Incorporating machine learning and PPI networks to identify mitochondrial fission-related immune markers in abdominal aortic aneurysms.

Purpose: The aim of this study is to investigate abdominal aortic aneurysm (AAA), a disease characterised by inflammation and progressive vasodilatation, for novel gene-targeted therapeutic loci. Methods: To do this, we used weighted co-expression network analysis (WGCNA) and differential gene analysis on samples from the GEO database. Additionally, we carried out enrichment analysis and determined that the blue module was of interest. Additionally, we performed an investigation of immune infiltration and discovered genes linked to immune evasion and mitochondrial fission. In order to screen for feature genes, we used two PPI network gene selection methods and five machine learning methods. This allowed us to identify the most featrue genes (MFGs). The expression of the MFGs in various cell subgroups was then evaluated by analysis of single cell samples from AAA. Additionally, we looked at the expression levels of the MFGs as well as the levels of inflammatory immune-related markers in cellular and animal models of AAA. Finally, we predicted potential drugs that could be targeted for the treatment of AAA. Results: Our research identified 1249 up-regulated differential genes and 3653 down-regulated differential genes. Through WGCNA, we also discovered 44 genes in the blue module. By taking the point where several strategies for gene selection overlap, the MFG (ITGAL and SELL) was produced. We discovered through single cell research that the MFG were specifically expressed in T regulatory cells, NK cells, B lineage, and lymphocytes. In both animal and cellular models of AAA, the MFGs' mRNA levels rose. Conclusion: We searched for the AAA novel targeted gene (ITGAL and SELL), which most likely function through lymphocytes of the B lineage, NK cells, T regulatory cells, and B lineage. This analysis gave AAA a brand-new goal to treat or prevent the disease.

Muscone inhibits angiotensin II-induced cardiac hypertrophy through the STAT3, MAPK and TGF-ß/SMAD signaling pathways.

BACKGROUND: Muscone is a chemical monomer derived from musk. Although many studies have confirmed the cardioprotective effects of muscone, the effects of muscone on cardiac hypertrophy and its potential mechanisms are unclear.The aim of the present study was to investigate the effect of muscone on angiotensin (Ang) II-induced cardiac hypertrophy. METHODS AND RESULTS: In the present study, we found for the first time that muscone exerted inhibitory effects on Ang II-induced cardiac hypertrophy and cardiac injury in mice. Cardiac function was analyzed by echocardiography measurement, and the degree of cardiac fibrosis was determined by the quantitative real-time polymerase chain reaction (qRT-PCR), Masson trichrome staining and western blot assay. Secondly, qRT-PCR experiment showed that muscone attenuated cardiac injury by reducing the secretion of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Moreover, western blot analysis found that muscone exerted cardio-protective effects by inhibiting phosphorylation of key proteins in the STAT3, MAPK and TGF-ß/SMAD pathways. In addition, CCK-8 and determination of serum biochemical indexes showed that no significant toxicity or side effects of muscone on normal cells and organs. CONCLUSIONS: Muscone could attenuate Ang II-induced cardiac hypertrophy, in part, by inhibiting the STAT3, MAPK, and TGF-ß/SMAD signaling pathways.

The influence of dipeptidyl peptidase-4 inhibitor on the progression of type B intramural hematoma.

Objectives: Investigating whether dipeptidyl peptidase-4 inhibitors (DPP4i) could influence the progression of type B intramural hematoma (IMHB) in patients with diabetes mellitus (DM). Materials and methods: Uncomplicated IMHB patients were matched by age, sex, and body mass index. Cox proportional hazard models were constructed to identify risk factors. A Kaplan-Meier survival analysis was used to estimate all-cause and aorta-related mortality. Results: Ninety-six matched IMHB patients were divided into Group A (n = 32, IMHB patients without DM), Group B (n = 32, IMHB patients with DMreceiving oral antidiabetic drugs [without DPP4i]) and Group C (n = 32, IMHB patients with DM receiving oral antidiabetic drugs [with DPP4i]). Group C had the lowest rate of aorta-related adverse events (3.1%), aorta-related mortality (0.0%) and reintervention (3.1%). Cox proportional hazard models revealed that a lower eosinophil count (per 0.1, HR, 0.48; 95% CI, 0.29-0.79, P = 0.004) and a higher neutrophil to lymphocyte ratio (NLR) (HR, 1.13; 95% CI, 1.05-1.21, P = 0.001) were associated with higher occurrences of aorta-related adverse events. A lower eosinophil count (per 0.1, HR, 0.40; 95% CI, 0.18-0.89, P = 0.025) and a higher NLR (HR, 1.19; 95% CI, 1.08-1.32, P = 0.001) were also associated with increased aorta-related mortality. Conclusion: DPP4i administration in DM patients with IMHB was associated with lower aorta-related mortality and more benign progression than in those who did not receive DPP4i or those without DM. Furthermore, a higher eosinophil count and a lower NLR ratio are potential protective factors that may explain the potential therapeutic benefit of DPP4i.

Rhein ameliorates transverse aortic constriction-induced cardiac hypertrophy via regulating STAT3 and p38 MAPK signaling pathways.

The progression from compensatory hypertrophy to heart failure is difficult to reverse, in part due to extracellular matrix fibrosis and continuous activation of abnormal signaling pathways. Although the anthraquinone rhein has been examined for its many biological properties, it is not clear whether it has therapeutic value in the treatment of cardiac hypertrophy and heart failure. In this study, we report for the first time that rhein can ameliorate transverse aortic constriction (TAC)-induced cardiac hypertrophy and other cardiac damage in vivo and in vitro. In addition, rhein can reduce cardiac hypertrophy by attenuating atrial natriuretic peptide, brain natriuretic peptide, and ß-MHC expression; cardiac fibrosis; and ERK phosphorylation and transport into the nucleus. Furthermore, the inhibitory effect of rhein on myocardial hypertrophy was similar to that of specific inhibitors of STAT3 and ERK signaling. In addition, rhein at therapeutic doses had no significant adverse effects or toxicity on liver and kidney function. We conclude that rhein reduces TAC-induced cardiac hypertrophy via targeted inhibition of the molecular function of ERK and downregulates STAT3 and p38 MAPK signaling. Therefore, rhein might be a novel and effective agent for treating cardiac hypertrophy and other cardiovascular diseases.

Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury.

The precise control of cardiomyocyte viability is imperative to combat myocardial ischemia-reperfusion injury (I/R), in which apoptosis and pyroptosis putatively contribute to the process. Recent researches indicated that GSDMD is involved in I/R as an executive protein of pyroptosis. However, its effect on other forms of cell death is unclear. We identified that GSDMD and GSDMD-N levels were significantly upregulated in the I/R myocardium of mice. Knockout of GSDMD conferred the resistance of the hearts to reperfusion injury in the acute phase of I/R but aggravated reperfusion injury in the chronic phase of I/R. Mechanistically, GSDMD deficiency induced the activation of PARylation and the consumption of NAD+ and ATP, leading to cardiomyocyte apoptosis. Moreover, PJ34, a putative PARP-1 inhibitor, reduced the myocardial injury caused by GSDMD deficiency. Our results reveal a novel action modality of GSDMD in the regulation of cardiomyocyte death; inhibition of GSDMD activates PARylation, suggesting the multidirectional role of GSDMD in I/R and providing a new theory for clinical treatment.

Progression of type B intramural hematoma in patients with obstructive sleep apnea.

OBJECTIVE: In the present study, we estimated the influence of obstructive sleep apnea (OSA) on the progression of type B intramural hematoma (IMHB). METHODS: A total of 127 patients had undergone sleep evaluations and esophageal pressure measurements. The variables associated with aorta-related adverse events and mortality were summarized by logistic regression analysis and Cox proportional hazard models. A competing risk analysis of death was used to estimate aorta- and non-aorta-related mortality. RESULTS: The OSA group had a greater aorta-related adverse events rate (46% vs 4%; P < .001). The mean nighttime systolic pressure (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.11-1.38; P < .001) was associated with aorta-related adverse events during the acute phase. Thoracic endovascular aortic repair (hazard ratio [HR], 16.2; 95% CI, 7.68-34.22, P < .001) and mean morning systolic pressure (HR, 1.43; 95% CI, 1.22-1.68; P < .001) were associated with a higher rate of aorta-related adverse events. OSA (HR, 3.19; 95% CI, 2.57-12.15; P < .001) and mean morning systolic pressure (HR, 1.59; 95% CI, 1.27-2.01; P = .002) were significantly associated with aorta-related mortality. Competing risk analysis revealed significantly higher aorta-related mortality in the OSA group (11.8% vs 2.0%; P = .0412). A neutrophil/lymphocyte ratio >3.52 (specificity, 90.2%; sensitivity, 89.5%) and mean platelet volume/platelet ratio >0.049 (specificity, 98.0%; sensitivity, 98.7%) had diagnostic value for detecting OSA in patients with IMHB. CONCLUSIONS: The presence of OSA led to a higher aorta-related adverse event rate and mortality in patients with IMHB. The variables associated with these outcomes included thoracic endovascular aortic repair, mean morning and nighttime systolic pressure, and OSA. The neutrophil/lymphocyte ratio and platelet volume/platelet ratio are valuable for detecting OSA in patients with IMHB.

Rosuvastatin exerts cardioprotective effect in lipopolysaccharide-mediated injury of cardiomyocytes in an MG53-dependent manner.

BACKGROUND: Myocarditis is a cardiomyopathy associated with the inflammatory response. Rosuvastatin (RS) demonstrates cardioprotective effect in the clinical setting, although its cellular and molecular mechanisms in ameliorating myocarditis are largely unknown. MG53 (muscle-specific E3 ligase Mitsugumin 53), a newly identified striated muscle-specific protein, is involved in skeletal muscle membrane repair. We aimed to explore whether RS mediated the repair of cardiomyocytes in an MG53-dependent manner. METHODS: The RS-induced upregulation of MG53 was determined using RT-qPCR and western blotting. A lipopolysaccharide (LPS)-induced cell inflammatory model was constructed using rat cardiac muscle cell H9C2. Inflammatory injury was evaluated according to the alterations of cell viability, mitochondrial membrane potential, cell apoptosis, and expression of pro-inflammatory cytokines (interleukin-1ß, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1). Small interfering RNAs (siRNAs) were used to silence MG53. The cardioprotective effect of RS and the inhibition of this protection by MG53 silence were evaluated in the forementioned in vitro model. The underlying mechanism was finally investigated using western blotting to detected the expressions of apoptotic markers (Bcl-2, Bax, Cleaved caspase-9, Cleaved caspase-3), cell cycle regulatory factors (Cyclin A, Cyclin E1, Cyclin D1, CDK2), and components involved in NF-κB signaling pathway (p-IκBa, Iκba, p-p65, p65). RESULTS: RS ameliorated LPS-induced inflammatory injury. RS upregulated the expression of MG53. MG53 was crucial for the RS-mediated repair response in vitro. Ablation of MG53 inhibited the RS-mediated protective effect. Furthermore, RS and MG53 interact in multiple signaling pathways to modulate recovery. CONCLUSION: RS exerts cardioprotective effect in an MG53-dependent manner. MG53 may serve as a novel drug target for myocarditis treatment.

Outcomes of uncomplicated Type B intramural hematoma patients with Type 2 diabetes mellitus.

OBJECTIVES: We aimed to summarize the clinical presentations, therapeutic approaches, and outcomes of Type B intramural hematoma (IMHB) patients with and without Type 2 diabetes mellitus (DM). METHODS: Patients with uncomplicated IMHBs were included between January 2016 and January 2018 and divided into two groups according to whether or not they had DM. We also assessed the potential diagnostic value of serum matrix metalloproteinase-9 (MMP-9) level and the association of it with the disease progression of uncomplicated IMHB patients with and without DM. RESULTS: A total of 149 patients were included (DM group [n = 60] and non-DM group [n = 89]). Patients in the non-DM group underwent thoracic endovascular aortic repair treatment more frequently (12% vs 2%, p = .028) and had a higher reintervention rate during the follow-up (9 in 81 patients, 11% vs. 2%, p = .043). There were significant differences between the two groups regarding the aorta-related mortality rate during the acute phase (9% vs. 0%, p = .042) and the all-cause mortality rate (22% vs. 7%, p = .011). Ulcer-like projection (ULP) development (during the acute phase; hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.15-1.79, p = .005), C-reactive protein (CRP) levels (HR, 2.08; 95% CI, 1.91-3.91, p = .003), and MMP-9 levels (HR, 15.77; 95% CI, 6.48-21.62, p < .001) were associated with an elevated risk for aorta-related mortality. CONCLUSIONS: IMHBs with DM have a considerably better prognosis and serum MMP-9 level appear to be a potential biomarker to predict the disease progression. ULP development (during the acute phase) and CRP levels are also associated with an elevated risk for aorta-related mortality.

Efficacy of immunosuppressive therapy in myocarditis: A 30-year systematic review and meta analysis.

AIMS: Myocarditis is an inflammation of the heart muscle, due to infectious, toxic or autoimmune causes. Literature reported controversial results in relation to the effect of immunosuppression (IS)/immunomodulation (IM). We aimed at assessing the effect of IS/IM by meta analysis. METHODS AND RESULTS: Using the P.R.I.S.M.A. approach, two researchers searched for relevant studies on PubMed, Embase, and the Central Registry of Controlled Trials of the Cochrane Library. Proposed MeSH terms were: "immunotherapy OR immune therapy OR immune modeling OR Immunosuppressive Agents" AND "combination OR combined with OR plus" AND "myocarditis OR cardiomyopathies OR inflammatory cardiomyopathy". The language was restricted to English. Reference lists of included articles and those relevant to the topic were hand searched for the identification of additional, potentially relevant articles. The cutoff date was from 1987 until 30th Nov 2019. Reported survival or mortality events or change of left ventricular ejection fraction (LVEF) after IS/IT were primary outcomes of the study; in addition, improvement of New York Heart Association class, follow-up biopsy (Bx) findings, viral genome clearance on Bx and recurrence of myocarditis were recorded if reported. Statistical analysis was conducted using Review Manager 5.3; 5452 studies were screened, of these 73 were assessed for eligibility, including 8 randomized control studies, 26 retrospective studies, 2 prospective studies and 1 case control study, 34 case reports and 2 case series. In prospective studies, the difference in mortality between the IS and control groups tended to be lower in the combined IS groups (12.5% vs. 18.2%) (95% CI of odds ratio 0.7(0.3, 1.64)) and the pooled difference of the increase of LVEF between the IS and control groups tended to be higher in the combined IS groups (95% CI 7.26 (-2.29, 16.81)). In retrospective studies, the difference of survival between the IS and control group was significantly in favor of IS (95%CI Hazard ratio 0.82(0.69, 0.96)). CONCLUSIONS: A tailored IS may be considered in myocarditis, depending on the phase of the disease, and the type of underlying autoimmune or immune-mediated form.

AGEs-RAGE axis causes endothelial-to-mesenchymal transition in early calcific aortic valve disease via TGF-ß1 and BMPR2 signaling.

Recent studies reported that advanced glycation end products (AGEs) and endothelial-to-mesenchymal transition (EndMT) were involved in the calcific aortic valve disease (CAVD). However, the roles of AGEs in EndMT in the development of CAVD have not been elucidated. In this study, six-week-old male Apoe-/- mice were divided into four groups based on the following feeding periods: 0, 2, 4, and 6 months. The latter three groups were further divided into three subgroups corresponding to the following diet treatments: normal diet, high-fat diet + normal saline injection, and high-fat diet + aminoguanidine injection. Weight gain was monitored weekly. Finally, heart echocardiographic assessments were performed, and serum lipid levels, the protein expression and the histological changes in the aortic valves were determined. Results showed that the AGE inhibitor aminoguanidine alleviated the transaortic valve velocity and decreased the total cholesterol and low-density lipoprotein cholesterol levels. Calcification and carboxymethyl-lysine deposition were firstly detected around the aortic valve surfaces, whereas aminoguanidine injection attenuated their accumulation. In the early stage, HFD-activated AGEs-RAGE signaling resulted in the alpha-smooth muscle actin (α-SMA) upregulation and the vascular endothelium cadherin (VE-cadherin) downregulation on the valve endothelial layer. The activation resulted in early the transforming growth factor-ß1 (TGF-ß1) and the alkaline phosphatase (ALP) upregulation, and simultaneously reduced the bone morphogenetic protein receptor type II (BMPR2) expression. However, aminoguanidine restricted these proteins changes by inhibiting the interaction of AGEs and RAGE. In addition, immunofluorescence images showed obvious double-positive staining of ALP and α-SMA on the valve surfaces, revealing the contribution of EndMT to the early calcification. Therefore, this study demonstrates that activation of the AGEs-RAGE axis induced EndMT, promoting the progression of the aortic valve calcification in the initial stage via the counteraction of BMPR2 and TGF-ß1 signaling.

Outcomes of type A intramural hematoma: Influence of diabetes mellitus.

OBJECTIVES: We aimed to investigate whether uncomplicated type A intramural hematoma (IMHA) patients with type 2 diabetes mellitus (DM) who underwent a "wait-and-watch strategy" and tight glycemic control had similar clinical outcomes as patients without DM who received the same treatment strategy. METHODS: Between January 2010 and December 2016, uncomplicated IMHA patients with and without diabetes mellitus were included and were propensity score-matched to improve the balance between the two groups. Cox proportional hazard models were constructed to identify the specific factors associated with aorta-related mortality. The Fine-Gray model for the competing risk analysis was used to estimate the aorta-related and nonaorta-related mortality in different groups during the follow-up period. RESULTS: A total of 109 IMHA patients were included in this study, and 66 patients were included after matching. Patients without DM experienced significantly more aorta-related adverse events (51.6% vs 13.3%; P = .001) and reinterventions than patients in the DM group (29.0% vs 6.7%; P = .023). Cox regression analysis revealed that a higher matrix metalloproteinase-9 level (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.39-2.09; P < .001) and larger maximum aortic diameter (HR, 1.41; 95% CI, 1.11-1.80; P = .005) were associated with higher aorta-related mortality. The competing risk analysis revealed a significantly higher aorta-related mortality during the follow-up period in the no DM group than in the DM group (36.4%; 95% CI, 11.6%-82.3%; P = .0294). CONCLUSIONS: Uncomplicated IMHA patients with DM (receiving the "wait-and-watch strategy" and tight glycemic control) may have lower aorta-related mortality and rates of aorta-related adverse events and reinterventions than the no DM group.

The evolution of treatments for uncomplicated type B intramural hematoma patients.

OBJECTIVES: We aimed to investigate whether uncomplicated type B intramural hematoma (IMHB) patients with known evolution predictors could benefit from more aggressive therapy. METHODS: Retrospective analysis was performed in uncomplicated IMHB patients with evolution predictors between January 2001 and August 2018. Cox proportional hazard models were constructed to identify the specific factors associated with aorta-related mortality. RESULTS: A total of 226 uncomplicated acute IMHB patients with evolution predictors were included. The conventional therapy group included 187 patients, and the other 39 patients received the more aggressive therapy. Aorta-related mortality in the first year was higher in the conventional therapy group than in the more aggressive therapy group (15% vs 2.5%, P = .035), and more patients died after thoracic endovascular aortic repair (TEVAR) (13 of 27 patients, 48.1% vs 2.5%, P < .001). The more aggressive therapy group had a higher rate of hematoma resolution than the conventional therapy group (81.6% vs 62.2%, P = .024), a lower possibility of hematoma worsening (2.6% vs 17.0%, P = .021), and a lower reintervention rate (0% vs 11.9%, P = .028). Cox regression analysis revealed that a higher rate of focal intimal disruption (FID) development (hazard ratio [HR], 3.99; 95% confidence interval [CI], 1.16-11.46, P = .010), and a higher C-reactive protein (CRP) level (HR, 1.27; 95% CI, 1.16-1.40, P < .001) were associated with increased aorta-related mortality. CONCLUSIONS: More aggressive therapy for uncomplicated IMHB patients with evolution predictors during the acute phase may result in better clinical outcomes. A higher rate of FID development and a higher CRP level are associated with increased aorta-related mortality.

Immunogenicity analysis of decellularized cardiac scaffolds after transplantation into rats.

Aim: Cardiac extracellular matrix (cECM) scaffolds are promising biomaterials for clinical applications. Our aim is to determine the immunogenicity of decellularized scaffolds from different sources for use as artificial organs during organ transplantation. Materials & methods: We transplanted Lewis rats with syngeneic (Lewis rat cECM), allogeneic (BN rat cECM) or xenogeneic (hamster cECM) decellularized cardiac scaffolds. Acute vascular and cellular rejection was quantified by immunohistochemistry and immune cell infiltration. Results: BN rat and hamster hearts were rejected following transplantation. BN and hamster cECMs had similarly low immunogenicity compared with Lewis rat cECMs and did not lead to increased rejection. Conclusion: We found that scaffolds from all sources did not induce vascular or cellular rejection and exhibited low immunogenicity.

Certain aortic geometries and hemodynamics are associated with FID development and impact the evolution of uncomplicated type B intramural hematoma during the acute phase.

OBJECTIVES: It is difficult to predict the evolution of uncomplicated type B intramural hematoma (IMHB) with a focal intimal disruption (FID) in the acute phase. The aims of this study were to investigate the predictors of FIDs and summarize the risk factors for the evolution of uncomplicated IMHB in the acute phase. METHODS: Eighty-six patients with uncomplicated IMHB were included and were divided according to the development of an FID during the acute phase: the FID group (n = 32) and the no-FID group (n = 54). Geometric measurements and computed fluid dynamic calculations were based on a computed tomography scan performed on admission. Multivariate logistic regression analysis was used to estimate the predictors of FID development. RESULTS: Thirty-two (37%) patients developed an FID. Patients with an FID had higher C-reactive protein levels (18.6 ± 2.3 vs 8.1 ± 0.2 mg/dL, P < 0.001) and white blood cell counts (10.3 ± 2.1 vs 7.5 ± 1.7 109 /L, P < 0.001). The no-FID group had lower occurrences of disease progression (15% vs 64%, P < 0.001) and aorta-related mortality (6% vs 25%, P = 0.016). Multivariate logistic regression analysis indicated a significant risk for the occurrence of an FID with a larger maximum aortic diameter (OR, 1.35; 95% CI, 1.05-1.73, P = 0.020), thicker hematoma (OR, 2.20; 95% CI, 1.40-3.48, P = 0.001), and higher oscillatory shear index (per 0.01 unit, OR, 1.74; 95% CI, 1.21-2.49, P = 0.003). The aorta-related mortality during the acute phase was 25% (n = 8). CONCLUSIONS: Certain aortic conditions, including ta larger aortic diameter, thicker hematoma and higher oscillatory shear stress, are associated with the FID development and result in worse clinical outcomes.

Comparison of dynamic changes in aortic diameter during the cardiac cycle measured by computed tomography angiography and transthoracic echocardiography.

OBJECTIVE: This study aimed to examine the relationship between dynamic changes in aortic diameter and corresponding measurement methods. METHODS: Consecutive adult (nonaneurysmal) patients being surgically treated for heart disease (mean age, 51 ± 11 years; range, 29-76 years; N = 25) were included in this study. All patients underwent transthoracic echocardiography (TTE), computed tomography angiography (CTA), and intraoperative ultrasound (IOUS). Anteroposterior diameters were measured at 1 cm above the junction of the aortic sinus, the proximal 1 cm of the innominate artery, and the midpoint of the two. RESULTS: The average diameter of the proximal ascending aorta in systole/diastole measured by IOUS was 32.07 ± 2.03/30.27 ± 2.05 mm (paired t-test: difference, 1.80 ± 0.46 mm; P < .001). The average diameters of the proximal ascending aorta measured by nonelectrocardiography-gated CTA and TTE were 31.45 ± 1.97 mm and 29.7 ± 1.84 mm, respectively. The average diameter of the mid and distal ascending aorta in systole/diastole measured by IOUS was 32.35 ± 1.95/30.57 ± 1.94 mm (paired t-test: difference, 1.78 ± 0.44 mm; P < .001) and 32.32 ± 1.92/30.67 ± 1.90 mm (paired t-test: difference, 1.65 ± 0.42 mm; P < .001), respectively. The average diameter of the mid and distal ascending aorta measured by CTA was 31.74 ± 1.92 mm and 31.59 ± 1.96 mm, respectively. At each location, the difference in the aortic diameter between systole and diastole was statistically significant (all P values <.001; paired t-test). The minimum and maximum changes in the diameter between systole and diastole were 0.90 mm and 2.70 mm. In all, 96% (24/25) of the average diameters derived from IOUS and CTA at the three locations were within the concordance limit in systole, and 92% to 100% (23/25 to 25/25) were within the concordance limit in diastole. The average diameters derived from IOUS and TTE images of the proximal ascending aorta were within the bounds of the concordance limit 92% (23/25) of the time in systole and 100% (25/25) of the time in diastole. The average diameters derived from CTA and TTE images of the proximal ascending aorta were within the bounds of the concordance limit 88% (22/25) of the time. Pearson correlation coefficients between these groups ranged from 0.905 to 0.982 (all P values <.01). CONCLUSIONS: The ascending aorta diameters measured by nonelectrocardiography-gated CTA and TTE were consistent with the IOUS measurements.

Inhibition of C-X-C motif chemokine 10 reduces graft loss mediated by memory CD8+ T cells in a rat cardiac re-transplant model.

The interaction of chemokine (C-X-C motif) ligand 10 (CXCL10) with its receptor (CXCR3) is a critical process in recruiting donor reactive T cells to a graft and alloantigen-specific memory T (Tm) cells exert a principal function in promoting graft dysfunction during accelerated cardiac rejection. However, whether CXCL10 chemokine exerts any effects on acute accelerated rejection mediated by CD8+ Tm cells in a re-transplant model has remained elusive. The present study established a cardiac transplant model by advanced microsurgery technology and improved organ storage. A novel rat model of cardiac re-transplantation was established at 40 days following primary heart transplant. The experiment included two parts, and when models were established, the rats were divided into two groups: Primary cardiac transplant (HTx) and re-transplantation without treatment (HRTx). In part 1, recipients from part 2, including re-transplantation without treatment (HRTx+NS) and re-transplantation treated with anti-CXCL10 antibodies (500 µg every other day by intraperitoneal injection; HRTx+CXCL10 Abs group). The graft survival time was observed and graft infiltration by inflammatory cells was assessed via histology of cardiac graft sections; in addition, the gene expression and the serum concentration of CXCL10 in each group was assessed. Indexes such as rejection-associated cytokines were assayed by reverse-transcription quantitative PCR and ELISA kits, and flow cytometry of splenocytes was used to detect Tm cells in the re-transplantation groups. The results demonstrated that level of CXCL10 was significantly increased and the graft mean survival time was shortened accompanied with aggravated lymphocyte cell infiltration in the HRTx group when compared that in the HTx group; in addition, the serum levels and mRNA expression of interleukin (IL)-2 and interferon (IFN)-γ were increased, while transforming growth factor (TGF)-ß was decreased in the HRTx group. Furthermore, neutralization of CXCL10 prolonged the graft mean survival time and delayed accelerated rejection. Compared with that in the HRTx+NS group, serum levels and graft tissue mRNA expression of IFN-γ and IL-2 were decreased in the HRTx+CXCL10 Abs group, while TGF-ß mRNA was significantly increased but the serum concentration was not significantly affected. In addition, there was no difference in IL-10 between the two groups, while delayed accelerated rejection paralleled with inflammatory cell infiltration decreased and the proliferation and differentiation of CD8+ Tm cells in secondary lymphoid organs were reduced in the HRTx+CXCL10 Abs group vs. those in the HRTx+NS group. The present study demonstrated that CXCL10 had a crucial role in cardiac transplantation and re-transplantation, and that treatment with CXCL10 antibodies delays accelerated acute rejection mediated by Tm cells in a rat model of cardiac re-transplantation.

A New Concept of the Old Inhibitor NSC 74859 in Alleviating Cardiac Allograft Rejection and Extending Allograft Survival in Mice.

BACKGROUND STAT1/4 has been suggested to be involved in cardiac allograft rejection. However, no direct evidence regarding STAT3 has been established in cardiac allograft rejection. Here, we hypothesized that inhibition of STAT3 attenuates cardiac allograft rejection. MATERIAL AND METHODS To test our hypothesis, homotopic mouse heart transplantation was carried out in syngeneic C57BL/6 to C57BL/6 strain mice with or without oral gavage with NSC 74859, an inhibitor of STAT3. The immune response was investigated using real-time PCR for CD4 and CD8 surface makers of T cells and CD14 of monocytes and cytokines, including IL-2, IL-15, and IL-6 of allografts at 3, 6, and 9 days after transplantation. Prognosis was also evaluated. RESULTS We found that allografts with oral gavage of NSC 74859 whose CD4, CD8 T, and CD14 monocytes were significantly lower than that of allograft without oral gavage of NSC 74859, and the same was true for the expression of IL-2, IL-15, and IL-6. Immunohistochemical analysis of grafts showed reduced infiltration of monocytes/macrophages into the graft myocardium. Survival was also markedly extended in the NSC 74859 group. CONCLUSIONS Inhibition of IL-6/STAT3 using NSC 74859 was shown to remarkably alleviate cardiac allograft rejection in mice, indicating that the target against IL-6/STAT3 pathway might be clinically used as an alternative therapy for cardiac allograft rejection.

Effect of isoflurane + N2O inhalation and propofol + fentanyl anesthesia on myocardial function as assessed by cardiac troponin, caspase-3, cyclooxygenase-2 and inducible nitric oxide synthase expression.

The aim of this study was to evaluate the effect of isoflurane + N2O inhalation and propofol + fentanyl anesthesia on myocardial function as assessed by cardiac troponin T (cTnT). A total of 60 patients were randomized into two groups: isoflurane + N2O inhalation (n=30) and propofol + fentanyl anesthesia (n=30). The findings demonstrated that there was no significant difference between the two experimental groups in terms of cTnT levels, demographic properties or hemodynamic parameters. Isoflurane + N2O inhalation and propofol + fentanyl anesthesia, respectively, were also investigated in a rat model of myocardial infarction. Myocardial cell damage, inflammation and oxidative stress levels, caspase-3/9 activities and cyclooxygenase-2 protein expression were markedly decreased, although there was no statistical significance difference between the two experimental groups. Notably, inducible nitric oxide synthase protein expression in the isoflurane + N2O inhalation group was significantly higher than that of the propofol + fentanyl anesthesia group (P<0.01). In conclusion, isoflurane + N2O inhalation and propofol + fentanyl anesthesia are not associated with risks for myocardial function.

Preoperative application of combination of portal venous injection of donor spleen cells and intraperitoneal injection of rapamycin prolongs the survival of cardiac allografts in mice.

OBJECTIVE: To investigate the effects of preoperative portal venous injection of donor spleen cells (PVIDSC) and intraperitoneal injection of rapamycin in the acute rejection of cardiac allograft in mice and the underlying mechanisms. METHODS: Homogenous female B6 mice and BALB/c mice were used as recipients and donors of heart transplantation. These mice were randomly divided into different groups and received PVIDSC alone, rapamycin alone, or PVIDSC and rapamycin combined therapy. In addition, the underlying mechanism was studied by measuring a number of cytokines. RESULTS: Preoperative combination of PVIDSC and intraperitoneal injection of rapamycin significantly prolonged the survival of heterotopic cardiac allograft in mice, but had no effects on the survival time of cardiac allografts in mice pre-sensitized by skin grafting. Preoperative combination of PVIDSC and intraperitoneal injection of rapamycin increased the expression of IL-10 and Foxp3 and reduced the expression of INF-. Short-term preoperative administration of rapamycin promotes the expression of CD4+CD25+Foxp3+ regulator T cells. However, preoperative using alone of rapamycin, or combination of PVIDSC and rapamycin had no effects on the inhibition of proliferation of memory T cells. CONCLUSIONS: Preoperative application of combination of PVIDSC and rapamycin significantly prolonged the survival time of cardiac allografts in mice but not in mice pre-sensitized by skin grafting. This may be explained by the fact that combination of PVIDSC and rapamycin inhibited the cellular immune response and induced the expression of IL-10 from Tr1 cells and CD4+CD25+FoxP3+ regulatory T cells.