Mass Spectrometry Imaging-Based Single-Cell Lipidomics Profiles Metabolic Signatures of Heart Failure.

Heart failure (HF), leading as one of the main causes of mortality, has become a serious public health issue with high prevalence around the world. Single cardiomyocyte (CM) metabolomics promises to revolutionize the understanding of HF pathogenesis since the metabolic remodeling in the human hearts plays a vital role in the disease progression. Unfortunately, current metabolic analysis is often limited by the dynamic features of metabolites and the critical needs for high-quality isolated CMs. Here, high-quality CMs were directly isolated from transgenic HF mice biopsies and further employed in the cellular metabolic analysis. The lipids landscape in individual CMs was profiled with a delayed extraction mode in time-of-flight secondary ion mass spectrometry. Specific metabolic signatures were identified to distinguish HF CMs from the control subjects, presenting as possible single-cell biomarkers. The spatial distributions of these signatures were imaged in single cells, and those were further found to be strongly associated with lipoprotein metabolism, transmembrane transport, and signal transduction. Taken together, we systematically studied the lipid metabolism of single CMs with a mass spectrometry imaging method, which directly benefited the identification of HF-associated signatures and a deeper understanding of HF-related metabolic pathways.

Acylation-stimulating protein and heart failure progression in arrhythmogenic right ventricular cardiomyopathy.

AIMS:Our previous studies suggested that the complement system was critical in the prognosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). The acylation-stimulating protein (ASP), generated through the alternate complement pathway, was reported to regulate lipogenesis and triglyceride storage. This study aimed to investigate the role of ASP in predicting adverse cardiac events in an ARVC cohort.METHODS AND RESULTS:We enrolled 111 ARVC patients and 106 healthy volunteers, and measured their plasma ASP levels using enzyme-linked immunosorbent assays. Plasma ASP levels were significantly higher in the ARVC patients than in the healthy controls (2325.22 ± 20.08 vs. 2189.75 ± 15.55, P < 0.001), with a similar trend observed in the myocardial explant assay. Spearman correlation analysis indicated plasma ASP level associated with cardiac structural (right ventricular internal dimension, P = 0.006) and functional remodelling (left ventricular ejection fraction, P = 0.002) in ARVC patients. The ARVC patients were followed up for an average of 17.79 ± 1.09 months. Heart failure-associated events (HFAEs) were defined as heart transplantation, on a cardiac transplant list, or death due to end-stage heart failure. Plasma ASP levels in patients with HFAEs were significantly higher than in those without clinical events (2486.03 ± 26.70 vs. 2268.83 ± 23.51, P < 0.001) or those with malignant arrhythmic events (2486.03 ± 26.70 vs. 2297.80 ± 60.46, P = 0.008). LASSO (least absolute shrinkage and selection operator) and multivariable Cox regression analyses showed the ASP level (HR = 1.004, 95% CI [1.002,1.006], P = 0.002) was an independent predictor for adverse HFAEs in ARVC patients. The spline-fitting procedure was applied to illustrate the HFAE-free probabilities at different time points.CONCLUSIONS:Our results suggest that plasma ASP may be a useful biomarker in prediction of adverse HF-associated events in ARVC patients.

The impact of antiplatelet therapy on the descending thoracic aorta fate and long-term prognosis of extensive repaired type A aortic dissection.

OBJECTIVES:To evaluate the impact of antiplatelet therapy on the long-term descending thoracic aorta (DTA) fate and prognosis of extensive repaired type A aortic dissection (TAAD).METHODS:1147 eligible TAAD patients from January 2010 to December 2019 were stratified into non-antiplatelet (n = 754) and antiplatelet groups (n = 393). The primary end points were overall survival, and DTA remodelling, including false lumen (FL) thrombosis and aortic redilation. The secondary end points were DTA reintervention or rupture and major bleeding events (MBEs).RESULTS:The 5-year overall survival rates were 95.6% and 94.3% in the non-antiplatelet and antiplatelet groups (P = 0.53), respectively. In the stent covering segment, the 1-year FL complete thrombosis rates were 92.1% and 92.4% in the non-antiplatelet and antiplatelet groups (P = 0.27), respectively, while in the stent uncovering segment, the 5-year FL complete thrombosis rates were 47.1% and 56.5% in the non-antiplatelet and antiplatelet groups (P = 0.12), respectively. Antiplatelet therapy was not an independent predictor of aortic redilation at the pulmonary artery bifurcation (β±SE = -0.128 ± 0.203, P = 0.53), diaphragm (β±SE = 0.143 ± 0.152, P = 0.35) or coeliac artery (β±SE = 0.049 ± 0.136, P = 0.72) levels. With death as a competing risk, the cumulative incidences of DTA reintervention or rupture at 5 years were 4.6% and 4.0% in the non-antiplatelet and antiplatelet groups (sHR = 0.85, 95% CI, 0.49∼1.19; P = 0.58), respectively, and the 5-year cumulative incidences of MBEs were 2.1% and 2.3% in the non-antiplatelet and antiplatelet groups (sHR = 0.82, 95% CI, 0.56∼2.67; P = 0.62), respectively.CONCLUSIONS:Antiplatelet therapy did not impact long-term DTA FL thrombosis, redilation, reintervention or rupture, MBEs or overall survival on extensive repaired TAAD. Thus, antiplatelet therapy can be administered as indicated on extensive repaired TAAD.

Hybrid Technique on the Total Arch Replacement for Type A Aortic Dissection: 12-year Clinical and Radiographical Outcomes From a Single Center.

Objective:Hybrid total arch replacement (HTAR) was an alternative for type A aortic dissection (TAAD). This study aimed to evaluate the clinical and radiographical outcomes of HTAR for TAAD and to evaluate the clinical outcomes of performing this procedure under mild hypothermia.Methods:A total of 209 patients who underwent HTAR for TAAD were retrospectively analyzed and stratified into mild (n = 48) and moderate (n = 161) hypothermia groups to evaluate the effects of mild hypothermia on the clinical outcomes. Long-term clinical outcomes were evaluated by the overall survival and adverse aortic events (AAEs). A total of 176 patients with preoperative and at least one-time postoperative aortic computed tomography angiography in our institute were included for evaluating the late aortic remodeling (aortic diameter and false lumen thrombosis).Results:The median follow-up period was 48.3 (interquartile range [IQR] = 28.4-73.7) months. The overall survival rate was 88.0, 83.2, and 77.1% at the 1, 5, and 10 years, respectively, and in the presence of death as a competing risk, the cumulative incidence of AAEs was 4.8, 9.9, and 12.1% at the 1, 5, and 10 years. The aortic diameters were stable in the descending thoracic and abdominal aorta (P > 0.05 in all the measured aortic segments). A total of 100% complete false lumen thrombosis rate in the stent covered and distal thoracic aorta were achieved at 1 year (64/64) and 4 years (18/18), respectively after HTAR. The overall composite adverse events morbidity and mortality were 18.7 and 10.0%. Mild hypothermia (31.2, IQR = 30.2-32.0) achieved similar composite adverse events morbidity (mild: 14.6 vs. moderate: 19.9%, P = 0.41) and early mortality (mild: 10.4 vs. moderate: 9.9%, P = 1.00) compared with moderate hypothermia (median 27.7, IQR = 27-28.1) group, but mild hypothermia group needed shorter cardiopulmonary bypass (mild: 111, IQR = 93-145 min vs. moderate: 136, IQR = 114-173 min, P < 0.001) and aortic cross-clamping (mild: 45, IQR = 37-56 min vs. moderate: 78, IQR = 54-107 min, P < 0.001) time.Conclusion:Hybrid total arch replacement achieved desirable early and long-term clinical outcomes for TAAD. Performing HTAR under mild hypothermia was as safe as under moderate hypothermia. After HTAR for TAAD, dissected aorta achieved desirable aortic remodeling, presenting as stable aortic diameters and false lumen complete thrombosis. In all, HTAR is a practical treatment for TAAD.

Interleukin 2 receptor subunit beta as a novel hub gene plays a potential role in the immune microenvironment of abdominal aortic aneurysms.

BACKGROUND:Abdominal aortic aneurysm (AAA) is potentially life threatening and characterized by immune-inflammatory cell infiltration and extracellular matrix degradation. Currently, pharmacotherapy mainly aims to control risk factors without reversion of the dilated aorta. This study analyzed the immune-inflammatory response and identified the immune-related hub genes of AAA.METHOD:Gene Expression Omnibus datasets (GSE57691, GSE47472 and GSE7084) were downloaded. After identification of GSE57691 differentially expressed genes (DEGs), weighted gene co-expression network analysis of the DEGs was performed. Through enrichment analysis of each module and screening in Immunology Database and Analysis Portal, immune-related hub genes were identified via protein-protein interaction (PPI) network construction and lasso regression. CIBERSORT was utilized to analyze AAA immune infiltration. The correlations between the immune-related hub genes and infiltrating immune cells were investigated. Receiver operating characteristic (ROC) curve analysis was performed to determine immune-related hub gene cutoff values, which were validated in GSE47472 and GSE7084.RESULT:In GSE57691, 1,018 DEGs were identified. Five modules were identified in the co-expression network. The blue and green modules were found to be related to immune-inflammatory responses, and 61 immune-related genes were identified. PPI and lasso regression analyses identified FOS, IL-6 and IL2RB as AAA immune-related hub genes. CIBERSORT analysis indicated significantly increased infiltration of naive B cells, memory activated CD4 T cells, follicular helper T cells, monocytes and M1 macrophages and significantly decreased infiltration of M2 macrophages in AAA compared with normal samples. IL2RB was more strongly associated with immune infiltration in AAA than were FOS and IL6. The IL2RB area under the ROC curve (AUC) value was > 0.9 in both the training and validation set, demonstrating its strong, stable diagnostic value in AAA.CONCLUSION:AAA and normal samples had different immune infiltration statuses. IL2RB was identified as an immune-related hub gene and a potential hub gene with significant diagnostic value in AAA.

Multifaceted Spatial and Functional Zonation of Cardiac Cells in Adult Human Heart.

Cardiac xenotransplantation: a promising way to treat advanced heart failure.

Cardiac xenotransplantation (CXTx) might be a promising approach to bridge the gap between the supply and demand of a donor heart. The survival of cardiac xenograft has been significantly extended in pig-to-nonhuman primate (NHP) CXTx, with records of 195 days and 945 days for orthotropic and heterotopic CXTx, respectively. To present the history of CXTx, we list the reported clinical CXTx, compare pigs and NHPs as sources of hearts, and compare three different kinds of preclinical CXTx models. The application of genetically modified pigs and novel immunosuppressive drugs accelerates the development of CXTx, and we summarize the reported pig-to-NHP CXTx with detailed information. Besides, we discuss the underlining mechanisms and potential preventive strategies of immunological barriers, including hyperacute rejection, acute humoral xenograft rejection, acute cellular xenograft rejection, chronic rejection, coagulation dysfunction, and systemic inflammation. Though intense cellular infiltration in cardiac xenograft has only been documented in a small number of studies, we especially stress the importance of cellular rejection in CXTx, because we believe it is often masked by the rapid and strong humoral response and it may eventually become a more important and common type of xenograft rejection. In addition, we conclude other obstacles as well as possible solutions in CXTx, such as perioperative cardiac xenograft dysfunction, detrimental xenograft overgrowth, and porcine endogenous retroviruses. Finally, we briefly introduce several other approaches that have been proposed to deal with the organ heart shortage crisis, and we firmly believe that CXTx provides the best near-term solution.

Impact of frozen elephant trunk on the outcomes of thoracoabdominal aortic repair with normothermic iliac perfusion.

Background:Frozen elephant trunk technique (FET) has been proven to provide an excellent landing zone for second-stage thoracoabdominal (TA) aortic repair. The aim of this study was to evaluate the impact of FET in TA aortic repair with normothermic iliac perfusion.Methods:From January 2008 to December 2019, 144 patients undergoing TA repair with normothermic iliac perfusion were enrolled in this study. Early and mid-term outcomes of patients with previous FET implantation (group A, n = 62) were compared with patients without previous FET implantation (group B, n = 82). The logistic regression analysis was performed to investigate the risk factors for adverse events, which were defined as early death, permanent stroke, permanent paraplegia, or permanent renal failure necessitating dialysis.Results:The proximal aortic clamp time and operating time was 14.26 ± 5.57 min and 357.40 ± 94.51 respectively in group A, which were both significantly shorter than that in group B (18.67 ± 5.24 min and 18.67 ± 5.24 min). The incidence of adverse event was significantly lower in group A than that in group B (9.7% vs. 25.6%, P = 0.027). There was no significant difference between two groups with regard to other complications or late outcomes. In addition, age >50 years, a Ccr < 90 ml/min/1.73 m2 and the operating time were identified as significant risk factors through logistic regression analysis for adverse events of TA repair.Conclusions:The FET technique simplifies the operative technique of proximal anastomosis, decreases the operating time and improves the early outcomes in TA repair, whereas does not provide a significant benefit with regard to late outcomes. Long-term follow-up and studies with larger sample sizes are necessary for further confirmation.

Novel plasma biomarkers predicting biventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of the myocardium and ventricular arrhythmias. Biventricular involvement in ARVC may lead to heart failure. This study aimed to investigate the role of plasma biomarkers soluble (s)ST2, Galectin-3 (Gal-3) and GDF-15 in predicting biventricular involvement and adverse outcomes in ARVC.METHODS AND RESULTS:ARVC patients from 2 independent cohorts, were studied. The Bejing (Chinese) cohort (n = 108) was the discovery cohort, whereas the Zurich (Swiss) cohort (n = 47) served as validation. All patients had a definite ARVC diagnosis at time of blood withdrawal. Biomarkers were independently correlated with NT-proBNP and left ventricular (LV)-function. ARVC patients with LV involvement had higher levels of sST2 and GDF-15 as compared to controls and patients with isolated right ventricle (RV) involvement. sST2 and GDF-15 were significantly correlated with late gadolinium enhancement in CMR and with adverse heart failure outcomes. Gal-3 was elevated in ARVC patients with and without LV involvement. The combined use of the three biomarkers (sST2, GDF-15 and NT-proBNP) showed the best performance in predicting LV involvement in both cohorts. Plasma drawn from the coronary arteries and coronary sinus indicated a transmyocardial elevation of sST2, but no transmyocardial gradient of GDF-15. After heart transplantation, both sST2 and GDF-15 returned to near-normal levels.CONCLUSION:Our study showed that sST2 and GDF-15 may predict biventricular involvement in ARVC. The combined use of sST2, GDF-15 and NT-proBNP showed the best prediction of biventricular involvement in ARVC.

Investigation of Lipid Metabolism in Dynamic Progression of Coronary Artery Atherosclerosis of Humans by Time-of-Flight Secondary Ion Mass Spectrometry.

Alterations in lipid metabolites in coronary artery tissues are phenotypic changes in the progression of atherosclerosis (AS). A full picture of the spatiotemporal distribution of lipid metabolites in coronary AS is needed for a deeper understanding of its pathology and the identification of potential biomarkers of disease progression. In this work, the changes in species, quantity, and distribution of lipid metabolites at different stages of AS, which were standardized by the disease areas, were analyzed through the high spatial resolution- and high sensitivity-time-of-flight secondary ion mass spectrometry (ToF-SIMS) under delayed extraction mode. Based on high lateral resolution imaging, we further analyzed the ToF-SIMS data extracted from the subregions of AS lesion tissues at different disease progression stages by semiquantitative comparison, clustering analysis (t-stochastic neighbor embedding and HCA), and KEGG enrichment. Thus, a much-detailed description of lipids' features in coronary AS was achieved. We constructed a ToF-SIMS mass spectrometry database of coronary AS lipids. 40 specific lipid metabolites with distinctive patterns between different pathological stages were obtained. Chemical imaging unveiled further details regarding the spatial distribution of lipids. Moreover, linoleic acid and arachidonic acid metabolic pathway were predicted to be critical in AS progression.

Mass Spectrometry Imaging-Based Single-Cell Lipidomics Profiles Metabolic Signatures of Heart Failure.

Heart failure (HF), leading as one of the main causes of mortality, has become a serious public health issue with high prevalence around the world. Single cardiomyocyte (CM) metabolomics promises to revolutionize the understanding of HF pathogenesis since the metabolic remodeling in the human hearts plays a vital role in the disease progression. Unfortunately, current metabolic analysis is often limited by the dynamic features of metabolites and the critical needs for high-quality isolated CMs. Here, high-quality CMs were directly isolated from transgenic HF mice biopsies and further employed in the cellular metabolic analysis. The lipids landscape in individual CMs was profiled with a delayed extraction mode in time-of-flight secondary ion mass spectrometry. Specific metabolic signatures were identified to distinguish HF CMs from the control subjects, presenting as possible single-cell biomarkers. The spatial distributions of these signatures were imaged in single cells, and those were further found to be strongly associated with lipoprotein metabolism, transmembrane transport, and signal transduction. Taken together, we systematically studied the lipid metabolism of single CMs with a mass spectrometry imaging method, which directly benefited the identification of HF-associated signatures and a deeper understanding of HF-related metabolic pathways.

Acylation-stimulating protein and heart failure progression in arrhythmogenic right ventricular cardiomyopathy.

AIMS:Our previous studies suggested that the complement system was critical in the prognosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). The acylation-stimulating protein (ASP), generated through the alternate complement pathway, was reported to regulate lipogenesis and triglyceride storage. This study aimed to investigate the role of ASP in predicting adverse cardiac events in an ARVC cohort.METHODS AND RESULTS:We enrolled 111 ARVC patients and 106 healthy volunteers, and measured their plasma ASP levels using enzyme-linked immunosorbent assays. Plasma ASP levels were significantly higher in the ARVC patients than in the healthy controls (2325.22 ± 20.08 vs. 2189.75 ± 15.55, P < 0.001), with a similar trend observed in the myocardial explant assay. Spearman correlation analysis indicated plasma ASP level associated with cardiac structural (right ventricular internal dimension, P = 0.006) and functional remodelling (left ventricular ejection fraction, P = 0.002) in ARVC patients. The ARVC patients were followed up for an average of 17.79 ± 1.09 months. Heart failure-associated events (HFAEs) were defined as heart transplantation, on a cardiac transplant list, or death due to end-stage heart failure. Plasma ASP levels in patients with HFAEs were significantly higher than in those without clinical events (2486.03 ± 26.70 vs. 2268.83 ± 23.51, P < 0.001) or those with malignant arrhythmic events (2486.03 ± 26.70 vs. 2297.80 ± 60.46, P = 0.008). LASSO (least absolute shrinkage and selection operator) and multivariable Cox regression analyses showed the ASP level (HR = 1.004, 95% CI [1.002,1.006], P = 0.002) was an independent predictor for adverse HFAEs in ARVC patients. The spline-fitting procedure was applied to illustrate the HFAE-free probabilities at different time points.CONCLUSIONS:Our results suggest that plasma ASP may be a useful biomarker in prediction of adverse HF-associated events in ARVC patients.

The impact of antiplatelet therapy on the descending thoracic aorta fate and long-term prognosis of extensive repaired type A aortic dissection.

OBJECTIVES:To evaluate the impact of antiplatelet therapy on the long-term descending thoracic aorta (DTA) fate and prognosis of extensive repaired type A aortic dissection (TAAD).METHODS:1147 eligible TAAD patients from January 2010 to December 2019 were stratified into non-antiplatelet (n = 754) and antiplatelet groups (n = 393). The primary end points were overall survival, and DTA remodelling, including false lumen (FL) thrombosis and aortic redilation. The secondary end points were DTA reintervention or rupture and major bleeding events (MBEs).RESULTS:The 5-year overall survival rates were 95.6% and 94.3% in the non-antiplatelet and antiplatelet groups (P = 0.53), respectively. In the stent covering segment, the 1-year FL complete thrombosis rates were 92.1% and 92.4% in the non-antiplatelet and antiplatelet groups (P = 0.27), respectively, while in the stent uncovering segment, the 5-year FL complete thrombosis rates were 47.1% and 56.5% in the non-antiplatelet and antiplatelet groups (P = 0.12), respectively. Antiplatelet therapy was not an independent predictor of aortic redilation at the pulmonary artery bifurcation (β±SE = -0.128 ± 0.203, P = 0.53), diaphragm (β±SE = 0.143 ± 0.152, P = 0.35) or coeliac artery (β±SE = 0.049 ± 0.136, P = 0.72) levels. With death as a competing risk, the cumulative incidences of DTA reintervention or rupture at 5 years were 4.6% and 4.0% in the non-antiplatelet and antiplatelet groups (sHR = 0.85, 95% CI, 0.49∼1.19; P = 0.58), respectively, and the 5-year cumulative incidences of MBEs were 2.1% and 2.3% in the non-antiplatelet and antiplatelet groups (sHR = 0.82, 95% CI, 0.56∼2.67; P = 0.62), respectively.CONCLUSIONS:Antiplatelet therapy did not impact long-term DTA FL thrombosis, redilation, reintervention or rupture, MBEs or overall survival on extensive repaired TAAD. Thus, antiplatelet therapy can be administered as indicated on extensive repaired TAAD.

Hybrid Technique on the Total Arch Replacement for Type A Aortic Dissection: 12-year Clinical and Radiographical Outcomes From a Single Center.

Objective:Hybrid total arch replacement (HTAR) was an alternative for type A aortic dissection (TAAD). This study aimed to evaluate the clinical and radiographical outcomes of HTAR for TAAD and to evaluate the clinical outcomes of performing this procedure under mild hypothermia.Methods:A total of 209 patients who underwent HTAR for TAAD were retrospectively analyzed and stratified into mild (n = 48) and moderate (n = 161) hypothermia groups to evaluate the effects of mild hypothermia on the clinical outcomes. Long-term clinical outcomes were evaluated by the overall survival and adverse aortic events (AAEs). A total of 176 patients with preoperative and at least one-time postoperative aortic computed tomography angiography in our institute were included for evaluating the late aortic remodeling (aortic diameter and false lumen thrombosis).Results:The median follow-up period was 48.3 (interquartile range [IQR] = 28.4-73.7) months. The overall survival rate was 88.0, 83.2, and 77.1% at the 1, 5, and 10 years, respectively, and in the presence of death as a competing risk, the cumulative incidence of AAEs was 4.8, 9.9, and 12.1% at the 1, 5, and 10 years. The aortic diameters were stable in the descending thoracic and abdominal aorta (P > 0.05 in all the measured aortic segments). A total of 100% complete false lumen thrombosis rate in the stent covered and distal thoracic aorta were achieved at 1 year (64/64) and 4 years (18/18), respectively after HTAR. The overall composite adverse events morbidity and mortality were 18.7 and 10.0%. Mild hypothermia (31.2, IQR = 30.2-32.0) achieved similar composite adverse events morbidity (mild: 14.6 vs. moderate: 19.9%, P = 0.41) and early mortality (mild: 10.4 vs. moderate: 9.9%, P = 1.00) compared with moderate hypothermia (median 27.7, IQR = 27-28.1) group, but mild hypothermia group needed shorter cardiopulmonary bypass (mild: 111, IQR = 93-145 min vs. moderate: 136, IQR = 114-173 min, P < 0.001) and aortic cross-clamping (mild: 45, IQR = 37-56 min vs. moderate: 78, IQR = 54-107 min, P < 0.001) time.Conclusion:Hybrid total arch replacement achieved desirable early and long-term clinical outcomes for TAAD. Performing HTAR under mild hypothermia was as safe as under moderate hypothermia. After HTAR for TAAD, dissected aorta achieved desirable aortic remodeling, presenting as stable aortic diameters and false lumen complete thrombosis. In all, HTAR is a practical treatment for TAAD.

Interleukin 2 receptor subunit beta as a novel hub gene plays a potential role in the immune microenvironment of abdominal aortic aneurysms.

BACKGROUND:Abdominal aortic aneurysm (AAA) is potentially life threatening and characterized by immune-inflammatory cell infiltration and extracellular matrix degradation. Currently, pharmacotherapy mainly aims to control risk factors without reversion of the dilated aorta. This study analyzed the immune-inflammatory response and identified the immune-related hub genes of AAA.METHOD:Gene Expression Omnibus datasets (GSE57691, GSE47472 and GSE7084) were downloaded. After identification of GSE57691 differentially expressed genes (DEGs), weighted gene co-expression network analysis of the DEGs was performed. Through enrichment analysis of each module and screening in Immunology Database and Analysis Portal, immune-related hub genes were identified via protein-protein interaction (PPI) network construction and lasso regression. CIBERSORT was utilized to analyze AAA immune infiltration. The correlations between the immune-related hub genes and infiltrating immune cells were investigated. Receiver operating characteristic (ROC) curve analysis was performed to determine immune-related hub gene cutoff values, which were validated in GSE47472 and GSE7084.RESULT:In GSE57691, 1,018 DEGs were identified. Five modules were identified in the co-expression network. The blue and green modules were found to be related to immune-inflammatory responses, and 61 immune-related genes were identified. PPI and lasso regression analyses identified FOS, IL-6 and IL2RB as AAA immune-related hub genes. CIBERSORT analysis indicated significantly increased infiltration of naive B cells, memory activated CD4 T cells, follicular helper T cells, monocytes and M1 macrophages and significantly decreased infiltration of M2 macrophages in AAA compared with normal samples. IL2RB was more strongly associated with immune infiltration in AAA than were FOS and IL6. The IL2RB area under the ROC curve (AUC) value was > 0.9 in both the training and validation set, demonstrating its strong, stable diagnostic value in AAA.CONCLUSION:AAA and normal samples had different immune infiltration statuses. IL2RB was identified as an immune-related hub gene and a potential hub gene with significant diagnostic value in AAA.

Multifaceted Spatial and Functional Zonation of Cardiac Cells in Adult Human Heart.

Cardiac xenotransplantation: a promising way to treat advanced heart failure.

Cardiac xenotransplantation (CXTx) might be a promising approach to bridge the gap between the supply and demand of a donor heart. The survival of cardiac xenograft has been significantly extended in pig-to-nonhuman primate (NHP) CXTx, with records of 195 days and 945 days for orthotropic and heterotopic CXTx, respectively. To present the history of CXTx, we list the reported clinical CXTx, compare pigs and NHPs as sources of hearts, and compare three different kinds of preclinical CXTx models. The application of genetically modified pigs and novel immunosuppressive drugs accelerates the development of CXTx, and we summarize the reported pig-to-NHP CXTx with detailed information. Besides, we discuss the underlining mechanisms and potential preventive strategies of immunological barriers, including hyperacute rejection, acute humoral xenograft rejection, acute cellular xenograft rejection, chronic rejection, coagulation dysfunction, and systemic inflammation. Though intense cellular infiltration in cardiac xenograft has only been documented in a small number of studies, we especially stress the importance of cellular rejection in CXTx, because we believe it is often masked by the rapid and strong humoral response and it may eventually become a more important and common type of xenograft rejection. In addition, we conclude other obstacles as well as possible solutions in CXTx, such as perioperative cardiac xenograft dysfunction, detrimental xenograft overgrowth, and porcine endogenous retroviruses. Finally, we briefly introduce several other approaches that have been proposed to deal with the organ heart shortage crisis, and we firmly believe that CXTx provides the best near-term solution.

Impact of frozen elephant trunk on the outcomes of thoracoabdominal aortic repair with normothermic iliac perfusion.

Background:Frozen elephant trunk technique (FET) has been proven to provide an excellent landing zone for second-stage thoracoabdominal (TA) aortic repair. The aim of this study was to evaluate the impact of FET in TA aortic repair with normothermic iliac perfusion.Methods:From January 2008 to December 2019, 144 patients undergoing TA repair with normothermic iliac perfusion were enrolled in this study. Early and mid-term outcomes of patients with previous FET implantation (group A, n = 62) were compared with patients without previous FET implantation (group B, n = 82). The logistic regression analysis was performed to investigate the risk factors for adverse events, which were defined as early death, permanent stroke, permanent paraplegia, or permanent renal failure necessitating dialysis.Results:The proximal aortic clamp time and operating time was 14.26 ± 5.57 min and 357.40 ± 94.51 respectively in group A, which were both significantly shorter than that in group B (18.67 ± 5.24 min and 18.67 ± 5.24 min). The incidence of adverse event was significantly lower in group A than that in group B (9.7% vs. 25.6%, P = 0.027). There was no significant difference between two groups with regard to other complications or late outcomes. In addition, age >50 years, a Ccr < 90 ml/min/1.73 m2 and the operating time were identified as significant risk factors through logistic regression analysis for adverse events of TA repair.Conclusions:The FET technique simplifies the operative technique of proximal anastomosis, decreases the operating time and improves the early outcomes in TA repair, whereas does not provide a significant benefit with regard to late outcomes. Long-term follow-up and studies with larger sample sizes are necessary for further confirmation.

Novel plasma biomarkers predicting biventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of the myocardium and ventricular arrhythmias. Biventricular involvement in ARVC may lead to heart failure. This study aimed to investigate the role of plasma biomarkers soluble (s)ST2, Galectin-3 (Gal-3) and GDF-15 in predicting biventricular involvement and adverse outcomes in ARVC.METHODS AND RESULTS:ARVC patients from 2 independent cohorts, were studied. The Bejing (Chinese) cohort (n = 108) was the discovery cohort, whereas the Zurich (Swiss) cohort (n = 47) served as validation. All patients had a definite ARVC diagnosis at time of blood withdrawal. Biomarkers were independently correlated with NT-proBNP and left ventricular (LV)-function. ARVC patients with LV involvement had higher levels of sST2 and GDF-15 as compared to controls and patients with isolated right ventricle (RV) involvement. sST2 and GDF-15 were significantly correlated with late gadolinium enhancement in CMR and with adverse heart failure outcomes. Gal-3 was elevated in ARVC patients with and without LV involvement. The combined use of the three biomarkers (sST2, GDF-15 and NT-proBNP) showed the best performance in predicting LV involvement in both cohorts. Plasma drawn from the coronary arteries and coronary sinus indicated a transmyocardial elevation of sST2, but no transmyocardial gradient of GDF-15. After heart transplantation, both sST2 and GDF-15 returned to near-normal levels.CONCLUSION:Our study showed that sST2 and GDF-15 may predict biventricular involvement in ARVC. The combined use of sST2, GDF-15 and NT-proBNP showed the best prediction of biventricular involvement in ARVC.

Investigation of Lipid Metabolism in Dynamic Progression of Coronary Artery Atherosclerosis of Humans by Time-of-Flight Secondary Ion Mass Spectrometry.

Alterations in lipid metabolites in coronary artery tissues are phenotypic changes in the progression of atherosclerosis (AS). A full picture of the spatiotemporal distribution of lipid metabolites in coronary AS is needed for a deeper understanding of its pathology and the identification of potential biomarkers of disease progression. In this work, the changes in species, quantity, and distribution of lipid metabolites at different stages of AS, which were standardized by the disease areas, were analyzed through the high spatial resolution- and high sensitivity-time-of-flight secondary ion mass spectrometry (ToF-SIMS) under delayed extraction mode. Based on high lateral resolution imaging, we further analyzed the ToF-SIMS data extracted from the subregions of AS lesion tissues at different disease progression stages by semiquantitative comparison, clustering analysis (t-stochastic neighbor embedding and HCA), and KEGG enrichment. Thus, a much-detailed description of lipids' features in coronary AS was achieved. We constructed a ToF-SIMS mass spectrometry database of coronary AS lipids. 40 specific lipid metabolites with distinctive patterns between different pathological stages were obtained. Chemical imaging unveiled further details regarding the spatial distribution of lipids. Moreover, linoleic acid and arachidonic acid metabolic pathway were predicted to be critical in AS progression.