Melatonin suppresses atherosclerosis by ferroptosis inhibition via activating NRF2 pathway.

Melatonin (MLT), a conserved small indole compound, exhibits anti-inflammatory and antioxidant properties, contributing to its cardioprotective effects. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with atherosclerosis disease risk, and is known as an atherosclerosis risk biomarker. This study aimed to investigate the impact of MLT on Lp-PLA2 expression in the atherosclerotic process and explore the underlying mechanisms involved. In vivo, ApoE-/- mice were fed a high-fat diet, with or without MLT administration, after which the plaque area and collagen content were assessed. Macrophages were pretreated with MLT combined with ox-LDL, and the levels of ferroptosis-related proteins, NRF2 activation, mitochondrial function, and oxidative stress were measured. MLT administration significantly attenuated atherosclerotic plaque progression, as evidenced by decreased plaque area and increased collagen. Compared with those in the high-fat diet (HD) group, the levels of glutathione peroxidase 4 (GPX4) and SLC7A11 (xCT, a cystine/glutamate transporter) in atherosclerotic root macrophages were significantly increased in the MLT group. In vitro, MLT activated the nuclear factor-E2-related Factor 2 (NRF2)/SLC7A11/GPX4 signaling pathway, enhancing antioxidant capacity while reducing lipid peroxidation and suppressing Lp-PLA2 expression in macrophages. Moreover, MLT reversed ox-LDL-induced ferroptosis, through the use of ferrostatin-1 (a ferroptosis inhibitor) and/or erastin (a ferroptosis activator). Furthermore, the protective effects of MLT on Lp-PLA2 expression, antioxidant capacity, lipid peroxidation, and ferroptosis were decreased in ML385 (a specific NRF2 inhibitor)-treated macrophages and in AAV-sh-NRF2 treated ApoE-/- mice. MLT suppresses Lp-PLA2 expression and atherosclerosis processes by inhibiting macrophage ferroptosis and partially activating the NRF2 pathway.

Acoustic Activation Imaging With Intravenous Perfluoropropane Nanodroplets Results in Selective Bioactivation of the Risk Area.

BACKGROUND: Acoustically activatable perfluoropropane droplets (PD) can be formulated from commercially available microbubble preparations. Diagnostic transthoracic ultrasound frequencies have resulted in acoustic activation (AA) predominately within myocardial infarct zones (IZ). OBJECTIVE: We hypothesized that the AA area following acute coronary ischemia/reperfusion (I/R) would selectively enhance the developing scar zone, and target bioeffects specifically to this region. METHODS: We administered intravenous PD in 36 rats and 20 pigs at various stages of myocardial scar formation (30 minutes, 1 day, and 7 days post I/R) to determine what effect infarct age had on the AA within the IZ. This was correlated with histology, myeloperoxidase activity, and tissue nitrite activity. RESULTS: The degree of AA within the IZ in rats was not associated with collagen content, neutrophil infiltration, or infarct age. AA within 24 hours of I/R was associated with increased nitric oxide utilization selectively within the IZ (P < .05 compared with remote zone). The spatial extent of AA in pigs correlated with infarct size only when performed before sacrifice at 7 days (r = .74, P < .01). CONCLUSIONS: Acoustic activation of intravenous PD enhances the developing scar zone following I/R, and results in selective tissue nitric oxide utilization.

Nomograms based on preoperative multimodal ultrasound of papillary thyroid carcinoma for predicting central lymph node metastasis.

OBJECTIVES: To establish a nomogram for predicting central lymph node metastasis (CLNM) based on the preoperative clinical and multimodal ultrasound (US) features of papillary thyroid carcinoma (PTC) and cervical LNs. METHODS: Overall, 822 patients with PTC were included in this retrospective study. A thyroid tumor ultrasound model (TTUM) and thyroid tumor and cervical LN ultrasound model (TTCLNUM) were constructed as nomograms to predict the CLNM risk. Areas under the curve (AUCs) evaluated model performance. Calibration and decision curves were applied to assess the accuracy and clinical utility. RESULTS: For the TTUM training and test sets, the AUCs were 0.786 and 0.789 and bias-corrected AUCs were 0.786 and 0.831, respectively. For the TTCLNUM training and test sets, the AUCs were 0.806 and 0.804 and bias-corrected AUCs were 0.807 and 0.827, respectively. Calibration and decision curves for the TTCLNUM nomogram exhibited higher accuracy and clinical practicability. The AUCs were 0.746 and 0.719 and specificities were 0.942 and 0.905 for the training and test sets, respectively, when the US tumor size was ≤ 8.45 mm, while the AUCs were 0.737 and 0.824 and sensitivity were 0.905 and 0.880, respectively, when the US tumor size was > 8.45 mm. CONCLUSION: The TTCLNUM nomogram exhibited better predictive performance, especially for the CLNM risk of different PTC tumor sizes. Thus, it serves as a useful clinical tool to supply valuable information for active surveillance and treatment decisions. KEY POINTS: • Our preoperative noninvasive and intuitive prediction method can improve the accuracy of central lymph node metastasis (CLNM) risk assessment and guide clinical treatment in line with current trends toward personalized treatments. • Preoperative clinical and multimodal ultrasound features of primary papillary thyroid carcinoma (PTC) tumors and cervical LNs were directly used to build an accurate and easy-to-use nomogram for predicting CLNM. • The thyroid tumor and cervical lymph node ultrasound model exhibited better performance for predicting the CLNM of different PTC tumor sizes. It may serve as a useful clinical tool to provide valuable information for active surveillance and treatment decisions.

In vivo degradation and neovascularization of silk fibroin implants monitored by multiple modes ultrasound for surgical applications.

BACKGROUND: In this paper we aimed to investigate the neovascularization and biodegradation of the silk fibroin in vivo using multiple modes ultrasound, including two-dimensional, three-dimensional and contrast-enhanced ultrasound by quantifying the echo intensity, volume and contrast enhancement of the silk fibroin implants. METHOD: A total of 56 male Wistar rats were randomly divided into two groups and 4%(w/v) silk hydrogels were injected subcutaneously at hind limb or upper back of the rats respectively to compare the biodegradation rate in different sites of the body. The implants were observed at day 0, 4, 8, 12, 16, 18, 20 with multiple modes ultrasound. RESULTS: The echo intensity of silk fibroin implants increased and the volume decreased gradually, and complete degradation was confirmed 18 and 20 days after subcutaneous implantation at the upper back and at the hind limb respectively. This demonstrated that the silk fibroin embedded in the upper back degraded slightly faster than that in the hind limb. Additionally, the neovascularization revealed by the contrast enhancement values of CEUS showed that there was a relatively low enhancement (< 5 dB) during day 4 to day 16, followed by moderate enhancement at day 18 (5-20 dB), and a significant enhancement at day 20 (> 40 dB). CONCLUSION: This study suggests that multiple modes ultrasound imaging could be an ideal method to evaluate the degradation and neovascularization of biomaterial implants in vivo for surgical applications.

Three-dimensional transesophageal echocardiographic study of aortic-mitral valve coupling after coronary artery bypass grafting.

AIMS: To observe the geometric changes in aortic-mitral valve coupling (AMC) on three-dimensional transesophageal echocardiography and the factors leading to decreased mitral regurgitation (MR) after coronary artery bypass grafting (CABG). METHODS AND RESULTS: This study included 23 patients undergoing CABG for coronary artery disease. Fifteen patients with moderate to severe MR were separately analyzed to determine whether the severity of MR influences the geometric change in AMC. Echocardiographic examinations were performed pre- and post-CABG, and the studied parameters were obtained using Siemens Auto Valve Analysis software. The effective mitral regurgitant orifice area, left ventricular ejection fraction (LVEF), end-diastolic volume (EDV), and end-systolic volume (ESV) were measured pre- and post-CABG using Philips QLAB software. Ischemic MR, EDV, and ESV significantly decreased (all P < 0.05) and LVEF significantly improved (P < 0.05) after CABG. There were no significant differences between the pre- and post-CABG mitral valve (MV) parameters, aortic valve parameters, aortic-mitral annular angle, or centroid distance (all P > 0.05). Patients with moderate to severe MR exhibited the same results. CONCLUSION: The results of this study show that CABG does not cause an acute change in the geometry of AMC. Improved left ventricular function might increase the closing force of the MV, leading to decreased MR after CABG alone. MR significantly improved after CABG alone without MV treatment in the present study. This result may help to guide surgeons in choosing the optimal surgical methods for individual patients.

Evaluation of Left Ventricular Regional Systolic Function Using Tissue Doppler Echocardiography After Mesenchymal Stem Cell Transplantation in Rabbits With Myocardial Infarction.

OBJECTIVES: The aim of this work was to assess left ventricular (LV) regional systolic function in rabbits with myocardial infarction after allogeneic mesenchymal stem cell (MSC) transplantation using quantitative tissue velocity imaging. METHODS: Thirty New Zealand White rabbits were assigned into 3 groups randomly: a sham-operated group (n = 10), a myocardial infarction (MI) group (n = 10), and a MSC transplantation group (n = 10). Mesenchymal stem cells (1 × 10(7) in total) were delivered into 5 spots around the left anterior descending artery (LAD) blood supply area via direct intramyocardial injections 1 hour after LAD ligation in the MSC group, whereas the MI group received the same amount of phosphate-buffered saline injections. Echocardiography was performed before LAD ligation and 1 day and 2 weeks after MSC transplantation, respectively. The peak systolic velocity (Vs) of each LV wall segment was measured. The myocardial slices were harvested for histologic staining after the last echocardiographic examination. RESULTS: The velocity curves for the LV myocardium before LAD ligation had a trend showing that the Vs value decreased gradually from basal to apical segments. The Vs values for the LV segments around the infarcted area in the MSC group decreased significantly compared with the sham group (P < .05) 1 day after MSC transplantation, whereas they increased significantly 2 weeks after MSC transplantation compared with 1 day after LAD ligation (P < .05). CONCLUSIONS: This study demonstrates that quantitative tissue velocity imaging may provide a promising approach to quantitatively assessing LV regional systolic function before and after MSC transplantation.

Ultrasound Detection of Myocardial Ischemic Memory Using an E-Selectin Targeting Peptide Amenable to Human Application.

Vascular endothelial leukocyte adhesion molecules, such as E-selectin, are acutely upregulated in myocardial ischemia/reperfusion and are thus "ischemic memory" biomarkers for recent cardiac ischemia. We sought to develop an ultrasound molecular imaging agent composed of microbubbles (MBs) targeted to E-selectin to enable the differential diagnosis of myocardial ischemia in patients presenting with chest pain of unclear etiology. Biodegradable polymer MBs were prepared bearing a peptide with specific human E-selectin affinity (MBESEL). Control MBs had scrambled peptide (MBCTL) or nonspecific IgG (MBIgG). MBESEL adhesion to activated rat endothelial cells (ECs) was confirmed in vitro in a flow system and in vivo with intravital microscopy of rat cremaster microcirculation. Ultrasound molecular imaging of recent myocardial ischemia was performed in rats 4 hours after transient (15 minutes) coronary occlusion. MBESEL adhesion was higher to inflamed versus normal ECs in vitro; there was no difference in MBCTL or MBIgG adhesion to inflamed versus normal ECs. There was greater adhesion of MBESEL to inflamed versus noninflamed microcirculation and minimal adhesion of MBCTL or MBIgG under any condition. Ultrasound imaging after injection of MBSEL demonstrated persistent contrast enhancement of the previously ischemic region. Videointensity in postischemic myocardium after MBESEL was higher than that in the nonischemic bed (11.6 ± 2.7 dB vs 3.6 ± 0.8 dB, p < .02) and higher than that after MBCTL (4.0 ± 1.0 dB, p < .03) or MBIgG (1.7 ± 0.1 dB, p < .03). MBs targeted to E-selectin via a short synthetic peptide with human E-selectin binding affinity enables echocardiographic detection of recent ischemia, setting the stage for clinical myocardial ischemic memory imaging to identify acute coronary syndromes.

Ultrasound detection of myocardial ischemic memory using an E-selectin targeting peptide amenable to human application.

Vascular endothelial leukocyte adhesion molecules, such as E-selectin, are acutely upregulated in myocardial ischemia/reperfusion and are thus "ischemic memory" biomarkers for recent cardiac ischemia. We sought to develop an ultrasound molecular imaging agent composed of microbubbles (MBs) targeted to E-selectin to enable the differential diagnosis of myocardial ischemia in patients presenting with chest pain of unclear etiology. Biodegradable polymer MBs were prepared bearing a peptide with specific human E-selectin affinity (MBESEL). Control MBs had scrambled peptide (MBCTL) or nonspecific IgG (MBIgG). MBESEL adhesion to activated rat endothelial cells (ECs) was confirmed in vitro in a flow system and in vivo with intravital microscopy of rat cremaster microcirculation. Ultrasound molecular imaging of recent myocardial ischemia was performed in rats 4 hours after transient (15 minutes) coronary occlusion. MBESEL adhesion was higher to inflamed versus normal ECs in vitro; there was no difference in MBCTL or MBIgG adhesion to inflamed versus normal ECs. There was greater adhesion of MBESEL to inflamed versus noninflamed microcirculation and minimal adhesion of MBCTL or MBIgG under any condition. Ultrasound imaging after injection of MBSEL demonstrated persistent contrast enhancement of the previously ischemic region. Videointensity in postischemic myocardium after MBESEL was higher than that in the nonischemic bed (11.6 ± 2.7 dB vs 3.6 ± 0.8 dB, p < .02) and higher than that after MBCTL (4.0 ± 1.0 dB, p < .03) or MBIgG (1.7 ± 0.1 dB, p < .03). MBs targeted to E-selectin via a short synthetic peptide with human E-selectin binding affinity enables echocardiographic detection of recent ischemia, setting the stage for clinical myocardial ischemic memory imaging to identify acute coronary syndromes.

Low-intensity pulsed ultrasound improves myocardial ischaemia‒reperfusion injury via migrasome-mediated mitocytosis.

During myocardial ischaemia‒reperfusion injury (MIRI), the accumulation of damaged mitochondria could pose serious threats to the heart. The migrasomes, newly discovered mitocytosis-mediating organelles, selectively remove damaged mitochondria to provide mitochondrial quality control. Here, we utilised low-intensity pulsed ultrasound (LIPUS) on MIRI mice model and demonstrated that LIPUS reduced the infarcted area and improved cardiac dysfunction. Additionally, we found that LIPUS alleviated MIRI-induced mitochondrial dysfunction. We provided new evidence that LIPUS mechanical stimulation facilitated damaged mitochondrial excretion via migrasome-dependent mitocytosis. Inhibition the formation of migrasomes abolished the protective effect of LIPUS on MIRI. Mechanistically, LIPUS induced the formation of migrasomes by evoking the RhoA/Myosin II/F-actin pathway. Meanwhile, F-actin activated YAP nuclear translocation to transcriptionally activate the mitochondrial motor protein KIF5B and Drp1, which are indispensable for LIPUS-induced mitocytosis. These results revealed that LIPUS activates mitocytosis, a migrasome-dependent mitochondrial quality control mechanism, to protect against MIRI, underlining LIPUS as a safe and potentially non-invasive treatment for MIRI.

Effect of Ambient Conditions on Acoustic Activation of the Perfluoropropane Droplets Within the Infarct Zone.

BACKGROUND: Acoustically activated perfluoropropane droplets (PD) formulated from lipid encapsulated microbubble preparations produce a delayed myocardial contrast enhancement that preferentially highlights the infarct zones (IZ). Since activation of PDs may be temperature sensitive, it is unclear what effect body temperature (BT) has on acoustic activation (AA). OBJECTIVE: We sought to determine whether the microvascular retention and degree of myocardial contrast intensity (MCI) would be affected by BT at the time of intravenous injection. METHODS: We administered intravenous (IV) PD in nine rats following 60 min of ischemia followed by reperfusion. Injections in these rats were given at temperatures above and below 36.5°C, with high MI activation in both groups at 3 or 6 min following IV injection (IVI). In six additional rats (three in each group), IV PDs were given only at one temperature (<36.5°C or ≥36.5°C), permitting a total of 12 comparisons of different BT. Differences in background subtracted MCI at 3-6 min post-injection were compared in the infarct zone (IZ) and remote zone (RZ). Post-mortem lung hematoxylin and eosin (H&E) staining was performed to assess the effect potential thermal activation on lung tissue. RESULTS: Selective MCI within the IZ was observed in 8 of 12 rats who received IVI of PDs at <36.5°C, but none of the 12 rats who had IVI at the higher temperature (p < 0.0001). Absolute MCI following droplet activation was significantly higher in both the IZ and RZ when given at the lower BT. H&E indicated significant red blood extravasation in 5/7 rats who had had IV injections at higher BT, and 0/7 rats who had IV PDs at <36.5°C. CONCLUSIONS: Selective IZ enhancement with AA of intravenous PDs is possible, but temperature sensitive. Thermal activation appears to occur when PDs are given at higher temperatures, preventing AA, and increasing unwanted bioeffects.

Low-intensity pulsed ultrasound protects from inflammatory dilated cardiomyopathy through inciting extracellular vesicles.

AIMS: CD4+ T cells are activated during inflammatory dilated cardiomyopathy (iDCM) development to induce immunogenic responses that damage the myocardium. Low-intensity pulsed ultrasound (LIPUS), a novel physiotherapy for cardiovascular diseases, has recently been shown to modulate inflammatory responses. However, its efficacy in iDCM remains unknown. Here, we investigated whether LIPUS could improve the severity of iDCM by orchestrating immune responses and explored its therapeutic mechanisms. METHODS AND RESULTS: In iDCM mice, LIPUS treatment reduced cardiac remodelling and dysfunction. Additionally, CD4+ T cell inflammatory responses were suppressed. LIPUS increased Treg cells while decreasing Th17 cells. LIPUS mechanically stimulates endothelial cells, resulting in increased secretion of extracellular vesicles (EVs), which are taken up by CD4+ T cells and alter their differentiation and metabolic patterns. Moreover, EVs selectively loaded with microRNA (miR)-99a are responsible for the therapeutic effects of LIPUS. The hnRNPA2B1 translocation from the nucleus to the cytoplasm and binding to caveolin-1 and miR-99a confirmed the upstream mechanism of miR-99a transport. This complex is loaded into EVs and taken up by CD4+ T cells, which further suppress mTOR and TRIB2 expression to modulate cellular differentiation. CONCLUSION: Our findings revealed that LIPUS uses an EV-dependent molecular mechanism to protect against iDCM progression. Therefore, LIPUS is a promising new treatment option for iDCM.

Ultrasound radiomics models based on multimodal imaging feature fusion of papillary thyroid carcinoma for predicting central lymph node metastasis.

Objective: This retrospective study aimed to establish ultrasound radiomics models to predict central lymph node metastasis (CLNM) based on preoperative multimodal ultrasound imaging features fusion of primary papillary thyroid carcinoma (PTC). Methods: In total, 498 cases of unifocal PTC were randomly divided into two sets which comprised 348 cases (training set) and 150 cases (validition set). In addition, the testing set contained 120 cases of PTC at different times. Post-operative histopathology was the gold standard for CLNM. The following steps were used to build models: the regions of interest were segmented in PTC ultrasound images, multimodal ultrasound image features were then extracted by the deep learning residual neural network with 50-layer network, followed by feature selection and fusion; subsequently, classification was performed using three classical classifiers-adaptive boosting (AB), linear discriminant analysis (LDA), and support vector machine (SVM). The performances of the unimodal models (Unimodal-AB, Unimodal-LDA, and Unimodal-SVM) and the multimodal models (Multimodal-AB, Multimodal-LDA, and Multimodal-SVM) were evaluated and compared. Results: The Multimodal-SVM model achieved the best predictive performance than the other models (P < 0.05). For the Multimodal-SVM model validation and testing sets, the areas under the receiver operating characteristic curves (AUCs) were 0.910 (95% CI, 0.894-0.926) and 0.851 (95% CI, 0.833-0.869), respectively. The AUCs of the Multimodal-SVM model were 0.920 (95% CI, 0.881-0.959) in the cN0 subgroup-1 cases and 0.828 (95% CI, 0.769-0.887) in the cN0 subgroup-2 cases. Conclusion: The ultrasound radiomics model only based on the PTC multimodal ultrasound image have high clinical value in predicting CLNM and can provide a reference for treatment decisions.

Quantification of plaque neovascularization using contrast ultrasound: a histologic validation.

AIMS: The density of vasa vasorum within atherosclerotic plaque correlates with histologic features of plaque vulnerability in post-mortem studies. Imaging methods to non-invasively detect vasa vasorum are limited. We hypothesized that contrast ultrasound (CUS) can quantify vasa vasorum during atherosclerosis progression. METHODS AND RESULTS: New Zealand white rabbits received a high-fat diet for 3 weeks, and bilateral femoral artery stenosis was induced by balloon injury. Contrast ultrasound femoral imaging was performed at baseline and 2, 4, and 6 weeks post injury to quantify adventitial videointensity. At each imaging time point 10 vessels were sectioned and stained with haematoxylin and eosin and von-Willebrand factor. Adventitial vasa vasorum density was quantified by counting the number of stained microvessels and their total cross-sectional area. Plaque size (per cent lumen area) progressed over time (P < 0.001), as did adventitial vasa vasorum density (P < 0.001). Plateau peak videointensity also progressed, demonstrating a strong linear correlation with histologic vasa vasorum density (P < 0.001). Receiver operating characteristic analysis indicated that a three-fold increase in median adventitial videointensity had a sensitivity of 100% and specificity of 88% for predicting abnormal neovascularization. CONCLUSION: We have histologically validated that CUS quantifies the development of adventitial vasa vasorum associated with atherosclerosis progression. This imaging technique has the potential for characterizing prognostically significant plaque features.

Deep learning for the diagnosis of suspicious thyroid nodules based on multimodal ultrasound images.

Objectives: This study aimed to differentially diagnose thyroid nodules (TNs) of Thyroid Imaging Reporting and Data System (TI-RADS) 3-5 categories using a deep learning (DL) model based on multimodal ultrasound (US) images and explore its auxiliary role for radiologists with varying degrees of experience. Methods: Preoperative multimodal US images of 1,138 TNs of TI-RADS 3-5 categories were randomly divided into a training set (n = 728), a validation set (n = 182), and a test set (n = 228) in a 4:1:1.25 ratio. Grayscale US (GSU), color Doppler flow imaging (CDFI), strain elastography (SE), and region of interest mask (Mask) images were acquired in both transverse and longitudinal sections, all of which were confirmed by pathology. In this study, fivefold cross-validation was used to evaluate the performance of the proposed DL model. The diagnostic performance of the mature DL model and radiologists in the test set was compared, and whether DL could assist radiologists in improving diagnostic performance was verified. Specificity, sensitivity, accuracy, positive predictive value, negative predictive value, and area under the receiver operating characteristics curves (AUC) were obtained. Results: The AUCs of DL in the differentiation of TNs were 0.858 based on (GSU + SE), 0.909 based on (GSU + CDFI), 0.906 based on (GSU + CDFI + SE), and 0.881 based (GSU + Mask), which were superior to that of 0.825-based single GSU (p = 0.014, p< 0.001, p< 0.001, and p = 0.002, respectively). The highest AUC of 0.928 was achieved by DL based on (G + C + E + M)US, the highest specificity of 89.5% was achieved by (G + C + E)US, and the highest accuracy of 86.2% and sensitivity of 86.9% were achieved by DL based on (G + C + M)US. With DL assistance, the AUC of junior radiologists increased from 0.720 to 0.796 (p< 0.001), which was slightly higher than that of senior radiologists without DL assistance (0.796 vs. 0.794, p > 0.05). Senior radiologists with DL assistance exhibited higher accuracy and comparable AUC than that of DL based on GSU (83.4% vs. 78.9%, p = 0.041; 0.822 vs. 0.825, p = 0.512). However, the AUC of DL based on multimodal US images was significantly higher than that based on visual diagnosis by radiologists (p< 0.05). Conclusion: The DL models based on multimodal US images showed exceptional performance in the differential diagnosis of suspicious TNs, effectively increased the diagnostic efficacy of TN evaluations by junior radiologists, and provided an objective assessment for the clinical and surgical management phases that follow.

Assessment of Left Ventricular Global Myocardial Work in Patients With Different Degrees of Coronary Artery Stenosis by Pressure-Strain Loops Analysis.

Global myocardial work (MW) analysis by pressure-strain loops (PSL) allows the non-invasive assessment of left ventricular (LV) function. We aimed to investigate the relationship between LV global MW and the degree of coronary artery stenosis in suspected coronary artery disease (CAD) patients with normal LV ejection fraction and regional wall motion. A total of 164 suspected CAD patients were divided into four groups according to coronary artery angiography. The results showed that global work efficiency (GWE) as the most significant predictor in all MW parameters had the optimal cut-off value of 94.5% for detecting moderate stenosis, and the sensitivity and specificity was 89.7% and 85.8%, respectively. A cut-off value of 94.0% for GWE was the most significant predictor of severe stenosis, and the sensitivity and specificity was 81.4% and 76.1%, respectively. In conclusion, LV global MW is a sensitive tool in detecting the degree of coronary artery stenosis and a potential valuable method to provide early diagnosis for CAD patients.

Prognostic potential of layer-specific global longitudinal strain in patients with non-ST-segment elevated acute coronary syndrome and preserved left ventricular ejection fraction.

This study sought to investigate the prognostic potential of layer-specific global longitudinal strain (GLS) in predicting cardiac events among non-ST-segment elevated acute coronary syndrome (NSTE-ACS) patients with preserved LVEF. In this prospective study, we enrolled 160 consecutive NSTE-ACS patients with preserved LVEF (≥ 50%) who underwent successful percutaneous coronary intervention (PCI). Transthoracic two-dimensional echocardiography examinations were performed within 48 h of admission (before PCI). Cardiac events were defined as all-cause death, re-infarction, and hospitalization for heart failure. During a median follow-up of 30.2 months, 23 patients (14.4%) developed cardiac events. GLS for all three myocardial layers were reduced in patients with adverse outcome (all P < 0.001). Yet GLSendo (area under curves = 0.85) and GLSmid (area under curves = 0.83) showed relatively higher predictive power than GLSepi when identifying patients with cardiac events. The best cut-off value of GLSendo was - 20.8%, with a diagnostic sensitivity and specificity of 87% and 71% respectively. A significant increase in the risk of cardiac events development was shown among patients with impaired layer GLS (log-rank test, P < 0.001). In conclusion, NSTE-ACS patients with preserved LVEF, layer GLS assessed before PCI all had good abilities to predict cardiac events, which might provide more prognostic information against conventional echocardiographic risk factors.

Targeted galectin-7 inhibition with ultrasound microbubble targeted gene therapy as a sole therapy to prevent acute rejection following heart transplantation in a Rodent model.

BACKGROUND: Despite significant advances in transplantation, acute cellular rejection (AR) remains a major obstacle that is most prevalent in the first months post heart transplantation (HT). Current treatments require high doses of immunosuppressive drugs followed by maintenance therapies that have systemic side effects including early infection. In this study, we attempted to prevent AR with a myocardial-targeted galectin-7-siRNA delivery method using cationic microbubbles (CMBs) combined with ultrasound targeted microbubble destruction (UTMD) to create local immunosuppression in a rat abdominal heterotopic heart transplantation acute rejection model. METHODS AND RESULTS: Galectin-7-siRNA (siGal-7) bound to CMBs were synthesized and effective ultrasound-targeted delivery of siGal-7 into target cells confirmed in vitro. Based on these observations, three transplant rat models were tested：①isograft (ISO); ② Allograft (ALLO) +UTMD; and ③ALLO + PBS. UTMD treatments were administered at 1, 3, 5, 7 days after HT. Galectin 7 expression was reduced by 50% compared to ALLO + PBS (p < 0.005), and this was associated with significant reductions in both galectin 7 and Interleukin-2 protein levels (p < 0.001). The ALLO + UTMD group had Grade II or less inflammatory infiltration and myocyte damage in 11/12 rats using International Society For Heart and Lung Transplantation grading, compared to 0/12 rats with this grading in the ALLO + PBS group at 10 days post HT (p < 0.001). CONCLUSIONS: Ultrasound-targeted galectin-7-siRNA knockdown with UTMD can prevent acute cellular rejection in the early period after allograft heart transplantation without the need for systemic immunosuppression. KEY WORDS: Microbubble, Acute Rejection, Heart Transplantation, Galectin-7, RNA.

Mesenchymal Stromal Cells from Patients with Cyanotic Congenital Heart Disease are Optimal Candidate for Cardiac Tissue Engineering.

Engineered heart tissues (EHTs) are regarded as being the most promising alternative to synthetic materials, and autologous mesenchymal stem cells (MSCs) are widely used as seeding cells. However, few studies have evaluated the feasibility of using MSCs from patients with cyanotic congenital heart disease (C-CHD) as seeding cells for EHTs, in comparison with cells from patients of acyanotic congenital heart disease (A-CHD). In the present study, we cultured MSCs from A-CHD and C-CHD patients in normoxia or hypoxia conditions, and compared their pro-angiogenic, anti-apoptotic and inflammation-modulatory potentials. In vivo, we seeded the cells into collagen patches conjugated with, or without, proangiogenic cytokines, which were used to repair the right ventricular outflow tract (RVOT) of rats. The in vitro results showed that C-CHD MSCs expressed higher levels of VEGFA and VEGFR2, and secreted more pro-angiogenic and anti-inflammatory cytokines under hypoxic conditions. On the other hand, apoptosis-related genes from C-CHD MSCs were modulated adaptably, converting these cells into an anti-apoptotic phenotype. In vivo studies demonstrated that in 4 weeks after RVOT reconstruction, cytokine-immobilized patches seeded with C-CHD MSCs exhibited preserved morphology, prolonged cell survival and enhanced angiogenesis compared to A-CHD MSCs. C-CHD MSCs that undergo "naturally hypoxic precondition" present a better cell source for EHTs, which would provide a promising individualized biomaterial for C-CHD patients.

Assessment of global and regional left ventricular function after surgical revascularization in patients with coronary artery disease by real-time triplane echocardiography.

OBJECTIVE: The purpose of this study was to evaluate the capability of real-time triplane echocardiography (RT3PE) for monitoring global and regional systolic function of the left ventricle (LV) after surgical revascularization and for evaluating the effect of surgery and predicting restenosis. METHODS: Forty-nine patients underwent RT3PE before and at 10 days and 1, 3, and 6 months after coronary artery bypass grafting (CABG). The global systolic function of the LV was assessed with the parameters of end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), and stroke volume (SV). The regional myocardial deformation was detected by triplane strain rate imaging. Recovery of myocardial function after surgery and the correlation between global and regional function were investigated. RESULTS: In 41 of the 49 patients, the EDV and ESV decreased, and the EF and SV increased gradually and showed statistical significance at 3 and 6 months after surgery (P < .05; P < .01). The systolic strain rate (SR(sys)) and systolic strain (S(sys)) increased, and the postsystolic strain index (PSI) decreased progressively after CABG, with significant changes in almost all studied segments at 6 months (P < .05; P < .01). In addition, recovery of the SR(sys), S(sys), and PSI at each follow-up stage after surgery correlated well with EF improvement, with a positive correlation between the SR(sys), S(sys), and EF and a negative correlation between the PSI and EF. Restenosis was suspected in the other 8 patients. The sensitivity, specificity, and accuracy of RT3PE to predict restenosis were 75.00%, 89.47%, and 85.19%, respectively. CONCLUSIONS: Real-time triplane echocardiography can be used to quantitatively assess global and regional myocardial function. It may represent a new, powerful method to monitor improvement of myocardial function after CABG and to predict restenosis.

Identification of a correlation between the sonographic appearance and molecular subtype of invasive breast cancer: A review of 311 cases.

PURPOSE: To identify the ultrasound and clinical features related to the different molecular subtypes of invasive breast cancer. METHODS: Sonographic and clinical data of 311 surgically confirmed breast cancer cases were retrospectively reviewed and compared based on various subtypes. RESULTS: Luminal A (LA) breast cancers were associated with a low histologic grade, spiculated margins, an echogenic rim and posterior acoustic attenuation. The human epidermal growth factor receptor 2-positive (HER2+) subtype was characterized by a high grade, indistinct and spiculated margins, enhanced posterior acoustics, calcifications, and vascularity. Triple negative breast cancers (TNBCs) were more likely to present with a high tumor grade, circumscribed and microlobulated margins, and the absence of an echogenic rim and calcifications; to be markedly hypoechoic; and to have posterior acoustic enhancement and hypovascularity. Luminal B (LB) cancers were more likely to be associated with an indistinct margin and relative vascularity. CONCLUSION: Our study demonstrated that the sonographic and clinical features of breast cancer were significantly correlated with the molecular subtype. The imaging findings of the different subtypes and their biological implications may provide additional auxiliary information for clinical diagnosis, systemic treatment and prognosis prediction.