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1.
Life Sci ; 232: 116635, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31283925

RESUMO

AIMS: The pathological cardiac hypertrophy will develop into heart failure, which has no effective treatment currently. Previous studies have proved that microRNAs (miRNAs) participate in the development of cardiac hypertrophy and regulate the pathological progress. In this study, we want to investigate the role of microRNA-92b-3p (miR-92b-3p) in cardiomyocyte hypertrophy and the mechanisms involved. MATERIALS AND METHODS: Neonatal mouse ventricular cells (NMVCs) were isolated from the hearts of 1-3-d-old newborn C57BL6 mice. The isolated NMVCs were induced hypertrophic phenotype by Angiotensin-II (Ang-II) and the cell size was examined by FITC-phalloidin staining assay. The expression of miR-92b-3p was determined by quantitative real-time PCR (qRT-qPCR). MRNA and protein level of ß-MHC, ACTA1 and HAND2 in NMVCs transfected with miR-92b-3p mimic and inhibition were assessed by RT-qPCR assay and western blot assay, respectively. Dual luciferase assay was used to verify the interaction between miR-92b-3p and the 3'-untranslated region (UTR) of HAND2 gene. KEY FINDINGS: MiR-92b-3p and HAND2 were significantly increased in Ang-II-induced NMVCs. Overexpression of miR-92b-3p can ameliorate Ang-II-induced cardiomyocyte hypertrophy. MiR-92b-3p negatively regulated HAND2 expression at the transcriptional level. Both miR-92b-3p mimic and HAND2 siRNA could efficiently inhibit Ang-II-induced hypertrophy in mouse cardiomyocytes. SIGNIFICANCE: MiR-92b-3p inhibits Ang-II-induced cardiomyocyte hypertrophy via targeting HAND2.


Assuntos
Angiotensina II/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/patologia , Regiões 3' não Traduzidas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Modelos Animais de Doenças , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Ventrículos do Coração/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima
2.
Nat Commun ; 10(1): 2760, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235787

RESUMO

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.


Assuntos
Redes Reguladoras de Genes/genética , Insuficiência Cardíaca/genética , Miócitos Cardíacos/patologia , Fosfoproteínas Fosfatases/metabolismo , Animais , Benzenoacetamidas , Células Cultivadas , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fosfoproteínas Fosfatases/genética , Cultura Primária de Células , Piridinas , Locos de Características Quantitativas/genética , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA/métodos
3.
Rev Assoc Med Bras (1992) ; 65(5): 592-595, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31166432

RESUMO

Hypertension may occur with left ventricular (LV) diastolic dysfunction, and the consequence may be symptoms and signs of heart failure (HF). Hepatojugular reflux (HJR), described as a sign of regurgitation of the tricuspid valve, may reflect structural and functional changes of the LV in the hypertensive patient. The signal may be present in the presence of HF. Case: male, 49 years old with uncontrolled blood pressure. Physical examination showed jugular turgescence, HJR, and elevated blood pressure. Complementary exams showed signs of atrial and left ventricular overload in the electrocardiogram and, the echocardiogram showed left atrium volume increase, concentric LV hypertrophy and signs of grade I diastolic dysfunction. DISCUSSIO: The HJR present correlates with pulmonary artery pressure and probably reflect the increase in central blood volume.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Veias Jugulares/fisiopatologia , Volume Sistólico/fisiologia , Insuficiência da Valva Tricúspide/fisiopatologia , Disfunção Ventricular Esquerda/fisiopatologia , Ecocardiografia , Eletrocardiografia , Insuficiência Cardíaca/patologia , Humanos , Hipertensão/fisiopatologia , Veias Jugulares/patologia , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Tricúspide/patologia
4.
Mol Med Rep ; 19(6): 5281-5290, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059043

RESUMO

Heart failure (HF) secondary to acute myocardial infarction (AMI) is a public health concern. The current study aimed to investigate differentially expressed genes (DEGs) and their possible function in HF post­myocardial infarction. The GSE59867 dataset included microarray data from peripheral blood samples obtained from HF and non­HF patients following AMI at 4 time points (admission, discharge, and 1 and 6 months post­AMI). Time­series DEGs were analyzed using R Bioconductor. Functional enrichment analysis was performed, followed by analysis of protein­protein interactions (PPIs). A total of 108 DEGs on admission, 32 DEGs on discharge, 41 DEGs at 1 month post­AMI and 19 DEGs at 6 months post­AMI were identified. Among these DEGs, 4 genes were downregulated at all the 4 time points. These included fatty acid desaturase 2, leucine rich repeat neuronal protein 3, G­protein coupled receptor 15 and adenylate kinase 5. Functional enrichment analysis revealed that these DEGs were mainly enriched in 'inflammatory response', 'immune response', 'toll­like receptor signaling pathway' and 'NF­κß signaling pathway'. Furthermore, PPI network analysis revealed that C­X­C motif chemokine ligand 8 and interleukin 1ß were hub genes. The current study identified candidate DEGs and pathways that may serve important roles in the development of HF following AMI. The results obtained in the current study may guide the development of novel therapeutic agents for HF following AMI.


Assuntos
Biologia Computacional/métodos , Regulação da Expressão Gênica , Insuficiência Cardíaca/patologia , Infarto do Miocárdio/patologia , Adulto , Idoso , Bases de Dados Genéticas , Regulação para Baixo , Ácidos Graxos Dessaturases/genética , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Humanos , Interleucina-1beta/genética , Interleucina-8/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Proteínas de Neoplasias/genética , Mapeamento de Interação de Proteínas/métodos
6.
Georgian Med News ; (288): 69-72, 2019 Mar.
Artigo em Russo | MEDLINE | ID: mdl-31101779

RESUMO

Despite the success achieved in the study and treatment of chronic heart failure, this syndrome still remains one of the most difficult and predictable unreliable pathologies. Moreover, in recent years there has been a tendency of growth of such patients. Based on the above, the attention of scientists focuses on new concepts that involve the study of new biomarkers of cardiac damage and the definition of their role in the progression of heart failure. Based on studies conducted by numerous authors, the paper analyzes the importance of new biomarkers of myocardial damage in the development of heart failure. The manuscript describes biomarkers of damage (troponin T, galectin 3, lipocalin, Cystatin C): nature: the causes and mechanisms of their growth, increase and activity. Biomarkers of myocardial damage are shown to have diagnostic and high predicted values. Their temporary definition provides additional information for stratifying the risks of possible complications. It also gives us the opportunity to allocate patients with high risks in a timely manner and eliminate possible adverse complications.


Assuntos
Biomarcadores , Insuficiência Cardíaca , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/patologia , Humanos , Miocárdio/patologia , Prognóstico , Troponina T
7.
Nat Commun ; 10(1): 2168, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092830

RESUMO

Adult cardiac tissue undergoes a rapid process of dedifferentiation when cultured outside the body. The in vivo environment, particularly constant electromechanical stimulation, is fundamental to the regulation of cardiac structure and function. We investigated the role of electromechanical stimulation in preventing culture-induced dedifferentiation of adult cardiac tissue using rat, rabbit and human heart failure myocardial slices. Here we report that the application of a preload equivalent to sarcomere length (SL) = 2.2 µm is optimal for the maintenance of rat myocardial slice structural, functional and transcriptional properties at 24 h. Gene sets associated with the preservation of structure and function are activated, while gene sets involved in dedifferentiation are suppressed. The maximum contractility of human heart failure myocardial slices at 24 h is also optimally maintained at SL = 2.2 µm. Rabbit myocardial slices cultured at SL = 2.2 µm remain stable for 5 days. This approach substantially prolongs the culture of adult cardiac tissue in vitro.


Assuntos
Insuficiência Cardíaca/patologia , Coração/fisiologia , Contração Miocárdica/fisiologia , Miocárdio/patologia , Técnicas de Cultura de Tecidos/métodos , Adulto , Animais , Biomimética/métodos , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Miocárdio/citologia , Miocárdio/ultraestrutura , Coelhos , Ratos , Ratos Sprague-Dawley , Sarcômeros/fisiologia
8.
Health Psychol ; 38(5): 369-375, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045419

RESUMO

OBJECTIVE: This study evaluated agreement between the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Depression scale and the Beck Depression Inventory (BDI-II) in patients with heart failure and comorbid major depression. METHOD: The BDI-II and the computerized adaptive test version of the PROMIS® Depression scale were administered at baseline to 158 participants in a randomized controlled trial of cognitive behavior therapy for major depression in patients with heart failure. A crosswalk table (Choi, Schalet, Cook, & Cella, 2014) was used to transform the PROMIS® scores into "linked" BDI-II equivalent scores. Bland-Altman plots, histograms, and scatterplots were used to visualize the agreement between these scores at baseline and 6 months, and intraclass correlation coefficients (ICCs) were calculated for each occasion to quantify the agreement. Treatment effects and change scores were also examined. RESULTS: The measures agreed moderately at baseline (ICC = 0.52, p < .0001) and strongly at 6 months (ICC = 0.77, p < .0001), but on average, the linked and observed BDI-II scores differed by 3.1 points at baseline (p < .0001) and -0.17 points at 6 months (p = .78). The discrepancies were considerably larger in many individual cases on both occasions. CONCLUSIONS: The PROMIS® Depression scale is likely to play an important role in research on depression in patients with heart failure, but for now, it should be used in addition to rather than instead of the BDI-II in studies in which the BDI-II would ordinarily be used. Additional research is needed to evaluate the validity and utility of the PROMIS® Depression scale in patients with heart failure. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Depressão/psicologia , Insuficiência Cardíaca/psicologia , Medidas de Resultados Relatados pelo Paciente , Comorbidade , Depressão/epidemiologia , Feminino , Insuficiência Cardíaca/patologia , Humanos , Masculino , Pessoa de Meia-Idade
9.
Toxicon ; 164: 16-19, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30946913

RESUMO

The aim of this paper was to report an outbreak of avocado poisoning in rabbits in Salta, Argentina. Fourteen rabbits died of congestive heart failure within 30 h of ingesting fresh avocado leaves from pruned trees. They showed clinical signs of respiratory and cardiac distress. Full necropsies of four rabbits were performed and samples were collected for histopathology. The gross pathological observation included pleural and pericardial effusion, pulmonary oedema, slight ascites; the hearts appeared flabby and markedly pale. In addition, the stomach content consisted mostly of green feed with large amounts of avocado leaves. Epidermal fragments of Persea americana were identified by microhistological analysis of gastric content to get most efficiently to a correct diagnosis. Histopathological examination revealed degeneration and necrosis of myocytes and a mononuclear cellular infiltration mainly involving the myocardium and, to a lesser extent, the liver, lung and kidneys. Our observations indicate that avocado leaves should be avoided in the green diet of rabbits.


Assuntos
Insuficiência Cardíaca/veterinária , Persea/envenenamento , Folhas de Planta/envenenamento , Intoxicação por Plantas/veterinária , Animais , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/patologia , Derrame Pericárdico/induzido quimicamente , Derrame Pericárdico/veterinária , Intoxicação por Plantas/patologia , Derrame Pleural/induzido quimicamente , Derrame Pleural/veterinária , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/patologia , Edema Pulmonar/veterinária , Coelhos
10.
Int J Mol Sci ; 20(7)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974752

RESUMO

Activated protein C (APC) is a vitamin-K dependent plasma serine protease, which functions as a natural anticoagulant to downregulate thrombin generation in the clotting cascade. APC also modulates cellular homeostasis by exhibiting potent cytoprotective and anti-inflammatory signaling activities. The beneficial cytoprotective effects of APC have been extensively studied and confirmed in a number of preclinical disease and injury models including sepsis, type-1 diabetes and various ischemia/reperfusion diseases. It is now well-known that APC modulates downstream cell signaling networks and transcriptome profiles when it binds to the endothelial protein C receptor (EPCR) to activate protease-activated receptor 1 (PAR1) on various cell types. However, despite much progress, details of the downstream signaling mechanism of APC and its crosstalk with other signaling networks are far from being fully understood. In this review, we focus on the cardioprotective properties of APC in ischemic heart disease and heart failure with a special emphasis on recent discoveries related to the modulatory effect of APC on AMP-activated protein kinase (AMPK), PI3K/AKT, and mTORC1 signaling pathways. The cytoprotective properties of APC might provide a novel strategy for future therapies in cardiac diseases.


Assuntos
Anticoagulantes/metabolismo , Insuficiência Cardíaca/metabolismo , Isquemia Miocárdica/metabolismo , Proteína C/metabolismo , Transdução de Sinais , Animais , Coagulação Sanguínea , Receptor de Proteína C Endotelial/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Isquemia Miocárdica/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Receptor PAR-1/metabolismo
12.
Nat Commun ; 10(1): 1802, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30996254

RESUMO

The primary cause of heart failure is the loss of cardiomyocytes in the diseased adult heart. Previously, we reported that the miR-17-92 cluster plays a key role in cardiomyocyte proliferation. Here, we report that expression of miR-19a/19b, members of the miR-17-92 cluster, is induced in heart failure patients. We show that intra-cardiac injection of miR-19a/19b mimics enhances cardiomyocyte proliferation and stimulates cardiac regeneration in response to myocardial infarction (MI) injury. miR-19a/19b protected the adult heart in two distinctive phases: an early phase immediately after MI and long-term protection. Genome-wide transcriptome analysis demonstrates that genes related to the immune response are repressed by miR-19a/19b. Using an adeno-associated virus approach, we validate that miR-19a/19b reduces MI-induced cardiac damage and protects cardiac function. Finally, we confirm the therapeutic potential of miR-19a/19b in protecting cardiac function by systemically delivering miR-19a/19b into mice post-MI. Our study establishes miR-19a/19b as potential therapeutic targets to treat heart failure.


Assuntos
Terapia Genética/métodos , Insuficiência Cardíaca/patologia , MicroRNAs/administração & dosagem , MicroRNAs/metabolismo , Infarto do Miocárdio/terapia , Animais , Proliferação de Células/genética , Dependovirus/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Insuficiência Cardíaca/terapia , Ventrículos do Coração/patologia , Humanos , Injeções Intralesionais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Regeneração/genética
13.
Cardiovasc Diabetol ; 18(1): 45, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935417

RESUMO

BACKGROUND: Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure. METHODS AND RESULTS: The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin. CONCLUSIONS: Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Hipertensão/complicações , Miocárdio/patologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Função do Átrio Esquerdo/efeitos dos fármacos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fibrose , Regulação da Expressão Gênica , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/fisiopatologia , Masculino , Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Recuperação de Função Fisiológica , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Basic Res Cardiol ; 114(3): 19, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30887214

RESUMO

Heart failure is a consequence of various cardiovascular diseases and associated with poor prognosis. Despite progress in the treatment of heart failure in the past decades, prevalence and hospitalisation rates are still increasing. Heart failure is typically associated with cardiac remodelling. Here, inflammation and fibrosis are thought to play crucial roles. During cardiac inflammation, immune cells invade the cardiac tissue and modulate tissue-damaging responses. Cardiac fibrosis, however, is characterised by an increased amount and a disrupted composition of extracellular matrix proteins. As evidence exists that cardiac inflammation and fibrosis are potentially reversible in experimental and clinical set ups, they are interesting targets for innovative heart failure treatments. In this context, animal models are important as they mimic clinical conditions of heart failure patients. The advantages of mice in this respect are short generation times and genetic modifications. As numerous murine models of heart failure exist, the selection of a proper disease model for a distinct research question is demanding. To facilitate this selection, this review aims to provide an overview about the current understanding of the pathogenesis of cardiac inflammation and fibrosis in six frequently used murine models of heart failure. Hence, it compares the models of myocardial infarction with or without reperfusion, transverse aortic constriction, chronic subjection to angiotensin II or deoxycorticosterone acetate, and coxsackievirus B3-induced viral myocarditis in this context. It furthermore provides information about the clinical relevance and the limitations of each model, and, if applicable, about the recent advancements in their methodological proceedings.


Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca/etiologia , Animais , Fibrose , Insuficiência Cardíaca/patologia , Camundongos , Miocardite/complicações , Miocárdio/patologia
15.
Int J Mol Sci ; 20(6)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884846

RESUMO

Research on microcirculatory alterations in human heart disease is essential to understand the genesis of myocardial contractile dysfunction and its evolution towards heart failure. The use of contrast agents in magnetic resonance imaging is an important tool in medical diagnostics related to this dysfunction. Contrast agents significantly improve the imaging by enhancing the nuclear magnetic relaxation rates of water protons in the tissues where they are distributed. Gadolinium complexes are widely employed in clinical practice due to their high magnetic moment and relatively long electronic relaxation time. In this study, the behavior of gadolinium ion as a contrast agent was investigated by two complementary methods, relaxometry and secondary ion mass spectrometry. The study examined the distribution of blood flow within the microvascular network in ex vivo Langendorff isolated rat heart models, perfused with Omniscan® contrast agent. The combined use of secondary ion mass spectrometry and relaxometry allowed for both a qualitative mapping of agent distribution as well as the quantification of gadolinium ion concentration and persistence. This combination of a chemical mapping and temporal analysis of the molar concentration of gadolinium ion in heart tissue allows for new insights on the biomolecular mechanisms underlying the microcirculatory alterations in heart disease.


Assuntos
Gadolínio/administração & dosagem , Insuficiência Cardíaca/diagnóstico por imagem , Coração/diagnóstico por imagem , Imagem por Ressonância Magnética , Animais , Meios de Contraste/administração & dosagem , Coração/efeitos dos fármacos , Insuficiência Cardíaca/patologia , Humanos , Microcirculação/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Ratos , Espectrometria de Massa de Íon Secundário , Água/química
16.
BMC Pharmacol Toxicol ; 20(1): 16, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30841920

RESUMO

BACKGROUND: The development of heart failure is accompanied by complex changes in cardiac electrophysiology and functional properties of cardiomyocytes and fibroblasts. Histone deacetylase (HDAC) inhibitors hold great promise for the pharmaceutical therapy of several malignant diseases. Here, we describe novel effects of the class I HDAC inhibitor Entinostat on electrical and structural remodeling in an in vivo model of pacing induced heart failure. METHODS: Rabbits were implanted a pacemaker system, subjected to rapid ventricular pacing and treated with Entinostat or placebo, respectively. Following stimulation, rabbit hearts were explanted and subsequently subjected to electrophysiological studies and further immunohistological analyses of left ventricles. RESULTS: In vivo, rapid ventricular stimulation caused a significant prolongation of monophasic action potential duration compared to sham hearts (from 173 ± 26 ms to 250 ± 41 ms; cycle length 900 ms; p < 0.05) and an increased incidence of Early afterdepolarisations (+ 150%), while treatment with Entinostat in failing hearts could partially prevent this effect (from 250 ± 41 ms to 170 ± 53 ms, p < 0.05; reduction in EAD by 50%). Entinostat treatment partially restored KCNH2 and Cav1.3 gene expressions in failing hearts, and inhibited the development of cardiac fibrosis in vivo. CONCLUSION: In a rabbit model of heart failure, Entinostat diminishes heart failure related prolongation of repolarization and partially restores KCNH2 and Cav1.3 expression. In addition, Entinostat exerts antifibrotic properties both in vitro and in vivo. Thus, Entinostat might be an interesting candidate for the pharmaceutical therapy of heart failure directed against structural and electrical remodeling.


Assuntos
Benzamidas/farmacologia , Insuficiência Cardíaca/patologia , Inibidores de Histona Desacetilases/farmacologia , Piridinas/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Potenciais de Ação , Animais , Canais de Cálcio Tipo L/fisiologia , Canal de Potássio ERG1/fisiologia , Feminino , Fibrose , Coração/efeitos dos fármacos , Coração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Miocárdio/patologia , Coelhos
17.
Chin Med J (Engl) ; 132(7): 819-826, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30829708

RESUMO

BACKGROUND: The early identification of heart failure (HF) risk may favorably affect outcomes, and the combination of multiple biomarkers may provide a more comprehensive and valuable means for improving the risk of stratification. This study was conducted to assess the importance of individual cardiac biomarkers creatine kinase MB isoenzyme (CK-MB), B-type natriuretic peptide (BNP), galectin-3 (Gal-3) and soluble suppression of tumorigenicity-2 (sST2) for HF diagnosis, and the predictive performance of the combination of these four biomarkers was analyzed using random forest algorithms. METHODS: A total of 193 participants (80 patients with HF and 113 age- and gender-matched healthy controls) were included from June 2017 to December 2017. The correlation and regression analysis were conducted between cardiac biomarkers and echocardiographic parameters. The accuracy and importance of these predictor variables were assessed using random forest algorithms. RESULTS: Patients with HF exhibited significantly higher levels of CK-MB, BNP, Gal-3, and sST2. BNP exhibited a good independent predictive capacity for HF (AUC 0.956). However, CK-MB, sST2, and Gal-3 exhibited a modest diagnostic performance for HF, with an AUC of 0.709, 0.711, and 0.777, respectively. BNP was the most important variable, with a remarkably higher mean decrease accuracy and Gini. Furthermore, there was a general increase in predictive performance using the multi-marker model, and the sensitivity, specificity was 91.5% and 96.7%, respectively. CONCLUSION: The random forest algorithm provides a robust method to assess the accuracy and importance of predictor variables. The combination of CK-MB, BNP, Gal-3, and sST2 achieves improvement in prediction accuracy for HF.


Assuntos
Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Adulto , Algoritmos , Biomarcadores/sangue , Biomarcadores/metabolismo , Creatina Quinase Forma MB/sangue , Creatina Quinase Forma MB/metabolismo , Ecocardiografia , Feminino , Galectina 3/sangue , Galectina 3/metabolismo , Insuficiência Cardíaca/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Peptídeo Natriurético Encefálico/metabolismo
18.
Heart Fail Clin ; 15(2): 179-189, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30832810

RESUMO

The cardiology community lacks a taxonomy to prioritize the origins of the complex myocardial pathology underlying heart failure. The key question, "Why does heart muscle fail?", remains unanswered. A large body of literature indicates that myocardial fibrosis represents a principal pathway mediating outcomes in heart failure. Cardiac amyloidosis illustrates how excess protein in the myocardial interstitium culminates in severe heart failure with a dismal prognosis. Robust methods now exist to quantify myocardial fibrosis. Investigators possess the tools to finally establish unequivocally that myocardial fibrosis represents one of the principal pathways mediating outcomes in heart failure that imparts vulnerability.


Assuntos
Cicatriz/patologia , Fibrose/patologia , Insuficiência Cardíaca/patologia , Miocárdio/patologia , Amiloidose/complicações , Amiloidose/patologia , Cicatriz/complicações , Fibrose/complicações , Humanos
19.
Pharm Biol ; 57(1): 48-54, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30905241

RESUMO

CONTEXT: Heart failure (HF) is one of the most serious diseases worldwide. Astragaloside IV (ASI) is widely used for the treatment of cardiovascular disease in China. OBJECTIVE: To evaluate the protective effect of ASI on the HF in a Sprague-Dawley rat model of left coronary artery ligation, and investigate the angiogenesis-related mechanisms. MATERIALS AND METHODS: Left coronary artery was ligated to induce a rat model of HF, and the rats were treated with vehicle (saline) or different doses of ASI (0.1, 0.3 and 1 mg/kg/day) by oral gavage for 6 weeks. Cardiac function was evaluated by echocardiography. Infarct size was determined by triphenyltetrazolium chloride staining. Cardiac vascular density was analyzed by microangiography. Real-time PCR, Western blot and chromatin immunoprecipitation were performed to investigate the mechanisms. RESULTS: ASI treatment improved the body weight and survival rate of HF rats, as well as the cardiac function of HF rats, with significantly improved ejection fraction (75.27 ± 5.75% vs. 36.26 ± 4.14%) and fractional shortening (45.39 ± 3.66% vs. 17.88 ± 1.32%). ASI reduced the infarct size of the HF rats by 47%. ASI promoted angiogenesis, with increased vascular density (2.08-fold) and induced mRNA expression of CD31 (1.81-fold) and VEGF (2.70-fold) in the ischemic heart. Furthermore, ASI induced the phosphorylation of JAK (1.89-fold) and STAT3 (2.95-fold), as well as the activity of VEGF promoter which was regulated by STAT3. DISCUSSION AND CONCLUSIONS: ASI alleviated HF by promoting angiogenesis through JAK-STAT3 pathway, providing novel alternative strategies to prevent HF in the future.


Assuntos
Indutores da Angiogênese/farmacologia , Vasos Coronários/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Janus Quinases/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Modelos Animais de Doenças , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Estimativa de Kaplan-Meier , Masculino , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Miocárdio/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3 , Transdução de Sinais/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
20.
Int Heart J ; 60(2): 384-391, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30799377

RESUMO

The physiological control of appetite regulation involves circulating hormones with orexigenic (ghrelin) and anorexigenic (cholecystokinin) properties that induce alterations in energy intake via perceptions of hunger and satiety. We sought to investigate the relationship between appetite-regulating hormones and the cachexia associated with chronic heart failure.We randomized male Sprague-Dawley rats into myocardial infarction (MI) or sham operation (SO) groups. The levels of brain natriuretic peptide (BNP), cholecystokinin (CCK) and ghrelin in the plasma of all rats were detected by enzyme-linked immunosorbent assay (ELISA); the expression of BNP, CCK, and ghrelin in the myocardial tissue of all rats were detected by western blotting, immunohistochemistry, real-time polymerase chain reaction (PCR); myocardial morphology was assessed by microscopy.Plasma BNP and CCK levels in the cardiac cachexia (CC) groups and the heart failure non-cachexia (HF-nc) groups were significantly higher than those in the control groups (P < 0.01), and the expression of BNP and CCK in the myocardial tissue of rats: in CC groups and HF-nc groups were increased compared with the corresponding control groups (P < 0.01). In contrast, Plasma and cardiac expression of ghrelin decreased compared with the sham group (P < 0.01). Furthermore, plasma CCK levels were positively correlated with BNP concentrations (P < 0.001) and significantly negatively correlated with the ejection fraction (P < 0.001) in model animals; plasma ghrelin levels were negatively associated with BNP levels (P = 0.0023) and positively associated with ejection fraction (P = 0.0042).The appetite-regulating hormones (ghrelin and CCK) may present as a potential significant biomarker for cachexia associated with chronic heart failure.


Assuntos
Apetite/fisiologia , Caquexia , Colecistocinina , Grelina , Insuficiência Cardíaca , Peptídeo Natriurético Encefálico , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Caquexia/metabolismo , Caquexia/patologia , Caquexia/fisiopatologia , Colecistocinina/sangue , Colecistocinina/metabolismo , Correlação de Dados , Grelina/sangue , Grelina/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Peptídeo Natriurético Encefálico/sangue , Peptídeo Natriurético Encefálico/metabolismo , Ratos , Ratos Sprague-Dawley , Volume Sistólico
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