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.

Morphological characteristics of in-stent restenosis with different degrees of area stenosis: an optical coherence tomography study.

The morphological characteristics of in-stent restenosis (ISR) in relation to varying degrees of area stenosis have not been comprehensively examined. This study aimed to explore the tissue characteristics of patients experiencing ISR with different degrees of area stenosis through the utilization of optical coherence tomography (OCT). In total, 230 patients with ISR who underwent OCT were divided into the following three groups: area stenosis (AS) < 70% (n = 26); 70-80% (n = 119) and AS ≥ 80% (n = 85). Among the 230 patients, the clinical presentation as stable angina was 61.5% in AS < 70%, followed by 47.2% in 70% < AS ≤ 80%, and 31.8% in AS ≥ 80% (P = 0.010). The OCT findings showed that heterogeneous neointima, ISNA, LRP, neointima rupture, TCFA-like pattern, macrophage infiltration, red and white thrombus was more common with AS increased. Ordinal logistic regression analysis showed that higher AS was associated with previous dyslipidemia (odds ratio [OR], 4.754; 95% confidence interval [CI], 1.419-15.927, P = 0.011), neointimal rupture (OR: 3.640; 95% CI, 1.169-11.325, P = 0.026), red thrombus (OR: 4.482; 95% CI, 1.269-15.816, P = 0.020) and white thrombus (OR: 5.259; 95% CI, 1.660-16.659, P = 0.005). Patients with higher degrees of area stenosis in the context of ISR exhibited a greater number of discernible morphological characteristics as identified through OCT analysis. Furthermore, previous dyslipidemia, neointimal rupture, white thrombus and red thrombus were highly associated with and the progression of ISR lesions.

Association of the monocytes to high-density lipoprotein cholesterol ratio with in-stent neoatherosclerosis and plaque vulnerability: An optical coherence tomography study.

BACKGROUND: Monocyte-to-high-density lipoprotein cholesterol ratio (MHR) is an independent predictor of atherosclerosis and in-stent restenosis (ISR). However, the association between MHR and the incidence of in-stent neoatherosclerosis (ISNA) remains to be validated. METHODS: This study included 216 patients with acute coronary syndrome who had 220 ISR lesions and had undergone optical coherence tomography (OCT). All eligible patients were divided into three groups according to their MHR tertile level. OCT characteristics were comparatively analyzed between groups of different MHR levels, and univariate and multivariate logistic regression analyses were constructed to assess correlations between MHR level and ISNA as well as in-stent thin-cap fibroatheroma (TCFA). A receiver operating characteristic curve was used to determine the optimal MHR thresholds for predicting ISNA and in-stent TCFA. RESULTS: The incidence of ISNA (70.3% vs. 61.1% vs. 20.3%, P < 0.001) and in-stent TCFA (40.5% vs. 31.9% vs. 6.8%, P < 0.001) was the highest in the third tertile, followed by the second and first tertiles, respectively. Multivariate analysis revealed that MHR was independently associated with ISNA (odds ratio [OR], 7.212; 95% confidence interval [CI], 1.287-40.416; P = 0.025) and in-stent TCFA (OR, 5.610; 95% CI, 1.743-18.051; P = 0.004) after adjusting for other clinical factors. The area under the curve was 0.745 (95% CI, 0.678-0.811; P < 0.001) for the prediction of ISNA and 0.718 (95% CI, 0.637-0.778; P < 0.001) for the prediction of in-stent TCFA. CONCLUSION: MHR levels are an independent risk factor for ISNA.

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.

Serum lipidomics reveals phosphatidylethanolamine and phosphatidylcholine disorders in patients with myocardial infarction and post-myocardial infarction-heart failure.

BACKGROUND: Myocardial infarction (MI) and post-MI-heart failure (pMIHF) are a major cause of death worldwide, however, the underlying mechanisms of pMIHF from MI are not well understood. This study sought to characterize early lipid biomarkers for the development of pMIHF disease. METHODS: Serum samples from 18 MI and 24 pMIHF patients were collected from the Affiliated Hospital of Zunyi Medical University and analyzed using lipidomics with Ultra High Performance Liquid Chromatography and Q-Exactive High Resolution Mass Spectrometer. The serum samples were tested by the official partial least squares discriminant analysis (OPLS-DA) to find the differential expression of metabolites between the two groups. Furthermore, the metabolic biomarkers of pMIHF were screened using the subject operating characteristic (ROC) curve and correlation analysis. RESULTS: The average age of the 18 MI and 24 pMIHF participants was 57.83 ± 9.28 and 64.38 ± 10.89 years, respectively. The B-type natriuretic peptide (BNP) level was 328.5 ± 299.842 and 3535.96 ± 3025 pg/mL, total cholesterol(TC) was 5.59 ± 1.51 and 4.69 ± 1.13 mmol/L, and blood urea nitrogen (BUN) was 5.24 ± 2.15 and 7.20 ± 3.49 mmol/L, respectively. In addition, 88 lipids, including 76 (86.36%) down-regulated lipids, were identified between the patients with MI and pMIHF. ROC analysis showed that phosphatidylethanolamine (PE) (12:1e_22:0) (area under the curve [AUC] = 0.9306) and phosphatidylcholine (PC) (22:4_14:1) (AUC = 0.8380) could be potential biomarkers for the development of pMIHF. Correlation analysis showed that PE (12:1e_22:0) was inversely correlated with BNP and BUN, but positively correlated with TC. In contrast, PC (22:4_14:1) was positively associated with both BNP and BUN, and was negatively associated with TC. CONCLUSIONS: Several lipid biomarkers were identified that could potentially be used to predict and diagnose patients with pMIHF. PE (12:1e_22:0) and PC (22:4_14:1) could sufficiently differentiate between patients with MI and pMIHF.

CircERBB2IP promotes post-infarction revascularization via the miR-145a-5p/Smad5 axis.

Myocardial infarction is one of the leading diseases causing death and disability worldwide, and the revascularization of damaged tissues is essential for myocardial-injury repair. Circular RNAs (circRNAs) are widely involved in physiological and pathological processes in various systems throughout the body, and the role of circRNAs in cardiovascular disease is gaining attention. In this study, we determined that circERBB2IP is highly expressed in the hearts of newborn mice. Silencing or overexpression of circERBB2IP inhibited and promoted angiogenesis in vivo and in vitro, respectively. Mechanistically, the transcription factor GATA4 promotes the production of circERBB2IP. Furthermore, circERBB2IP functioned as an endogenous miR-145a-5p sponge and was able to sequester and repress miR-145a-5p activity, which led to an increased expression level of Smad5. In summary, circERBB2IP can promote angiogenesis after myocardial infarction through the miR-145a-5p/Smad5 axis. These data suggest that circERBB2IP may be a potential therapeutic target for the treatment of 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.

Gene polymorphism associated with angiotensinogen (M235T), endothelial lipase (584C/T) and susceptibility to coronary artery disease: a meta-analysis.

OBJECTIVE: To explore the association between the variant M235T locus of angiotensinogen (AGT) gene, 584C/T locus of Endothelial lipase (EL) gene, and coronary artery disease (CAD) by meta-analysis. METHODS: The case-control studies on the association between AGT/EL gene polymorphism and CAD were collected through searching PubMed, Excerpta Medica Database (EMBASE), Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang databases up to 1 March 2020. Stata 15.0 software was used for analysis. RESULTS: A total of 29 articles met the inclusion criteria. After analyzing, it was found that the M235T polymorphism of AGT gene was associated with the occurrence of CAD. In the allele model (T vs. M), OR = 1.38 (P

Exosomal circHIPK3 Released from Hypoxia-Pretreated Cardiomyocytes Regulates Oxidative Damage in Cardiac Microvascular Endothelial Cells via the miR-29a/IGF-1 Pathway.

BACKGROUND/AIMS: Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that regulate gene expression in eukaryotes. Recently, exosomes from cardiomyocytes (CMs) have been found to facilitate cell proliferation and survival by transporting various bioactive molecules, including circRNA. However, the functions of exosomal circRNAs are not clear. The present research is aimed at determining whether circHIPK3 released from hypoxia-pretreated CMs is transferred into cardiac microvascular endothelial cells (CMVECs) by exosomes and becomes functionally active in the CMVECs under oxidative stress conditions. METHODS: Quantitative polymerase chain reactions were conducted to detect the expression pattern of circHIPK3 in CMVECs under oxidative stress. Annexin V-FITC/propidium iodide (PI) staining assays, TUNEL assays, ROS assays, and Western blot analysis were conducted to detect the role of exosomal circHIPK3 in CMVEC function in vitro. Luciferase activity assays and RNA immunoprecipitation studies were conducted in vitro to reveal the mechanism of circHIPK3-mediated CMVEC function. RESULTS: circHIPK3 expression was significantly upregulated in hypoxic exosomes (HPC-exos) compared with normoxic exosomes (Nor-exos). Moreover, HPC-exos induced stronger antioxidant effects than Nor-exos. The silencing or overexpression of circHIPK3 changed CMVEC survival under oxidative conditions in vitro. Furthermore, circHIPK3 silencing in HPC-exos abrogated the protective effects of HPC-exos in CMVECs, as shown by increased levels of apoptosis, ROS, MDA, and proapoptotic proteins. circHIPK3 acted as an endogenous miR-29a sponge to sequester and inhibit miR-29a activity, which led to increased IGF-1 expression. The ectopic expression of miR-29a mimicked the effect of circHIPK3 silencing in CMVECs in vitro. CONCLUSIONS: circHIPK3 in HPC-exos plays a role in CMVECs under oxidative conditions through miR-29a-mediated IGF-1 expression, leading to a decrease in oxidative stress-induced CMVECs dysfunction. These data suggest that the exosomal circRNA in CMs is a potential target to control CMVECs dysfunction under oxidative conditions.

Exosomes Derived from miR-214-Enriched Bone Marrow-Derived Mesenchymal Stem Cells Regulate Oxidative Damage in Cardiac Stem Cells by Targeting CaMKII.

Cardiac stem cells (CSCs) have emerged as one of the most promising stem cells for cardiac protection. Recently, exosomes from bone marrow-derived mesenchymal stem cells (BMSCs) have been found to facilitate cell proliferation and survival by transporting various bioactive molecules, including microRNAs (miRs). In this study, we found that BMSC-derived exosomes (BMSC-exos) significantly decreased apoptosis rates and reactive oxygen species (ROS) production in CSCs after oxidative stress injury. Moreover, a stronger effect was induced by exosomes collected from BMSCs cultured under hypoxic conditions (Hypoxic-exos) than those collected from BMSCs cultured under normal conditions (Nor-exos). We also observed greater miR-214 enrichment in Hypoxic-exos than in Nor-exos. In addition, a miR-214 inhibitor or mimics added to modulate miR-214 levels in BMSC-exos revealed that exosomes from miR-214-depleted BMSCs partially reversed the effects of hypoxia-induced exosomes on oxidative damage in CSCs. These data further confirmed that miR-214 is the main effector molecule in BMSC-exos that protects CSCs from oxidative damage. miR-214 mimic and inhibitor transfection assays verified that CaMKII is a target gene of miR-214 in CSCs, with exosome-pretreated CSCs exhibiting increased miR-214 levels but decreased CaMKII levels. Therefore, the miR-214/CaMKII axis regulates oxidative stress-related injury in CSCs, such as apoptosis, calcium homeostasis disequilibrium, and excessive ROS accumulation. Collectively, these findings suggest that BMSCs release miR-214-containing exosomes to suppress oxidative stress injury in CSCs through CaMKII silencing.