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.

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.

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.

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.

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.

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).

Pancoronary plaque characteristics and clinical outcomes in acute coronary syndrome patients with cancer history.

BACKGROUND AND AIMS: The prevalence of acute coronary syndrome (ACS) patients with cancer history is increasing and it is associated with higher mortality. However, there is limited evidence on the characteristics of coronary plaque in ACS patients with cancer history. This study explored the pancoronary plaque characteristics in ACS patients with cancer history by optical coherence tomography (OCT). METHODS: A total of 306 ACS patients treated by 3-vessel OCT at the time of percutaneous coronary intervention (PCI) were included, retrospectively. Patients were divided into two groups according to the presence or absence of cancer history: one group with cancer history (n = 98) and a matched group without cancer history (n = 208). RESULTS: A total of 314 culprit lesions and 514 nonculprit lesions were identified by OCT in this study. In culprit lesions, ACS patients with cancer history had higher incidence of thin cap fibroatheroma (TCFA) (p = 0.016), cholesterol crystals (p = 0.028), calcification (p = 0.001) and thrombus (p = 0.001), and had thinner fibrous cap thickness (FCT) (p = 0.011), greater maximum lipid arc (p = 0.042) and lipid index (p < 0.001), compared to matched ACS patients without cancer history. In nonculprit lesions, ACS patients with cancer history had higher prevalence of high-risk plaque (14.7% vs. 7.7%, p = 0.017), nonculprit rupture (14.7% vs. 6.3%, p = 0.003), and TCFA (52.2% vs. 28.3%, p < 0.001), and had higher incidence of calcification (p = 0.003), thrombus (p = 0.029), cholesterol crystals (p = 0.002) and microchannels (p = 0.029). These non-culprit lesions had longer lesion length (p = 0.001), thinner FCT (p < 0.001), greater maximum lipid arc (p = 0.016) and lipid index (p < 0.001). CONCLUSIONS: ACS patients with cancer history showed more high-risk plaque features in culprit and nonculprit lesions, compared with ACS patients without cancer history. Therefore, ACS patients with cancer history may have greater pancoronary vulnerability. This may predict a poorer prognosis for ACS patients with cancer history.

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.

Clinical Characteristics and Prognosis of MINOCA Caused by Atherosclerotic and Nonatherosclerotic Mechanisms Assessed by OCT.

BACKGROUND: Myocardial infarction with nonobstructive coronary artery (MINOCA) is a heterogeneous syndrome caused by different pathophysiologic mechanisms. There is limited evidence regarding prognosis of patients with MINOCA caused by different mechanisms. OBJECTIVES: The present study aimed to assess the underlying mechanisms of MINOCA by optical coherence tomography (OCT) and to correlate with clinical outcomes. METHODS: Patients with MINOCA were divided into 2 groups based on OCT findings: atherosclerotic MINOCA (Ath-MINOCA) and nonatherosclerotic MINOCA (non-Ath-MINOCA). Major adverse cardiac events (MACE) were defined as cardiac death, nonfatal MI, target lesion revascularization, stroke, and rehospitalization for unstable or progressive angina. RESULTS: Among 7,423 patients with a clinical diagnosis of MI who underwent angiography, 190 of 294 MINOCA were studied using OCT. The causes of Ath-MINOCA (n = 99, 52.1%) were plaque erosion (n = 64, 33.7%), plaque rupture (n = 33, 17.4%), and calcified nodule (n = 2, 1.1%) whereas the causes of non-Ath-MINOCA (n = 91, 47.9%) were spontaneous coronary artery dissection (n = 8, 4.2%), coronary spasm (n = 9, 4.7%), and unclassified cause (n = 74, 38.9%). The 1-year MACE was 15.3% for Ath-MINOCA vs 4.5% for non-Ath-MINOCA (P = 0.015). An atherosclerotic cause was an independent predictor of MACE (HR: 5.36 [95% CI: 1.08-26.55]; P = 0.040), mainly driven by target lesion revascularization and rehospitalization, despite the composite endpoint including cardiac death and MI showing no difference. CONCLUSIONS: OCT identified a cause in 61.1% of MINOCA, in which Ath-MINOCA represents an important and distinct MINOCA subset. Ath-MINOCA were more common and associated with worse outcomes. (Incidence Rate of Heart Failure After Acute Myocardial Infarction With Optimal Treatment; NCT03297164; Paradigm Shift in the Treatment of Patients With ACS; NCT02041650).

Risk Stratification in Acute Coronary Syndrome by Comprehensive Morphofunctional Assessment With Optical Coherence Tomography.

Background: Artificial intelligence enables simultaneous evaluation of plaque morphology and computational physiology from optical coherence tomography (OCT). Objectives: This study sought to appraise the predictive value of major adverse cardiovascular events (MACE) by combined plaque morphology and computational physiology. Methods: A total of 604 patients with acute coronary syndrome who underwent OCT imaging in ≥1 nonculprit vessel during index coronary angiography were retrospectively enrolled. A novel morphologic index, named the lipid-to-cap ratio (LCR), and a functional parameter to evaluate the physiologic significance of coronary stenosis from OCT, namely, the optical flow ratio (OFR), were calculated from OCT, together with classical morphologic parameters, like thin-cap fibroatheroma (TCFA) and minimal lumen area. Results: The 2-year cumulative incidence of a composite of nonculprit vessel-related cardiac death, cardiac arrest, acute myocardial infarction, and ischemia-driven revascularization (NCV-MACE) at 2 years was 4.3%. Both LCR (area under the curve [AUC]: 0.826; 95% CI: 0.793-0.855) and OFR (AUC: 0.838; 95% CI: 0.806-0.866) were superior to minimal lumen area (AUC: 0.618; 95% CI: 0.578-0.657) in predicting NCV-MACE at 2 years. Patients with both an LCR of >0.33 and an OFR of ≤0.84 had significantly higher risk of NCV-MACE at 2 years than patients in whom at least 1 of these 2 parameters was normal (HR: 42.73; 95% CI: 12.80-142.60; P < 0.001). The combination of thin-cap fibroatheroma and OFR also identified patients at higher risk of future events (HR: 6.58; 95% CI: 2.83-15.33; P < 0.001). Conclusions: The combination of LCR with OFR permits the identification of a subgroup of patients with 43-fold higher risk of recurrent cardiovascular events in the nonculprit vessels after acute coronary syndrome.

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.

Prevalence and prognostic significance of DNMT3A- and TET2- clonal haematopoiesis-driver mutations in patients presenting with ST-segment elevation myocardial infarction.

BACKGROUND: Clonal haematopoiesis driven by mutations in DNMT3A or TET2 has recently been identified as a new risk factor for cardiovascular disease. Experimental studies suggest that these mutations may enhance inflammation which accelerates the disease progression. We aim to investigate the prevalence of mutations in DNMT3A and TET2 and their association with prognosis of patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Targeted deep sequencing for DNMT3A and TET2 and inflammatory cytokines (IL-1ß, IL-6, TNF-α, INF-γ) were analyzed in 485 patients with STEMI. Major adverse cardiac events (MACE) was a composite of death, myocardial infarction, stroke, or hospitalization due to heart failure. FINDINGS: Patients carrying DNMT3A- or TET2-CH-driver mutations with a variant allele frequency (VAF) ≥2% were found in 12.4% (60 of 485) of STEMI patients and experienced an increased incidence of the death (30.9% vs 15.5%, P = 0.001) and MACE (44.5% vs 21.8%, P < 0.001) compared to those who did not, during a median follow up of 3.0 (interquartile range: 2.4-3.4) years. After adjusting for confounders, mutation remained an independent predictor of death (HR = 1.967, 95% CI 1.103-3.507, P = 0.022) and MACE (HR = 1.833, 95% CI 1.154-2.912, P = 0.010). Concentrations of plasma IL-1ß (P = 0.010) and IL-6 (P = 0.011) were significantly elevated in DNMT3A/TET2 VAF≥2% group. INTERPRETATION: DNMT3A- or TET2-CH-driver mutations with a VAF≥2% were observed in over 10% STEMI patients, and were significantly associated with poorer prognosis, which might be explained by higher levels of inflammatory cytokines in mutations carriers. FUNDING: National Natural Science Foundation of China; National Key R&D Program of China.

Comprehensive Assessment of Coronary Calcification in Intravascular OCT Using a Spatial-Temporal Encoder-Decoder Network.

Coronary calcification is a strong indicator of coronary artery disease and a key determinant of the outcome of percutaneous coronary intervention. We propose a fully automated method to segment and quantify coronary calcification in intravascular OCT (IVOCT) images based on convolutional neural networks (CNN). All possible calcified plaques were segmented from IVOCT pullbacks using a spatial-temporal encoder-decoder network by exploiting the 3D continuity information of the plaques, which were then screened and classified by a DenseNet network to reduce false positives. A novel data augmentation method based on the IVOCT image acquisition pattern was also proposed to improve the performance and robustness of the segmentation. Clinically relevant metrics including calcification area, depth, angle, thickness, volume, and stent-deployment calcification score, were automatically computed. 13844 IVOCT images with 2627 calcification slices from 45 clinical OCT pullbacks were collected and used to train and test the model. The proposed method performed significantly better than existing state-of-the-art 2D and 3D CNN methods. The data augmentation method improved the Dice similarity coefficient for calcification segmentation from 0.615±0.332 to 0.756±0.222, reaching human-level inter-observer agreement. Our proposed region-based classifier improved image-level calcification classification precision and F1-score from 0.725±0.071 and 0.791±0.041 to 0.964±0.002 and 0.883±0.008, respectively. Bland-Altman analysis showed close agreement between manual and automatic calcification measurements. Our proposed method is valuable for automated assessment of coronary calcification lesions and in-procedure planning of stent deployment.

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.

Predictors of non-stenting strategy for acute coronary syndrome caused by plaque erosion: four-year outcomes of the EROSION study.

BACKGROUND: The EROSION study demonstrated that patients with an acute coronary syndrome (ACS) caused by plaque erosion could be treated with antithrombotic therapy without stenting. However, the long-term prognosis of this strategy is still unclear. AIMS: The aim of this study was to test whether a non-stenting antithrombotic strategy was still effective at four-year follow-up and to explore potential predictors of long-term prognosis. METHODS: This study was a long-term follow-up of the EROSION study. Follow-up was conducted by phone call or clinical visit. Patients were divided into two groups - those with target lesion revascularisation (the TLR group), and the non-TLR group. RESULTS: Out of 55 patients who completed one-month follow-up, 52 patients finished four-year follow-up. The median duration was 4.8 years (range, 4.2-5.8 years). The majority of patients remained free from events, and all patients were free from hard endpoints (death, myocardial infarction, stroke, bypass surgery, or heart failure). Only one patient had gastrointestinal bleeding, and 11 patients underwent TLR. Patients in the non-TLR group had more optical coherence tomography (OCT) thrombus reduction from baseline to one month; 95% of patients in the non-TLR group versus 45% in the TLR group (p=0.001) met the primary endpoint (thrombus volume reduction >50%). Angiographic results showed that the TLR group had less improvement in diameter stenosis (p=0.014) at one month compared with the non-TLR group. CONCLUSIONS: Four-year follow-up findings reconfirmed the safety of an antithrombotic therapy without stenting for ACS caused by erosion. Patients with better response to antithrombotic therapy in the first month were less likely to require stent implantation during the next four years.

Relationship between elevated plasma ceramides and plaque rupture in patients with ST-segment elevation myocardial infarction.

BACKGROUND AND AIMS: Ceramides (Cer) are an atherogenic substance. However, the associations between specific plasma Cer levels and culprit plaque morphology in ST-segment elevation myocardial infarction (STEMI) patients are unclear. METHODS: The study consisted of two parallel cohorts. 100 consecutive patients with STEMI were screened as discovery cohort. In the validation cohort, we separately screened 30 normal donors, 30 stable angina pectoris (SAP) and 315 STEMI patients. All STEMI patients underwent emergency percutaneous intervention (PCI) and optical coherence tomography (OCT) examination for culprit plaque. Based on established diagnostic criteria, STEMI patients were classified into plaque rupture (PR) and plaque erosion (PE) group, respectively. Rapid resolution liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (RRLC-Q-TOF/MS) was used to evaluate plasma Cer levels of the screened patients. RESULTS: STEMI patients had higher plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1) and Cer(d18:1/24:0) levels than normal donors and SAP patients (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). Plasma Cer levels were significantly higher in STEMI patients with PR than with PE (p < 0.001, p < 0.001, p = 0.008 and p = 0.006, respectively). The frequency of PR increased with increasing tertiles of plasma Cer (adjusted p for trend = 0.004, 0.044, 0.021 and 0.133, respectively). The fully adjusted per SD odds ratios (95% confidence interval) for PR were 9.375 (2.496-35.215) for Cer(d18:1/16:0), 3.586 (1.588-8.089) for Cer(d18:1/18:0), 8.171 (1.764-37.857) for Cer(d18:1/24:1), and 3.831 (1.288-11.289) for Cer(d18:1/24:10). CONCLUSIONS: The study documented novel, positive and independent associations between plasma Cer concentrations and the presence of PR, suggesting plasma Cer may act as potential biomarkers for PR to improve risk stratification.