Plaque Ruptures Are Related to High Plaque Stress and Strain Conditions: Direct Verification by Using In Vivo OCT Rupture Data and FSI Models.

BACKGROUND: While it has been hypothesized that high plaque stress and strain may be related to plaque rupture, its direct verification using in vivo coronary plaque rupture data and full 3-dimensional fluid-structure interaction models is lacking in the current literature due to difficulty in obtaining in vivo plaque rupture imaging data from patients with acute coronary syndrome. This case-control study aims to use high-resolution optical coherence tomography-verified in vivo plaque rupture data and 3-dimensional fluid-structure interaction models to seek direct evidence for the high plaque stress/strain hypothesis. METHODS: In vivo coronary plaque optical coherence tomography data (5 ruptured plaques, 5 no-rupture plaques) were acquired from patients using a protocol approved by the local institutional review board with informed consent obtained. The ruptured caps were reconstructed to their prerupture morphology using neighboring plaque cap and vessel geometries. Optical coherence tomography-based 3-dimensional fluid-structure interaction models were constructed to obtain plaque stress, strain, and flow shear stress data for comparative analysis. The rank-sum test in the nonparametric test was used for statistical analysis. RESULTS: Our results showed that the average maximum cap stress and strain values of ruptured plaques were 142% (457.70 versus 189.22 kPa; P=0.0278) and 48% (0.2267 versus 0.1527 kPa; P=0.0476) higher than that for no-rupture plaques, respectively. The mean values of maximum flow shear stresses for ruptured and no-rupture plaques were 145.02 dyn/cm2 and 81.92 dyn/cm2 (P=0.1111), respectively. However, the flow shear stress difference was not statistically significant. CONCLUSIONS: This preliminary case-control study showed that the ruptured plaque group had higher mean maximum stress and strain values. Due to our small study size, larger scale studies are needed to further validate our findings.

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.

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).

LncRNA MEG3 attenuates the malignancy of retinoblastoma cells through inactivating PI3K /Akt/mTOR signaling pathway.

Retinoblastoma (RB) is the most common neoplasm found in the eye of children. There are increasing interests to develop targeted gene therapy for this disease. This study was performed to investigate the impact of long non-coding RNA (lncRNA) MEG3 on the biological features of RB cells. Vector overexpressing MEG3 was constructed and introduced into two RB cell lines. Transfected RB cells were assessed for proliferation, apoptosis, migration ability, expression levels of important genes in the PI3K/Akt/mTOR signaling pathway using qRT-PCR and Western blot analysis. Xenograft mouse models were constructed to determine the tumorigenicity of RB cells overexpressing MEG3. MEG3 mRNA level was significantly lower in RB cells than in non-cancer cells (p < 0.01). Overexpressing MEG3 resulted in significant reduction in cell proliferation (p < 0.05), migration (p < 0.01) and significant increase in apoptosis (p < 0.01). After overexpressing MEG3, p-PI3K, p-Akt and p-mTOR levels were significantly downregulated (p < 0.01). Furthermore, in the xenograft model, RB cells overexpressing MEG3 generated significantly smaller tumors as compared to RB cells that did not overexpress MEG3 (p < 0.05). Our data suggest that MEG3 increases apoptosis and reduces tumorigenicity of RB cells through inactivating the PI3K/Akt/mTOR pathway. Therefore, MEG3 could be further investigated as a potential new therapeutic agent and target for RB therapy.

Optical Coherence Tomography Assessment of Coronary Lesions Associated With Microvascular Dysfunction in ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Microvascular reperfusion following percutaneous coronary intervention (PCI) is associated with the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). We investigated how plaque characteristics detected by optical coherence tomography (OCT) in STEMI patients affect the status of the microcirculation during PCI.Methods and Results: This retrospective, single-center study was a post hoc analysis basedon the multicenter SALVAGE randomized control trial (NCT03581513) that enrolled 629 STEMI patients, and finally we enrolled 235 patients who underwent PCI and pre-intervention OCT. Microvascular perfusion was evaluated using the Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion frame count (TMPFC). Patients were divided into 3 groups based on the change in TMPFC from before to after PCI: improving TMPFC (n=11; 4.7%), stable TMPFC (n=182; 77.4%), and worsening TMPFC group (n=42; 17.9%). The proportion of patients with a microcirculation dysfunction before reperfusion was 11.9%, which increased significantly by (P=0.079) 8.5% to 20.4% after reperfusion. Compared with plaque characteristics in the stable and worsening TMPFC groups, the improving TMPFC group had fewer thrombi (90.7% and 90.5% vs. 89.4%, respectively; P=0.018), a lower proportion of plaque rupture (66.5% and 66.3% vs. 54.5%, respectively; P=0.029), and a lower proportion of lipid-rich plaques (89.6% and 88.1% vs. 63.6%, respectively; P=0.036). CONCLUSIONS: PCI may not always achieve complete myocardial reperfusion. Thrombi, plaque rupture, and lipid-rich plaques detected by OCT can indicate microcirculation dysfunction during the reperfusion period.

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.

Oxidative Stress-Mediated Programmed Cell Death: a Potential Therapy Target for Atherosclerosis.

Nowadays, as a type of orderly and active death determined by genes, programmed cell death (PCD), including apoptosis, pyroptosis, ferroptosis, and necroptosis, has attracted much attention owing to its participation in numerous chronic cardiovascular diseases, especially atherosclerosis (AS), a canonical chronic inflammatory disease featured by lipid metabolism disturbance. Abundant researches have reported that PCD under distinct internal conditions fulfills different roles of atherosclerotic pathological processes, including lipid core expansion, leukocyte adhesion, and infiltration. Noteworthy, emerging evidence recently has also suggested that oxidative stress (OS), an imbalance of antioxidants and oxygen free radicals, has the potential to mediate PCD occurrence via multiple ways, including oxidization and deubiquitination. Interestingly, more recently, several studies have proposed that the mediating mechanisms could effect on the atherosclerotic initiation and progression significantly from variable aspects, so it is of great clinical importance to clarify how OS-mediated PCD and AS interact. Herein, with the aim of summarizing potential and sufficient atherosclerotic therapy targets, we seek to provide extensive analysis of the specific regulatory mechanisms of PCD mediated by OS and their multifaceted effects on the entire pathological atherosclerotic progression.

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.

The chromatin remodeler Brg1 is required for formation and maintenance of hematopoietic stem cells.

Hematopoietic stem and progenitor cells (HSPCs) have the ability to self-renew and differentiate into various blood cells, thus playing an important role in maintenance of lifelong hematopoiesis. Brahma-related gene 1 (BRG1), which acts as the ATP subunit of mammalian SWI-SNF-related chromatin remodeling complexes, is involved in human acute myeloid leukemia and highly expresses in short-term HSPCs. But its role and regulatory mechanism for HSPC development have not yet been well established. Here, we generated a brg1 knockout zebrafish model using TALEN technology. We found that in brg1-/- embryo, the primitive hematopoiesis remained well, while definitive hematopoiesis formation was significantly impaired. The number of hemogenic endothelial cells was decreased, further affecting definitive hematopoiesis with reduced myeloid and lymphoid cells. During embryogenesis, the nitric oxide (NO) microenvironment in brg1-/- embryo was seriously damaged and the reduction of HSPCs could be partially rescued by a NO donor. Chromatin immunoprecipitation (ChIP) assays showed that BRG1 could bind to the promoter of KLF2 and trigger its transcriptional activity of NO synthase. Our findings show that Brg1 promotes klf2a expression in hemogenic endothelium and highlight a novel mechanism for HSPC formation and maintenance.

Association of the age shock index with coronary plaque characteristics in ST-segment elevation myocardial infarction: A 3-vessel optical coherence tomography study.

OBJECTIVES: We investigated whether the age shock index (SI) was associated with coronary plaque characteristics in patients with ST-segment elevation myocardial infarction (STEMI) using optical coherence tomography (OCT). BACKGROUND: The age SI is a simple clinical parameter that effectively predicts poor clinical outcomes among patients with STEMI. METHODS: This retrospective study evaluated 408 STEMI patients who underwent 3-vessel OCT during emergency percutaneous coronary interventions at a single center between January 2017 and October 2018. Patients were divided into groups with low or high age SI values (<41 vs. ≥41). Plaque characteristics were compared between the two groups for both culprit lesions (n = 408) and non-culprit lesions (n = 1,077). RESULTS: In culprit lesions, patients with a high age SI (≥41) were more likely to have plaque rupture (61.0% vs. 56.8%, p = .002) and thinner fibrous caps (fibrous cap thickness [FCT]: 40.0 [33.0-53.0] µm vs. 46.0 [36.0-63.8] µm, p = .021). In non-culprit lesions, patients with a high age SI were more likely to have high-risk plaques (29.9% vs. 17.8%, p = .018; simultaneous presence of a minimal lumen area of <3.5 mm2 , maximum lipid arc of >180°, FCT of <75 µm, and macrophage accumulation). Plaque-based analyses revealed that patients with a high age SI had larger lipid cores and lesser FCT. CONCLUSIONS: Patients with STEMI and a high age SI had increased risks of culprit plaque rupture and high-risk non-culprit plaques, and vulnerable plaque features at the culprit and non-culprit lesions. Therefore, a high age SI in patients with STEMI may indicate greater pancoronary vulnerability.

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.

Optical Coherence Tomography-Based Patient-Specific Residual Multi-Thrombus Coronary Plaque Models With Fluid-Structure Interaction for Better Treatment Decisions: A Biomechanical Modeling Case Study.

Intracoronary thrombus from plaque erosion could cause fatal acute coronary syndrome (ACS). A conservative antithrombotic therapy has been proposed to treat ACS patients in lieu of stenting. It is speculated that the residual thrombus after aspiration thrombectomy would influence the prognosis of this treatment. However, biomechanical mechanisms affecting intracoronary thrombus remodeling and clinical outcome remain largely unknown. in vivo optical coherence tomography (OCT) data of a coronary plaque with two residual thrombi after antithrombotic therapy were acquired from an ACS patient with consent obtained. Three OCT-based fluid-structure interaction (FSI) models with different thrombus volumes, fluid-only, and structure-only models were constructed to simulate and compare the biomechanical interplay among blood flow, residual thrombus, and vessel wall mimicking different clinical situations. Our results showed that residual thrombus would decrease coronary volumetric flow rate by 9.3%, but elevate wall shear stress (WSS) by 29.4% and 75.5% at thrombi 1 and 2, respectively. WSS variations in a cardiac cycle from structure-only model were 12.1% and 13.5% higher at the two thrombus surfaces than those from FSI model. Intracoronary thrombi were subjected to compressive forces indicated by negative thrombus stress. Tandem intracoronary thrombus might influence coronary hemodynamics and solid mechanics differently. Computational modeling could be used to quantify biomechanical conditions under which patients could receive patient-specific treatment plan with optimized outcome after antithrombotic therapy. More patient studies with follow-up data are needed to continue the investigation and better understand mechanisms governing thrombus remodeling process.

Knockout of tnni1b in zebrafish causes defects in atrioventricular valve development via the inhibition of the myocardial wnt signaling pathway.

The proper development of atrioventricular (AV) valves is critical for heart morphogenesis and for the formation of the cardiac conduction system. Defects in AV valve development are the most common type of congenital heart defect. Cardiac troponin I ( ctnni), a structural and regulatory protein involved in cardiac muscle contraction, is a subunit of the troponin complex, but the functions and molecular mechanisms of ctnni during early heart development remain unclear. We created a knockout zebrafish model in which troponin I type 1b ( tnni1b) ( Tnni-HC, heart and craniofacial) was deleted using the clustered regularly interspaced short palindromic repeat/clustered regularly interspaced short palindromic repeat-associated protein system. In the homozygous mutant, the embryos showed severe pericardial edema, malformation of the heart tube, reduction of heart rate without contraction and with almost no blood flow, heart cavity congestion, and lack of an endocardial ring or valve leaflet, resulting in 88.8 ± 6.0% lethality at 7 d postfertilization. Deletion of tnni1b caused the abnormal expression of several markers involved in AV valve development, including bmp4, cspg2, has2, notch1b, spp1, and Alcam. Myocardial re-expression of tnni1b in mutants partially rescued the pericardial edema phenotype and AV canal (AVC) developmental defects. We further showed that tnni1b knockout in zebrafish and ctnni knockdown in rat h9c2 myocardial cells inhibited cardiac wnt signaling and that myocardial reactivation of wnt signaling partially rescued the abnormal expression of AVC markers caused by the tnni1b deletion. Taken together, our data suggest that tnni1b plays a vital role in zebrafish AV valve development by regulating the myocardial wnt signaling pathway.-Cai, C., Sang, C., Du, J., Jia, H., Tu, J., Wan, Q., Bao, B., Xie, S., Huang, Y., Li, A., Li, J., Yang, K., Wang, S., Lu, Q. Knockout of tnni1b in zebrafish causes defects in atrioventricular valve development via the inhibition of myocardial wnt signaling pathway.

Clinical use of intracoronary imaging. Part 2: acute coronary syndromes, ambiguous coronary angiography findings, and guiding interventional decision-making: an expert consensus document of the European Association of Percutaneous Cardiovascular Interventions.

This consensus document is the second of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS), optical coherence tomography (OCT), and near infrared spectroscopy (NIRS)-IVUS. Beyond guidance of stent selection and optimization of deployment, invasive imaging facilitates angiographic interpretation and may guide treatment in acute coronary syndrome. Intravascular imaging can provide additional important diagnostic information when confronted with angiographically ambiguous lesions and allows assessment of plaque morphology enabling identification of vulnerability characteristics. This second document focuses on useful imaging features to identify culprit and vulnerable coronary plaque, which offers the interventional cardiologist guidance on when to adopt an intracoronary imaging-guided approach to the treatment of coronary artery disease and provides an appraisal of intravascular imaging-derived metrics to define the haemodynamic significance of coronary lesions.

Identification of a new adtrp1-tfpi regulatory axis for the specification of primitive myelopoiesis and definitive hematopoiesis.

A genomic variant in the human ADTRP [androgen-dependent tissue factor (TF) pathway inhibitor (TFPI) regulating protein] gene increases the risk of coronary artery disease, the leading cause of death worldwide. TFPI is the TF pathway inhibitor that is involved in coagulation. Here, we report that adtrp and tfpi form a regulatory axis that specifies primitive myelopoiesis and definitive hematopoiesis, but not primitive erythropoiesis or vasculogenesis. In zebrafish, there are 2 paralogues for adtrp (i.e., adtrp1 and adtrp2). Knockdown of adtrp1 expression inhibits the specification of hemangioblasts, as shown by decreased expression of the hemangioblast markers, etsrp, fli1a, and scl; blocks primitive hematopoiesis, as shown by decreased expression of pu.1, mpo, and l-plastin; and disrupts the specification of hematopoietic stem cells (definitive hematopoiesis), as shown by decreased expression of runx1 and c-myb However, adtrp1 knockdown does not affect erythropoiesis during primitive hematopoiesis (no effect on gata1 or h-bae1) or vasculogenesis (no effect on kdrl, ephb2a, notch3, dab2, or flt4). Knockdown of adtrp2 expression does not have apparent effects on all markers tested. Knockdown of adtrp1 reduced the expression of tfpi, and hematopoietic defects in adtrp1 morphants were rescued by tfpi overexpression. These data suggest that the regulation of tfpi expression is one potential mechanism by which adtrp1 regulates primitive myelopoiesis and definitive hematopoiesis.-Wang, L., Wang, X., Wang, L., Yousaf, M., Li, J., Zuo, M., Yang, Z., Gou, D., Bao, B., Li, L., Xiang, N., Jia, H., Xu, C., Chen, Q., Wang, Q. K. Identification of a new adtrp1-tfpi regulatory axis for the specification of primitive myelopoiesis and definitive hematopoiesis.

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.

Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions.

This Consensus Document is the first of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The first document appraises the role of intracoronary imaging to guide percutaneous coronary interventions (PCIs) in clinical practice. Current evidence regarding the impact of intracoronary imaging guidance on cardiovascular outcomes is summarized, and patients or lesions most likely to derive clinical benefit from an imaging-guided intervention are identified. The relevance of the use of IVUS or OCT prior to PCI for optimizing stent sizing (stent length and diameter) and planning the procedural strategy is discussed. Regarding post-implantation imaging, the consensus group recommends key parameters that characterize an optimal PCI result and provides cut-offs to guide corrective measures and optimize the stenting result. Moreover, routine performance of intracoronary imaging in patients with stent failure (restenosis or stent thrombosis) is recommended. Finally, strengths and limitations of IVUS and OCT for guiding PCI and assessing stent failures and areas that warrant further research are critically discussed.

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.