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1.
Monaldi Arch Chest Dis ; 90(4)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33169595

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a public health emergency and a pandemic of international concern. As of April 31st,  the reported cases of COVID-19 are three million in 186 countries. Reported case fatality has crossed 200 thousand among which more than fifty thousand has been in the USA. Most patients present with symptoms of fever, cough, and shortness of breath following exposure to other COVID-19 patients. Respiratory manifestations predominate in patients with mild, moderate, severe illness. Imaging of patients with COVID-19 consistently reports various pulmonary parenchymal involvement. In this article we wanted to reinforce and review the various reported imaging patterns of cardiac and mediastinal involvement in COVID-19 patients. Among patients with COVID 19 who underwent various imaging of chest various cardiac findings including pericardial effusion, myocarditis, cardiomegaly has been reported. Most of these findings have been consistently reported in patients with significant acute myocardial injury, and fulminant myocarditis. Acute biventricular dysfunction has also been reported with subsequent improvement of the same following clinical improvement. Details of cardiac MRI is rather limited. In a patient with clinical presentation of acute myocarditis, biventricular myocardial interstitial edema, diffuse biventricular hypokinesia, increased ventricular wall thickness, and severe LV dysfunction has been reported. Among patients with significant clinical improvement in LV structure and function has also been documented. With increasing number of clinical cases, future imaging studies will be instrumental in identifying the various cardiac manifestations, and their relation to clinical outcome.


Assuntos
Cardiomegalia/diagnóstico por imagem , Infecções por Coronavirus/diagnóstico por imagem , Coração/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico por imagem , Miocardite/diagnóstico por imagem , Derrame Pericárdico/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico por imagem , Betacoronavirus , Cardiomegalia/fisiopatologia , Angiografia Coronária , Infecções por Coronavirus/fisiopatologia , Ecocardiografia , Edema/diagnóstico por imagem , Edema/fisiopatologia , Coração/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Isquemia Miocárdica/fisiopatologia , Miocardite/fisiopatologia , Pandemias , Derrame Pericárdico/fisiopatologia , Pneumonia Viral/fisiopatologia , Radiografia Torácica , Recuperação de Função Fisiológica , Tomografia Computadorizada por Raios X , Disfunção Ventricular/diagnóstico por imagem , Disfunção Ventricular/fisiopatologia , Disfunção Ventricular Esquerda/fisiopatologia
2.
J Vis Exp ; (163)2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32986029

RESUMO

Based on twice transverse aortic constrictions (TACs) in mice, it is proved that myocardial hypertrophic preconditioning (MHP) could attenuate cardiomyocyte hypertrophy and slow down progression to heart failure. For novices, however, the MHP model is usually quite difficult to establish because of the technical obstacles in ventilator operation, opening the chest repeatedly, and bleeding caused by debanding. To facilitate this model, to increase the surgical success rate and to reduce the incidence of bleeding, we switched to absorbable sutures for the first TAC combing with a ventilator-free technique. Using a 2-week absorbable suture, we demonstrated that this procedure could cause significant myocardial hypertrophy in 2 weeks; and 4 weeks after surgery, myocardial hypertrophy was almost completely regressed to the baseline. Using this protocol, the operators could master the MHP model easily with a lower operation mortality.


Assuntos
Aorta/patologia , Aorta/cirurgia , Cardiomegalia/etiologia , Miocárdio/patologia , Suturas , Anestesia , Animais , Aorta/diagnóstico por imagem , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Constrição , Modelos Animais de Doenças , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Ligadura , Masculino , Camundongos Endogâmicos C57BL , Pressão , Sístole
3.
PLoS Comput Biol ; 16(8): e1008074, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804929

RESUMO

Congestive heart failure is characterized by suppressed cardiac output and arterial filling pressure, leading to renal retention of salt and water, contributing to further volume overload. Mathematical modeling provides a means to investigate the integrated function and dysfunction of heart and kidney in heart failure. This study updates our previously reported integrated model of cardiac and renal functions to account for the fluid exchange between the blood and interstitium across the capillary membrane, allowing the simulation of edema. A state of heart failure with reduced ejection fraction (HF-rEF) was then produced by altering cardiac parameters reflecting cardiac injury and cardiovascular disease, including heart contractility, myocyte hypertrophy, arterial stiffness, and systemic resistance. After matching baseline characteristics of the SOLVD clinical study, parameters governing rates of cardiac remodeling were calibrated to describe the progression of cardiac hemodynamic variables observed over one year in the placebo arm of the SOLVD clinical study. The model was then validated by reproducing improvements in cardiac function in the enalapril arm of SOLVD. The model was then applied to prospectively predict the response to the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin, which has been shown to reduce heart failure events in HF-rEF patients in the recent DAPAHF clinical trial by incompletely understood mechanisms. The simulations predict that dapagliflozin slows cardiac remodeling by reducing preload on the heart, and relieves congestion by clearing interstitial fluid without excessively reducing blood volume. This provides a quantitative mechanistic explanation for the observed benefits of SGLT2i in HF-rEF. The model also provides a tool for further investigation of heart failure drug therapies.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Rim/fisiopatologia , Modelos Cardiovasculares , Volume Sistólico/fisiologia , Compostos Benzidrílicos/uso terapêutico , Cardiomegalia/fisiopatologia , Líquido Extracelular/fisiologia , Glucosídeos/uso terapêutico , Coração/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/fisiologia , Humanos , Miócitos Cardíacos/fisiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
4.
PLoS One ; 15(7): e0232507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645007

RESUMO

Sex-related differences in cardiovascular diseases are highly complex in humans and model-dependent in experimental laboratory animals. The objective of this work was to comprehensively investigate key sex differences in the response to acute and prolonged adrenergic stimulation in C57Bl/6NCrl mice. Cardiac function was assessed by trans-thoracic echocardiography before and after acute adrenergic stimulation (a single sub-cutaneous dose of isoproterenol 10 mg/kg) in 15 weeks old male and female C57Bl/6NCrl mice. Thereafter, prolonged adrenergic stimulation was achieved by sub-cutaneous injections of isoproterenol 10 mg/kg/day for 14 days in male and female mice. Cardiac function and morphometry were assessed by trans-thoracic echocardiography on the 15th day. Thereafter, the mice were euthanized, and the hearts were collected. Histopathological analysis of myocardial tissue was performed after staining with hematoxylin & eosin, Masson's trichrome and MAC-2 antibody. Gene expression of remodeling and fibrotic markers was assessed by real-time PCR. Cardiac function and morphometry were also measured before and after isoproterenol 10 mg/kg/day for 14 days in groups of gonadectomized male and female mice and sham-operated controls. In the current work, there were no statistically significant differences in the positive inotropic and chronotropic effects of isoproterenol between male and female C57Bl/6NCrl. After prolonged adrenergic stimulation, there was similar degree of cardiac dysfunction, cardiac hypertrophy, and myocardial fibrosis in male and female mice. Similarly, prolonged isoproterenol administration induced hypertrophic and fibrotic genes in hearts of male and female mice to the same extent. Intriguingly, gonadectomy of male and female mice did not have a significant impact on isoproterenol-induced cardiac dysfunction as compared to sham-operated animals. The current work demonstrated lack of significant sex-related differences in isoproterenol-induced cardiac hypertrophy, dysfunction, and fibrosis in C57Bl/6NCrl mice. This study suggests that female sex may not be sufficient to protect the heart in this model of isoproterenol-induced cardiac dysfunction and underscores the notion that sexual dimorphism in cardiovascular diseases is highly model-dependent.


Assuntos
Cardiopatias/fisiopatologia , Caracteres Sexuais , Animais , Biomarcadores/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/metabolismo , Cardiopatias/patologia , Isoproterenol/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia
5.
Clin Sci (Lond) ; 134(12): 1319-1331, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32542395

RESUMO

Aldosterone, as a major product of renin-angiotensin-aldosterone system (RAAS), determines multiple pathophysiological processes in cardiovascular diseases. The excess inflammatory response is one of the key profiles in aldosterone-mediated cardiac remodeling. However, the potential mechanisms of aldosterone/inflammatory signaling were still not fully disclosed. The present study aimed to investigate whether TIR-domain-containing adapter-inducing interferon-ß (Trif) participated in the aldosterone-induced cardiac remodeling, and to explore potential molecular mechanisms. Trif knockout mice and their littermates were osmotically administrated with aldosterone (50 µg/kg per day) for 21 and 42 days. The cardiac structural analysis, functional parameters, and mitochondrial function were measured. Aldosterone dose- or time-dependently increased the levels of TRIF in primary mouse cardiomyocytes or mouse heart tissues. Trif deficiency protected against aldosterone-induced cardiac hypertrophy, fibrosis and dysfunction. Moreover, Trif deficiency also suppressed aldosterone-induced cardiac inflammatory response and mitochondrial injuries. Mechanistically, overexpression of cardiac microRNAs (miR)-34a reversed the cardiac benefits of Trif deficiency in aldosterone-treated mice. Taken together, Trif/miR-34a axis could provide a novel molecular mechanism for explaining aldosterone-induced cardiac hypertrophy, fibrosis and functional disorders.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Coração/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/patologia , MicroRNAs/metabolismo , Remodelação Ventricular , Aldosterona , Animais , Animais Recém-Nascidos , Cardiomegalia/fisiopatologia , Fibrose , Coração/diagnóstico por imagem , Masculino , Camundongos Knockout , Mitocôndrias/patologia
6.
Nat Commun ; 11(1): 2551, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439985

RESUMO

Forkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling. However, specific role(s) of individual FoxO family members in stress-induced growth and remodeling of cardiomyocytes remains unknown. Here, we report that FoxO1, but not FoxO3, activity is essential for reciprocal regulation of types II and III iodothyronine deiodinases (Dio2 and Dio3, respectively), key enzymes involved in intracellular TH metabolism. We further show that Dio2 is a direct transcriptional target of FoxO1, and the FoxO1-Dio2 axis governs TH-induced hypertrophic growth of neonatal cardiomyocytes in vitro and in vivo. Utilizing transverse aortic constriction as a model of hemodynamic stress in wild-type and cardiomyocyte-restricted FoxO1 knockout mice, we unveil an essential role for the FoxO1-Dio2 axis in afterload-induced pathological cardiac remodeling and activation of TRα1. These findings demonstrate a previously unrecognized FoxO1-Dio2 signaling axis in stress-induced cardiomyocyte growth and remodeling and intracellular TH homeostasis.


Assuntos
Proteína Forkhead Box O1/metabolismo , Iodeto Peroxidase/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Hormônios Tireóideos/metabolismo , Animais , Animais Recém-Nascidos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica , Iodeto Peroxidase/antagonistas & inibidores , Iodeto Peroxidase/genética , Camundongos , Camundongos Knockout , Ratos , Transdução de Sinais , Remodelação Ventricular
7.
Am J Cardiol ; 125(9): 1339-1346, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32164912

RESUMO

Basal septal hypertrophy (BSH) is commonly seen in patients with systemic hypertension and has been associated with increased afterload. The impact of localized hypertrophy on left ventricular (LV) and left atrial (LA) function is still unclear. Our aim is to investigate if BSH is a marker of a more pronounced impact of hypertension on cardiac function in the early stages of hypertensive heart disease. An echocardiogram was performed in 163 well-controlled hypertensive patients and 22 healthy individuals. BSH was defined by a basal-to-mid septal thickness ratio ≥1.4. LV dimensions and mass were evaluated. LV global and regional deformation was assessed by 2-dimensional (2D) speckle tracking echocardiography, and LV diastolic function by 2D and Doppler imaging. LA function was evaluated with phasic volume indices calculated from 2D and 3-dimensional volumes, as well as speckle tracking echocardiography. The population was 54% men, mean age 57 (53 to 60) years. BSH was seen in 20% (n = 32) of the hypertensive cohort. Patients with BSH showed decreased regional LV systolic deformation, impaired LV relaxation with a higher proportion of indeterminate LV diastolic function, and LA functional impairment defined by a reduction of reservoir strain and a change in LA functional dynamics. In conclusion, in well-controlled hypertension impairment of LV and LA function is present in patients with early LV remodeling and localized hypertrophy. BSH might be useful as an early marker of the burden of hypertensive heart disease.


Assuntos
Cardiomegalia/etiologia , Hipertensão/complicações , Septo Interventricular/patologia , Função do Átrio Esquerdo , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Estudos de Coortes , Ecocardiografia , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Função Ventricular Esquerda , Septo Interventricular/diagnóstico por imagem , Septo Interventricular/fisiopatologia
8.
Hipertens. riesgo vasc ; 37(1): 22-32, ene.-mar. 2020. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-188670

RESUMO

Reactive cardiac hypertrophy (CH) is an increase in heart mass in response to hemodynamic overload. Exercise-induced CH emerges as an adaptive response with improved cardiac function, in contrast to pathological CH that represents a risk factor for cardiovascular health. The Na+/H+ exchanger (NHE-1) is a membrane transporter that not only regulates intracellular pH but also intracellular Na+ concentration. In the scenario of cardiovascular diseases, myocardial NHE-1 is activated by a variety of stimuli, such as neurohumoral factors and mechanical stress, leading to intracellular Na+ overload and activation of prohypertrophic cascades. NHE-1 hyperactivity is intimately linked to heart diseases, including ischemia-reperfusion injury, maladaptive CH and heart failure. In this review, we will present evidence to support that the NHE-1 hyperactivity constitutes a "switch on/off" for the pathological phenotype during CH development. We will also discuss some classical and novel strategies to avoid NHE-1 hyperactivity, and that are therefore worthwhile to improve cardiovascular health


La hipertrofia cardiaca (HC) reactiva es un incremento de la masa cardiaca, como respuesta a la sobrecarga hemodinámica. La HC inducida por ejercicio surge de una respuesta adaptativa con mejora de la función cardiaca, en contraste a la HC patológica, que representa un factor de riesgo para la salud cardiovascular. El intercambiador Na+/H+ (NHE-1) es un transportador de la membrana que no solo regula el pH intracelular, sino también la concentración de Na+ intracelular. En el escenario de las enfermedades cardiovasculares, el NHE-1 miocárdico se activa por una serie de estímulos, tales como los factores neurohumorales y el estrés mecánico, que origina una sobrecarga intracelular de Na+ y la activación de cascadas pro-hipertróficas. La hiperactividad de NHE-1 está íntimamente ligada a las enfermedades cardiacas, incluyendo lesión por isquemia-reperfusión, HC mal adaptada e insuficiencia cardiaca. En esta revisión, presentaremos la evidencia que respalda que la hiperactividad de NHE-1 constituye una «conexión/desconexión» para el fenotipo patológico durante el desarrollo de la HC. También trataremos algunas estrategias clásicas y nuevas para evitar la hiperactividad de NHE-1 y, por tanto, mejorar considerablemente la salud cardiovascular


Assuntos
Humanos , Cardiomegalia/fisiopatologia , Fatores de Risco , Trocadores de Sódio-Hidrogênio/administração & dosagem , Hipertensão/tratamento farmacológico , Hemodinâmica , Trocadores de Sódio-Hidrogênio/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico
9.
Arq Bras Cardiol ; 114(2): 305-312, 2020 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32215503

RESUMO

Familial lipodystrophy is a rare genetic condition in which individuals have, besides metabolic changes and body fat deposits, a type of cardiomyopathy that has not been well studied. Many of the patients develop cardiovascular changes, the most commonly reported in the literature being the expression of a type of hypertrophic cardiomyopathy. This article, presented as a bibliographic review, reviews the clinical and cardiovascular imaging aspects in this scenario of cardiomyopathy in a rare metabolic disease, based on the latest scientific evidence published in the area. Despite the frequent association of congenital lipodystrophy and ventricular hypertrophy described in the literature, the pathophysiological mechanisms of this cardiomyopathy have not yet been definitively elucidated, and new information on cardiac morphological aspects is emerging in the aegis of recent and advanced imaging methods, such as cardiac magnetic resonance.


Assuntos
Cardiomegalia/etiologia , Cardiomiopatia Hipertrófica/etiologia , Lipodistrofia Generalizada Congênita/complicações , Lipodistrofia Parcial Familiar/complicações , Tecido Adiposo/fisiopatologia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda , Lipodistrofia Generalizada Congênita/diagnóstico por imagem , Lipodistrofia Generalizada Congênita/fisiopatologia , Lipodistrofia Parcial Familiar/diagnóstico por imagem , Lipodistrofia Parcial Familiar/fisiopatologia , Imagem por Ressonância Magnética
10.
Oxid Med Cell Longev ; 2020: 7147498, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082481

RESUMO

Musa balbisiana Colla (Family: Musaceae), commonly known as banana and native to India and other parts of Asia, is very rich in nutritional value and has strong antioxidant potential. In the present study, we have developed Musa balbisiana (MB) fruit pulp powder and evaluated its cardioprotective effect in cardiac hypertrophy, which is often associated with inflammation and oxidative stress. An ultra-high-pressure liquid chromatography-mass spectrometer (UPLC-MS/MS) has been used for the detection and systematic characterization of the phenolic compounds present in Musa balbisiana fruit pulp. The cardioprotective effect of MB was evaluated in a rat model of isoproterenol- (ISO-) induced cardiac hypertrophy by subcutaneous administration of isoproterenol (5 mg/kg-1/day-1), delivered through an alzet minipump for 14 days. Oral administration of MB fruit pulp powder (200 mg/kg/day) significantly (p < 0.001) decreased heart weight/tail length ratio and cardiac hypertrophy markers like ANP, BNP, ß-MHC, and collagen-1 gene expression. MB also attenuated ISO-induced cardiac inflammation and oxidative stress. The in vivo data were further confirmed in vitro in H9c2 cells where the antihypertrophic and anti-inflammatory effect of the aqueous extract of MB was observed in the presence of ISO and lipopolysaccharide (LPS), respectively. This study strongly suggests that supplementation of dried Musa balbisiana fruit powder can be useful for the prevention of cardiac hypertrophy via the inhibition of inflammation and oxidative stress.


Assuntos
Antioxidantes/farmacologia , Cardiomegalia/tratamento farmacológico , Frutas/metabolismo , Inflamação/metabolismo , Musa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/farmacologia , Animais , Fator Natriurético Atrial/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Linhagem Celular , Cromatografia Líquida , Colágeno/genética , Colágeno/metabolismo , Frutas/química , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Inflamação/complicações , Inflamação/tratamento farmacológico , Isoproterenol/administração & dosagem , Isoproterenol/toxicidade , Lipopolissacarídeos/farmacologia , Masculino , Musa/química , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Peptídeo Natriurético Encefálico/metabolismo , Polifenóis/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Miosinas Ventriculares/metabolismo
11.
J Cardiovasc Pharmacol Ther ; 25(4): 354-363, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32052660

RESUMO

BACKGROUND: Insulin resistance (IR) is a well-known risk factor for cardiovascular complications. This study aimed to investigate the effect of a dietary model of IR in mice on cardiac remodeling, cardiac ß-arrestin2 signaling, and the protective effects of carvedilol as a ß-arrestin-biased agonist. METHODS AND RESULTS: Insulin resistance was induced by feeding mice high-fructose/high-fat diet (HFrHFD) for 16 weeks. Carvedilol was adiministered for 4 weeks starting at week 13. At the end of the experiment, body weight, heart weight, left and right ventricular thickness, visceral fat weight, fasting blood glucose (FBG), serum insulin, IR index, and serum endothelin-1 were measured. In addition, cardiac tissue samples were histopathologically examined. Also, cardiac levels of cardiotrophin-1, ß-arrestin2, phosphatidylinositol 4,5 bisphosphate (PIP2), diacylglycerol (DAG), and phosphoserine 473 Akt (pS473 Akt) were measured. Results showed significant increases in the FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, cardiac fibrosis, and degenerated cardiac myofibrils in HFrHFD-fed mice associated with a significant reduction in cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. On the other hand, carvedilol significantly reduced the heart weight, FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, left ventricular thickness, right ventricular fibrosis, and degeneration of cardiac myofibrils. In addition, carvedilol significantly increased cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. CONCLUSION: Carvedilol enhances cardiac ß-arrestin2 signaling and reduces cardiac remodeling in HFrHFD-fed mice.


Assuntos
Cardiomegalia/prevenção & controle , Carvedilol/farmacologia , Resistência à Insulina , Miócitos Cardíacos/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , beta-Arrestina 2/agonistas , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Citocinas/metabolismo , Dieta Hiperlipídica , Açúcares da Dieta , Modelos Animais de Doenças , Fibrose , Frutose , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Remodelação Ventricular/efeitos dos fármacos , beta-Arrestina 2/metabolismo
12.
Clin Sci (Lond) ; 134(3): 359-377, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31985010

RESUMO

Hypertensive cardiac hypertrophy (HCH) is a common cause of heart failure (HF), a major public health problem worldwide. However, the molecular bases of HCH have not been completely elucidated. Neuron-derived orphan receptor-1 (NOR-1) is a nuclear receptor whose role in cardiac remodelling is poorly understood. The aim of the present study was to generate a transgenic mouse over-expressing NOR-1 in the heart (TgNOR-1) and assess the impact of this gain-of-function on HCH. The CAG promoter-driven transgenesis led to viable animals that over-expressed NOR-1 in the heart, mainly in cardiomyocytes and also in cardiofibroblasts. Cardiomyocytes from TgNOR-1 exhibited an enhanced cell surface area and myosin heavy chain 7 (Myh7)/Myh6 expression ratio, and increased cell shortening elicited by electric field stimulation. TgNOR-1 cardiofibroblasts expressed higher levels of myofibroblast markers than wild-type (WT) cells (α 1 skeletal muscle actin (Acta1), transgelin (Sm22α)) and were more prone to synthesise collagen and migrate. TgNOR-1 mice experienced an age-associated remodelling of the left ventricle (LV). Angiotensin II (AngII) induced the cardiac expression of NOR-1, and NOR-1 transgenesis exacerbated AngII-induced cardiac hypertrophy and fibrosis. This effect was associated with the up-regulation of hypertrophic (brain natriuretic peptide (Bnp), Acta1 and Myh7) and fibrotic markers (collagen type I α 1 chain (Col1a1), Pai-1 and lysyl oxidase-like 2 (Loxl2)). NOR-1 transgenesis up-regulated two key genes involved in cardiac hypertrophy (Myh7, encoding for ß-myosin heavy chain (ß-MHC)) and fibrosis (Loxl2, encoding for the extracellular matrix (ECM) modifying enzyme, Loxl2). Interestigly, in transient transfection assays, NOR-1 drove the transcription of Myh7 and Loxl2 promoters. Our findings suggest that NOR-1 is involved in the transcriptional programme leading to HCH.


Assuntos
Cardiomegalia/genética , Cardiomegalia/patologia , Progressão da Doença , Regulação da Expressão Gênica , Miocárdio/patologia , Membro 3 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Angiotensina II , Animais , Biomarcadores/metabolismo , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Colágeno/metabolismo , Modelos Animais de Doenças , Eletrocardiografia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Inflamação/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Transcrição Genética , Remodelação Ventricular
13.
Stroke ; 51(3): 938-943, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31893985

RESUMO

Background and Purpose- Atrial cardiopathy and atherosclerotic plaque are two potential mechanisms underlying embolic strokes of undetermined source (ESUS). The relationship between these two mechanisms among ESUS patients remains unclear. A better understanding of their association may inform targeted secondary prevention strategies. Methods- We examined the association between atrial cardiopathy and atherosclerotic plaque in the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), which enrolled 7213 patients with recent ESUS during 2014 to 2017. For this analysis, we included patients with data on left atrial dimension, location of brain infarction, and cervical large artery plaque. The variables of primary interest were left atrial diameter and cervical plaque ipsilateral to brain infarction. Secondary markers of atrial cardiopathy were premature atrial contractions on Holter monitoring and newly diagnosed atrial fibrillation. For descriptive purposes, left atrial enlargement was defined as ≥4.7 cm. Multivariable logistic regression was used to examine the association between atrial cardiopathy markers and ipsilateral plaque after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, current smoking, and hyperlipidemia. Results- Among 3983 eligible patients, 235 (5.9%) had left atrial enlargement, 939 (23.6%) had ipsilateral plaque, and 94 (2.4%) had both. Shared risk factors for left atrial enlargement and ipsilateral plaque were male sex, white race, hypertension, tobacco use, and coronary artery disease. Despite shared risk factors, increasing left atrial dimension was not associated with ipsilateral plaque after adjustment for covariates (odds ratio per cm, 1.1 [95% CI, 1.0-1.2]; P=0.08). We found no consistent associations between secondary markers of atrial cardiopathy and ipsilateral plaque. Conclusions- In a large population of patients with ESUS, we did not observe a notable association between atrial cardiopathy and atherosclerotic plaque, and few patients had both conditions. These findings suggest that atrial cardiopathy and atherosclerotic plaque may be distinct, nonoverlapping risk factors for stroke among ESUS patients.


Assuntos
Infarto Encefálico , Cardiomegalia , Embolia Intracraniana , Placa Aterosclerótica , Rivaroxabana/administração & dosagem , Acidente Vascular Cerebral , Idoso , Biomarcadores/sangue , Infarto Encefálico/sangue , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/fisiopatologia , Cardiomegalia/sangue , Cardiomegalia/tratamento farmacológico , Cardiomegalia/fisiopatologia , Feminino , Átrios do Coração/fisiopatologia , Humanos , Embolia Intracraniana/sangue , Embolia Intracraniana/tratamento farmacológico , Embolia Intracraniana/fisiopatologia , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/sangue , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/fisiopatologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia
14.
Circ Res ; 126(4): 456-470, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31896304

RESUMO

RATIONALE: Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood. OBJECTIVE: To investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction. METHODS AND RESULTS: Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death. CONCLUSIONS: These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.


Assuntos
Dinaminas/metabolismo , Lipídeos/análise , Miócitos Cardíacos/metabolismo , Acetilação , Animais , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Morte Celular/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Dinaminas/genética , Feminino , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hipertensão/etiologia , Hipertensão/metabolismo , Macaca mulatta , Masculino , Camundongos Endogâmicos C57BL , Mutação , Miócitos Cardíacos/patologia , Obesidade/etiologia , Obesidade/metabolismo , Ratos Sprague-Dawley
15.
Am J Obstet Gynecol ; 222(1): 79.e1-79.e9, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31336074

RESUMO

BACKGROUND: Preeclampsia and fetal growth restriction share some pathophysiologic features and are both associated with placental insufficiency. Fetal cardiac remodeling has been described extensively in fetal growth restriction, whereas little is known about preeclampsia with a normally grown fetus. OBJECTIVE: To describe fetal cardiac structure and function in pregnancies complicated by preeclampsia and/or fetal growth restriction as compared with uncomplicated pregnancies. STUDY DESIGN: This was a prospective, observational study including pregnancies complicated by normotensive fetal growth restriction (n=36), preeclampsia with a normally grown fetus (n=35), preeclampsia with fetal growth restriction (preeclampsia with a normally grown fetus-fetal growth restriction, n=42), and 111 uncomplicated pregnancies matched by gestational age at ultrasound. Fetal echocardiography was performed at diagnosis for cases and recruitment for uncomplicated pregnancies. Cord blood concentrations of B-type natriuretic peptide and troponin I were measured at delivery. Univariate and multiple regression analysis were conducted. RESULTS: Pregnancies complicated by preeclampsia and/or fetal growth restriction showed similar patterns of fetal cardiac remodeling with larger hearts (cardiothoracic ratio, median [interquartile range]: uncomplicated pregnancies 0.27 [0.23-0.29], fetal growth restriction 0.31 [0.26-0.34], preeclampsia with a normally grown fetus 0.31 [0.29-0.33), and preeclampsia with fetal growth restriction 0.28 [0.26-0.33]; P<.001) and more spherical right ventricles (right ventricular sphericity index: uncomplicated pregnancies 1.42 [1.25-1.72], fetal growth restriction 1.29 [1.22-1.72], preeclampsia with a normally grown fetus 1.30 [1.33-1.51], and preeclampsia with fetal growth restriction 1.35 [1.27-1.46]; P=.04) and hypertrophic ventricles (relative wall thickness: uncomplicated pregnancies 0.55 [0.48-0.61], fetal growth restriction 0.67 [0.58-0.8], preeclampsia with a normally grown fetus 0.68 [0.61-0.76], and preeclampsia with fetal growth restriction 0.66 [0.58-0.77]; P<.001). Signs of myocardial dysfunction also were observed, with increased myocardial performance index (uncomplicated pregnancies 0.78 z scores [0.32-1.41], fetal growth restriction 1.48 [0.97-2.08], preeclampsia with a normally grown fetus 1.15 [0.75-2.17], and preeclampsia with fetal growth restriction 0.45 [0.54-1.94]; P<.001) and greater cord blood B-type natriuretic peptide (uncomplicated pregnancies 14.2 [8.4-30.9] pg/mL, fetal growth restriction 20.8 [13.1-33.5] pg/mL, preeclampsia with a normally grown fetus 31.8 [16.4-45.8] pg/mL and preeclampsia with fetal growth restriction 37.9 [15.7-105.4] pg/mL; P<.001) and troponin I as compared with uncomplicated pregnancies. CONCLUSION: Fetuses of preeclamptic mothers, independently of their growth patterns, presented cardiovascular remodeling and dysfunction in a similar fashion to what has been previously described for fetal growth restriction. Future research is warranted to better elucidate the mechanism(s) underlying fetal cardiac adaptation in these conditions.


Assuntos
Cardiomegalia/epidemiologia , Retardo do Crescimento Fetal/epidemiologia , Coração Fetal/diagnóstico por imagem , Pré-Eclâmpsia/epidemiologia , Disfunção Ventricular/epidemiologia , Remodelação Ventricular , Adulto , Cardiomegalia/sangue , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Ecocardiografia , Feminino , Sangue Fetal , Coração Fetal/fisiopatologia , Idade Gestacional , Humanos , Peptídeo Natriurético Encefálico/sangue , Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Espanha/epidemiologia , Troponina I/sangue , Disfunção Ventricular/sangue , Disfunção Ventricular/diagnóstico por imagem , Disfunção Ventricular/fisiopatologia
16.
J Pharmacol Sci ; 142(1): 34-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31791657

RESUMO

Atrial dilation is an independent risk factor for the development of atrial fibrillation (AF) and modulates the efficacy of anti-AF drugs, leading to the unsatisfactory control of AF. Pre-clinical studies showed anti-AF effects of acehytisine, a multi-ion channel inhibitor, in atria without structural and/or electrophysiological abnormalities, but information is limited regarding its anti-AF efficacy in dilated atria. We evaluated anti-AF effects of acehytisine at 4 and 10 mg/kg intravenously infused over 10 min using 8-week-old Wistar rats (n = 5; male) with atrial dilation caused by aorto-venocaval shunt (AVS). Echocardiography showed that atria were enlarged by +26.9% after one month of operation in AVS rats compared with sham-operated rats (n = 4; male). Electrophysiological examinations indicated burst pacing-induced AF reached 206 s. Acehytisine at doses of 4 and 10 mg/kg decreased the duration of burst pacing-induced AF with prolongation of Wenckebach cycle length and P wave duration in a dose-dependent manner. Importantly, the drug effectively terminated the persistent AF that was resistant to multiple programmed electrical stimulations in one rat. Therefore, these results provide in vivo evidence that acehytisine may be beneficial for preventing and terminating persistent AF in dilated atria.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Animais , Fibrilação Atrial/etiologia , Cardiomegalia/fisiopatologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/patologia , Insuficiência Cardíaca/fisiopatologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Masculino , Estrutura Molecular , Ratos , Ratos Wistar
17.
Sci Rep ; 9(1): 19154, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844105

RESUMO

Little is still known about the effect of dietary patterns on left ventricular hypertrophy (LVH). Here, we derived dietary patterns by principal component analysis (PCA) and evaluated their association with LV structure, function, and remodelling. Our cross-sectional study included 438 members (aged 25-65 years; 59.1% women) of the Kardiovize Brno 2030 with no history of cardiovascular disease. Two dietary patterns were derived using PCA, namely prudent and western. Primary outcomes were echocardiographic parameters and LV geometric patterns, such as concentric LV remodelling (cLVR), concentric LVH (cLVH), and eccentric LVH (eLVH). Interestingly, participants with high adherence to the prudent dietary pattern had decreased odds of cLVH after adjustment for socio-demographic, clinical and behavioral covariates (OR = 0.24, 95% CI = 0.08-0.88; p = 0.031). By contrast, several echocardiographic parameters increased with increasing adherence to the western dietary pattern, which resulted in higher odds of cLVH among participants with high adherence (OR = 5.38, 95% CI = 1.17-23.58; p = 0.035). Although our findings may have an immediate relevance for public-health strategies, further large-size prospective studies should be encouraged to better understand the observed association and their causality.


Assuntos
Comportamento Alimentar , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Remodelação Ventricular , Adulto , Idoso , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Eletrocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade
18.
J Pharm Pharmacol ; 71(12): 1822-1831, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31612504

RESUMO

OBJECTIVES: This study aimed to evaluate berberine (BBR) effects on myocardial hypertrophy (MH) and associated mechanisms. METHODS: BBR effects on MH were evaluated in rats with constriction of abdominal aorta (CAA). qRT-PCR assay was used to measure MH-related genes, long non-coding RNAs (lncRNAs) and autophagy-related genes expressions. Western blot was performed to detect autophagy markers expression. Filamentous actin and phalloidin expressions were detected using immunofluorescence assay. KEY FINDINGS: BBR significantly attenuated CAA-induced MH and cardiomyocyte enlargement. CAA upregulated ß myosin heavy chain and atrial natriuretic peptide expressions in heart tissues, which was attenuated by BBR. BBR suppressed myocardial infarction associated transcript (MIAT) expression in rats with CAA. p62 mRNA expression was upregulated and beclin1 and autophagy related 5 were downregulated in CAA versus control groups. The effects were abolished by BBR. In vitro studies showed that BBR ameliorated angiotensin II-induced MH and attenuated Ang II-induced MIAT expression in H9C2 cells. Expressions of phosphorylated mTOR, phosphorylated AMPK and LC3 were upregulated in H9C2 cells after Ang II stimulation, and the effects were abolished by BBR. CONCLUSIONS: BBR exerted beneficial effects on MH induced by CCA, and the mechanisms were associated with decreased MIAT expression and enhanced autophagy.


Assuntos
Berberina/farmacologia , Cardiomegalia/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , RNA Longo não Codificante/genética , Animais , Autofagia/efeitos dos fármacos , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Masculino , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
19.
PLoS One ; 14(10): e0223164, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31581204

RESUMO

Pimobendan has gained enormous importance in the treatment of mitral valve disease in dogs. The current consensus statement of the American College of Veterinary Internal Medicine (ACVIM) recommends a treatment for dogs with symptomatic disease and dogs with asymptomatic disease with radiographic and echocardiographic signs of cardiomegaly. To investigate whether these dogs also benefit from a therapy with pimobendan, 21 dogs with mitral valve disease ACVIM B1 underwent a standardized submaximal exercise test on a treadmill. In this double-blinded and randomized study, the animals were divided into two groups, one receiving pimobendan and the other a placebo. At the first visit and at every follow-up appointment (at days 90 and 180), heart rate during the complete exercise test and lactate before and after running were measured. In addition to this, a questionnaire was completed by the dogs' owners and all dogs were given an echocardiographic examination to detect any changes and to observe if the disease had progressed. Due to the diagnosis of leishmaniosis, one dog in the pimobendan group was retrospectively removed from the study so that 20 dogs were included for statistical analysis. No differences were observed at any time between the pimobendan-group and the placebo-group regarding heart rate. At day 180, the increase in lactate after exercise was significantly lower than in the placebo-group. The increase in the pimobendan-group at day 180 was lower than at day 90. Most of the dog owners from the pimobendan-group declared that their dogs were more active at day 90 (6/10) and at day 180 (8/10), while most dog owners from the placebo-group observed no changes regarding activity at day 90 (8/10) and day 180 (6/10). It can be concluded that the results of this study indicate that some dogs with mitral valve disease ACVIM B1 might benefit from a therapy with pimobendan.


Assuntos
Cardiomegalia/complicações , Ecocardiografia , Doenças das Valvas Cardíacas/tratamento farmacológico , Doenças das Valvas Cardíacas/veterinária , Ácido Láctico/sangue , Valva Mitral/patologia , Aptidão Física/fisiologia , Piridazinas/farmacologia , Animais , Cardiomegalia/fisiopatologia , Doenças do Cão/tratamento farmacológico , Cães , Teste de Esforço , Feminino , Sopros Cardíacos/complicações , Sopros Cardíacos/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/fisiopatologia , Masculino , Valva Mitral/diagnóstico por imagem , Valva Mitral/fisiopatologia , Corrida
20.
EMBO Mol Med ; 11(11): e9127, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31532577

RESUMO

The function of nuclear receptor corepressor 1 (NCoR1) in cardiomyocytes is unclear, and its physiological and pathological implications are unknown. Here, we found that cardiomyocyte-specific NCoR1 knockout (CMNKO) mice manifested cardiac hypertrophy at baseline and had more severe cardiac hypertrophy and dysfunction after pressure overload. Knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine-induced cardiomyocyte hypertrophy. Mechanistic studies revealed that myocyte enhancer factor 2a (MEF2a) and MEF2d mediated the effects of NCoR1 on cardiomyocyte hypertrophy. The receptor interaction domains (RIDs) of NCoR1 interacted with MEF2a to repress its transcriptional activity. Furthermore, NCoR1 formed a complex with MEF2a and class IIa histone deacetylases (HDACs) to suppress hypertrophy-related genes. Finally, overexpression of RIDs of NCoR1 in the heart attenuated cardiac hypertrophy and dysfunction induced by pressure overload. In conclusion, NCoR1 cooperates with MEF2 and HDACs to repress cardiac hypertrophy. Targeting NCoR1 and the MEF2/HDACs complex may be an attractive therapeutic strategy to tackle pathological cardiac hypertrophy.


Assuntos
Cardiomegalia/fisiopatologia , Regulação da Expressão Gênica , Miócitos Cardíacos/fisiologia , Correpressor 1 de Receptor Nuclear/metabolismo , Animais , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Redes Reguladoras de Genes , Humanos , Fatores de Transcrição MEF2/metabolismo , Camundongos , Camundongos Knockout , Correpressor 1 de Receptor Nuclear/deficiência , Ligação Proteica , Mapeamento de Interação de Proteínas
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