Association between periprocedural myocardial injury and neointimal characteristics in patients with in-stent restenosis: an optical coherence tomography study.

Background: The relationship between neointimal characteristics of in-stent restenosis (ISR) and periprocedural myocardial injury (PMI) remains unclear. Therefore, this study aimed to investigate the relationship between PMI and neointimal characteristics of ISR by using optical coherence tomography (OCT). Methods: This was a retrospective study. We enrolled 140 patients diagnosed with ISR with normal baseline high-sensitivity troponin T (hs-cTnT) levels who underwent OCT and subsequent revascularization by means of drug-coated balloon (DCB) or drug-eluting stent (DES) between October 2018 and October 2022 in the Affiliated Hospital of Zunyi Medical University. Based on the 4th universal definition of myocardial infarction, patients whose hs-cTnT were increased five times above the upper reference limit (URL) after percutaneous coronary interventions (PCI) were deemed to PMI. The patients were subdivided into PMI (n=53) and non-PMI (n=87) groups. In the univariable analysis, variables in the baselines, angiography characteristics and OCT findings were analyzed with binary logistic regression. A P value of <0.2 was included in the multivariable model. Multivariable logistic regression analysis was used to identify the independent predictors of PMI. Results: The prevalence of intra-intimal microvessels in patients with PMI was higher than in those without PMI (58.5% vs. 32.2%, P=0.003). The ratio of intra-stent plaque rupture (PR) was also higher in patients with PMI (60.4% vs. 40.2%, P=0.021). Multivariable logistic regression analysis showed that intra-intimal microvessels [odds ratio (OR): 3.193, 95% confidence interval (CI): 1.280-7.966; P=0.013] and intra-stent PR (OR: 2.124, 95% CI: 1.153-4.732; P=0.035) were independently associated with PMI. Conclusions: Intra-intimal microvessels and intra-stent PR were independently associated with PMI. Accurate identification and recognition of intra-intimal microvessels and intra-stent PR may be helpful in preventing PMI.

Association Between Serum Uric Acid Levels and Neoatherosclerosis.

Neoatherosclerosis is a major cause of stent failure after percutaneous coronary intervention. Metabolism such as hyperuricemia is associated with in-stent restenosis (ISR). However, the association between serum uric acid (sUA) levels and in-stent neoatherosclerosis (ISNA) has never been validated.A total of 216 patients with 220 ISR lesions who had undergone optical coherence tomography (OCT) of culprit stents were included in this study. According to their sUA levels, eligible patients were divided into two groups [normal-sUA group: sUA < 7 mg/dL, n = 126, and high-sUA group: sUA ≥ 7 mg/dL, n = 90]. OCT findings were analyzed and compared between the normal- and high-sUA groups.The incidence of ISNA (63.0% versus 43.0%, P = 0.004) was significantly higher in the high-sUA group than in the normal-sUA group. Lipid plaques (66.3% versus 43.0%, P < 0.001) and thin-cap fibroatheroma (38.0% versus 18.0%, P = 0.001) were observed more frequently in the restenotic tissue structure in patients in the high-sUA group than in those in the normal-sUA group. Meanwhile, univariate (OR: 1.208, 95% CI: 1.037-1.407; P = 0.015) and multivariate (OR: 1.254, 95% CI: 1.048-1.501; P = 0.013) logistic regression analyses indicated that sUA levels were an independent risk factor for ISNA after adjusting for relevant risk factors.The high-sUA levels were an independent risk factor for the occurrence of neoatherosclerosis in patients with ISR via OCT.

Hypoxia Induces M2 Macrophages to Express VSIG4 and Mediate Cardiac Fibrosis After Myocardial Infarction.

M2 macrophage-mediated tissue repair plays an important role in acute myocardial infarction (AMI). Additionally, VSIG4, which is mainly expressed on tissue-resident and M2 macrophages, is crucial for the regulation of immune homeostasis; however, its effects on AMI remain unknown. In this study, we aimed to investigate the functional significance of VSIG4 in AMI using VSIG4 knockout and adoptive bone marrow transfer chimeric models. We also determined the function of cardiac fibroblasts (CFs) through gain- or loss-of-function experiments. We showed that VSIG4 promotes scar formation and orchestrates the myocardial inflammatory response after AMI, while also promoting TGF-ß1 and IL-10. Moreover, we revealed that hypoxia promotes VSIG4 expression in cultured bone marrow M2 macrophages, ultimately leading to the conversion of CFs to myofibroblasts. Our results reveal a crucial role for VSIG4 in the process of AMI in mice and provide a potential immunomodulatory therapeutic avenue for fibrosis repair after AMI.

Exosomal MiR-29a in Cardiomyocytes Induced by Angiotensin II Regulates Cardiac Microvascular Endothelial Cell Proliferation, Migration and Angiogenesis by Targeting VEGFA.

BACKGROUND: Exosomes released from cardiomyocytes (CMs) potentially play an important role in angiogenesis through microRNA (miR) delivery. Studies have reported an important role for miR-29a in regulating angiogenesis and pathological myocardial hypertrophy. However, whether CMderived exosomal miR-29a is involved in regulating cardiac microvascular endothelial cell (CMEC) homeostasis during myocardial hypertrophy has not been determined. METHODS: Angiotensin II (Ang II) was used to induce CM hypertrophy, and ultracentrifugation was then used to extract exosomes from a CM-conditioned medium. CMECs were cocultured with a conditioned medium in the presence or absence of exosomes derived from CMs (Nor-exos) or exosomes derived from angiotensin II-induced CMs (Ang II-exos). Moreover, a rescue experiment was performed using CMs or CMECs infected with miR-29a mimics or inhibitors. Tube formation assays, Transwell assays, and 5-ethynyl-20-deoxyuridine (EdU) assays were then performed to determine the changes in CMECs treated with exosomes. The miR-29a expression was measured by qRT-PCR, and Western blotting and flow cytometry assays were performed to evaluate the proliferation of CMECs. RESULTS: The results showed that Ang II-induced exosomal miR-29a inhibited the angiogenic ability, migratory function, and proliferation of CMECs. Subsequently, the downstream target gene of miR- 29a, namely, vascular endothelial growth factor (VEGFA), was detected by qRT-PCR and Western blotting, and the results verified that miR-29a targeted the inhibition of the VEGFA expression to subsequently inhibit the angiogenic ability of CMECs. CONCLUSION: Our results suggest that exosomes derived from Ang II-induced CMs are involved in regulating CMCE proliferation, migration, and angiogenesis by targeting VEGFA through the transfer of miR-29a to CMECs.

Development of a machine learning model to predict the risk of late cardiogenic shock in patients with ST-segment elevation myocardial infarction.

BACKGROUND: The in-hospital mortality of patients with ST-segment elevation myocardial infarction (STEMI) increases to more than 50% following a cardiogenic shock (CS) event. This study highlights the need to consider the risk of delayed calculation in developing in-hospital CS risk models. This report compared the performances of multiple machine learning models and established a late-CS risk nomogram for STEMI patients. METHODS: This study used logistic regression (LR) models, least absolute shrinkage and selection operator (LASSO), support vector regression (SVM), and tree-based ensemble machine learning models [light gradient boosting machine (LightGBM) and extreme gradient boosting (XGBoost)] to predict CS risk in STEMI patients. The models were developed based on 1,598 and 684 STEMI patients in the training and test datasets, respectively. The models were compared based on accuracy, the area under the curve (AUC), recall, precision, and Gini score, and the optimal model was used to develop a late CS risk nomogram. Discrimination, calibration, and the clinical usefulness of the predictive model were assessed using C-index, calibration plotd, and decision curve analyses. RESULTS: A total of 2282 STEMI patients recruited between January 1, 2016 and May 31, 2020, were included in the complete dataset. The linear models built using LASSO and LR showed the highest overall predictive power, with an average accuracy over 0.93 and an AUC above 0.82. With a C-index of 0.811 [95% confidence interval (CI): 0.769-0.853], the LASSO nomogram showed good differentiation and proper calibration. In internal validation tests, a high C-index value of 0.821 was achieved. Decision curve analysis (DCA) and clinical impact curve (CIC) examination showed that compared with the previous score-based models, the LASSO model showed superior clinical relevance. CONCLUSIONS: In this study, five machine learning methods were developed for in-hospital CS prediction. The LASSO model showed the best predictive performance. This nomogram could provide an accurate prognostic prediction for CS risk in patients with STEMI.

CircUbe3a from M2 macrophage-derived small extracellular vesicles mediates myocardial fibrosis after acute myocardial infarction.

Objective: This study aimed to explore the role of circular RNAs (circRNAs) in M2 macrophage (M2M)-derived small extracellular vesicles (SEVs) in myocardial fibrosis development. Methods: The regulatory role of M2M-derived extracellular vesicles (EVs) was evaluated in a mouse model of acute myocardial infarction. Immunofluorescence, quantitative real-time PCR (RT-qPCR), nanoparticle tracking analysis, Western blot analysis and electron microscopy were used to identify macrophages, large extracellular vesicles (LEVs) and SEVs. The circRNA expression profiles of M0 macrophages (M0Ms) and M2Ms were determined by microarray analysis. Bioinformatic analysis, cell coculture and cell proliferation assays were performed to investigate the expression, function, and regulatory mechanisms of circUbe3a in vitro. qPCR, RNA immunoprecipitation (RIP), dual-luciferase reporter assays, RNA fluorescence in situ hybridization (RNA-FISH), Western blot analysis and a series of rescue experiments were used to verify the correlation among circUbe3a, miR-138-5p and RhoC. Results: CircUbe3a from M2M-derived SEVs triggered functional changes in cardiac fibroblasts (CFs). CircUbe3a was synthesized and loaded into SEVs during increased M2M infiltration after myocardial infarction. The fusion of the released SEVs with the plasma membrane likely caused the release of circUbe3a into the cytosol of CFs. Silencing or overexpressing circUbe3a altered CF proliferation, migration, and phenotypic transformation in vitro. We confirmed that circUbe3a plays a crucial role in enhancing functional changes in CFs by sponging miR-138-5p and then translationally repressing RhoC in vitro. In vivo, the addition of M2M-derived SEVs or overexpression of circUbe3a significantly exacerbated myocardial fibrosis after acute myocardial infarction, and these effects were partially abolished by circUbe3a-specific shRNA. Conclusions: Our findings suggest that M2M-derived circUbe3a-containing SEVs promote the proliferation, migration, and phenotypic transformation of CFs by directly targeting the miR-138-5p/RhoC axis, which may also exacerbate myocardial fibrosis after acute myocardial infarction.

CircHIPK3 regulates the autophagy and apoptosis of hypoxia/reoxygenation-stimulated cardiomyocytes via the miR-20b-5p/ATG7 axis.

Autophagy and apoptosis are involved in myocardial ischemia/reperfusion (I/R) injury. Research indicates that circular RNA HIPK3 (circHIPK3) is crucial to cell autophagy and apoptosis in various cancer types. However, the role of circHIPK3 in the regulation of cardiomyocyte autophagy and apoptosis during I/R remains unknown. Our study aimed to examine the regulatory effect of circHIPK3 during myocardial I/R and investigate its mechanism in cardiomyocyte autophagy and apoptosis. Methods and results. The expression of circHIPK3 was upregulated during myocardial I/R injury and hypoxia/reoxygenation (H/R) injury of cardiomyocytes. To study the potential role of circHIPK3 in myocardial H/R injury, we performed gain-of-function and loss-of-function analyses of circHIPK3 in cardiomyocytes. Overexpression of circHIPK3 significantly promoted H/R-induced cardiomyocyte autophagy and cell injury (increased intracellular reactive oxygen species (ROS) and apoptosis) compared to those in the control group, while silencing of circHIPK3 showed the opposite effect. Further research found that circHIPK3 acted as an endogenous miR-20b-5p sponge to sequester and inhibit miR-20b-5p activity, resulting in increased ATG7 expression. In addition, miR-20b-5p inhibitors reversed the decrease in ATG7 induced by silencing circHIPK3. Conclusions. CircHIPK3 can accelerate cardiomyocyte autophagy and apoptosis during myocardial I/R injury through the miR-20b-5p/ATG7 axis. These data suggest that circHIPK3 may serve as a potential therapeutic target for I/R.

Effect of Telemedicine on Quality of Care in Patients with Coexisting Hypertension and Diabetes: A Systematic Review and Meta-Analysis.

Background: With the development of technology and the need for individualized and continuous support for patients with chronic conditions, telemedicine has been widely used. Despite the potential benefits of telemedicine, little is known about its effect on the quality of care (QoC) in people with hypertension and comorbid diabetes, who face more challenges in disease management than those with hypertension or diabetes alone. This study aimed to examine the effect of telemedicine on QoC for patients with hypertension and comorbid diabetes by synthesizing findings from clinical trials. Methods: This systematic review and meta-analysis were developed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four major electronic databases from inception to March 2020 were searched. Studies were screened using predetermined criteria. Data were extracted and tabulated into tables. The primary outcomes were QoC indicators, including outcomes (e.g., blood pressure [BP] and glycemic control), process, and experience of care. Quantitative data were pooled and presented in forest plots. Qualitative narratives were also used. Results: Five studies from four clinical trials were included in this review, with intervention durations ranging from 3 to 6 months. Telemedicine significantly decreased BP by 10.4/4.8 mm/Hg, but its effect on glycemic control was inconsistent. Telemedicine also improved experience of care (e.g., patient perception and engagement). Various indicators for process of care were assessed, including medication adherence, BP monitoring, and self-efficacy, with mixed findings. Conclusions: Telemedicine has great potential to improve the QoC, particularly outcomes of care, for patients with hypertension and comorbid diabetes. Health care professionals may consider using available telemedicine to facilitate communication and interaction with their patients, thereby helping them with disease management. Long-term, large-scale studies are needed to test the generalizability and sustainability of the telemedicine programs.

Exosomal CircHIPK3 Released from Hypoxia-Induced Cardiomyocytes Regulates Cardiac Angiogenesis after Myocardial Infarction.

Exosomes play critical roles in mediating cell-to-cell communication by delivering noncoding RNAs (including miRNAs, lncRNAs, and circRNAs). Our previous study found that cardiomyocytes (CMs) subjected to hypoxia released circHIPK3-rich exosomes to regulate oxidative stress damage in cardiac endothelial cells. However, the role of exosomes in regulating angiogenesis after myocardial infarction (MI) remains unknown. The aim of this study was to establish the effects of exosomes derived from hypoxia-induced CMs on the migration and angiogenic tube formation of cardiac endothelial cells. Here, we reported that hypoxic exosomes (HPC-exos) can effectively reduce the infarct area and promote angiogenesis in the border surrounding the infarcted area. HPC-exos can also promote cardiac endothelial cell migration, proliferation, and tube formation in vitro. However, these effects were weakened after silencing circHIPK3 in hypoxia-induced CMs. We further verified that silencing and overexpressing circHIPK3 changed cardiac endothelial cell proliferation, migration, and tube formation in vitro by regulating the miR-29a expression. In addition, exosomal circHIPK3 derived from hypoxia-induced CMs first led to increased VEGFA expression by inhibiting miR-29a activity and then promoted accelerated cell cycle progression and proliferation in cardiac endothelial cells. Overexpression of miR-29a mimicked the effect of silencing circHIPK3 on cardiac endothelial cell activity in vitro. Thus, our study provides a novel mechanism by which exosomal circRNAs are involved in the communication between CMs and cardiac endothelial cells.

[Expression of SDF-1/CXCR4 in acute infarct myocardium after implantation of bone marrow mesenchymal stem cells in rats].

OBJECTIVE: To explore the role of stromal cell derived factor-1 (SDF-1)/CXCR4 axis in acute infarct myocardium after an implantation of bone marrow mesenchymal stem cells (MSCs) in rats. METHODS: The animals were anesthetized by an intraperitoneal injection of pentobarbital sodium. Left anterior thoracotomy through 3/4 intercostals region was performed and then left anterior descending coronary arteries were ligated for modeling acute myocardial infarction. The MSCs were injected into the area of acute infarct myocardium after a 10-minute ligation of left anterior descending coronary artery. The different concentration and expression of SDF-1/CXCR4 in the area of acute myocardial infarction and left ventricular function were analyzed. RESULTS: At day 28 post-transplantation, the vascular density in MSCs implant group were significantly higher than that in control group (P<0.05). And left ventricular function in MSCs implant group improved significantly than that in control group too (P<0.05). At the same time, the expressions of SDF-1 and CXCR4 in topical injection sites of infarct myocardium were significantly higher than those in control group (P<0.05). In MSCs implant group, the level of SDF-1/CXCR4 peaked at Day 1 post-transplantation and then it declined. CONCLUSIONS: After the implantation of MSCs into acute infarct myocardium, there is vascular regeneration and the level of SDF-1/CXCR4 increases so that left ventricular function improves. And the mechanism may be due to an up-regulation of SDF-1/CXCR4 axis.

[Establishing an animal model for carotid artery stenosis in rabbits].

OBJECTIVE: To establish an animal model for carotid artery stenosis in rabbits. METHODS: Forty New Zealand White rabbits were randomly divided into two groups, for 4-week and 8-week experiment, respectively. All rabbits were fed with a diet with 1.5% cholesterol for one week before the experiment started. The right common carotid arteries (RCCA) of the rabbits were then injured with nitrogen gas (100 mL/min x 5 min), with the left common carotid arteries (LCCA) serving as a control (self control). An additional 5 rabbits were fed with high cholesterol diet only without exposure to nitrogen gas (control group). Angiography and pathology tests were performed to evaluate the stenosis of carotid arteries. RESULTS: Four weeks after exposure to nitrogen gas, early atheromatosis appeared, with lesions showing fatty streak and fibrous plaque, and thickened focal arterial walls. The lumens showed light-stenosis. The angiography showed 20%-30% artery stenosis. Eight weeks after exposure to nitrogen gas, the lesions proceeded to mature fibrous plaque or atheromatous plaque stages, with entire arterial walls thickened and remarkable lumens stenosis. The angiography showed 60% -80% artery stenosis, and two arteries were totally occluded. No artherosclerosis and stenosis were seen in the self control arteries and control groups. CONCLUSION: The animal model for carotid artery stenosis can be effectively established in rabbits with nitrogen gas injury along with high cholesterol-feeding.

[rhG-CSF promotes re-endothelialization and attenuates intima hyperplasia in carotid artery of rabbits post balloon catheter injury].

OBJECTIVE: To investigate the effect of rhG-CSF on mobilizing bone marrow-MSCs, re-endothelialization and intima hyperplasia in carotid artery of rabbits post balloon catheter injury. METHODS: Rabbits were treated with rhG-CSF (25 microg/kg, twice daily, i.p, n = 35) or saline (n = 32) for 5 days, then, carotid arteries of rabbits were injured by balloon catheter. The number of peripheral MSCs was detected with FACS. The morphology of injured artery was examined with hematoxylin and eosin stain, PCNA was determined with immunohistochemistry. RESULTS: (1) Number of peripheral MSCs was similar at baseline and significantly increased at 24 hours and peaked at 7 days and remained increased till 14 days post rhG-CSF. (2) Significant endothelial cell deletion was evidenced in the control group, while scatter endothelial cells was observed in the rhG-CSF group at 1 week post injury. Two weeks after injury, new endothelial area was significantly higher in rhG-CSF group compared to control group. At 4 weeks post injury, endothelial connection was evidenced and regularly displayed in rhG-CSF treated group. (3) PCNA-positive cells in the tunica intima were significantly lower in rhG-CSF treated rabbits at 7, 14 and 28 days compared that in control rabbits (all P < 0.01). CONCLUSION: rhG-CSF could mobilize the bone marrow-MSCs and promote re-endothelialization and attenuate intima hyperplasia post balloon catheter injury in carotid arteries of rabbits.