Biomimetic Nano-Degrader Based CD47-SIRPα Immune Checkpoint Inhibition Promotes Macrophage Efferocytosis for Cardiac Repair.

CD47-SIRPα axis is an immunotherapeutic target in tumor therapy. However, current monoclonal antibody targeting CD47-SIRPα axis is associated with on-target off-tumor and antigen sink effects, which significantly limit its potential clinical application. Herein, a biomimetic nano-degrader is developed to inhibit CD47-SIRPα axis in a site-specific manner through SIRPα degradation, and its efficacy in acute myocardial infarction (AMI) is evaluated. The nano-degrader is constructed by hybridizing liposome with red blood cell (RBC) membrane (RLP), which mimics the CD47 density of senescent RBCs and possesses a natural high-affinity binding capability to SIRPα on macrophages without signaling capacity. RLP would bind with SIRPα and induce its lysosomal degradation through receptor-mediated endocytosis. To enhance its tissue specificity, Ly6G antibody conjugation (aRLP) is applied, enabling its attachment to neutrophils and accumulation within inflammatory sites. In the myocardial infarction model, aRLP accumulated in the infarcted myocardium blocks CD47-SIRPα axis and subsequently promoted the efferocytosis of apoptotic cardiomyocytes by macrophage, improved heart repair. This nano-degrader efficiently degraded SIRPα in lysosomes, providing a new strategy for immunotherapy with great clinical transformation potential.

Sex Differences in Coronary Inflammation and Atherosclerosis Phenotypes in Response to Imaging Marker of Stress-Related Neural Activity.

BACKGROUND: Sex-specific differences in coronary phenotypes in response to stress have not been elucidated. This study investigated the sex-specific differences in the coronary computed tomography angiography-assessed coronary response to mental stress. METHODS: This retrospective study included patients with coronary artery disease and without cancer who underwent resting 18F-fluorodexoyglucose positron emission tomography/computed tomography and coronary computed tomography angiography within 3 months. 18F-flourodeoxyglucose resting amygdalar uptake, an imaging biomarker of stress-related neural activity, coronary inflammation (fat attenuation index), and high-risk plaque characteristics were assessed by coronary computed tomography angiography. Their correlation and prognostic values were assessed according to sex. RESULTS: A total of 364 participants (27.7% women and 72.3% men) were enrolled. Among those with heightened stress-related neural activity, women were more likely to have a higher fat attenuation index (43.0% versus 24.0%; P=0.004), while men had a higher frequency of high-risk plaques (53.7% versus 39.3%; P=0.036). High amygdalar 18F-flourodeoxyglucose uptake (B-coefficient [SE], 3.62 [0.21]; P<0.001) was selected as the strongest predictor of fat attenuation index in a fully adjusted linear regression model in women, and the first-order interaction term consisting of sex and stress-related neural activity was significant (P<0.001). Those with enhanced imaging biomarkers of stress-related neural activity showed increased risk of major adverse cardiovascular event both in women (24.5% versus 5.1%; adjusted hazard ratio, 3.62 [95% CI, 1.14-17.14]; P=0.039) and men (17.2% versus 6.9%; adjusted hazard ratio, 2.72 [95% CI, 1.10-6.69]; P=0.030). CONCLUSIONS: Imaging-assessed stress-related neural activity carried prognostic values irrespective of sex; however, a sex-specific mechanism linking psychological stress to coronary plaque phenotypes existed in the current hypothesis-generating study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05545618.

Genetically Engineered Macrophages Co-Loaded with CD47 Inhibitors Synergistically Reconstruct Efferocytosis and Improve Cardiac Remodeling Post Myocardial Ischemia Reperfusion Injury.

Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK （main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.

Deubiquitinase OTUB1 regulates doxorubicin-induced cardiotoxicity via deubiquitinating c-MYC.

BACKGROUND: Doxorubicin (DOX), an anthracycline drug widely used in antitumor therapies, has dose-dependent toxicity that can cause cardiomyocyte apoptosis and oxidative stress, thus limiting its clinical application. OTUB1 (ovarian tumor associated proteinase B1) is an OTU superfamily deubiquitinase that effectively regulates cell proliferation, inflammatory responses, apoptosis, and oxidative stress by specifically removing K48- and K63-linked ubiquitination; however, its role in DOX-induced cardiotoxicity remains unknown. MATERIALS AND METHODS: A DOX-induced subacute cardiotoxicity mouse model was established by intraperitoneal injection, and cardiac injury was assessed by echocardiography, serum cardiac markers, and histopathological staining. Western blotting, qRT-PCR, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) immunohistochemistry were used to analyze cell apoptosis, tissue oxidative stress was assessed by superoxide dismutase (SOD) activity, malondialdehyde (MDA), and glutathione peroxidase (GSH-PX) activity. Cell counting kit-8 (CCK-8) assay, TUNEL staining, Western blotting, qRT-PCR, and reactive oxygen species (ROS) flow cytometry were applied on isolated neonatal mice cardiomyocytes to assess apoptosis and oxidative stress. Differentially expressed genes were analyzed using RNA sequencing and clustering analyses. c-MYC inhibitor 10,058-F4 and siRNA targeting c-Myc were used to investigate the roles of c-MYC in OTUB1's regulations of DOX-induced cardiotoxicity. Immunoprecipitation and Western blotting were performed to reveal the deubiquitinating effects of OTUB1 on c-MYC expression. RESULTS: We found that global Otub1-knockdown in vivo alleviated the subacute DOX treatment-induced cardiac dysfunction, fibrosis, and cardiomyocyte atrophy. Mechanistically, unbiased RNA sequencing and molecular biology experiments revealed that cardiomyocyte apoptosis, inflammation, and oxidative stress in DOX-induced cardiotoxicity were significantly compromised in the Otub1-knockdown group. Further in vitro studies have shown that c-MYC, a critical regulator of apoptosis, is indispensable in OTUB1's regulations of DOX-induced cardiotoxicity. Deubiquitinating effects of OTUB1 on K48- and K63-linked ubiquitination of c-MYC protein are essential for promoting cardiomyocyte apoptosis and oxidative responses. CONCLUSIONS: OTUB1-c-MYC inhibition protected cardiomyocytes against DOX-induced apoptosis and oxidative stress, suggesting that OTUB1 is a potential translational therapeutic target for preventing DOX-induced cardiotoxicity.

Stress-Related Neural Activity Associates With Coronary Plaque Vulnerability and Subsequent Cardiovascular Events.

BACKGROUND: Stress-related neural activity (SNA) assessed by amygdalar activity can predict cardiovascular events. However, its mechanistic linkage with plaque vulnerability is not fully elucidated. OBJECTIVES: The authors aimed to investigate the association of SNA with coronary plaque morphologic and inflammatory features as well as their ability in predicting major adverse cardiovascular events (MACE). METHODS: A total of 299 patients with coronary artery disease (CAD) and without cancer underwent 18F-fluorodexoyglucose positron emission tomography/computed tomography (PET/CT) and available coronary computed tomographic angiography (CCTA) between January 1, 2013, and December 31, 2020. SNA and bone-marrow activity (BMA) were assessed with validated methods. Coronary inflammation (fat attenuation index [FAI]) and high-risk plaque (HRP) characteristics were assessed by CCTA. Relations between these features were analyzed. Relations between SNA and MACE were assessed with Cox models, log-rank tests, and mediation (path) analyses. RESULTS: SNA was significant correlated with BMA (r = 0.39; P < 0.001) and FAI (r = 0.49; P < 0.001). Patients with heightened SNA are more likely to have HRP (40.7% vs 23.5%; P = 0.002) and increase risk of MACE (17.2% vs 5.1%, adjusted HR 3.22; 95% CI: 1.31-7.93; P = 0.011). Mediation analysis suggested that higher SNA associates with MACE via a serial mechanism involving BMA, FAI, and HRP. CONCLUSIONS: SNA is significantly correlated with FAI and HRP in patients with CAD. Furthermore, such neural activity was associated with MACE, which was mediated in part by leukopoietic activity in the bone marrow, coronary inflammation, and plaque vulnerability.

COX5A Alleviates Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress, Mitochondrial Dysfunction and Cardiomyocyte Apoptosis.

Doxorubicin (DOX) as a chemotherapeutic agent can cause mitochondrial dysfunction and heart failure. COX5A has been described as an important regulator of mitochondrial energy metabolism. We investigate the roles of COX5A in DOX-induced cardiomyopathy and explore the underlying mechanisms. C57BL/6J mice and H9c2 cardiomyoblasts were treated with DOX, and the COX5A expression was assessed. An adeno-associated virus serum type 9 (AAV9) and lenti-virus system were used to upregulate COX5A expression. Echocardiographic parameters, morphological and histological analyses, transmission electron microscope and immunofluorescence assays were used to assess cardiac and mitochondrial function. In a human study, we found that cardiac COX5A expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to the control group. COX5A was significantly downregulated following DOX stimulation in the heart of mice and H9c2 cells. Reduced cardiac function, decreased myocardium glucose uptake, mitochondrial morphology disturbance, reduced activity of mitochondrial cytochrome c oxidase (COX) and lowered ATP content were detected after DOX stimulation in mice, which could be significantly improved by overexpression of COX5A. Overexpression of COX5A effectively protected against DOX-induced oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, the phosphorylation of Akt (Thr308) and Akt (Ser473) were also decreased following DOX treatment, which could be reserved by the upregulation of COX5A. Furthermore, PI3K inhibitors abrogated the protection effects of COX5A against DOX-induced cardiotoxicity in H9c2 cells. Thus, we identified that PI3K/Akt signaling was responsible for the COX5A-mediated protective role in DOX-induced cardiomyopathy. These results demonstrated the protective effect of COX5A in mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis, providing a potential therapeutic target in DOX-induced cardiomyopathy.

Epigenetically altered macrophages promote development of diabetes-associated atherosclerosis.

Background: Atherosclerosis (AS) risk is elevated in diabetic patients, but the underlying mechanism such as involvement of epigenetic control of foam macrophages remains unclear. We have previously shown the importance of immune regulation on endothelial cells to AS development in diabetes. In this study, we examined the hypothesis that diabetes may promote AS through modification of the epigenetic status of macrophages. Methods: We employed the Laser Capture Microdissection (LCM) method to evaluate the expression levels of key epigenetic regulators in both endothelial cells and macrophages at the AS lesions of patients. We then assessed the correlation between the significantly altered epigenetic regulator and serum levels of low-density Lipoprotein (LDL), triglycerides (TRIG) and high-density Lipoprotein (HDL) in patients. In vitro, the effects of high glucose on glucose utilization, lactate production, succinate levels, oxygen consumption and polarization in either undifferentiated or differentiated bone marrow-derived macrophages (BMDMs) were analyzed. The effects of depleting this significantly altered epigenetic regulator in macrophages on AS development were assessed in AS-prone diabetic mice. Results: Histone deacetylase 3 (HDAC3) was identified as the most significantly altered epigenetic regulator in macrophages from the AS lesions in human diabetic patients. The levels of HDAC3 positively correlated with high serum LDL and TRIG, as well as low serum HDL. High glucose significantly increased glucose utilization, lactate production, succinate levels and oxygen consumption in cultured macrophages, and induced proinflammatory M1-like polarization. Macrophage depletion of HDAC3 significantly attenuated AS severity in AS-prone diabetic mice. Conclusion: Epigenetically altered macrophages promote development of diabetes-associated AS, which could be prevented through HDAC3 depletion.

L-carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1-Parkin-dependent mitophagy through the CPT1a-PHB2-PARL pathways.

AIM: To explore the beneficial effects of L-carnitine on cardiac microvascular dysfunction in diabetic cardiomyopathy from the perspectives of mitophagy and mitochondrial integrity. METHODS: Male db/db and db/m mice were randomly assigned to groups and were treated with L-carnitine or a solvent for 24 weeks. Endothelium-specific PARL overexpression was attained via adeno-associated virus serotype 9 (AAV9) transfection. Adenovirus (ADV) vectors overexpressing wild-type CPT1a, mutant CPT1a, or PARL were transfected into endothelial cells exposed to high glucose and free fatty acid (HG/FFA) injury. Cardiac microvascular function, mitophagy, and mitochondrial function were analyzed by immunofluorescence and transmission electron microscopy. Protein expression and interactions were assessed by western blotting and immunoprecipitation. RESULTS: L-carnitine treatment enhanced microvascular perfusion, reinforced endothelial barrier function, repressed the endothelial inflammatory response, and maintained the microvascular structure in db/db mice. Further results demonstrated that PINK1-Parkin-dependent mitophagy was suppressed in endothelial cells suffering from diabetic injury, and these effects were largely alleviated by L-carnitine through the inhibition of PARL detachment from PHB2. Moreover, CPT1a modulated the PHB2-PARL interaction by directly binding to PHB2. The increase in CPT1a activity induced by L-carnitine or amino acid mutation (M593S) enhanced the PHB2-PARL interaction, thereby improving mitophagy and mitochondrial function. In contrast, PARL overexpression inhibited mitophagy and abolished all the beneficial effects of L-carnitine on mitochondrial integrity and cardiac microvascular function. CONCLUSION: L-carnitine treatment enhanced PINK1-Parkin-dependent mitophagy by maintaining the PHB2-PARL interaction via CPT1a, thereby reversing mitochondrial dysfunction and cardiac microvascular injury in diabetic cardiomyopathy.

Isorhapontigenin Attenuates Cardiac Microvascular Injury in Diabetes via the Inhibition of Mitochondria-Associated Ferroptosis Through PRDX2-MFN2-ACSL4 Pathways.

Ferroptosis is a newly identified form of regulated cell death that is driven by iron overload and uncontrolled lipid peroxidation, but the role of ferroptosis in cardiac microvascular dysfunction remains unclear. Isorhapontigenin (ISO) is an analog of resveratrol and possesses strong antioxidant capacity and cardiovascular-protective effects. Moreover, ISO has been shown to alleviate iron-induced oxidative damage and lipid peroxidation in mitochondria. Therefore, the current study aimed to explore the benefits of ISO treatment on cardiac microvascular dysfunction in diabetes and the possible mechanisms involved, with a focus on ferroptosis and mitochondria. Our data revealed that ISO treatment improved microvascular density and perfusion in db/db mice by mitigating vascular structural damage, normalizing nitric oxide (NO) production via endothelial NO synthase activation, and enhancing angiogenetic ability via vascular endothelial growth factor receptor 2 phosphorylation. PRDX2 was identified as a downstream target of ISO, and endothelial-specific overexpression of PRDX2 exerted effects on the cardiac microvascular function that were similar to those of ISO treatment. In addition, PRDX2 mediated the inhibitive effects of ISO treatment on ferroptosis by suppressing oxidative stress, iron overload, and lipid peroxidation. Further study suggested that mitochondrial dynamics and dysfunction contributed to ferroptosis, and ISO treatment or PRDX2 overexpression attenuated mitochondrial dysfunction via MFN2-dependent mitochondrial dynamics. Moreover, MFN2 overexpression suppressed the mitochondrial translocation of ACSL4, ultimately inhibiting mitochondria-associated ferroptosis. In contrast, enhancing mitochondria-associated ferroptosis via ACSL4 abolished the protective effects of ISO treatment on cardiac microcirculation. Taken together, the results of the present work demonstrated the beneficial effects of ISO treatment on cardiac microvascular protection in diabetes by suppressing mitochondria-associated ferroptosis through PRDX2-MFN2-ACSL4 pathways.

Aortic valve calcification predicts poor outcomes after primary percutaneous coronary intervention.

BACKGROUND: Aortic valve calcification (AVC) is associated with increased cardiovascular risk in the general population. We sought to investigate whether AVC identified by transthoracic echocardiography could be a predictor of long-term adverse events after primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction. METHODS: Patients undergoing primary PCI were consecutively enrolled in this cohort study between 1 January 2009 and 31 December 31 2018. The presence of AVC was identified by transthoracic echocardiography one to three days after PCI. The primary endpoint was major adverse cardiovascular and cerebral events (MACCE) during follow-up. Propensity score matching was adopted to adjust for the baseline differences between groups. RESULTS: Of 2117 patients enrolled in the study, 566 (26.7%) were found to have AVC. Patients with AVC were older, more likely to be women, and disposed to have comorbidities and complex lesions. During a median follow-up period of 6.1 years, 699 cases of MACCE occurred, including 243 (42.9%) cases in patients with AVC and 456 (29.4%) cases in patients without AVC. After 1:1 propensity score matching, the presence of AVC increased the risk of MACCE (adjusted hazard ratio: 1.442, 95% confidence interval: 1.186 to 1.754, p < 0.001). This difference persisted when sensitivity and subgroup analyses were made. CONCLUSIONS: AVC identified by transthoracic echocardiography independently increased the long-term risk of MACCE after primary PCI in patients with acute myocardial infarction. This imaging feature will contribute to better risk stratification in this population.

Targeted immunomodulation therapy for cardiac repair by platelet membrane engineering extracellular vesicles via hitching peripheral monocytes.

Immune regulation therapies have been considered promising in the treatment of myocardial ischemia reperfusion (MI/R) injury. Mesenchymal stem cells derived extracellular vesicles (MSC-EVs) are of great potential for immune modulation by reprogramming macrophages but their therapeutic efficacy is hindered by insufficient targeting ability in vivo. Herein, we introduced the platelet membrane modified EVs (P-EVs) based on membrane fusion method to mimic the binding ability of platelets to monocytes. In the mouse model of MI/R injury, the intravenously injected P-EVs were mainly carried by circulating monocytes into the ischemic myocardium. In the inflammatory microenvironment, those monocytes subsequently differentiated into macrophages with enhanced phagocytosis, which probably promoted in-situ endocytosis of the superficial P-EVs by monocytes differentiated macrophages in large quantities. Then, the P-EVs successfully escaped from the macrophage lysosome and released the functional microRNAs (miRNAs) into the cytosol which facilitated the inflammatory macrophages (M1 phenotype) reprogramming to reparative macrophages (M2 phenotype). Finally, the immune microenvironment was regulated to realize cardiac repair. Thus, we supposed that the most likely delivery method was that monocytes mediated P-EVs migration into ischemic myocardium where P-EVs were mainly in-situ endocytosed by monocytes derived macrophages, which holds potential for immunoregulation on MI/R and other immune-related diseases in the future.

Rosuvastatin Alleviates Coronary Microembolization-Induced Cardiac Injury by Suppressing Nox2-Induced ROS Overproduction and Myocardial Apoptosis.

To explore the mechanism by which rosuvastatin prevents coronary microembolism (CME)-induced cardiac injury and cardiomyocyte apoptosis. Animal and cell models of CME were established and treated with different doses of rosuvastatin. Echocardiography and histological staining were applied to assess left ventricular function and cardiac injury. Masson trichrome staining was used to evaluate fibrin deposition in the myocardium. The activity of lactate dehydrogenase (LDH) in serum and cell culture supernatant was detected. TUNEL staining and flow cytometry were used to evaluate apoptosis in myocardium and cardiomyocytes, respectively. The activity of ROS was revealed by DHE staining. The expression levels of Nox2, cleaved caspase-3, cytochrome C, p53, Bax and Bcl-2 were also detected. Rosuvastatin pretreatment improved the left ventricular function of CME mice and reduced inflammatory cell infiltration and fibrin deposition in the myocardium. Rosuvastatin reduced the production of ROS by inhibiting the expression of Nox2. Rosuvastatin also downregulated pro-apoptotic proteins cleaved caspase-3, cytochrome C, p53 and Bax, and upregulated anti-apoptotic Bcl-2. Rosuvastatin mitigates CME-induced cardiac injury by inhibiting Nox2-induced ROS overproduction and alleviating p53/Bax/Bcl-2-dependent cardiomyocyte apoptosis.

Cardiac Wnt5a and Wnt11 promote fibrosis by the crosstalk of FZD5 and EGFR signaling under pressure overload.

Progressive cardiac fibrosis accelerates the development of heart failure. Here, we aimed to explore serum Wnt5a and Wnt11 levels in hypertension patients, the roles of Wnt5a and Wnt11 in cardiac fibrosis and potential mechanisms under pressure overload. The pressure overload mouse model was built by transverse aortic constriction (TAC). Cardiac fibrosis was analyzed by Masson's staining. Serum Wnt5a or Wnt11 was elevated and associated with diastolic dysfunction in hypertension patients. TAC enhanced the expression and secretion of Wnt5a or Wnt11 from cardiomyocytes (CMs), cardiac fibroblasts (CFs), and cardiac microvascular endothelial cells (CMECs). Knockdown of Wnt5a and Wnt11 greatly improved cardiac fibrosis and function at 4 weeks after TAC. In vitro, shWnt5a or shWnt11 lentivirus transfection inhibited pro-fibrotic effects in CFs under mechanical stretch (MS). Similarly, conditional medium from stretched-CMs transfected with shWnt5a or shWnt11 lentivirus significantly suppressed the pro-fibrotic effects induced by conditional medium from stretched-CMs. These data suggested that CMs- or CFs-derived Wnt5a or Wnt11 showed a pro-fibrotic effect under pressure overload. In vitro, exogenous Wnt5a or Wnt11 activated ERK and p38 (fibrotic-related signaling) pathway, promoted the phosphorylation of EGFR, and increased the expression of Frizzled 5 (FZD5) in CFs. Inhibition or knockdown of EGFR greatly attenuated the increased FZD5, p-p38, and p-ERK levels, and the pro-fibrotic effect induced by Wnt5a or Wnt11 in CFs. Si-FZD5 transfection suppressed the increased p-EGFR level, and the fibrotic-related effects in CFs treated with Wnt5a or Wnt11. In conclusion, pressure overload enhances the secretion of Wnt5a or Wnt11 from CMs and CFs which promotes cardiac fibrosis by activation the crosstalk of FZD5 and EGFR. Thus, Wnt5a or Wnt11 may be a novel therapeutic target for the prevention of cardiac fibrosis under pressure overload.

Reattempt Percutaneous Coronary Intervention of Chronic Total Occlusions after Prior Failures: A Single-Center Analysis of Strategies and Outcomes.

OBJECTIVE: The initial recanalization rate of coronary chronic total occlusions (CTOs) is >85% when performed by experienced operators, but only 10% of prior failed CTO patients receive reattempted recanalization. This retrospective study analyzed the success rate and strategies used in reattempt percutaneous coronary intervention (PCI) of CTOs after prior failures. METHODS: Overall, 206 patients with 212 CTOs were enrolled. All patients with prior recanalization failures received reattempt PCIs from January 2015 to March 2019 at Zhongshan Hospital, Fudan University. Data on clinical factors (age, sex, comorbidities, left ventricular ejection fraction, history of cigarette usage, and revascularization), angiographic characteristics of CTOs (target lesion, Japanese Chronic Total Occlusion (J-CTO) score, the morphology of CTO lesions, and collateral channel scale), strategies (procedural approach and use of devices), and major adverse events were obtained and analyzed. RESULTS: The mean age of enrolled patients was 60.96 ± 12.36 years, with a male predominance of 90.3%. Of the patients, 47.1% had a prior myocardial infarction and 70.4% underwent stent implantation previously, while the in-stent occlusion rate was 6.6%. CTOs were primarily localized in the left anterior descending artery (43.9%) and the right coronary artery (43.9%). 80.7% of lesions were classified as very difficult (J-CTO score ≥3), and the overall success rate was 81.1%. In multivariable regression analysis, J-CTO score, collateral channel scale, application of coronary multispiral computed tomography angiography, dual injection, intravascular ultrasound, active greeting technique, parallel wiring, and CTO morphology were predictors of recanalization success. There were no significant differences in rates of procedural complications between the final recanalization success and failure groups. CONCLUSIONS: Recanalization of complex CTOs is associated with high success rate and low complication rates when performed by high-volume CTO operators and after multiple reattempts.

Is MVD the effective treatment for poorly controlled hypertension?

BACKGROUND: Studies have shown that microvascular decompression (MVD) surgery could improve the clinical symptoms of hemifacial spasm (HFS) and decrease the blood pressure (BP) in patients with refractory hypertension. More positive long-term results are required to establish MVD as a treatment option for high blood pressure (HBP) and to refine the patient selection criteria. METHODS: From October 2015 to September 2018, based on patient selection for cases with both HFS and poorly controlled HBP of nervous origin, MVD surgeries were performed on 12 patients aiming for better BP control. The patients were followed-up for at least 2 years. The surgical outcomes and associated factors were analyzed. RESULTS: With respect to neurovascular compression (NVC) of facial nerve, the intra-operative findings concurred with pre-operative radiological findings except that in one case. Intra-operatively ipsilateral cranial nerve (CN) IX-X root exit zone (REZ) and rostral ventrolateral medulla (RVLM) NVCs were confirmed and concordant with pre-operative radiological findings in all 12 cases. 9 Of the 12 cases were completely free of facial spasm after surgery. 2 patients achieved partial relief. 1 patient still suffered from frequent facial spasm. 10 out of 12 patients achieved BP lowering after surgery. The BP of those 10 patients stayed at a relatively stable scale over the follow-up period. Although statistical significance was not obtained, for patients who are operated on the left side and those who have only 1 offensive artery, the surgery might lead to better BP control. CONCLUSIONS: MVD is a safe and effective treatment for hypertension due to central nervous system (CNS) NVC in patients with both HBP and HFS. Further studies are required to examine long-term outcomes and establish criteria for patient selection.

Rosuvastatin protects against coronary microembolization-induced cardiac injury via inhibiting NLRP3 inflammasome activation.

Coronary microembolization (CME), a common reason for periprocedural myocardial infarction (PMI), bears very important prognostic implications. However, the molecular mechanisms related to CME remain largely elusive. Statins have been shown to prevent PMI, but the underlying mechanism has not been identified. Here, we examine whether the NLRP3 inflammasome contributes to CME-induced cardiac injury and investigate the effects of statin therapy on CME. In vivo study, mice with CME were treated with 40 mg/kg/d rosuvastatin (RVS) orally or a selective NLRP3 inflammasome inhibitor MCC950 intraperitoneally (20 mg/kg/d). Mice treated with MCC950 and RVS showed improved cardiac contractile function and morphological changes, diminished fibrosis and microinfarct size, and reduced serum lactate dehydrogenase (LDH) level. Mechanistically, RVS decreased the expression of NLRP3, caspase-1, interleukin-1ß, and Gasdermin D N-terminal domains. Proteomics analysis revealed that RVS restored the energy metabolism and oxidative phosphorylation in CME. Furthermore, reduced reactive oxygen species (ROS) level and alleviated mitochondrial damage were observed in RVS-treated mice. In vitro study, RVS inhibited the activation of NLRP3 inflammasome induced by tumor necrosis factor α plus hypoxia in H9c2 cells. Meanwhile, the pyroptosis was also suppressed by RVS, indicated by the increased cell viability, decreased LDH and propidium iodide uptake in H9c2 cells. RVS also reduced the level of mitochondrial ROS generation in vitro. Our results indicate the NLRP3 inflammasome-dependent cardiac pyroptosis plays an important role in CME-induced cardiac injury and its inhibitor exerts cardioprotective effect following CME. We also uncover the anti-pyroptosis role of RVS in CME, which is associated with regulating mitochondrial ROS.

Nur77 deficiency exacerbates cardiac fibrosis after myocardial infarction by promoting endothelial-to-mesenchymal transition.

Cardiac fibrosis is a reparative process after myocardial infarction (MI), which leads to cardiac remodeling and finally heart failure. Endothelial-to-mesenchymal transition (EndMT) is induced after MI and contributes to cardiac fibrosis after MI. Orphan nuclear receptor Nur77 is a key regulator of inflammation, angiogenesis, proliferation, and apoptosis in vascular endothelial cells. Here, we investigated the role of orphan nuclear receptor Nur77 in EndMT and cardiac fibrosis after MI. Cardiac fibrosis was induced through MI by ligation of the left anterior descending coronary artery. We demonstrated that Nur77 knockout aggravated cardiac dysfunction and cardiac fibrosis 30 days after MI. Moreover, Nur77 deficiency resulted in enhanced EndMT as shown by increased expression of FSP-1, SM22α, Snail, and decreased expression of PECAM-1 and eNOS compared with wild-type mice after MI. Then, we found overexpression Nur77 in human coronary artery endothelial cells significantly inhibited interleukin 1ß and transforming growth factor ß2-induced EndMT, as shown by a reduced transition to a fibroblast-like phenotype and preserved angiogenesis potential. Mechanistically, we demonstrated that Nur77 downregulated EndMT by inhibiting the nuclear factor-κB-dependent pathway. In conclusion, Nur77 is involved in cardiac fibrosis by inhibiting EndMT and may be a promising target for therapy of cardiac fibrosis after MI.

Poor cardiovascular health status among Chinese women.

BACKGROUND: Systematic investigation and analysis of cardiovascular health status (CVHS) of Chinese women is rare. This study aimed to assess CVHS and atherosclerotic cardiovascular disease (ASCVD) burden in the Chinese women physicians (CWP) and community-based non-physician cohort (NPC). METHODS: In this prospective, multicenter, observational study, CVHS using the American Heart Association (AHA) defined 7 metrics (such as smoking and fasting glucose) and ASCVD risk factors including hypertension, hyperlipidemia and type-2 diabetes were evaluated in CWP compared with NPC. RESULTS: Of 5832 CWP with a mean age of 44 ± 7 years, only 1.2% achieved the ideal CVHS and 90.1% showed at least 1 of the 7 AHA CVHS metrics at a poor level. Total CVHS score was significantly decreased and ASCVD risk burden was increased in postmenopausal subjects in CWP although ideal CVHS was not significantly influenced by menopause. Compared to 2596 NPC, fewer CWP had ≥ 2 risk factors (8% vs. 27%, P < 0.001); CWP scored significantly higher on healthy factors, a composite of total cholesterol, blood pressure, fasting glucose (P < 0.001), but, poorly on healthy behaviors (P < 0.001), specifically in the physical activity component; CWP also showed significantly higher levels of awareness and rates of treatment for hypertension and hyperlipidemia, but, not for type-2 diabetes. CONCLUSION: Chinese women's cardiovascular health is far from ideal and risk intervention is sub-optimal. Women physicians had lower ASCVD burden, scored higher in healthy factors, but, took part in less physical activity than the non-physician cohort. These results call for population-specific early and improved risk intervention.

Ticagrelor Pharmacokinetics and Pharmacodynamics in Chinese Patients with STEMI and NSTEMI Without Opioid Administration.

INTRODUCTION: The pharmacodynamics (PD) and pharmacokinetics (PK) study of ticagrelor loading dose (LD) in Chinese patients with acute coronary syndrome (ACS) without opioid administration has never been investigated. Therefore, the aim of this study was to evaluate the antiplatelet effects and the PK parameters of ticagrelor in Chinese patients with ACS without opioid administration. METHODS: A sample size of 30 eligible patients with ACS were enrolled in this study. Blood samples were obtained predose and 1, 2, 4, 8, and 12 h after 180 mg LD of ticagrelor. P2Y12 reactivity units (PRU) and plasma concentrations of ticagrelor and its two metabolites were measured. RESULTS: In total, 15 patients were admitted to ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI) groups, respectively. For patients with NSTEMI, PRU declined significantly during the first 4 h and maintained a relatively stable antiplatelet effect from 4 to 12 h after LD. A similar trend was found in the STEMI group without significant differences of PRU in each designed time compared with patients with NSTEMI (P > 0.05). Tmax of metabolite AR-C124910XX was 4 h after LD for both groups. There were no significant differences for drug concentration, Cmax, or AUC of ticagrelor and AR-C124910XX between patients with STEMI and NSTEMI (P > 0.05). CONCLUSIONS: For Chinese patients with ACS, at least 4 h was needed to achieve an adequate antiplatelet effect for ticagrelor LD. There were no differences in PK or PD between Chinese patients with STEMI and NSTEMI. CLINICAL TRIAL REGISTRATION: ChiCTR1800014764.