Translational large animal model of coronary microvascular embolism: characterization by serial cardiac magnetic resonance and histopathology.

This study aimed to construct a large animal model of coronary microvascular embolism, and investigate whether it could mimic the clinical imaging phenotypes of myocardial hypoperfusion in patients with ST-segment elevation myocardial infarction (STEMI). Nine minipigs underwent percutaneous coronary embolization with microspheres, followed by cardiac magnetic resonance (CMR) on week 1, 2 and 4 post operation. Microvascular obstruction (MVO) was defined as the isolated hypointense core within the enhanced area on late gadolinium enhancement images, which evolved during a 4-week follow-up. Fibrotic fraction of the segments was measured by Masson trichrome staining using a panoramic analysis software. Iron deposit and macrophage infiltration were quantified based on Perl's blue and anti-CD163 staining, respectively. Seven out of 9 (77.8%) minipigs survived and completed all of the imaging follow-ups. Four out of 7 (57.1%) minipigs were identified as transmural infarct with MVO. The systolic wall thickening (SWT) of MVO zone was similar to that of infarct zone (P = 0.762). Histopathology revealed transmural deposition of collagen, with microvessels obstructed by microspheres. The fibrotic fraction of infarct with MVO segments was similar to that of infarct without MVO segments (P = 0.954). The fraction of iron deposit in infarct with MVO segments was higher than that of infarct without MVO segments (P < 0.05), but the fraction of macrophage infiltration between these two segments did not show statistical difference (P = 0.723). Large animal model of coronary microvascular embolism could mimic most clinical imaging phenotypes of myocardial hypoperfusion in patients with STEMI, demonstrated by serial CMR and histopathology.

Prognostic Factors and Survival of Chinese Patients with Cardiac Amyloidosis.

Purpose: To identify the survival and prognostic factors for cardiac amyloidosis (CA) in Chinese patients. Methods: This was a prospective cohort study of 72 patients diagnosed with CA and admitted to the PLA General Hospital between November 2017 and April 2021. Demographic, clinical, laboratory, electrocardiographic, conventional ultrasound, endocardial LS during LV systole (LV ENDO LSsys), and myocardial strain data were recorded. Survival was assessed. All-cause mortality was the endpoint. Follow-up was censored on September 30, 2021. Results: The mean follow-up was 17.1 ± 12.9 months. Among the 72 patients, 39 died, 23 survived, and 10 were lost to follow-up. Mean survival for all patients was 24.7 ± 2.2 months. Mean survival was 32.7 ± 2.4 months among patients with NYHA class II, 26.6 ± 3.4 months for NYHA class III, and 5.8 ± 1.1 months for NYHA class IV. The multivariate Cox proportional hazard regression model showed that NYHA class (HR = 3.42, 95% CI: 1.36-8.65, P = 0.002), log-proBNP level (HR = 1.40, 95% CI: 1.17-5.83, P = 0.03), and ENDO LSsys of the LV basal level (HR = 1.25, 95% CI: 1.05-1.95, P = 0.004) were independent prognostic factors for CA. Conclusion: NYHA class, proBNP level, and ENDO LSsys of the LV basal level were independently associated with the survival of patients with CA.

Deep learning-based measurement of echocardiographic data and its application in the diagnosis of sudden cardiac death.

This study aimed to evaluate the potential of deep learning applied to the measurement of echocardiographic data in patients with sudden cardiac death (SCD). 320 SCD patients who met the inclusion and exclusion criteria underwent clinical evaluation, including age, sex, BMI, hypertension, diabetes, cardiac function classification, and echocardiography. The diagnostic value of deep learning model was observed by dividing the patients into two groups: training group (n=160) and verification group (n=160), as well as two groups of healthy volunteers (n=200 for each group) during the same period. Logistic regression analysis showed that MLVWT, LVEDD, LVEF, LVOT-PG, LAD, E/e' were all risk factors for SCD. Subsequently, a deep learning-based model was trained using the collected images of the training group. The optimal model was selected based on the identification accuracy of the validation group and showed an accuracy of 91.8%, sensitivity of 80.00%, and specificity of 91.90% in the training group. The AUC value of the ROC curve of the model was 0.877 for the training group and 0.995 for the validation groups. This approach demonstrates high diagnostic value and accuracy in predicting SCD, which is clinically important for the early detection and diagnosis of SCD.

Longitudinal real world correlation study of blood pressure and novel features of cerebral magnetic resonance angiography by artificial intelligence analysis on elderly cognitive impairment.

Objective: This study aims to investigate novel clinical risk factors for cognitive impairment (CI) in elderly. Methods: A total of 3221 patients (259 patients with CI and 2,962 subjects without CI) were recruited into this nested case-control study who underwent cerebral magnetic resonance angiography (MRA) from 2007 to 2021. All of the clinical data with MRA imaging were recorded followed by standardization processing blindly. The maximum stenosis score of the posterior circulatory artery, including the basilar artery, and bilateral posterior cerebral artery (PCA), was calculated by the cerebral MRA automatic quantitative analysis method. Logistic regression (LR) analysis was used to evaluate the relationship between risk factors and CI. Four machine learning approaches, including LR, decision tree (DT), random forest (RF), and support vector machine (SVM), employing 5-fold cross-validation were used to establish CI predictive models. Results: After matching with age and gender, 208 CI patients and 208 control subjects were finalized the follow-up (3.46 ± 3.19 years) with mean age at 84.47 ± 6.50 years old. Pulse pressure (PP) in first tertile (<58 mmHg) (OR 0.588, 95% confidence interval (CI): 0.362-0.955) was associated with a decreased risk for CI, and ≥50% stenosis of the left PCA (OR 2.854, 95% CI: 1.387-5.872) was associated with an increased risk for CI after adjusting for body mass index, myocardial infarction, and stroke history. Based on the means of various blood pressure (BP) parameters, the performance of the LR, DT, RF and SVM models accurately predicted CI (AUC 0.740, 0.786, 0.762, and 0.753, respectively) after adding the stenosis score of posterior circulatory artery. Conclusion: Elderly with low pulse differential pressure may have lower risk for cognitive impairment. The hybrid model combined with the stenosis score of posterior circulatory artery, clinical indicators, and the means of various BP parameters can effectively predict the risk of CI in elderly individuals.

Osteopontin targeted theranostic nanoprobes for laser-induced synergistic regression of vulnerable atherosclerotic plaques.

Vulnerable atherosclerotic plaque (VASPs) is the major pathological cause of acute cardiovascular event. Early detection and precise intervention of VASP hold great clinical significance, yet remain a major challenge. Photodynamic therapy (PDT) realizes potent ablation efficacy under precise manipulation of laser irradiation. In this study, we constructed theranostic nanoprobes (NPs), which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging. The NPs were formulated from human serum albumin (HSA) conjugated with a high affinity-peptide targeting osteopontin (OPN) and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine (TPZ). After intravenous injection into atherosclerotic mice, the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery. Under the visible guidance of fluorescence and MR dual-model imaging, the precise near-infrared (NIR) laser irradiation generated massive reactive oxygen species (ROS), which resulted in efficient plaque ablation and amplified hypoxia within VASPs. In response to the elevated hypoxia, the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages. After therapeutic administration of the NPs for 2 weeks, the plaque area and the degree of carotid artery stenosis were markedly reduced. Furthermore, the formulated NPs displayed excellent biocompatibility. In conclusion, the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.

Dual-modality Imaging of Angiogenesis in Unstable Atherosclerotic Plaques with VEGFR2-Targeted Upconversion Nanoprobes in vivo.

AIM: Angiogenesis plays a major role in atherosclerotic plaque development and instability. Our study aims to develop a novel optical and magnetic resonance (MR) dual-modality molecular imaging probe to early detect unstable plaques in vivo by targeting biomarkers of angiogenesis in murine models of atherosclerosis (AS). METHODS: Immunofluorescence and western blot were used to detect the expression of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in activated Human Umbilical Vein Endothelial Cells (HUVECs). After synthesis and identification of novel short peptide VRBP1-targeted VEGFR2, HUVECs were co-cultured with FITC-VRBP1 to test specific affinity of VRBP1. Then VRBP1-UCNPstargeting VEGFR2 were constructed by conjugating VRBP1 to the surface of NaGdF4:Yb,Er@NaGdF4 nanoparticles. The characterization of the nanoparticles was performed by transmission electron microscopy (TEM), distribution of size, hydrodynamic size, zeta potential, absorption spectra, emission spectra, imaging intensity of different concentrations, binding affinity and cytotoxicity of nanoprobes in vitro. The upconversion luminescence (UCL) and MR imaging were performed to identify unstable atherosclerotic plaque in ApoE-/- mice in vivo and ex vivo. Morphological staining was used to verify AS model and angiogenesis, and Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES) was used to confirm accumulation of the nanoparticles after imaging. RESULTS: After induced by hypoxia and ox-LDL, the expression of VEGFR2 in activated HUVECs was enhanced. FITC-VRBP1 can specifically bind to the HUVECs. Characterization of the nanoparticles showed that particles size is uniform with a stable structure, specific optical and MR signal, good binding affinity to VEGFR2 and low cytotoxicity. In vivo and ex vivo UCL imaging and quantitative analysis revealed that distinctive optical signal was observed in the regions of left carotid common arteries (LCCAs) of AS group after injection of VRBP1-UCNPs. Higher signal intensity on T1-weighted MR imaging appeared in the LCCA wall of AS group after injection. The results of morphological staining demonstrated angiogenesis in the atherosclerotic plaques, Gd ions in LCCAs, aortic arch and renal arteries bifurcations detected by ICP-AES confirmed accumulation of the nanoparticles in plaque. CONCLUSIONS: We successfully design and synthesize a novel UCNPs using peptide VRBP1 targeting to VEGFR2. In vivo imaging demonstrates that VRBP1-UCNPs can be used to perform optical/MR dual-modality imaging targeting angiogenesis in plaques, which is a promising technique to early detect unstable atherosclerosis.

Effect of long-term intensive cholesterol control on the plaque progression in elderly based on CTA cohort study.

OBJECTIVES: To investigate the long-term effects of intensive LDL cholesterol-lowering treatments on lumen stenosis severity, plaque calcification, spotty calcifications, percent calcified plaque volume (PCPV), and Agatston coronary artery calcium score (CACS) based on coronary computed tomography angiography (CCTA) in elderly patients. METHODS: A total of 240 patients over 60 years old (comprising 754 lesions) who underwent serial CCTA were retrospectively enrolled in this 5-year cohort study. Patients were divided into three groups: an intensive lipid-lowering group, a lipid-lowering group, and a control group. The stenosis severity, plaque volume (PV), plaque composition, PCPV, and high-risk plaque (HRP) presence were quantitatively analyzed. The CACS was calculated at baseline and follow-up. RESULTS: All patients were male with an average age of 66.8 ± 5.8 years old. Over time, increases in the percentages of obstructive coronary lesions (p < 0.001) were observed. Compared with those at baseline, the percentage of obstructive lesions remained unchanged (p = 0.077), and the percentage of spotty calcifications significantly decreased (p < 0.05) at the follow-up CCTA scan in the intensive lipid-lowering group. Patients in the intensive lipid-lowering group demonstrated a higher progression in calcified PV, CACS, and PCPV (all p < 0.05), and a significantly greater attenuation in fibrous-fatty and lipid-rich PV (all p < 0.05) than patients in other groups. CONCLUSIONS: The PV and contents increased gradually with time in all groups. Intensive LDL-C lowering was associated with slower progression of stenosis severity and reduction of high-risk plaque features, with increased plaque calcification and higher progression in PCPV. Comprehensive serial plaque evaluations by CCTAs may contribute to further refinement of risk stratification and reasonable lipid-lowering treatment in elderly patients. KEY POINTS: • Intensive LDL-C lowering increased coronary calcification and percent calcified plaque volume progression. • Comprehensive serial plaque evaluations by serial CCTAs may help to refine risk stratification.

Risk predicting for acute coronary syndrome based on machine learning model with kinetic plaque features from serial coronary computed tomography angiography.

AIMS: More patients with suspected coronary artery disease underwent coronary computed tomography angiography (CCTA) as gatekeeper. However, the prospective relation of plaque features to acute coronary syndrome (ACS) events has not been previously explored. METHODS AND RESULTS: One hundred and one out of 452 patients with documented ACS event and received more than once CCTA during the past 12 years were recruited. Other 101 patients without ACS event were matched as case control. Baseline, follow-up, and changes of anatomical, compositional, and haemodynamic parameters [e.g. luminal stenosis, plaque volume, necrotic core, calcification, and CCTA-derived fractional flow reserve (CT-FFR)] were analysed by independent CCTA measurement core laboratories. Baseline anatomical, compositional, and haemodynamic parameters of lesions showed no significant difference between the two cohorts (P > 0.05). While the culprit lesions exhibited significant increase of luminal stenosis (10.18 ± 2.26% vs. 3.62 ± 1.41%, P = 0.018), remodelling index (0.15 ± 0.14 vs. 0.09 ± 0.01, P < 0.01), and necrotic core (4.79 ± 1.84% vs. 0.43 ± 1.09%, P = 0.019) while decrease of CT-FFR (-0.05 ± 0.005 vs. -0.01 ± 0.003, P < 0.01) and calcium ratio (-4.28 ± 2.48% vs. 4.48 ± 1.46%, P = 0.004) between follow-up CCTA and baseline scans in comparison to that of non-culprit lesion. The XGBoost model comprising the top five important plaque features revealed higher predictive ability (area under the curve 0.918, 95% confidence interval 0.861-0.968). CONCLUSIONS: Dynamic changes of plaque features are highly relative with subsequent ACS events. The machine learning model of integrating these lesion characteristics (e.g. CT-FFR, necrotic core, remodelling index, plaque volume, and calcium) can improve the ability for predicting risks of ACS events.

Melatonin Alleviates LPS-Induced Pyroptotic Cell Death in Human Stem Cell-Derived Cardiomyocytes by Activating Autophagy.

Endotoxemia in sepsis remains a problem due to a lack of effective strategies. Our previous studies have demonstrated that melatonin (Mel) protects against ischemic heart injury and arteriosclerosis. However, its role in endotoxemia-exposed cardiomyocytes remains poorly understood. This study explored, for the first time, the protective effect of Mel on the pyroptosis of human stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to lipopolysaccharide (LPS). Our results showed that treatment with 1 µM or 10 µM Mel for 12 h significantly improved 1 µg/ml LPS-induced hiPSC-CM injuries, as reflected by drastically decreased LDH release and increased cell viability, which was accompanied by the overt induction of autophagy. Specifically, Mel profoundly alleviated LPS-induced cell pyroptosis, as evidenced by decreased propidium iodide (PI) and active caspase-1 double-positive cell rates; suppressed the expression of NLRP3, cleaved caspase-1 (activated form of caspase-1), and GSDMD-NT (functional N-terminal fragment of GSDMD) expression; and inhibited the production of the cleaved IL-1ß and cleaved IL-18 cytokines. Additionally, double-membrane autophagosomes were observed in LPS-injured hiPSC-CMs treated with 1 µM or 10 µM Mel. The hiPSC-CMs treated with LPS exhibited considerably fewer acidic vesicles (as revealed by LAMP1 staining) and autophagosomes (as revealed by LC3-II staining); however, Mel reversed this outcome in a dose-dependent manner. Furthermore, coincubation with rapamycin (an autophagy activator) or 3-MA (an autophagy inhibitor) accentuated and attenuated the antipyroptotic actions of Mel, respectively. Collectively, our findings demonstrate that Mel shields hiPSC-CMs against pyroptosis during endotoxemia by activating autophagy.

Three-dimensional quantitative assessment of myocardial infarction via multimodality fusion imaging: methodology, validation, and preliminary clinical application.

BACKGROUND: The precise assessment of myocardial infarction (MI) is crucial both for therapeutic interventions in old MI and the development of new and effective techniques to repair injured myocardium. A novel method was developed to assess left ventricular (LV) quantitatively infarction through three-dimensional (3D) multimodality fusion based on computed tomography angiography (CTA) and technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) single-photon emission computed tomography (SPECT) images. This study sought to develop a 3D quantitative method for MI for pre-clinical study and clinical application. METHODS: Three months after the MI models were established in 20 minipigs, CTA and SPECT images were acquired separately, which were then aligned automatically with the constraints of the shape and the whole heart and LV myocardium position. Infarct ratios were quantified based on the 3D fusion images. The quantitative assessment was then experimentally validated via an ex vivo histology analysis using triphenyl-tetrazolium-chloride staining and subsequently applied to post-MI patients (n=8). RESULTS: The location of an infarct identified by the SPECT was consistent with that identified by an ex vivo heart in a 3D space. Infarct size determined by CTA-SPECT was correlated with infarct size assessed by triphenyl-tetrazolium-chloride pathology {27.6% [interquartile range (IQR) 17.1-34.7%] vs. 24.1% (IQR 14.7-32.5%), r2=0.99, P<0.01}. In clinical cases, the CTA-SPECT 3D fusion quantitative results were significantly correlated with the quantitative perfusion SPECT results (r=0.976, P<0.01). CONCLUSIONS: The proposed 3D fusion quantitative assessment method provides reliable and intuitive evaluations of infarction. This novel quantification technique enables whole heart quantification for the pre-operation evaluation and post-diagnosis management of old MI patients. It could also be applied to the design of 3D-printed cardiac patches.

A Thrombin-Responsive Nanoprobe for In Vivo Visualization of Thrombus Formation through Three-Dimensional Optical/Computed Tomography Hybrid Imaging.

Early spontaneous detection of thrombin activation benefits precise theranostics for thrombotic vascular disease. Herein, a thrombin-responsive nanoprobe conjugated by a FITC dye, PEGylated Fe3O4 nanoparticles, and a thrombin-sensitive peptide (LASG) was constructed to visualize thrombin activation and subsequent thrombosis in vivo. The FITC dye was linked to the LASG coated on the Fe3O4 nanoparticles for sensing the thrombin activity via the Förster resonance energy transfer effect. In vitro fluorescence imaging showed that the fluorescence signal intensity increased significantly after incubation with thrombin in contrast to that of the control group (p < 0.05), and the signal intensity was enhanced with the increase in thrombin concentration. Further in vivo fluorescence imaging also revealed that the signal elevated markedly in the left common carotid artery (LCCA) lesion of the mice thrombosis model after nanoprobe injection, in contrast to that of the control + nanoprobe group (p < 0.05). Moreover, the thrombin inhibitor bivalirudin could decrease the filling defect of the LCCA. Three-dimensional fusion images of micro-CT and fluorescence confirmed that filling defects in the LCCA were nicely colocalized with fluorescence signal caused by nanoprobes. The nanoplatform based on a thrombin-activatable visualization system could provide smart responsive and dynamic imaging of thrombosis in vivo.

The Incremental Prognostic Value of the Clinical Residual SYNTAX Score for Patients With Chronic Renal Insufficiency Undergoing Percutaneous Coronary Intervention.

Background: The residual SYNTAX score (RSS) is considered a powerful prognostic indicator for determining a reasonable revascularization strategy in patients undergoing percutaneous coronary intervention (PCI), but the absence of clinical parameters is one of the limitations of RSS, especially in the chronic renal insufficiency (CRI) comorbidity setting. The present work aimed to investigate the incremental prognostic value of clinical residual SYNTAX score (CRSS) compared with RSS in CRI cases after PCI. Methods: Totally 2,468 consecutive CRI cases who underwent PCI from January 2014 to September 2017 were included in this retrospective analysis. CRSS was obtained by multiplying RSS by the modified ACEF score. Individuals with CRSS >0 were considered to have incomplete revascularization and stratified by CRSS tertiles, the remaining cases constituted the complete revascularization (CR) group. The outcomes between these groups were compared. Results: At a median follow-up of 3 years, compared with CR group, individuals with CRSS >12 showed elevated rates of all clinical outcomes, and those with CRSS ≤ 12 showed similar all-cause and cardiac mortality rates. In multivariable analysis, CRSS was a powerful independent predictive factor of all clinical outcomes. The net reclassification improvement levels of CRSS over RSS for all-cause and cardiac mortality rates were 10.3% (p = 0.007) and 16.4% (p < 0.001), respectively. Compared with RSS, CRSS markedly ameliorated all-cause and cardiac mortality risk stratification. Conclusions: Compared with RSS, CRSS has incremental predictability for long-term all-cause and cardiac mortality in CRI cases following PCI.

IVUS\IVPA hybrid intravascular molecular imaging of angiogenesis in atherosclerotic plaques via RGDfk peptide-targeted nanoprobes.

Current intravascular imaging modalities face hurdles in the molecular evaluation of progressed plaques. This study aims to construct a novel hybrid imaging system (intravascular ultrasound/intravascular photoacoustic, IVPA/IVUS) via RGDfk peptide-targeted nanoparticles for monitoring angiogenesis in progressed atherosclerotic plaques in a rabbit model. An atherosclerotic rabbit model was induced by abdominal aorta balloon de-endothelialization followed by a high-fat diet. A human serum albumin (HSA)-based nanoprobe modified with RGDfk peptide was constructed by encapsulating indocyanine green (ICG) via electrostatic force (ICG-HSA-RGDfk NPs, IHR-NPs). A hybrid intravascular imaging system that combined IVUS and IVPA was self-assembled for RGDfk visualization within atherosclerotic plaques in the rabbit abdominal aorta. Through IHR-NPs and the hybrid IVUS/IVPA imaging platform, multiple comprehensive pieces of information on progressed plaques, including anatomical information, composition information and molecular information, can be obtained simultaneously, which may improve the precise diagnosis of plaque characteristics and the evaluation of early interventions for atherosclerosis.

Circulating Ceramide: A New Cardiometabolic Biomarker in Patients With Comorbid Acute Coronary Syndrome and Type 2 Diabetes Mellitus.

AIMS: This study investigated the association of circulating ceramides in patients with comorbid acute coronary syndrome and type 2 diabetes mellitus (ACS-DM). METHODS: A total of 761 patients with coronary heart disease who were admitted to the Department of Cardiology at the Chinese PLA General Hospital from March to August 2018 were enrolled in this study. Of these 761 patients, 282 were diagnosed with acute coronary syndrome (ACS). We selected 65 patients with ACS-DM (ACS-DM group; mean age 64.88 years; 38 men) and 65 patients with ACS but without any comorbidities (ACS group; mean age 64.68 years; 38 men); the two groups were matched by age and sex. We determined four circulating ceramides in 130 plasma samples: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0). The ceramides in plasma samples from patients with ACS and those from patients with ACS-DM were compared. Pearson correlation coefficients between individual ceramides and traditional cardiovascular risk factors for the whole study population were calculated. Multiple logistic regression models were used to evaluate the relativity between the ceramide and ACS-DM. RESULTS: Compared with the ACS group, the levels of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) and their ratios to Cer(d18:1/24:0) were higher in the ACS-DM group and Cer(d18:1/24:0) was lower in the ACS-DM group (P < 0.05). Correlation analysis demonstrated mild-to-moderate correlations of ceramide and traditional cardiovascular risk factors. There were relatively strong correlations of Cer(d18:1/18:0) and Cer(d18:1/24:1) with C-reactive protein, blood lipids, fasting blood glucose, and glycated hemoglobin A1c. In multiple logistic regression models, Cer(d18:1/18:0) [odds ratio (OR) 2.396; 95% confidence interval (CI) 1.103-5.205; P = 0.027], Cer(d18:1/24:1) (OR 2.826; 95% CI 1.158-6.896; P = 0.023), Cer(d18:1/18:0)/Cer(d18:1/24:0) (OR 2.242; 95% CI 1.103-4.555; P = 0.026), and Cer(d18:1/24:1)/Cer(d18:1/24:0) (OR 2.673; 95% CI 1.225-5.836; P = 0.014) were positively correlated with ACS-DM, and Cer(d18:1/24:0) (OR 0.200; 95% CI 0.051-0.778; P = 0.020) was negatively correlated with ACS-DM. CONCLUSION: Circulating ceramides are positively correlated with the risk of ACS-DM comorbidity. These results give a new insight into the pathogenesis of ACS-DM comorbidity and could provide new options for risk estimation.

Regulation of the cerebrovascular smooth muscle cell phenotype by mitochondrial oxidative injury and endoplasmic reticulum stress in simulated microgravity rats via the PERK-eIF2α-ATF4-CHOP pathway.

Microgravity exposure results in vascular remodeling and cardiovascular dysfunction. Here, the effects of mitochondrial oxidative stress on vascular smooth muscle cells (VSMCs) in rat cerebral arteries under microgravity simulated by hindlimb unweighting (HU) was studied. Endoplasmic reticulum (ER)-resident transmembrane sensor proteins and phenotypic markers of rat cerebral VSMCs were examined. In HU rats, CHOP expression was increased gradually, and the upregulation of the PERK-eIF2α-ATF4 pathway was the most pronounced in cerebral arteries. Furthermore, PERK/p-PERK signaling, CHOP, GRP78 and reactive oxygen species were augmented by PERK overexpression but attenuated by the mitochondria-targeting antioxidant MitoTEMPO. Meanwhile, p-PI3K, p-Akt and p-mTOR protein levels in VSMCs were increased in HU rat cerebral arteries. Compared with the control, HU rats exhibited lower α-SMA, calponin, SM-MHC and caldesmon protein levels but higher OPN and elastin levels in cerebral VSMCs. The cerebral VSMC phenotype transition from a contractile to synthetic phenotype in HU rats was augmented by PERK overexpression and 740Y-P but reversed by MitoTEMPO and the ER stress inhibitors tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). In summary, mitochondrial oxidative stress and ER stress induced by simulated microgravity contribute to phenotype transition of cerebral VSMCs through the PERK-eIF2a-ATF4-CHOP pathway in a rat model.

Ultrasound/Optical Dual-Modality Imaging for Evaluation of Vulnerable Atherosclerotic Plaques with Osteopontin Targeted Nanoparticles.

Because of the high mortality of coronary atherosclerotic heart diseases, it is necessary to develop novel early detection methods for vulnerable atherosclerotic plaques. Phenotype transformation of vascular smooth muscle cells (VSMCs) plays a vital role in progressed atherosclerotic plaques. Osteopontin (OPN) is one of the biomarkers for phenotypic conversion of VSMCs. Significant higher OPN expression is found in foam cells along with the aggravating capacity of macrophage recruitment due to its arginine-glycine-aspartate sequence and interaction with CD44. Herein, a dual-modality imaging probe, OPN targeted nanoparticles (Cy5.5-anti-OPN-PEG-PLA-PFOB, denoted as COP-NPs), is constructed to identify the molecular characteristics of high-risk atherosclerosis by ultrasound and optical imaging. Characterization, biocompatibility, good binding sensibility, and specificity are evaluated in vitro. For in vivo study, apolipoprotein E deficien (ApoE-/- ) mice fed with high fat diet for 20-24 weeks are used as atherosclerotic model. Ultrasound and optical imaging reveal that the nanoparticles are accumulated in the vulnerable atherosclerotic plaques. OPN targeted nanoparticles are demonstrated to be a good contrast agent in molecular imaging of synthetic VSMCs and foam cells, which can be a promising tool to identify the vulnerable atherosclerotic plaques.

Impact of the residual SYNTAX score on clinical outcomes after percutaneous coronary intervention for patients with chronic renal insufficiency.

OBJECTIVES: This study demonstrated the prognostic value of the residual SYNTAX score (rSS) for patients with chronic renal insufficiency (CRI). BACKGROUND: The rSS has been proposed as a useful tool for quantifying and stratifying the degree and complexity of residual stenosis and predicting long-term clinical outcomes following percutaneous coronary intervention (PCI). However, it has never been validated for patients with CRI. METHODS: A total of 2,468 consecutive patients with an estimated glomerular filtration rate <90 ml/min/1.73 m2 who underwent PCI were retrospectively enrolled. Patients with rSS >0 were defined as having incomplete revascularization and were stratified into the reasonable incomplete revascularization (RICR; 0 < rSS ≤ 8) group or the incomplete revascularization (ICR; rSS >8) group. Their outcomes were compared to those of the complete revascularization (CR) group. RESULTS: During follow-up (median, 3 years; range, 1.5-5 years), the ICR group had the highest incidence of all-cause death, cardiac death, myocardial infarction (MI), unplanned revascularization, stroke, and major adverse cardiovascular and cerebrovascular events (MACCE). Despite having higher rates of unplanned revascularization and MACCE, RICR group had comparable all-cause mortality, cardiac mortality, MI, and stroke with CR group. A multivariable Cox analysis indicated that rSS was an independent predictor of cardiac death, MI, unplanned revascularization, stroke, and MACCE. Furthermore, compared with baseline SYNTAX score, rSS had stronger prognostic accuracy when predicting the risk of unplanned revascularization, stroke, and MACCE at the 3-year follow-up. CONCLUSIONS: The rSS is a powerful indicator of clinical outcomes and may help determine reasonable levels of revascularization for patients with CRI following PCI.

A New Perspective of Migraine Symptoms in Patients With Congenital Heart Defect.

OBJECTIVE: To investigate the association between congenital heart defects (CHDs) and migraine and evaluate the efficacy of transcatheter defect closure from a new perspective. METHODS: The patients with CHDs who underwent transcatheter defect closure were screened in the medical database of Chinese PLA General Hospital from January 2006 to January 2017. The assessment included basic admission information, the 3-item ID Migraine Screener, and a detailed questionnaire administered by telephone or in an outpatient clinic. Patients were divided into ventricular septal defect (VSD) group and AP group (ie, patients with ASD or PFO) based on the type of defects. The latter group could be further divided into right-to-left shunt (RLS) group and left-to-right (LRS) shunt group. Each group contained 4 subgroups according to their migraine diagnosis before and after defect closure: persistent migraine (PM), relieved migraine (RM), without migraine (WM), and new-onset migraine (NM). RESULTS: The study recruited total 441 CHDs patients. Most patients in RLS group had migraine before and/or after surgery (76.4%, 42/55) and the proportion of them in NM group was higher than that of in LRS group (23.5%, 4/17 vs 6.8%, 18/266, P = .0418). Although the size of closure device or defect did not show significant differences, the ratios (R = size of closure/size of defect) were significantly higher in NM group than those in WM group (1.40 [1.26, 1.80] vs 1.22 [1.13, 1.38] in AP group, P = .00238; 1.38 [1.23, 1.50] vs 1.22 [1.13, 1.37] in LRS group, P = .024934, respectively). Further logistic regression analysis illustrated that larger R value was a risk factor for NM in AP group (OR 1.48, 95% CI 1.07-2.05, P = .0188). Besides, migraine symptoms decreased significantly after defect closure in PM group among patients with ASD and PFO. CONCLUSION: This study revealed several associations between migraine and CHDs, especially the large ratio of closure device size to defect size. High-quality randomized controlled trials and animal studies are needed to further investigate and clarify the underlying association between CHDs and migraine.

Poly(Lactide-Co-Glycolide)-Monomethoxy-Poly-(Polyethylene Glycol) Nanoparticles Loaded with Melatonin Protect Adipose-Derived Stem Cells Transplanted in Infarcted Heart Tissue.

Stem cell transplantation is a promising therapeutic strategy for myocardial infarction. However, transplanted cells face low survival rates due to oxidative stress and the inflammatory microenvironment in ischemic heart tissue. Melatonin has been used as a powerful endogenous antioxidant to protect cells from oxidative injury. However, melatonin cannot play a long-lasting effect against the hostile microenvironment. Nano drug delivery carriers have the ability to protect the loaded drug from degradation in physiological environments in a controlled manner, which results in longer effects and decreased side effects. Therefore, we constructed poly(lactide-co-glycolide)-monomethoxy-poly-(polyethylene glycol) (PLGA-mPEG) nanoparticles to encapsulate melatonin. We tested whether the protective effect of melatonin encapsulated by PLGA-mPEG nanoparticles (melatonin nanoparticles [Mel-NPs]) on adipose-derived mesenchymal stem cells (ADSCs) was enhanced compared to that of free melatonin both in vitro and in vivo. In the in vitro study, we found that Mel-NPs reduced formation of the p53- cyclophilin D complex, prevented mitochondrial permeability transition pores from opening, and rescued ADSCs from hypoxia/reoxygenation injury. Moreover, Mel-NPs can achieve higher ADSC survival rates than free melatonin in rat myocardial infarction areas, and the therapeutic effects of ADSCs pretreated with Mel-NPs were more apparent. Hence, the combination of Mel-NPs and stem cell transplantation may be a promising strategy for myocardial infarction therapy. Stem Cells 2018;36:540-550.