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1.
Theranostics ; 11(3): 1249-1268, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391533

RESUMO

Rationale: Maladaptive cardiac remodeling is a critical step in the progression of heart failure. Low-density lipoprotein receptor-related protein 6 (LRP6), a co-receptor of Wnt, has been implicated in cardiac protection. We aimed to study the role of cardiomyocyte-expressed LRP6 in cardiac remodeling under chronic pressure overload. Methods: Cardiac parameters were analyzed in inducible cardiac-specific LRP6 overexpressing and control mice subjected to transverse aortic constriction (TAC). Results: Cardiac LRP6 was increased at an early phase after TAC. Cardiomyocyte-specific LRP6 overexpression improved cardiac function and inhibited cardiac hypertrophy and fibrosis four weeks after TAC. The overexpression significantly inhibited ß-catenin activation, likely contributing to the inhibitory effect on cardiac hypertrophy after TAC. LRP6 overexpression reduced the expression and secretion of Wnt5a and Wnt11 by cardiomyocytes, and knockdown of Wnt5a and Wnt11 greatly inhibited cardiac fibrosis and dysfunction under pressure overload in vitro and in vivo. Cardiomyocyte-expressed LRP6 interacted with cathepsin D (CTSD, a protease) and promoted the degradation of Wnt5a and Wnt11, inhibiting cardiac fibrosis and dysfunction induced by TAC. The protease inhibitor leupeptin attenuated the interaction between LRP6 and CTSD, enhanced the expression of Wnt5a and Wnt11, and deteriorated cardiac function and fibrosis in cardiomyocyte-specific LRP6-overexpressing mice under pressure overload. Mutants from human patients, P1427Q of LRP6 and G316R of CTSD significantly inhibited the interaction between LRP6 and CTSD and increased Wnt5a and Wnt11 expression. Conclusion: Cardiomyocyte-expressed LRP6 promoted the degradation of Wnt5a and Wnt11 by regulating CTSD and inhibited cardiac fibrosis under pressure overload. Our study demonstrated a novel role of LRP6 as an anti-fibrosis regulator.

2.
Int J Cardiol ; 322: 1-8, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810548

RESUMO

BACKGROUND: Endothelial progenitor cells (EPCs) participate in angiogenesis and neocollateralization. This study assessed if circulating EPCs can predict long-term improvement of global left ventricular systolic function in patients with coronary chronic total occlusions (CTOs) underwent successful percutaneous coronary intervention (PCI). METHODS: In this single-center, prospective, observational study, 115 consecutive patients with CTOs were evaluated by standard transthoracic echocardiography (ECHO) before and 9-12 months after PCI. Numbers of circulating putative EPCs were determined by flow cytometry analysis of mononuclear cells isolated from peripheral blood samples drawn before and 72 h after PCI. RESULTS: At mean 11.3 ± 2.5 months post vs. before PCI (all P < .05): by SAQ-7 summary scores, angina frequency, physical limitation and quality of life scores were greater; by ECHO, LVEDd decreased and LVEF increased, which were more significant in patients with Rentrop grades 2/3 vs. 0/1. At 72 h post vs. before PCI, CD34+VEGFR-2+CD133- (0.82 ± 0.32 × 106/L vs. 1.00 ± 0.39 × 106/L, P = .003), CD34+VEGFR-2+CD133+ (0.24 ± 0.12 × 106/L vs. 0.27 ± 0.14 × 106/L, P = .028), and CD14+Tie2+VEGFR-2+ (6.60 ± 3.32 × 106/L vs. 7.82 ± 3.91 × 106/L, P = .006) cell numbers were lower. The baseline levels of CD34+VEGFR-2+cells (P = .001) and CD14+Tie2+VEGFR-2+cells (P < .001) were association with the grade of collateralization. In addition, the baseline and peri-procedural decrease of circulating CD34+VEGFR-2+ cells correlated with the increase of LVEF (P < .001, P < .001, respectively) and the decrease of LVEDd (P = .022, P = .029, respectively) at follow-up. CONCLUSIONS: In this small study, the baseline levels of circulating CD34+VEGFR-2+ EPCs and its reduction after successful revascularization of CTOs correlated with long-term improvement in global LV systolic function.

4.
Ann Transl Med ; 8(18): 1185, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33241034

RESUMO

Background: Despite prompt revascularization following acute myocardial infarction, poor myocardial perfusion commonly occurs due to impaired microvascular circulation and is an independent predictor of adverse outcomes. The current trial sought to examine the effects of salvianolate on myocardial perfusion in patients with ST-segment-elevation myocardial infarction (STEMI) who were undergoing primary percutaneous coronary intervention (PCI). Methods: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous salvianolate on the achievement of complete epicardial and myocardial reperfusion after PCI, defined as thrombolysis in myocardial infarction flow grade 3 and thrombolysis in myocardial infarction myocardial perfusion grade 3. We also measured plasma total creatine kinase-mass band fraction (CK-MB)-estimated infarct size and echocardiography-derived left ventricular ejection fraction and recorded the 30-day clinical and safety outcomes. A total of 536 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of salvianolate (n=265) or placebo (n=271). Results: Salvianolate administration exerted beneficial effects on coronary microcirculation. There was a trend of reduced myocardial infarct size in the salvianolate group compared to the placebo group (P=0.070), although no significant difference in left ventricular ejection fraction was found between the two groups. Conclusions: Salvianolate administration is associated with improved myocardial perfusion in patients with STEMI undergoing PCI. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes.

5.
Theranostics ; 10(21): 9663-9673, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32863952

RESUMO

Introduction: To explore the involvement of the cardiovascular system in coronavirus disease 2019 (COVID-19), we investigated whether myocardial injury occurred in COVID-19 patients and assessed the performance of serum high-sensitivity cardiac Troponin I (hs-cTnI) levels in predicting disease severity and 30-day in-hospital fatality. Methods: We included 244 COVID-19 patients, who were admitted to Renmin Hospital of Wuhan University with no preexisting cardiovascular disease or renal dysfunction. We analyzed the data including patients' clinical characteristics, cardiac biomarkers, severity of medical conditions, and 30-day in-hospital fatality. We performed multivariable Cox regressions and the receiver operating characteristic analysis to assess the association of cardiac biomarkers on admission with disease severity and prognosis. Results: In this retrospective observational study, 11% of COVID-19 patients had increased hs-cTnI levels (>40 ng/L) on admission. Of note, serum hs-cTnI levels were positively associated with the severity of medical conditions (median [interquartile range (IQR)]: 6.00 [6.00-6.00] ng/L in 91 patients with moderate conditions, 6.00 [6.00-18.00] ng/L in 107 patients with severe conditions, and 11.00 [6.00-56.75] ng/L in 46 patients with critical conditions, P for trend=0.001). Moreover, compared with those with normal cTnI levels, patients with increased hs-cTnI levels had higher in-hospital fatality (adjusted hazard ratio [95% CI]: 4.79 [1.46-15.69]). The receiver-operating characteristic curve analysis suggested that the inclusion of hs-cTnI levels into a panel of empirical prognostic factors substantially improved the prediction performance for severe or critical conditions (area under the curve (AUC): 0.71 (95% CI: 0.65-0.78) vs. 0.65 (0.58-0.72), P=0.01), as well as for 30-day fatality (AUC: 0.91 (0.85-0.96) vs. 0.77 (0.62-0.91), P=0.04). A cutoff value of 20 ng/L of hs-cTnI level led to the best prediction to 30-day fatality. Conclusions: In COVID-19 patients with no preexisting cardiovascular disease, 11% had increased hs-cTnI levels. Besides empirical prognostic factors, serum hs-cTnI levels upon admission provided independent prediction to both the severity of the medical condition and 30-day in-hospital fatality. These findings may shed important light on the clinical management of COVID-19.


Assuntos
Cardiomiopatias/etiologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Troponina I/sangue , Idoso , Cardiomiopatias/sangue , China , Estudos de Coortes , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos
6.
J Intensive Care ; 8: 49, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32665858

RESUMO

Background: Over 5,488,000 cases of coronavirus disease-19 (COVID-19) have been reported since December 2019. We aim to explore risk factors associated with mortality in COVID-19 patients and assess the use of D-dimer as a biomarker for disease severity and clinical outcome. Methods: We retrospectively analyzed the clinical, laboratory, and radiological characteristics of 248 consecutive cases of COVID-19 in Renmin Hospital of Wuhan University, Wuhan, China from January 28 to March 08, 2020. Univariable and multivariable logistic regression methods were used to explore risk factors associated with in-hospital mortality. Correlations of D-dimer upon admission with disease severity and in-hospital mortality were analyzed. Receiver operating characteristic curve was used to determine the optimal cutoff level for D-dimer that discriminated those survivors versus non-survivors during hospitalization. Results: Multivariable regression that showed D-dimer > 2.0 mg/L at admission was the only variable associated with increased odds of mortality [OR 10.17 (95% CI 1.10-94.38), P = 0.041]. D-dimer elevation (≥ 0.50 mg/L) was seen in 74.6% (185/248) of the patients. Pulmonary embolism and deep vein thrombosis were ruled out in patients with high probability of thrombosis. D-dimer levels significantly increased with increasing severity of COVID-19 as determined by clinical staging (Kendall's tau-b = 0.374, P = 0.000) and chest CT staging (Kendall's tau-b = 0.378, P = 0.000). In-hospital mortality rate was 6.9%. Median D-dimer level in non-survivors (n = 17) was significantly higher than in survivors (n = 231) [6.21 (3.79-16.01) mg/L versus 1.02 (0.47-2.66) mg/L, P = 0.000]. D-dimer level of > 2.14 mg/L predicted in-hospital mortality with a sensitivity of 88.2% and specificity of 71.3% (AUC 0.85; 95% CI = 0.77-0.92). Conclusions: D-dimer is commonly elevated in patients with COVID-19. D-dimer levels correlate with disease severity and are a reliable prognostic marker for in-hospital mortality in patients admitted for COVID-19.

7.
BMC Cardiovasc Disord ; 20(1): 325, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32635890

RESUMO

BACKGROUND: Provisional 1-stent technique is currently regarded as the default approach for the majority of bifurcation lesions. Nonetheless, 2-stent techniques may be required for complex bifurcations with high compromise risk or fatal consequences of side branch (SB) occlusion. Limitations exist in current approaches, as stents gap, multiple metal layers and stent malapposition caused by imprecise placement with fluoroscopic guide and intrinsic technical defects. This study was designed to investigate the effectiveness of the novel Szabo 2-stent technique for coronary bifurcation lesions. METHODS: In the Szabo 2-stent technique, one stent is precisely implanted at the SB ostium with Szabo technique resulting in a single strut protruding into the main vessel (MV). After MV rewiring and SB guidewire withdrawal, another stent is implanted in MV followed by proximal optimization technique, SB rewiring, and final kissing inflation (FKI). RESULTS: The technique tested successfully in silicone tubes (n = 9) with: procedure duration, 31.2 ± 6.8 min; MV and SB rewiring time, 26.8 ± 11.2 s and 33.3 ± 15 s; easy FKI; and 2.3 ± 0.5 balloons/procedure. Bifurcation lesions (n = 22) were treated with angiographic success in MV and SB, respectively: increased minimal lumen diameter (0.63 ± 0.32 mm to 3.20 ± 0.35 mm; 0.49 ± 0.37 mm to 2.67 ± 0.25 mm); low residual stenosis (12.4 ± 2.4%; 12.4 ± 2.3%); and intravascular ultrasound confirmed (n = 19) full coverage; minimal overlap and malapposition; minimal lumen area (2.4 ± 1.2 mm2; 2.1 ± 1.0 mm2); plaque burden (78.1 ± 11.3%; 71.6 ± 15.5%); and minimal stent area (9.1 ± 1.6 mm2; 6.1 ± 1.3 mm2). Periprocedural cardiac troponin increased in 1 asymptomatic patient without electrocardiographic change. There was no target lesion failure (cardiac death, myocardial infarction, target lesion revascularization) at 6-month follow-up. CONCLUSIONS: The Szabo 2-stent technique for bifurcation lesions provided acceptable safety and efficacy at short-term follow-up.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32488750

RESUMO

PURPOSE: Cardiac resynchronization therapy (CRT) is well acknowledged as an effective treatment for dyssynchronous heart failure. However, the molecular mechanism is unclear to date. Mitochondrial dysfunction and impaired energetic metabolism are two important mechanisms that lead to heart failure. Therefore, we aim to screen the changes of mitochondria-associated proteins and signaling pathways involved in heart failure and CRT treatment. METHODS: A total of 24 beagle dogs were randomly assigned into control (CON), heart failure (HF), or CRT group. Myocardial mitochondria from the free wall of left ventricle was extracted for isobaric tags for relative and absolute quantitation (iTRAQ) labeling coupled with two-dimensional liquid chromatography tandem mass spectrometry analysis (2DLC-MS/MS). RESULTS: A total of 2190 proteins were identified, among which 234 proteins were differentially expressed in HF compared with CON group, 151 proteins were differentially expressed in CRT compared with HF group. A total of 192 of the 234 differentially expressed proteins in HF group were changed oppositely by CRT treatment, and 128 of the 151 CRT-induced differentially expressed proteins showed opposite trend of expression to HF/CON. Gene Ontology analysis of the 128 proteins revealed that 16 were localized in mitochondria, 17 were associated with calcium signaling, and 7 could be secreted extracellularly for cell-to-cell signaling. Calpain-1 (CAPN1), which is localized to mitochondria and related to calcium signaling, was upregulated in HF and downregulated after CRT treatment. CRT treatment also improved mitochondrial morphology and function and reduced collagen areas of both interstitial and perivascular fibrosis. CONCLUSIONS: CRT treatment significantly improved cardiac function, reduced myocardial fibrosis, and enhanced mitochondrial function in the failing heart through CAPN1 downregulation.

9.
Biomaterials ; 255: 120168, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32562944

RESUMO

Stem cell-derived extracellular vesicles (EVs) have been demonstrated to be effective in heart repair and regeneration post infarction. However, the poor homing efficiency and low yields of these therapeutics remain the major obstacles before they can be used in the clinic. To improve the delivery efficiency of EVs to ischemia-injured myocardium, we modified mesenchymal stem cell (MSC)-derived EVs with monocyte mimics through the method of membrane fusion. Monocyte mimic-bioinspired MSC-EVs (Mon-Exos) exhibited enhanced targeting efficiency to injured myocardium by mimicking the recruitment feature of monocytes after MI/RI, thus contributing to these exclusive adhesive molecules on monocyte mimics, particularly the Mac1/LFA1-ICAM-1 interaction. Through this strategy, Mon-Exos were shown to promote endothelial maturation during angiogenesis and modulate macrophage subpopulations after MI/RI, consistent with MSC-Exos biofunctions, and eventually improve therapeutic outcomes in cardiac function and pathohistology changes after treatments in a mouse MI/RI model. Ultimately, this strategy might provide us with a better way to assess the effects of stem cell EVs and offer additional techniques to help clinicians better manage regenerative therapeutics for ischemic heart diseases.

10.
Ann Transl Med ; 8(7): 430, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32395474

RESUMO

Background: Coronavirus disease 2019 (COVID-19), caused by a novel coronavirus (designated as SARS-CoV-2) has become a pandemic worldwide. Based on the current reports, hypertension may be associated with increased risk of sever condition in hospitalized COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) was recently identified to functional receptor of SARS-CoV-2. Previous experimental data revealed ACE2 level was increased following treatment with ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Currently doctors concern whether these commonly used renin-angiotensin system (RAS) blockers-ACEIs/ARBs may increase the severity of COVID-19. Methods: We extracted data regarding 50 hospitalized hypertension patients with laboratory confirmed COVID-19 in the Renmin Hospital of Wuhan University from Feb 7 to Mar 03, 2020. These patients were grouped into RAS blockers group (Group A, n=20) and non-RAS blockers group (Group B, n=30) according to the basic blood pressure medications. All patients continued to use pre-admission antihypertensive drugs. Clinical severity (symptoms, laboratory and chest CT findings, etc.), clinical course, and short time outcome were analyzed after hospital admission. Results: Ten (50%) and seventeen (56.7%) of the Group A and Group B participants were males (P=0.643), and the average age was 52.65±13.12 and 67.77±12.84 years (P=0.000), respectively. The blood pressure of both groups was under effective control. There was no significant difference in clinical severity, clinical course and in-hospital mortality between Group A and Group B. Serum cardiac troponin I (cTnI) (P=0.03), and N-terminal (NT)-pro hormone BNP (NT-proBNP) (P=0.04) showed significant lower level in Group A than in Group B. But the patients with more than 0.04ng/mL or elevated NT-proBNP level had no statistical significance between the two groups. In patients over 65 years or under 65 years, cTnI or NT-proBNP level showed no difference between the two groups. Conclusions: We observed there was no obvious difference in clinical characteristics between RAS blockers and non-RAS blockers groups. These data suggest ACEIs/ARBs may have few effects on increasing the clinical severe conditions of COVID-19.

11.
BMC Cardiovasc Disord ; 20(1): 178, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32299366

RESUMO

BACKGROUND: Heart failure is associated with ventricular dyssynchrony and energetic inefficiency, which can be alleviated by cardiac resynchronization therapy (CRT) with approximately one-third of non-response rate. Thus far, there is no specific biomarker to predict the response to CRT in patients with heart failure. In this study, we assessed the role of the blood metabolomic profile in predicting the response to CRT. METHODS: A total of 105 dilated cardiomyopathy patients with severe heart failure who received CRT were included in our two-stage study. Baseline blood samples were collected prior to CRT implantation. The response to CRT was defined according to echocardiographic criteria. Metabolomic profiling of serum samples was carried out using ultrahigh performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. RESULTS: Seventeen metabolites showed significant differences in their levels between responders and non-responders, and these metabolites were primarily involved in six pathways, including linoleic acid metabolism, Valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, citrate cycle, tryptophan metabolism, and sphingolipid metabolism. A combination of isoleucine, tryptophan, and linoleic acid was identified as an ideal metabolite panel to distinguish responders from non-responders in the discovery set (n = 51 with an AUC of 0.981), and it was confirmed in the validation set (n = 54 with an AUC of 0.929). CONCLUSIONS: Mass spectrometry based serum metabolomics approach provided larger coverage of metabolome which can help distinguish CRT responders from non-responders. A combination of isoleucine, tryptophan, and linoleic acid may associate with significant prognostic values for CRT.


Assuntos
Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/terapia , Isoleucina/sangue , Ácido Linoleico/sangue , Metabolômica , Triptofano/sangue , Idoso , Biomarcadores/sangue , Terapia de Ressincronização Cardíaca/efeitos adversos , Cromatografia Líquida de Alta Pressão , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Resultado do Tratamento
12.
Adv Clin Exp Med ; 29(4): 493-497, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32338833

RESUMO

BACKGROUND: Patients with coronary chronic total occlusion (CTO) typically have collateralization of the distal vessel, and these collaterals can contribute to the relief of ischemia and anginal symptoms and to the preservation of ventricular function. OBJECTIVES: To investigate the preservation effect of coronary collateral circulation on left ventricular (LV) function in coronary CTO, and to explore the potential mechanism behind the development of coronary collateral circulation. MATERIAL AND METHODS: A total of 102 consecutive patients with coronary CTO were divided into 2 groups: the left ventricular ejection fraction (LVEF)-preserved group (LVEF ≥ 50%; n = 46) and the LVEF-decreased group (LVEF < 50%; n = 56). Clinical, angiographic and laboratory data was collected for all patients. The association between LVEF and coronary collateral circulation in coronary CTO patients was analyzed with multivariate logistic regression analysis, and the serum levels of VEGF-A and the mRNA expression levels of the VEGF-A gene were compared between different grades of coronary collateral circulation. RESULTS: Multivariate analysis revealed that Rentrop grades 2-3 and coexisting collateral pathways were independent predictors of LVEF preservation in coronary CTO patients. Patients with Rentrop grades 2-3 had smaller left ventricular end diastolic diameters (LVDd) and left ventricular end systolic diameters (LVSd), and they had larger LVEFs than the patients with Rentrop grades 0-1. Patients with Rentrop grades 2-3 also had higher serum levels of VEGF-A and higher mRNA expression levels of the VEGF-A gene in their peripheral blood mononuclear cells (PBMCs) than patients with Rentrop grades 0-1. Patients with coexisting collateral pathways had higher serum levels of VEGF-A and higher mRNA expression levels of the VEGF-A gene in PBMCs than patients without coexisting collateral pathways. CONCLUSIONS: Coronary collateral circulation is significantly associated with LVEF preservation, and VEGF-A might promote the formation of coronary collateral circulation.


Assuntos
Circulação Colateral , Circulação Coronária , Oclusão Coronária , Leucócitos Mononucleares , Fator A de Crescimento do Endotélio Vascular/sangue , Função Ventricular Esquerda/fisiologia , Angiografia Coronária , Humanos , Intervenção Coronária Percutânea , Volume Sistólico , Fator A de Crescimento do Endotélio Vascular/genética
13.
Mol Ther Nucleic Acids ; 19: 1299-1308, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32160702

RESUMO

Induction of endogenous cardiomyocyte (CM) proliferation is one of the key strategies for heart regeneration. Increasing evidence points to the potential role of microRNAs (miRNAs) in the regulation of CM proliferation. Here, we used human embryonic stem cell (hESC)-derived CMs (hESC-CMs) as a tool to identify miRNAs that promote CM proliferation. We profiled miRNA expression at an early stage of CM differentiation and identified a list of highly expressed miRNAs. Among these miRNAs, miR-25 was enriched in early-stage hESC-CMs, but its expression decreased over time. Overexpression of miR-25 promoted CM proliferation. RNA sequencing (RNA-seq) analysis revealed that genes related to cell-cycle signal were strongly influenced by miR-25 overexpression. We further showed that miR-25 promoted CM proliferation by targeting FBXW7. Finally, the function of miR-25 in the regulation of CM proliferation was demonstrated in zebrafish. Our study suggested that miR-25 is a promising molecule for heart regeneration.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32212039

RESUMO

It remains uncertain whether plasma D-dimer level can predict no-reflow in patients with STEMI who had pPCI after 48 h of symptom onset. This study retrospectively enrolled 229 consecutive patients who had pPCI for acute STEMI within 2-7 days of symptom onset between January 2008 and December 2018. Patients were divided into no-reflow group (TIMI flow grade 0-2) and reflow group (TIMI flow grade 3). Predictors of no-reflow were assessed by univariate and multivariate binary logistic regression analyses. Plasma D-dimer level can independently predict no-reflow in patients with STEMI who had pPCI within 2-7 days of symptom onset (OR 2.52 per 1 mg/L increase, 95% CI 1.16-5.47, p = 0.019). This finding indicated that pPCI may be safe and feasible for STEMI patients within 2-7 days of symptom onset with low D-dimer level. Graphical Abstract Plasma D-dimer level can independently predict no-reflow in patients with STEMI who had pPCI within 2-7 days of symptom onset. pPCI may be safe and feasible for STEMI patients within 2-7 days of symptom onset with low D-dimer level.

15.
Int J Nanomedicine ; 15: 901-912, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32103945

RESUMO

Background: Aortic valve disease is the most common valvular heart disease leading to valve replacement. The efficacy of pharmacological therapy for aortic valve disease is limited by the high mechanical stress at the aortic valves impairing the binding rate. We aimed to identify nanoparticle coating with entire platelet membranes to fully mimic their inherent multiple adhesive mechanisms and target the sclerotic aortic valve of apolipoprotein E-deficient (ApoE-/-) mice based on their multiple sites binding capacity under high shear stress. Methods: Considering the potent interaction of platelet membrane glycoproteins with components present in sclerotic aortic valves, platelet membrane-coated nanoparticles (PNPs) were synthetized and the binding capacity under high shear stress was evaluated in vitro and in vivo. Results: PNPs demonstrated effectively adhering to von Willebrand factor, collagen and fibrin under shear stresses in vitro. In an aortic valve disease model established in ApoE-/- mice, PNPs exhibited good targeting to sclerotic aortic valves by mimicking platelet multiple adhesive mechanisms. Conclusion: PNPs could provide a promising platform for the molecular diagnosis and targeting treatment of aortic valve disease.


Assuntos
Plaquetas/citologia , Doenças das Valvas Cardíacas/tratamento farmacológico , Nanopartículas/química , Nanopartículas/metabolismo , Animais , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Apolipoproteínas E/genética , Plaquetas/química , Membrana Celular/química , Colágeno/metabolismo , Modelos Animais de Doenças , Fibrina/metabolismo , Cardiopatias Congênitas , Doenças das Valvas Cardíacas/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Nanopartículas/uso terapêutico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Esclerose , Estresse Mecânico , Fator de von Willebrand/metabolismo
16.
J Mol Cell Cardiol ; 142: 65-79, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32087217

RESUMO

BACKGROUND: Reperfusion may cause injuries to the myocardium in ischemia situation. Emerging studies suggest that exosomes may serve as key mediators in myocardial ischemia/reperfusion (MI/R) injury. OBJECTIVE: The study was conducted to figure out the mechanism of M2 macrophage-derived exosomes (M2-exos) in MI/R injury with the involvement of microRNA-148a (miR-148a). METHODS AND RESULTS: M2 macrophages were prepared and M2-exos were collected and identified. Neonatal rat cardiomyocytes (NCMs) were extracted for in vitro hypoxia/reoxygenation (H/R) model establishment, while rat cardiac tissues were separated for in vivo MI/R model establishment. Differentially expressed miRNAs in NCMs and H/R-treated NCMs after M2-exos treatment were evaluated using microarray analysis. The target relation between miR-148a and thioredoxin-interacting protein (TXNIP) was identified using dual luciferase reporter gene assay. Gain- and loss- of function studies of miR-148a and TXNIP were performed to figure out their roles in MI/R injury. Meanwhile, the activation of the TLR4/NF-κB/NLRP3 inflammasome signaling pathway and pyroptosis of NCMs were evaluated. M2 macrophages carried miR-148a into NCMs. Over-expression of miR-148a enhanced viability of H/R-treated NCMs, reduced infarct size in vivo, and alleviated dysregulation of cardiac enzymes and Ca2+ overload in both models. miR-148a directly bound to the 3'-untranslated region (3'UTR) of TXNIP. Over-expressed TXNIP triggered the TLR4/NF-κB/NLRP3 signaling pathway activation and induced cell pyroptosis of NCMs, and the results were reproduced in in vivo studies. CONCLUSION: This study demonstrated that M2-exos could carry miR-148a to mitigate MI/R injury via down-regulating TXNIP and inactivating the TLR4/NF-κB/NLRP3 inflammasome signaling pathway. This study may offer new insights into MI/R injury treatment.

17.
Mol Ther Nucleic Acids ; 19: 437-445, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-31902743

RESUMO

Adult mammalian cardiomyocytes (CMs) retain a limited proliferative ability, which is insufficient for the repair of CM loss in ischemic cardiac injury. Regulation of the Hippo signaling pathway to promote endogenous CM proliferation has emerged as a promising strategy for heart regeneration. Previous studies have shown that the microRNA cluster miR302-367 negatively regulates the Hippo pathway, promoting CM proliferation. In this study, we identified another microRNA, miR-10b, that regulates the Hippo pathway and promotes cell proliferation in human embryonic stem cell-derived CMs (hESC-CMs). We observed that miR-10b expression was enriched in the early stage of CMs, but its expression was reduced over time. Overexpression of miR-10b promoted CM proliferation, while knockdown of miR-10b suppressed CM proliferation. Moreover, miR-10b protected CMs against apoptosis. miR-10b functions, in part, by directly targeting LATS1, which is a major component of the Hippo pathway. Our study suggests that miR-10b has promising potential for heart regeneration.

18.
Int J Nanomedicine ; 14: 6103-6115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447555

RESUMO

Purpose: Myocardial delivery of magnetic iron oxide nanoparticles (MNPs) might produce iron overload-induced myocardial injury, and the oxidative stress was regarded as the main mechanism. Therefore, we speculated antioxidant modification might be a reasonable strategy to mitigate the toxicity of MNPs. Methods and results: Antioxidant N-acetylcysteine (NAC) was loaded into magnetic mesoporous silica coated Fe3O4 nanoparticles. Neonatal rat hypoxia/reoxygenation (H/R) cardiomyocytes were incubated with nanoparticles for 24 hrs. NAC can effectively mitigate iron-induced oxidative injury of cardiomyocytes, evidenced by reduced production of MDA, 8-iso-PGF2α, and 8-OHDG and maintained concentrations of SOD, CAT, GSH-Px, and GSH in ELISA and biochemical tests; downregulated expression of CHOP, GRP78, p62, and LC3-II proteins in Western Blot, and less cardiomyocytes apoptosis in flow cytometric analysis. Conclusions: NAC modifying could suppress the toxic effects of Fe3O4 nanoparticles in H/R cardiomyocytes model in vitro, indicating a promising strategy to improve the safety of iron oxide nanoparticles.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Compostos Férricos/toxicidade , Nanopartículas de Magnetita/toxicidade , Miócitos Cardíacos/patologia , Oxigênio/farmacologia , Animais , Autofagia/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Nanopartículas de Magnetita/ultraestrutura , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Porosidade , Ratos , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/toxicidade
19.
EuroIntervention ; 15(3): e253-e260, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-30946014

RESUMO

AIMS: This study sought to demonstrate the incidence, predictors, and management of microcatheter collateral channel (CC) tracking failure in retrograde percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) lesions. METHODS AND RESULTS: Prospectively collected data from 371 consecutive retrograde CTO-PCI procedures between March 2015 and January 2018 were retrospectively analysed. The incidence of initial microcatheter CC tracking failure was 22.5% in 280 procedures with wire CC tracking success. For septal collaterals, CC grade 0-1 collaterals (odds ratio [OR]: 8.3; p<0.001), channel entry angle <90° (OR: 13.0; p=0.001), channel exit angle <90° (OR: 44.3; p=0.004), and Finecross MG as initial microcatheter (OR: 2.7; p=0.032) were independently related to initial microcatheter CC tracking failure. Meanwhile, the only predictor for epicardial collaterals was CC 1 collaterals (OR: 26.9; p<0.001). Frequently applied solutions included microcatheter switching (61.9%), and microcatheter switching combined with GUIDEZILLA (14.3%) or anchoring balloon technique (6.3%). CONCLUSIONS: Initial microcatheter CC tracking failure was found in nearly one quarter of procedures after wire CC tracking success. Independent angiographic predictors of initial microcatheter CC tracking failure included CC 0-1 collaterals, channel entry angle <90°, and channel exit angle <90° for septal collaterals, and CC 1 collaterals for epicardial collaterals.


Assuntos
Angioplastia Coronária com Balão , Oclusão Coronária , Intervenção Coronária Percutânea , Doença Crônica , Circulação Colateral , Angiografia Coronária , Humanos , Incidência , Estudos Retrospectivos , Resultado do Tratamento
20.
Stem Cells ; 37(5): 663-676, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30779865

RESUMO

Poor cell homing limits the efficacy of cardiac cellular therapy. The homing peptide, cysteine-arginine-glutamic acid-lysine-alanine (CREKA), targets fibrin effectively which is involved in the repair process of tissue injury. Here, we assessed if CREKA-modified stem cells had enhanced fibrin-mediated homing ability resulting in better functional recovery and structural preservation in a rat myocardial injury model. CREKA-modified mesenchymal stem cells (CREKA-MSCs) were obtained via membrane fusion with CREKA-modified liposomes. The fibrin targeting ability of CREKA-MSCs was examined both in vitro and in vivo. Under both static and flow conditions in vitro, CREKA significantly enhanced MSCs binding ability to fibrin clots (2.6- and 2.3-fold, respectively). CREKA-MSCs showed 6.5-fold higher accumulation than unmodified MSCs in injured rat myocardium one day after administration, resulting in better structural preservation and functional recovery. Fibrin is, therefore, a novel target for enhancing homing of transplanted cells to injured myocardium, and the delivery system of fibrin-targeting is on behalf of a universalizable platform technology for regenerative medicine. Stem Cells 2019;37:663-676.


Assuntos
Sistemas de Liberação de Medicamentos , Transplante de Células-Tronco Mesenquimais , Isquemia Miocárdica/terapia , Traumatismo por Reperfusão/terapia , Animais , Modelos Animais de Doenças , Fibrina/antagonistas & inibidores , Fibrina/genética , Fibrina/farmacologia , Humanos , Células-Tronco Mesenquimais/citologia , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Miocárdio/patologia , Nanopartículas/química , Oligopeptídeos/farmacologia , Ratos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
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