomography (OCT) and residual diameter stenosis <70% on coronary angiogram were treated with anti-thrombotic therapy without stenting. OCT was repeated at 1 month and thrombus volume was measured. The primary endpoint was >50% reduction of thrombus volume at 1 month compared with baseline. The secondary endpoint was a composite of cardiac death, recurrent ischaemia requiring revascularization, stroke, and major bleeding. Among 405 ACS patients with analysable OCT images, plaque erosion was identified in 103 (25.4%) patients. Sixty patients enrolled and 55 patients completed the 1-month follow-up. Forty-seven patients (47/60, 78.3%; 95% confidence interval: 65.8-87.9%) met the primary endpoint, and 22 patients had no visible thrombus at 1 month. Thrombus volume decreased from 3.7 (1.3, 10.9) mm3 to 0.2 (0.0, 2.0) mm3. Minimal flow area increased from 1.7 (1.4, 2.4) mm2 to 2.1 (1.5, 3.8) mm2. One patient died of gastrointestinal bleeding, and another patient required repeat percutaneous coronary intervention. The rest of the patients remained asymptomatic. CONCLUSION: For patients with ACS caused by plaque erosion, conservative treatment with anti-thrombotic therapy without stenting may be an option.

Plaque erosion delays vascular healing after drug eluting stent implantation in patients with acute coronary syndrome: An In Vivo Optical Coherence Tomography Study.

OBJECTIVES: To compare vascular healing after drug-eluting stent (DES) implantation between plaque rupture (PR) and plaque erosion (PE). BACKGROUND: Vascular response after stent implantation in patients with PR has been extensively studied. Little is known about vascular healing after stent implantation in PE. METHODS: Sixty-five ACS patients who received optical coherence tomography (OCT) imaging of the culprit lesions both before and after stent implantation at baseline as well as at 6 months were included in this study. Patients were divided into two groups: PR (n = 19) and PE (n = 24). Prestent thrombus burden and poststent intrastent structure (ISS) volume were analyzed during the index procedure. The ratio of uncovered to total stent struts per cross-section score (RUTTS) and neointimal thickness and area were measured at follow-up. RESULTS: OCT imaging showed that compared with PR, PE showed a significantly lower prestent thrombus score (34.2 ± 19.2 vs. 68.6 ± 44.2, P = 0.009) at baseline and a smaller poststent ISS volume (0.7 ± 0.9 mm3 vs. 2.1 ± 1.9 mm3 , P = 0.019). At the 6-month follow-up, PE showed a higher incidence of RUTTS >0.3 (12.2 ± 14.4 vs. 2.0 ± 4.5%, P = 0.003), thinner neointimal thickness (0.05 ± 0.02 mm vs. 0.12 ± 0.08 mm, P = 0.002), and smaller neointimal area (0.5 ± 0.2 vs. 1.2 ± 0.9 mm2 , P = 0.004) compared with PR. In a multivariate logistic model, PE was identified as an independent predictor for RUTTS >0.3. CONCLUSIONS: PE was associated with less favorable healing following DES implantation when compared to PR at 6 months, indicating longer dual-antiplatelet therapy may be necessary for patients with PE. © 2017 Wiley Periodicals, Inc.

Chronic total occlusion is associated with a higher incidence of malapposition and uncovered stent struts: OCT findings at 6 months following DES implantation.

OBJECTIVES: To compare stent coverage and malapposition in patients with chronic total occlusion (CTO) lesions and non-CTO lesions (including lipid-rich plaque [LRP] and non-lipid-rich plaque [non-LRP]) after drug-eluting stent (DES) implantation by optical coherence tomography (OCT). BACKGROUND: Different initial lesion characteristics may be related to heterogeneous vessel responses after DES implantation. However, the vessel response in patients with CTO and non-CTO lesions after stenting is unclear. Methods We retrospectively enrolled 64 patients with 68 target lesions. All of the patients underwent OCT imaging immediate after stenting and 6 months after stenting. LRP was defined as the plaque with lipid content in ≥2 quadrants. Non-LRP consisted of fibrous, fibrocalcific plaque, and lipid plaque with less than 2 quadrants lipid content. RESULTS: The malapposition (3.0%, 2.6% vs. 0.6%, P = 0.022), tissue protrusion (15.0% vs. 11.0% vs. 6.4%, P < 0.001), and intrastent thrombus (3.8% vs. 2.4% vs. 1.1%, P = 0.012) were more frequent in the CTO and LRP groups. At 6-month follow-up, malapposition (5.0% vs. 1.0% and 0.4%, P = 0.002) and cross sections with uncovered struts (23.4% vs. 8.2% and 6.6%, P < 0.001) were most frequently observed in the CTO group. Although the incidence of stent thrombosis was non-significantly higher in the CTO group than the other two groups, no events were observed in patients with CTO. CONCLUSIONS: Patients with CTO lesions showed unfavorable responses to DES in the acute phase as well as at the 6-month follow-up, indicating the important pathological link between the original lesion morphology underneath the stents and heterogeneous artery healing. © 2017 Wiley Periodicals, Inc.

Bivalirudin versus unfractionated heparin for residual thrombus burden: a frequency-domain optical coherence tomography study.

OBJECTIVES: This study aimed to compare the effect of bivalirudin and unfractionated heparin (UFH) on residual thrombus burden assessed by frequency-domain optical coherence tomography (FD-OCT), and on angiographic indices of microvascular obstruction (MVO). BACKGROUND: The efficacy of bivalirudin to inhibit thrombus formation inside the stent during percutaneous coronary interventions (PCI) as compared to UFH is unknown. METHODS: Sixty patients with coronary artery disease who underwent post-PCI FD-OCT were studied, including 20 patients treated with bivalirudin and 40 control patients treated with UFH, matched by clinical presentation, stent characteristics, and periprocedural medications. In-stent thrombus volume, thrombus score (number of quadrants with thrombus), and thrombus type (white/red) were assessed by FD-OCT. Thrombolysis in myocardial infarction (TIMI) flow grade, corrected TIMI frame count (cTFC), and Quantitative Blush Evaluator (QuBE) score were recorded. RESULTS: Patients treated with bivalirudin showed similar thrombus volume (0.14 mm(3) [0.00-0.88] vs. 0.13 mm(3) [0.00-0.63], P = 0.962), thrombus score (10 [0-25] vs. 8 [0-21], P = 0.849) and thrombus length (1.70 mm [0.00-4.10] vs. 1.40 mm [0.00-4.05], P = 0.968], as compared with patients treated with UFH. Patients in the bivalirudin group showed lower proportion of white thrombus (55.5% vs. 78.6%, P = 0.016). There was no significant difference in TIMI flow grade, cTFC, and QuBE score between the two groups. CONCLUSIONS: The present study showed similar residual thrombus burden and angiographic indices of MVO immediately after PCI between patients treated with bivalirudin and those treated with UFH.

Spatial heterogeneity of neoatherosclerosis and its relationship with neovascularization and adjacent plaque characteristics: optical coherence tomography study.

BACKGROUND: Development of neoatherosclerosis (NA) has been reported to be a potential cause of late stent failure. However, the distribution of NA and its relationship with neovascularization (NV) and adjacent plaque characteristics remain unclear. METHODS: We investigated 167 stents (40 bare-metal stents, 84 sirolimus-eluting stents, and 43 everolimus-eluting stents) with optical coherence tomography. Each stent was divided into the proximal section (PS), mid section (MS) and distal section (DS). Neoatherosclerosis was defined as lipid-laden neointima or calcification inside stent. Adjacent plaque characteristics were evaluated within 5 mm proximal and distal reference segments. RESULTS: Neoatherosclerosis was more frequent in PS and DS than in MS (PS 19.8% vs. MS 3.6% vs. DS 21%: PS vs. MS, P < .001: MS vs. DS, P < .001). Neovascularization in PS and DS was also more prevalent compared with that in MS (PS 15% vs. MS 5.4% vs. DS 13.8%: PS vs. MS, P = .001: MS vs. DS, P = .001). Neoatherosclerosis was more frequently observed in stents with intraintima NV (68.6% vs. 20.5%, P < .001). The incidence of NA was higher, when adjacent plaque was lipid (43.2% with lipid plaque vs. 12.2% without lipid plaque, P < .001). CONCLUSION: Neoatherosclerosis occurs more frequently at PS and DS. Neoatherosclerosis was associated with NV and adjacent lipid plaque, suggesting potential interrelationship between development of NA and NV and adjacent plaque characteristics.

Pancoronary plaque vulnerability in patients with acute coronary syndrome and ruptured culprit plaque: a 3-vessel optical coherence tomography study.

BACKGROUND: Recent studies described different clinical and underlying plaque characteristics between patients with and without plaque rupture presenting with acute coronary syndrome (ACS). In light of the systemic nature of atherosclerosis, we hypothesized that nonculprit plaques might also express different morphological features in these 2 groups of patients. METHODS: Thirty-eight patients with ACS who underwent 3-vessel optical coherence tomography imaging were identified from the Massachusetts General Hospital Optical Coherence Tomography Registry. Based on culprit plaque morphology, the study population was divided into 2 groups: patients with plaque rupture at the culprit lesion (group 1) and patients with nonruptured plaque at the culprit lesion (group 2). Prevalence and features of nonculprit plaques were compared between the 2 groups. RESULTS: A total of 118 nonculprit plaques were analyzed. Patients in group 1 (n = 17) had nonculprit plaques with higher prevalence of thin-cap fibroatheroma (52.9% vs 19.0%, P = .029) and disruption (35.3% vs 4.8%, P = .016) compared with patients in group 2 (n = 21). Nonculprit plaques in group 1 showed wider maximum lipid arc (198.9° ± 41.7° vs 170.2° ± 41.9°, P = .003), greater lipid length (7.8 ± 4.4 mm vs 5.1 ± 2.4 mm, P = .003), higher lipid index (1196.9 ± 700.5 vs 747.7 ± 377.3, P = .001), and thinner fibrous cap (107.0 ± 56.5 µm vs 137.3 ± 69.8 µm, P = .035) compared with those in group 2. CONCLUSIONS: The present study showed distinctive features of nonculprit plaques between patients with ACS caused by plaque rupture and patients with ACS caused by nonruptured plaques. Patients with plaque rupture had increased pancoronary vulnerability in nonculprit plaques, suggesting that a more aggressive treatment paradigm aiming at the stabilization of vulnerable plaques may offer additional benefit to these patients.

MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction.

BACKGROUND: Micheliolide (MCL), which is the active metabolite of parthenolide, has demonstrated promising clinical application potential. However, the effects and underlying mechanisms of MCL on atherosclerosis are still unclear. METHOD: ApoE-/- mice were fed with high fat diet, with or without MCL oral administration, then the plaque area, lipid deposition and collagen content were determined. In vitro, MCL was used to pretreat macrophages combined by ox-LDL, the levels of ferroptosis related proteins, NRF2 activation, mitochondrial function and oxidative stress were detected. RESULTS: MCL administration significantly attenuated atherosclerotic plaque progress, which characteristics with decreased plaque area, less lipid deposition and increased collagen. Compared with HD group, the level of GPX4 and xCT in atherosclerotic root macrophages were increased in MCL group obviously. In vitro experiment demonstrated that MCL increased GPX4 and xCT level, improved mitochondrial function, attenuated oxidative stress and inhibited lipid peroxidation to suppress macrophage ferroptosis induced with ox-LDL. Moreover, MCL inhibited KEAP1/NRF2 complex formation and enhanced NRF2 nucleus translocation, while the protective effect of MCL on macrophage ferroptosis was abolished by NRF2 inhibition. Additionally, molecular docking suggests that MCL may bind to the Arg483 site of KEAP1, which also contributes to KEAP1/NRF2 binding. Furthermore, Transfection Arg483 (KEAP1-R483S) mutant plasmid can abrogate the anti-ferroptosis and anti-oxidative effects of MC in macrophages. KEAP1-R483S mutation also limited the protective effect of MCL on atherosclerosis progress and macrophage ferroptosis in ApoE-/- mice. CONCLUSION: MCL suppressed atherosclerosis by inhibiting macrophage ferroptosis via activating NRF2 pathway, the related mechanism is through binding to the Arg483 site of KEAP1 competitively.

Achieved low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio predicts the pathophysiological evolution of lipid-rich plaques in acute coronary syndromes: an optical coherence tomography study.

Background: As a novel lipoprotein ratio, baseline low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (LHR) is closely related to the clinical outcomes of acute coronary syndromes (ACS) after percutaneous coronary intervention. However, the pathophysiological impact of achieved LHR (aLHR) on the evolution of non-culprit lipid-rich plaques has not been systematically explored. Methods: Between September 2013 and December 2018, ACS patients with both baseline and 1-year follow-up optical coherence tomography (OCT) examinations were included in current study. They were divided into two groups according to the median value of aLHR at 1 year. Results: Overall, 132 patients with 215 lipid-rich plaques were enrolled, with a median aLHR: 1.62. There were thinner fibrous cap thickness (FCT) (133.3 [70.0-180.0] µm vs. 160.0 [100.0-208.3] µm, p = 0.025) and higher prevalence of thin-cap fibroatheroma (TCFA) (24 [22.4%] vs. 13 [12.0%], p = 0.044) and CLIMA-defined high-risk plaques (12 [11.2%] vs. 3[2.8%], p = 0.015) in the high aLHR group at 1 year. Compared with other serum lipid indexes, aLHR showed the best robust correlation with the evolution of plaque vulnerability in both unadjusted and adjusted analyses. Cut-off value of aLHR to predict the progression of maximal lipid arc and FCT was 1.51. In the adjusted model, aLHR ≥1.51 was an independent predictor of TCFA [odds ratio (OR): 3.008, 95% CI: 1.370 to 6.605, p = 0.006] at 1 year. Conclusions: aLHR correlates well with the evolution of lipid-rich plaques and vulnerable phenotypes at 1-year follow-up, which might be an important and convenient serum indicator in the secondary prevention of ACS.