CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

The Effects of Inspiratory Muscle Training (IMT) on Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery: A Systematic Review and Meta-Analysis.

Background: To determine the effects of inspiratory muscle training (IMT) alone on inspiratory muscle strength and endurance, pulmonary function, pulmonary complications, and length of hospital stay in patients undergoing coronary artery bypass graft surgery (CABG). Methods: We conducted a literature search across databases (Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily; Ovid Embase; Ovid Cochrane Central Register of Controlled Trials; Ovid Cochrane Database of Systematic Reviews; and Scopus) from inception to December 2021. The eligibility criteria were randomized controlled trials that investigated the effects of IMT versus usual care or sham IMT in patients undergoing CABG. Results: A total of 12 randomized clinical trials with 918 patients were included in the meta-analysis. Postoperative IMT was associated with improved maximal inspiratory pressure (MIP), maximum inspiratory pressure (PImax), and six-minute walking test (6MWT) and with a decrease in length of hospital stay (LOS). For preoperative IMT, there was statistical significance between intervention and MIP, PImax, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), postoperative pulmonary complications (PPCs), and LOS. Pre- and postoperative IMT resulted in improvements in MIP. Conclusions: Isolated IMT in patients who underwent CABG improved their inspiratory muscle strength and endurance, pulmonary function, and 6MWT and helped decrease postoperative pulmonary complications and the length of hospital stay.

The effect of type 2 diabetes mellitus on multiple obstructive coronary artery disease.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) individuals easily develop three-vessel disease (3VD) coronary artery disease (CAD), there is very little information available about their left ventricle (LV) functions. The purpose of this study is to evaluate the LV function using two-dimensional speckle tracking echocardiography (2-D STE) in T2DM patients with 3VD. METHODS: One hundred and three consecutive patients with confirmed 3VD CAD were enrolled and divided into two groups, while 53 patients with DM and 50 patients without. The control group was composed of 30 age- and sex-matched healthy individuals. All patients underwent 2-D STE and standard echocardiograms. The durations of DM and the level of HbA1c were also recorded. RESULT: Between the 3VD-DM and 3VD-non-DM groups, normal echocardiography did not reveal any appreciable differences. However, patients with 3VD-DM had significantly lower global longitudinal strain (GLS) than those with 3VD-non-DM (15.87 ± 2.51 vs.17.56 ± 2.72, p < .05) by 2-D STE strain measurement. Besides, patients whose duration of DM excess 5 years showed significant lower GLS than those with less than 5 years duration (14.25 ± 2.31 vs. 16.65 ± 1.96, p = .007). However, there was no difference in GLS between the 3VD-DM patients with HbA1c ≥ 7% and HbA1c < 7%. CONCLUSIONS: Compared to patients with 3VD alone, those with 3VD-DM have a lower cardiac function. In 3VD-DM patients, the duration of DM is a significant factor that contributes to cardiac function deterioration, whereas, the glucose control state has limited influence.

Involvement of activation of C-met signaling pathway in CD151-induced HUVECs angiogenesis.

CD151 is a member of the tetraspanin family that is implicated as a promoter of pathological or physiological angiogenesis. C-Met is expressed on a variety of cells including vascular endothelial cells (VECs) and up-regulated during angiogenesis. In this study, we investigated whether CD151 regulated migration, proliferation, tube formation and angiogenesis of human umbilical VECs (HUVECs) with activation of C-Met. Moreover, we studied whether CD151 could affect the angiogenic molecules such as nitric oxide (NO), vascular cell adhesion molecule-1 (VCAM-1) and vascular endothelial growth factor (VEGF). The expression of CD151 was determined by Western blotting. The cell proliferation assay was performed using the cell counting kit-8 (CCK-8) method and cell migration was assessed in microchemotaxis chambers by using fetal bovine serum (FBS) as the chemotactic stimulus. The angiogenic molecules were evaluated using ELISA. The NO level was detected using NO detection kit. The potential involvement of various signaling pathways was explored using relevant antibodies. We found that proliferation, migration and tube formation of HUVECs were promoted by CD151 with activation of C-Met, FAK and CDC42, while they were suppressed with CD151 knockdown by RNAi. Similarly, the levels of NO, VCAM-1 and VEGF in HUVECs were increased by CD151, but they were inhibited with CD151 knockdown by RNAi. These data suggested that CD151 could promote migration, proliferation, tube formation and angiogenesis of HUVECs, which was possibly related to the C-Met signaling pathways.

Novel Insights into the Kallikrein-Kinin System in Fulminant Myocarditis: Physiological Basis and Potential Therapeutic Advances.

Fulminant myocarditis (FM) is characterized by rapid cardiac deterioration often instigated by an inflammatory cytokine storm. The kallikrein-kinin system (KKS) is a metabolic cascade known for releasing vasoactive kinins, such as bradykinin-related peptides, possessing diverse pharmacological activities that include inflammation, regulation of vascular permeability, endothelial barrier dysfunction, and blood pressure modulation. The type 1 and type 2 bradykinin receptors (B1R and B2R), integral components of the KKS system, mediate the primary biological effects of kinin peptides. This review aims to offer a comprehensive overview of the primary mechanisms of the KKS in FM, including an examination of the structural components, regulatory activation, and downstream signaling pathways of the KKS. Furthermore, it explores the involvement of the tissue kallikrein/B1R/inducible nitric oxide synthase (TK/B1R/iNOS) pathway in myocyte dysfunction, modulation of the immune response, and preservation of endothelial barrier integrity. The potential therapeutic advances targeting the inhibition of the KKS in managing FM will be discussed, providing valuable insights for the development of clinical treatment strategies.

Downregulation of the CD151 protects the cardiac function by the crosstalk between the endothelial cells and cardiomyocytes via exosomes.

BACKGROUND: Heart failure (HF) is the last stage in the progression of various cardiovascular diseases. Although it is documented that CD151 contributes to regulate the myocardial infarction, the function of CD151 on HF and involved mechanisms are still unclear. METHOD AND RESULTS: In the present study, we found that the recombinant adeno-associated virus (rAAV)-mediated endothelial cell-specific knockdown of CD151-transfected mice improved transverse aortic constriction (TAC)-induced cardiac function, attenuated myocardial hypertrophy and fibrosis, and increased coronary perfusion, whereas overexpression of the CD151 protein aggravated cardiac dysfunction and showed the opposite effects. In vitro, the cardiomyocytes hypertrophy induced by PE were significantly improved, while the proliferation and migration of cardiac fibroblasts (CFs) were significantly reduced, when co-cultured with the CD151-silenced endothelial cells (ECs). To further explore the mechanisms, the exosomes from the CD151-silenced ECs were taken by cardiomyocyte (CMs) and CFs, verified the intercellular communication. And the protective effects of CD151-silenced ECs were inhibited when exosome inhibitor (GW4869) was added. Additionally, a quantitative proteomics method was used to identify potential proteins in CD151-silenced EC exosomes. We found that the suppression of CD151 could regulate the PPAR signaling pathway via exosomes. CONCLUSION: Our observations suggest that the downregulation of CD151 is an important positive regulator of cardiac function of heart failure, which can regulate exosome-stored proteins to play a role in the cellular interaction on the CMs and CFs. Modulating the exosome levels of ECs by reducing CD151 expression may offer novel therapeutic strategies and targets for HF treatment.

Unusual presentation of systemic lupus erythematosus as hemophagocytic lymphohistiocytosis in a female patient: A case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disorder, often resulting in the immune-mediated injury of multiple organ systems, including primary HLH and secondary HLH (sHLH). Among them, sHLH results from infections, malignant, or autoimmune conditions, which have quite poor outcomes even with aggressive management and are more common in adults. CASE SUMMARY: We report a rare case of a 36-year-old female manifested with sHLH on background with systemic lupus erythematosus (SLE). During hospitalization, the patient was characterized by recurrent high-grade fever, petechiae and ecchymoses of abdominal skin, and pulmonary infection. Whole exon gene sequencing revealed decreased activity of natural killer cells. She received systematic treatment with Methylprednisolone, Etoposide, and anti-infective drugs. Intravenous immunoglobulin and plasmapheresis were applied when the condition was extremely acute and progressive. The patient recovered and did not present any relapse of the HLH for one year of follow-up. CONCLUSION: The case showed sHLH, thrombotic microvascular, and infection in the whole course of the disease, which was rarely reported by now. The treatment of the patient emphasizes that early recognition and treatment of sHLH in SLE patients was of utmost importance to improve the prognosis and survival rate of patients.

Expression profiles and potential functions of microRNAs in heart failure patients from the Uyghur population.

BACKGROUND AND PURPOSE: Existing studies have shown that circulating miRNA can be used as biomarkers of heart failure (HF). However, the circulating miRNA expression profile in Uyghur HF patients is unclear. In this study, we identified the miRNA profiles in the plasma of Uyghur HF patients and preliminarily explored their potential functions to provide new ideas for the diagnosis and treatment of HF. METHODS: Totally, 33 Uyghur patients with HF with reduced ejection fraction (<40%) were included in the HF group and 18 Uyghur patients without HF were included in the control group. First, high-throughput sequencing was used to identify differentially expressed miRNAs in the plasma of heart failure patients (n = 3) and controls (n = 3). Second, the differentially expressed miRNAs were annotated with online software and bioinformatics analysis was used to explore the critical roles of these circulating miRNAs in HF. Moreover, four selected differentially expressed miRNAs were validated by quantitative real-time PCR (qRT-PCR) in 15 controls and 30 HF patients. The diagnostic value of three successfully validated miRNAs for heart failure was assessed using receiver operating characteristic curve (ROC) analysis. Finally, to explore the expression levels of the three successfully validated miRNAs in HF hearts, thoracic aortic constriction (TAC) mice models were constructed and their expression in mice hearts was detected by qRT-PCR. RESULTS: Sixty-three differentially expressed miRNAs were identified by high-throughput sequencing. Of these 63 miRNAs, most were located on chromosome 14, and the OMIM database showed that 14 miRNAs were associated with HF. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that the target genes were mostly involved in ion or protein binding, the calcium signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, inositol phosphate metabolism, autophagy, and focal adhesion. Of the four selected miRNAs, hsa-miR-378d, hsa-miR-486-5p and hsa-miR-210-3p were successfully validated in the validation cohort and hsa-miR-210-3p had the highest diagnostic value for HF. Meanwhile, miR-210-3p was found to be significantly upregulated in the hearts of TAC mice. CONCLUSION: A reference set of potential miRNA biomarkers that may be involved in HF is constructed. Our study may provide new ideas for the diagnosis and treatment of HF.

Left ventricular function changes and echocardiographic predictors in adult survivors of fulminant myocarditis treated with the Chinese protocol.

Disagreement exists regarding the long-term prognosis and recovery of left ventricular (LV) function in patients with fulminant myocarditis (FM). This study reported the outcome and LV ejection fraction (EF) changes in FM treated with Chinese protocol, and assessed whether global longitudinal strain (GLS) by two-dimensional speckle tracking echocardiography (2-D STE) could provide additional information. This retrospective study included 46 FM adult patients who applied timely circulatory support and immunomodulatory therapy with adequate doses of both glucocorticoids and immunoglobulins as core approaches and survived after acute phase. They all presented with acute onset of cardiac symptoms < 2 weeks. LV end-diastolic dimensions, LVEF and GLS at discharge and 2-year were obtained and compared. We then performed linear regression and ROC analysis to determine independent factors to predict normalization of GLS at 2-year. At 2 years, the survival was 100% in our cohort. And the GLS improved modestly (15.40 ± 3.89% vs 17.24 ± 2.89%, P = 0.002). At two years, a proportion of patients whose LV function remained abnormal, being 22% evaluated by EF (< 55%) and higher to 37% by GLS (< 17%). Moreover, GLS at discharge but not at presentation correlated with GLS at 2-year (r = 0.402, P = 0.007). The FM adult treated with Chinese protocol have good survival and modest improvement of LV function during 2-year.

The pattern of late gadolinium enhancement by cardiac MRI in fulminant myocarditis and its prognostic implication: a two-year follow-up study.

Background: Myocardial fibrosis, as quantified by late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR), provides valuable prognostic information for patients with myocarditis. However, due to the low incidence rate of fulminant myocarditis (FM) and accordingly small sample size, the knowledge about the role of LGE to patients with FM is limited. Methods and results: A total of 44 adults with viral-FM receiving the Chinese treating regimen were included in this retrospective study. They were divided into the low LGE group and the high LGE group according to the ratio of LGE to left ventricular mass (LGE mass%). CMR exams and LGE were performed after hemodynamic assistance at discharge in all patients with FM. Routine echocardiography parameters and global longitudinal strain (GLS) at discharge and at 2-year follow-up were obtained and then compared. Both left ventricular ejection fraction (LVEF) and GLS showed no significant difference in both groups at discharge, whereas significant differences were observed at 2-year follow-up between two groups. Moreover, there were significant improvements of LVEF and GLS in the low LGE group, but not in the high LGE group during the 2-year period. Furthermore, LGE mass% was negatively correlated with GLS and LVEF. Conclusions: There were two distinct forms of LGE presentation in patients with FM. Moreover, the cardiac function of patients with low LGE was significantly better than those with high LGE at 2-year follow-up. LGE mass% at discharge provided significant prognosis information about cardiac function of patients with FM.

[Corrigendum] The tetraspanin CD151­ARSA mutant inhibits angiogenesis via the YRSL sequence.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, in Fig. 4A on p. 839, the 'CD151/24 h' and 'CD151­ARSA/48 h' panels appeared to contain overlapping sections of data, such that they were potentially derived from the same original source, where these panels were intended to show the results from differently performed experiments. The authors have re­examined their original data, and realize that the 'CD151­ARSA/48 h' panel was inadvertently placed incorrectly in the figure. The revised version of Fig. 4, now containing the correct data for the 'CD151­ARSA/48 h' experiment in Fig. 4A, is shown below. Note that this error did not adversely affect either the results or the overall conclusions reported in this study. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this. They also wish to apologize to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 7: 836­842, 2013; DOI: 10.3892/mmr.2012.1250].

CD151 promotes proliferation and migration of PC3 cells via the formation of CD151-integrin α3/α6 complex.

Over-expression of CD151 was found to be associated with metastasis and poor prognosis of prostatic carcinoma. This study was designed to examine the mechanism by which CD151 promotes the proliferation and migration of prostatic cancer cells. The pAAV-CD151, pAAV-GFP and pAAV-CD151-AAA mutant plasmids were constructed and used to transiently transfect PC3 cells (a prostatic carcinoma 3 cell line) by the mediation of Fugene HD. Then, the cells were assigned to control group, pAAV-GFP group, pAAV-CD151 group, and pAAV-CD151-AAA group respectively. Cell proliferation was evaluated by using the 3-[4,5-dimet-hylthiazol-2-yl]-2,5, diphenyltetrazolium bromide (MTT) method. Cell migration assay was performed by using Boyden chambers. The formation of CD151-integrin α3/α6 complex was determined by the method of co-immunoprecipitation. The protein expression levels of CD151 and extracellular signal-regulated kinase (ERK) were measured by Western blotting. The results showed that transfection of pAAV-CD151 or pAAV-CD151-AAA mutant increased the expression of CD151 protein in PC3 cells. Co-immunoprecipitation showed that more CD151-integrin α3/α6 complex was formed in the pAAV-CD151 group than in the control group, the pAAV-GFP group and the pAAV-CD151-AAA mutant group. Furthermore, the proliferative and migrating capacity of PC3 cells was substantially increased in the pAAV-CD151 group but inhibited in the pAAV-CD151-AAA mutant group. CD151 transfection increased the expression of phospho-ERK. Taken together, it was concluded that CD151 promotes the proliferation and migration of PC3 cells through the formation of CD151-integrin complex and the activation of phosphorylated ERK.

Support Life Club: A New Model Based on Social Media Group Chats and Social Activities That Can Improve Adherence and Clinical Outcomes in Patients Receiving Cardiac Rehabilitation.

Aim: To describe a new model, the Support Life Club (SLC), for participants of Phase II cardiac rehabilitation (CR) programs and to evaluate this model for adherence, completion rates, and clinical outcomes. Methods: This retrospective study involved 391 consecutive patients who participated in an outpatient CR program between September 2016 and May 2020. The intervention group (SLC) was comprised of 198 patients who participated in education, WeChat-based group activity as well as outdoor activities, while the control group (non-intervention) was comprised of 193 cases. All patients attended a 12-week supervised outpatient CR program (three sessions per week, each lasting 40min). The intervention and control groups were compared for completion rates, Cardiopulmonary Exercise Test (CPET) results, Six-minute Walk Test (6MWT) distances, and Patient Health Questionnaire-9 (PHQ-9) scores. Results: Patients in the intervention group attended at least 75% of the exercise training sessions more often than those in the control group (72.5% vs 40.41%, adjusted odds ratio (OR): 27.385; 95% CI: 10.2 to 73.6; P = 0.0000). Analysis of variance (2 × 2 ANOVA) revealed a significant group-by-time interaction in PHQ9 and 6MWT test results (p = 0.000). Conclusion: The addition of SLC to a cardiac rehabilitation program resulted in better outcomes for PHQ9 and 6MWT tests and may be a useful strategy to improve exercise adherence.

Diagnostic Accuracy of Global Longitudinal Strain for Detecting Exercise Intolerance in Patients with Ischemic Heart Disease.

Objective: Global longitudinal strain (GLS) is a sensitive and reproducible predictive factor in patients with ischemic heart disease (IHD), although its correlation with exercise tolerance is unknown. We aimed to identify the correlation between global longitudinal strain (GLS) and cardiopulmonary exercise testing (CPX) parameters and assess the prognostic implications and accuracy of GLS in predicting exercise intolerance in populations with ischemic heart disease (IHD) using CPET criteria. Methods: Prospectively, 108 patients with IHD underwent CPX and 2D speckle-tracking echocardiography. Correlation between GLS and multiple CPX variables was assessed using Spearman's correlation analysis and univariate regression analysis. A receiver operating characteristic (ROC) curve analysis was performed on GLS to detect exercise intolerance. Results: GLS was correlated with peak oxygen uptake (peak VO2; r = −0.438, p = 0.000), %PPeak VO2 (−0.369, p = 0.000), peak metabolic equivalents (METs@peak; r = −0.438, p < 0.01), and the minute ventilation−carbon dioxide production (VE/VCO2) slope (r = 0.257, p < 0.01). Weak-to-moderate correlations were also identified for the respiratory exchange rate at the anaerobic threshold (RER@AT), end-tidal carbon dioxide at the anaerobic threshold (PETCO2@AT), oxygen consumption at the anaerobic threshold (VO2@AT), carbon dioxide production at the anaerobic threshold (VCO2@AT), and metabolic equivalents at the anaerobic threshold (METs@AT; p < 0.01). On multivariate analysis, the results showed that age, the BMI, and GLS are independent predictors for reduced exercise capacity in patients with IHD (p < 0.01). The area under the ROC curve value of GLS for identifying patients with a peak VO2 of <14 mL/kg/min was 0.73 (p = 0.000). Conclusion: As a sensitive echocardiographic assessment of patients with ischemic heart disease, global longitudinal strain is an independent predictor of reduced exercise capacity and has a sensitivity of 74.2% and a specificity of 66.7% to detect exercise intolerance.

The Value of Cardiopulmonary Exercise Testing in Predicting the Severity of Coronary Artery Disease.

Background: There have been a limited number of quantitative studies on the relationship between coronary artery disease (CAD) and cardiorespiratory fitness (CRF), as measured by cardiopulmonary exercise testing (CPET). Thus, we aimed to investigate the association between CRF and the severity of coronary artery disease from the most comprehensive perspective possible, and to affirm the predictive value of CPET in the severity assessment of CAD. Methods: Our study included 280 patients with coronary angiography, who had undergone CPET in Tongji Hospital. The patients' CRF was measured through their peak oxygen uptake (VO2@peak), their oxygen uptake at the anaerobic threshold (VO2@AT) and through other parameters of CPET on a bicycle ergometer. The severity of the coronary artery disease was assessed in the following three layers: functionally significant lesions (quantitative flow ratio [QFR] ≤ 0.8), the number of stenotic coronary arteries (SCA, stenosis ≥ 50%) and the Gensini score. The correlation analyses were carried out between the CRF and the severity of the coronary artery disease. A ROC curve was plotted, and the AUC was calculated to distinguish the severe CAD and the non-severe CAD patients, as measured by the QFR, the number of SCA, and the Gensini score. Results: The VO2@AT and VO2@peak were inversely associated with the QFR. The VO2@AT, VO2@peak and VO2/kg@peak were associated with the number of SCA. Meanwhile, the VO2@AT, VO2/kg@AT, VO2@peak and VO2/kg@peak were associated with the Gensini score. An ROC analysis proved that a combination of traditional clinical risk factors and the VO2@peak/VO2prediction is valuable in predicting CAD severity. Conclusions: Our study demonstrated a strong and inverse association between CRF and the severity of CAD. A combination of traditional clinical risk factors and CRF is valuable in predicting CAD severity.

Soluble ST2 Is a Sensitive and Specific Biomarker for Fulminant Myocarditis.

Background The aim of the study was to identify biomarkers that can facilitate early diagnosis and treatment of fulminant myocarditis (FM) in order to reduce mortality. Methods and Results First, the expression profiles of circulating cytokines were determined in the plasma samples from 4 patients with FM and 4 controls using human cytokine arrays. The results showed that 39 cytokines from patients with FM were changed at admission. Among them, 8 cytokines returned to normal levels at discharge, including soluble ST2 (sST2), which showed the most marked dynamic changes from disease onset to resolution. Then, in a cohort of 76 patients with FM, 57 patients with acute hemodynamic dysfunction attributable to other causes, and 56 patients with non-FM, receiver operating characteristic curve analyses suggested that plasma sST2 level was able to differentiate FM from non-FM or other FM-unrelated acute heart failure more robustly N-terminal pro-B-type natriuretic peptide or cardiac troponin I. Moreover, longitudinal analysis of plasma sST2 was performed in 10 patients with FM during hospitalization and 16 patients with FM during follow-up. Finally, the diagnostic value was validated in an additional 26 patients with acute onset of unstable hemodynamics. The cutoff value of plasma sST2 for optimal diagnosis of FM was established at 58.39 ng/mL, where a sensitivity of 85.7% and specificity of 94.7% were achieved. Conclusions Elevated sST2 level was associated with mechanical stress or inflammation. Especially, sST2 might be used as a potential biomarker for the rapid diagnosis of FM, which was characterized by strong mechanical stretch stimulation and severe inflammatory response. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03268642.

Adeno-associated viral vector mediated and cardiac-specific delivery of CD151 gene in ischemic rat hearts.

Our previous studies demonstrated that CD151 gene promoted neovascularization in ischemic heart model. To improve the delivery efficacy and target specificity of CD151 gene to ischemic heart, we generated an adeno-associated virus (AAV) vector in which CD151 expression was controlled by the myosin light chain (MLC-2v) promoter to achieve the cardiac-specific expression of CD151 gene in ischemic myocardium and to limit unwanted CD151 expression in extracardiac organs. The function of this vector was examined in rat ischemic myocardium model. The protein expression of CD151 in the ischemic myocardium areas, liver and kidney was confirmed by using Western blot, while the microvessels within ischemic myocardium areas were detected by using immunohistochemistry. The results showed that MLC-2v significantly enhanced the expression of CD151 in ischemic myocardium, but attenuated its expression in other organs. The forced CD151 expression could increase the number of microvessels in the ischemic myocardium. This study demonstrates the AAV-mediated and MLC-2v regulated CD151 gene is highly expressed in the ischemic myocardium and cardiac-specific delivery that is more efficiently targets CD151 to the ischemia myocardium after myocardial infarction.

Myocardial strain features by 2D-STE during the course of fulminant myocarditis: Correlation with characteristics by CMR and clinical implications.

ABSTRACT: Myocardial strain analysis by 2D speckle tracking echocardiography could determine the left ventricular function. Our purpose is to investigate the global longitudinal strain (GLS) changes during the course of fulminant myocarditis (FM) and evaluate their correlation with cardiac magnetic resonance (CMR).Patients with clinical diagnosis of FM from June 30, 2017 to June 30, 2019 were screened prospectively. 18 survived patients (mean age 34 ±â€Š18 years) who had two scans of transthoracic echocardiography and underwent CMR were included.All patients had severely impaired left ventricular ejection fraction and GLS value at admission that improved significantly before discharge. The patients in the healed stage revealed elevated global native T1 and T2 relaxation time and extracellular volume fraction as well, which were 1408.3 ±â€Š88.3ms, 46.56 ±â€Š5.23ms, and 0.35 ±â€Š0.09, respectively. GLS from the second transthoracic echocardiography in the healed stage correlated significantly with global native T1 relaxation time (r =-0.574, P = .013) and with extracellular volume fraction (r = -0.582, P = .011), but not global native T2 relaxation time (r = -0.31, P = .211) and not with late gadolinium enhancement mass (r = 0.084, P = .743). In comparison, GLS at admission were not correlated with CMR parameters of fibrosis and oedema in the healed stage.GLS by 2D-STE may emerge as a new tool to monitor inflammatory myocardial injuries during the course of FM. FM in the acute healed stage has the presence of both chronic fibrosis and oedema which are correlated with GLS, but GLS at admission can't predict the early recovery of myocardial inflammation.

Management perspectives from the 2019 Wuhan international workshop on fulminant myocarditis.

Fulminant myocarditis (FM) is a form of acute myocardial inflammation leading to rapid-onset hemodynamic instability due to cardiogenic shock or life-threatening arrhythmias. As highlighted by recent registries, FM is associated with high rates of death and heart transplantation, regardless of the underlying histology. Because of a paucity of evidence-based management strategies exists for this disease, an International workshop on FM was held in Wuhan, China, in October 2019, in order to share knowledge on the disease and identify areas of consensus. The present report highlights both agreements and controversies in FM management across the world, focusing the attention on areas of opportunity, FM definition, the use of endomyocardial biopsy and viral identification on heart specimens, treatment algorithms including immunosuppression and the timing of circulatory support escalation. This report incorporates the most recent recommendations from national and international professional societies. Main areas of interest and aims of future prospective observational registries and randomized controlled trials were finally identified and suggested.

Activation of the ERK signaling pathway is involved in CD151-induced angiogenic effects on the formation of CD151-integrin complexes.

AIM: To assess the roles of extracellular signal-regulated kinase (ERK), p38, and CD151-integrin complexes on proliferation, migration, and tube formation activities of CD151-induced human umbilical vein endothelial cells (HUVECs). METHODS: CD151, anti-CD151 and CD151-AAA mutant were inserted into recombinant adeno-associated virus (rAAV) vectors and used to transfect HUVECs. After transfection, the expression of CD151 was measured. Proliferation was assessed using the 3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell migration was evaluated in Boyden transwell chambers using FBS as the chemotactic stimulus. The tube formation assay was performed on matrigel. The potential involvement of various signaling pathways was explored using selective inhibitors. RESULTS: CD151 gene delivery increased the expression of CD151 at both the mRNA and protein levels. Overexpression of CD151 promoted cell proliferation, migration and tube formation in vitro, and phosphorylation of ERK was also increased. Further, CD151-induced cell proliferation, migration, and tube formation were attenuated by the ERK inhibitor PD98059 (20 micromol/L) but not by a p38 inhibitor (SB203580, 20 micromol/L). Moreover, there was no significant difference in CD151 protein expression between the CD151 group and the CD151-AAA group, but the CD151-AAA mutant abrogated cellular proliferation, migration, and tube formation and decreased the phosphorylation of ERK. CONCLUSION: This study suggests that activation of the ERK signaling pathway may be involved in the angiogenic effects of CD151. Activation of ERK was dependent on the formation of CD151-integrin complexes. Therefore modulation of CD151 may be as a novel therapeutic strategy for regulating angiogenesis.