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1.
Anticancer Res ; 40(9): 5301-5307, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878821

RESUMO

BACKGROUND/AIM: The aim of this single center, non-randomized, open-label, uncontrolled, interventional trial was to determine the feasibility of continuous administration of low-dose human atrial natriuretic peptide (hANP) perioperatively during curative operation for colorectal cancer patients without history of acute heart failure. PATIENTS AND METHODS: The study included three males and two females ranging from 27 to 70 years old. Continuous intravenous injection of hANP solution was started before surgery. The primary endpoint was safety of hANP administration, and the secondary endpoints were perioperative changes in ANP, b-type natriuretic peptide, electrocardiogram (ECG), and lung function. RESULTS: The American Society of Anaesthesiologists physical status was 1, 2, and 3 in three, one, and one patient, respectively. Grade 2 hypotension was observed in one case. No marked changes were observed between pre- and post-operation in all cases. CONCLUSION: Perioperative low-dose hANP administration is feasible and safe in patients with curative colorectal cancer.


Assuntos
Fator Natriurético Atrial/administração & dosagem , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Insuficiência Cardíaca/prevenção & controle , Assistência Perioperatória , Complicações Pós-Operatórias/prevenção & controle , Adulto , Idoso , Biomarcadores , Neoplasias Colorretais/cirurgia , Eletrocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Avaliação de Sintomas , Resultado do Tratamento
2.
Am Heart J ; 227: 64-73, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32682105

RESUMO

BACKGROUND: Lifestyle factors may be important targets in the prevention of heart failure. The current knowledge on the relationship between lifestyle factors and heart failure originates mostly from observational studies. The objective of this study was to investigate causal associations of multiple lifestyle factors with heart failure risk by using Mendelian randomization. METHODS: We obtained summary statistics data for single nucleotide polymorphisms associated with the following 5 lifestyle factors at genome-wide significance in genome-wide association studies of European-descent individuals: smoking, alcohol consumption, coffee consumption, physical activity, and sleep duration. The corresponding data for heart failure were acquired from a genome-wide association study comprising 47,309 cases and 930,014 controls of European ancestry. For the primary analyses, we used the inverse-variance weighted method. RESULTS: Genetic predisposition to smoking initiation (ever smoked regularly) was robustly associated with a higher odds of heart failure (odds ratio: 1.28; 99% CI: 1.21-1.35). Genetically predicted longer sleep duration was associated with a lower odds of heart failure (odds ratio per hour/day: 0.73; 99% CI: 0.60-0.89). We found no associations of alcohol consumption, coffee consumption, and physical activity with heart failure. CONCLUSIONS: This Mendelian randomization study showed that smoking initiation increases heart failure risk, whereas longer sleep duration decreases the risk of heart failure. Sleep duration should be regarded as novel risk factor in heart failure prevention guidelines. The potential causal role of alcohol and coffee consumption and physical activity for heart failure warrants further investigation in future larger Mendelian randomization analyses.


Assuntos
Insuficiência Cardíaca/genética , Insuficiência Cardíaca/prevenção & controle , Estilo de Vida , Análise da Randomização Mendeliana , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Fatores de Risco
3.
Diab Vasc Dis Res ; 17(4): 1479164120945674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722930

RESUMO

AIM: We examined eligibility and preventable cardiovascular disease events in US adults with diabetes mellitus from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME). METHODS: We identified adults with diabetes mellitus eligible for EMPA-REG OUTCOME based on trial eligibility criteria available from the National Health and Nutrition Examination Surveys, 2007-2016. We estimated composite cardiovascular disease endpoints, as well as all-cause deaths, death from cardiovascular disease and hospitalizations for heart failure from trial treatment and placebo event rates, the difference indicating the preventable events. RESULTS: Among 29,629 US adults aged ⩾18 years (representing 231.9 million), 4672 (27.3 million) had diabetes mellitus, with 342 (1.86 million) meeting eligibility criteria of EMPA-REG OUTCOME. We estimated from trial primary endpoint event rates of 10.5% and 12.1% in the empagliflozin and placebo groups, respectively, that based on the 'treatment' of our 1.86 million estimated EMPA-REG OUTCOME eligible subjects, 12,066 (95% confidence interval: 10,352-13,780) cardiovascular disease events could be prevented annually. Estimated annual preventable deaths from any cause, cardiovascular causes and hospitalizations from heart failure were 17,078 (95% confidence interval: 14,652-19,504), 14,479 (95% confidence interval: 12,422-16,536) and 9467 (95% confidence interval: 8122-10,812), respectively. CONCLUSION: Empagliflozin, if provided to EMPA-REG OUTCOME eligible US adults, may prevent many cardiovascular disease events, cardiovascular and total deaths, as well as heart failure hospitalizations.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Tomada de Decisão Clínica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Definição da Elegibilidade , Glucosídeos/uso terapêutico , Seleção de Pacientes , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/mortalidade , Progressão da Doença , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia
4.
Cardiovasc Pathol ; 49: 107243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32629211

RESUMO

Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of cases of heart failure, which is the most common cause of hospitalization in US patients over the age of 65. HFpEF pathogenesis is increasingly believed to be due to pathological hypertrophy and fibrosis of the myocardium that may be a result of systemic inflammation from comorbid conditions such as hypertension, diabetes mellitus, chronic obstructive pulmonary disease, anemia, chronic kidney disease and others. It is believed that oxidative stress triggers a process of pathological hypertrophy and fibrosis in cardiac endothelial cells, which leads to increased left ventricle filling pressures and, eventually, symptoms of heart failure. Numerous recent major clinical trials that have examined various therapies aimed at improving mortality in HFpEF have emerged empty-handed and thus the search for effective management strategies continues. Over the last several years, there have been many new developments in the field of antisense oligonucleotide-based therapeutics, which involves using noncoding nucleic acid particles such as microRNA and small interfering RNA to repress the expression of specific messenger RNA. In this article, we review the concept of using oligonucleotide-based therapeutics to prevent or treat HFpEF by targeting a specific microRNA that has been implicated in the pathogenesis of myocardial fibrosis and hypertrophy, microRNA-21 (miR-21). We review the various evidence that implicates miR-21 in the process of myocardial fibrosis and discuss recent attempts to use antimiR-21 compounds to prevent fibrosis. We also discuss proposed methods for screening patients at high risk for HFpEF for diastolic dysfunction in order to determine which patients.


Assuntos
Terapia Genética/métodos , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/terapia , MicroRNAs/antagonistas & inibidores , Oligonucleotídeos Antissenso/uso terapêutico , Volume Sistólico , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda , Animais , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , MicroRNAs/genética , MicroRNAs/metabolismo , Resultado do Tratamento , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular
5.
Nutr Metab Cardiovasc Dis ; 30(7): 1070-1079, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32475628

RESUMO

The advent of Sodium Glucose Transporter 2-inhibitors (SGLT2-i) in recent years gave endocrinologists the opportunity to actively treat and prevent heart failure (HF) in patients with type 2 diabetes (T2DM). While the relationship between T2DM and HF has been extensively reviewed, previous works focused mostly on epidemiology, pathophysiology and treatment of HF in T2DM. The aim of our work was to aid health care professionals in identifying individuals at high risk for this dreadful complication. Recent guidelines recommend to use drugs with proven cardiovascular benefits (Glucagon-like peptide-1 receptor agonists (GLP1-RA) and SGLT2-i) in patients with previous cardiovascular disease (CVD) and to prefer SGLT2-i in patients with known HF. In everyday clinical practice, the choice between these two drug classes in patients without known HF or atherosclerotic CVD is mostly arbitrary and based on the side effect profile. Recently, risk stratification tools to estimate HF incidence have been developed in order to guide treatment with a view to bring precision medicine into diabetes care. With this purpose, we provide a review of the tools able to predict HF incidence for patients in primary CVD prevention as well as risk of future hospitalizations for patients with known HF.


Assuntos
Regras de Decisão Clínica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Incretinas/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tomada de Decisão Clínica , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Hospitalização , Humanos , Incidência , Incretinas/efeitos adversos , Prevenção Primária , Medição de Risco , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
6.
Clin Drug Investig ; 40(7): 665-669, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32449083

RESUMO

BACKGROUND AND OBJECTIVE: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have significant efficacy in reducing the risk of hospitalization for heart failure (hHF) or cardiovascular (CV) mortality in patients with type 2 diabetes mellitus (T2DM). However, there are differences in HF outcomes between the SGLT2i. Therefore, we compared the cost needed to achieve these outcomes between empagliflozin, canagliflozin, and dapagliflozin. METHODS: We calculated the cost needed to treat (CNT) in order to prevent one event of hHF or CV mortality, by multiplying the annualized number needed to treat (NNT) to prevent one event, by the annual cost of each therapy. Efficacy estimates were extracted from published randomized controlled trial (RCT) data. A sensitivity analysis was performed to mitigate differences between the RCT populations. Drug costs were extracted from the 2020 US National Average Drug Acquisition Cost listing. RESULTS: We figured empagliflozin's CNT to be $664,464 (95% CI $499,872-$1,097,280), $1,535,387 (95% CI $886,074-$3,210,501) for canagliflozin, and $2,693,145 (95% CI $1,639,563-$11,092,206) for dapagliflozin. The sensitivity analysis confirmed the cost advantage of empagliflozin. CONCLUSIONS: Our findings suggest that empagliflozin prescribed for preventing CV death or hHF in T2DM patients seems to be cost saving compared to treatment with canagliflozin, and dapagliflozin.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/mortalidade , Feminino , Glucosídeos/uso terapêutico , Custos de Cuidados de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/economia
7.
J Pharmacol Sci ; 143(3): 199-208, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32414690

RESUMO

The optimum strategy for heart failure (HF) treatment has yet to be elucidated. This study intended to test the benefit of a combination of valsartan (VAL) and perifosine (PER), a specific AKT inhibitor, in protecting against pressure overload induced mouse HF. Mouse were subjected to aortic banding (AB) surgery to establish HF models and then were given vehicle (HF), VAL (50 mg/kg/d), PER (30 mg/kg/d) or combination of VAL and PER for 4 weeks. Mouse with sham surgery treated with VEH were used for control (VEH). VAL or PER treatment could significantly alleviate mouse heart weight, attenuate cardiac fibrosis and improve cardiac function. The combination treatment of VAL and PER presented much better benefit compared with VAL or PER group respectively. PER treatment significantly inhibited AKT/GSK3ß/mTORC1 signaling. Besides the classic AT1 inhibition, VAL treatment significantly inhibited MAPK (ERK1/2) signaling. Furthermore, VAL and PER treatment could markedly prevent neonatal rat cardiomyocyte hypertrophy and the activation of neonatal rat cardiac fibroblast. Combination of VAL and PER also presented superior beneficial effects than single treatment of VAL or PER in vitro experiments respectively. This study presented that the combination of valsartan and PER may be a potential treatment for HF prevention.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Fosforilcolina/análogos & derivados , Pressão/efeitos adversos , Valsartana/administração & dosagem , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Glicogênio Sintase Quinase 3 beta/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Fosforilcolina/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Nutr Metab Cardiovasc Dis ; 30(7): 1106-1114, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32448716

RESUMO

BACKGROUND AND AIMS: Glucagon-like Peptide 1 Receptor Agonists (GLP1-RA) has been associated with a reduction of major cardiovascular events (MACE) and mortality on the basis of the results of cardiovascular outcome trials (CVOT). Several meta-analyses on this issue have been recently published; however, they were all restricted to CVOT, with the exclusion of all studies designed for other endpoints; moreover, other cardiovascular endpoints, such as atrial fibrillation and heart failure have not been fully explored. METHODS AND RESULTS: A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. We included 43 trials, enrolling 63,134 patients. A significant reduction of MACE (MH-OR 0.87 [0.83, 0.92]), all-cause mortality (MH-OR 0.89 [0.83, 0.96]), and a nonstatistical trend toward reduction of heart failure (MH-OR 0.93 [0.85, 1.01]) was observed - GLP1-RA did not increase the risk of atrial fibrillation (MH-OR 0.94 [0.84, 1.04]). CONCLUSION: The present meta-analysis confirms the favorable effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events, cardiovascular and all-cause mortality, stroke, and possibly myocardial infarction. Conversely, the effects on heart failure remain uncertain. Available data on atrial fibrillation seems to exclude any major safety issues in this respect. REGISTRATION NUMBER (PROSPERO): CRD42018115577.


Assuntos
Fibrilação Atrial/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Insuficiência Cardíaca/prevenção & controle , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/mortalidade , Fibrilação Atrial/fisiopatologia , Causas de Morte , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipoglicemiantes/efeitos adversos , Incidência , Incretinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/prevenção & controle , Fatores de Proteção , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Resultado do Tratamento
9.
Yakugaku Zasshi ; 140(4): 471-477, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32238626

RESUMO

Chronic heart failure is the final stage of such heart diseases as hypertension, cardiomyopathy, and myocardial infarction. Since the incidence of heart failure has increased in recent decades, heart failure is now a major public health problem in developed countries, including Japan. Recently, some studies have demonstrated that natural products, used as nutritional supplements, play an important role in preventing the development of heart failure in animal studies. In our previous study, we showed that curcumin, a natural polyphenol compound derived from Curcuma longa, exhibits therapeutic potency against heart failure. To establish the pharmacological therapeutic value of curcumin in heart failure, we have investigated the translational research of curcumin. This report reviews our basic studies and clinical trials using curcumin therapeutically to prevent heart failure, as well as the possibility of clinical applications of curcumin.


Assuntos
Produtos Biológicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Fitoterapia , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Animais , Disponibilidade Biológica , Curcuma/química , Modelos Animais de Doenças , Humanos , Polifenóis/isolamento & purificação , Polifenóis/farmacocinética , Ratos , Pesquisa Médica Translacional
10.
Lancet Diabetes Endocrinol ; 8(5): 418-435, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32333878

RESUMO

BACKGROUND: In our 2015 systematic review and meta-analysis of cardiovascular outcome trials for glucose-lowering drugs or strategies in people with or at risk of type 2 diabetes, we reported a modest reduction in atherosclerotic cardiovascular events and an increased risk of heart failure, but with heterogeneous effects by drug or intervention type. In view of the completion of many large cardiovascular outcome trials since our previous analysis, including trials of novel drugs that have shown beneficial effects on cardiovascular outcomes, we aimed to update our analysis to incorporate these findings. METHODS: We did an updated systematic review and meta-analysis of large cardiovascular outcome trials of glucose-lowering drugs or strategies in people with or at risk of type 2 diabetes. We searched Ovid MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials databases for reports of trials published from Nov 15, 2013 to Nov 20, 2019. We included randomised controlled trials with a minimum of 1000 adults (aged ≥19 years) with or at risk of type 2 diabetes, with major adverse cardiovascular events (MACE) as an outcome, and with follow-up of at least 12 months. We excluded trials with patients enrolled with an acute cardiovascular event. The main outcomes of interest were MACE (generally defined as a composite of cardiovascular death, myocardial infarction, or stroke) and heart failure. We calculated pooled risk ratios (RRs) and 95% CIs with inverse-variance random-effects models, did meta-regression to analyse treatment effects per difference in bodyweight achieved, and explored results stratified by baseline subgroups. FINDINGS: Our updated search yielded 30 eligible trials (n=225 305). The mean age of participants was 63·0 years (SD 8·4) and mean duration of diabetes was 9·4 years (6·6). After a mean follow-up of 3·8 years (1·8), 23 016 (10·2%) participants had MACE and 8169 (3·6%) had a heart failure event. Glucose-lowering drugs or strategies lowered the risk of MACE compared with standard care or placebo (RR 0·92, 95% CI 0·89-0·95, p<0·0001), with no overall effect on the risk of heart failure (0·98, 0·90-1·08, p=0·71). However, across drug classes or strategies, the magnitude and directionality of RR for heart failure varied (pinteraction<0·0001), with meta-regression showing that a decrease in bodyweight of 1 kg was associated with a 5·9% (3·9-8·0) relative decrease in the risk of heart failure (p<0·0001). Among trials that assessed drug classes or strategies associated with weight loss (intensive lifestyle changes, GLP-1 receptor agonists, or SGLT2 inhibitors), the risk reduction for MACE was consistent among participants with (0·87, 0·83-0·92) and without (0·92, 0·83-1·02) established cardiovascular disease at baseline (pinteraction=0·33). For heart failure, the RR for drug classes or strategies associated with weight loss was consistent among participants with (0·80, 0·73-0·89) and without (0·84, 0·74-0·95) cardiovascular disease at baseline (pinteraction=0·63). INTERPRETATION: Glucose-lowering drugs or strategies overall reduced the risk of fatal and non-fatal atherosclerotic events. The effect on heart failure was neutral overall but varied substantially by intervention type, with interventions associated with weight loss showing a beneficial effect. The cardiovascular and heart failure benefits of interventions associated with weight loss might extend to patients without established cardiovascular disease. FUNDING: None.


Assuntos
Aterosclerose/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Hipoglicemiantes/uso terapêutico , Idoso , Diabetes Mellitus Tipo 2/complicações , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
11.
Heart Fail Clin ; 16(2): 231-241, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32143767

RESUMO

Several cancer treatments cause cardiotoxicity that can lead to heart failure, coronary artery disease, arrhythmia, and pericardial disease. In this review, representative cases of heart failure following cardiotoxicity caused by trastuzumab, anthracycline, and hematopoietic stem cell transplantation are described with case notes. Additionally, other important points regarding cardiotoxicity related to heart failure are reported. During and after potentially cardiotoxic therapy, periodic cardiac examinations are recommended to detect any cardiovascular disorders; these are ameliorated if appropriately diagnosed at an earlier stage. It is important for cardiologists and oncologists to understand the pathophysiology of representative cardiovascular disease cases following cancer treatment.


Assuntos
Antraciclinas/farmacologia , Insuficiência Cardíaca , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Neoplasias/tratamento farmacológico , Trastuzumab/farmacologia , Antineoplásicos/farmacologia , Cardiotoxicidade , Monitoramento de Medicamentos/métodos , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos
12.
Circ Heart Fail ; 13(3): e006298, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32160771

RESUMO

BACKGROUND: MicroRNAs are small, noncoding RNAs that play a key role in gene expression. Accumulating evidence suggests that aberrant microRNA expression contributes to the heart failure (HF) phenotype; however, the underlying molecular mechanisms are not well understood. A better understanding of the mechanisms of action of microRNAs could potentially lead to targeted therapies that could halt the progression or even reverse HF. METHODS AND RESULTS: We found that microRNA-152 (miR-152) expression was upregulated in the failing human heart and experimental animal models of HF. Transgenic mice with cardiomyocyte-specific miR-152 overexpression developed systolic dysfunction (mean difference, -38.74% [95% CI, -45.73% to -31.74%]; P<0.001) and dilated cardiomyopathy. At the cellular level, miR-152 overexpression perturbed mitochondrial ultrastructure and dysregulated key genes involved in cardiomyocyte metabolism and inflammation. Mechanistically, we identified Glrx5 (glutaredoxin 5), a critical regulator of mitochondrial iron homeostasis and iron-sulfur cluster synthesis, as a direct miR-152 target. Finally, a proof-of-concept of the therapeutic efficacy of targeting miR-152 in vivo was obtained by utilizing a locked nucleic acid-based inhibitor of miR-152 (LNA 152) in a murine model of HF subjected to transverse aortic constriction. We demonstrated that animals treated with LNA-152 (n=10) showed preservation of systolic function when compared with locked nucleic acid-control treated animals (n=9; mean difference, 18.25% [95% CI, 25.10% to 11.39%]; P<0.001). CONCLUSIONS: The upregulation of miR-152 expression in the failing myocardium contributes to HF pathophysiology. Preclinical evidence suggests that miR-152 inhibition preserves cardiac function in a model of pressure overload-induced HF. These findings offer new insights into the pathophysiology of HF and point to miR-152-Glrx5 axis as a potential novel therapeutic target.


Assuntos
Antagomirs/administração & dosagem , Inativação Gênica , Insuficiência Cardíaca/prevenção & controle , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Aorta/fisiopatologia , Aorta/cirurgia , Estudos de Casos e Controles , Modelos Animais de Doenças , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Ligadura , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Mitocôndrias Cardíacas/genética , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Miócitos Cardíacos/ultraestrutura , Estudo de Prova de Conceito , Volume Sistólico , Função Ventricular Esquerda
13.
Diabetes Res Clin Pract ; 162: 108112, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32198123

RESUMO

Large cardiovascular outcome trials (CVOTs) have lent support to a cardiovascular protection with the use of SGLT2-inhibitors (SGLT2is) and GLP1-Receptor Agonists (GLP1-RAs) in subjects with type 2 diabetes. These two classes of novel glucose lowering agents have been shown to have a similar effect on the risk reduction of Major Adverse Cardiovascular Events (MACE: nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality). Nonetheless, they may not be simply interchangeable. Rather, careful evaluation of all the results of CVOTs leads identification of different effects that may allow profiling of the ideal individuals with T2DM who may benefit most from the use of one or the other class of agents. These differences include effect on heart failure, stroke and diabetic kidney disease that have prompt recent guidelines and recommendation for the treatment of type 2 diabetes to suggest the preferential use of SGLT2is in those with evidence of heart failure and impaired kidney function, while both SGLT2i and GLP1-RAs with proven effect could be use in those with prevalent atherosclerotic cardiovascular disease. This review discusses all these elements of differentiation along with others that in the future may help establishing the best cardiorenal benefit for individuals with T2DM.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Aterosclerose/prevenção & controle , Diabetes Mellitus Tipo 2/mortalidade , Nefropatias Diabéticas/prevenção & controle , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipoglicemiantes/farmacologia , Infarto do Miocárdio , Comportamento de Redução do Risco , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
16.
Nat Commun ; 11(1): 1058, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32103002

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is critically involved in cardiovascular physiology and pathology, and is currently clinically evaluated to treat acute lung failure. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is an ACE2-like enzyme to decrease angiotensin II levels in mice. In protein 3D structure analysis, B38-CAP homolog shares structural similarity to mammalian ACE2 with low sequence identity. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1-7, as well as other known ACE2 target peptides. Treatment with B38-CAP suppressed angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. Moreover, B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice. Our data identify the bacterial B38-CAP as an ACE2-like carboxypeptidase, indicating that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure.


Assuntos
Carboxipeptidases/farmacologia , Cardiomegalia/tratamento farmacológico , Fibrose/tratamento farmacológico , Hipertensão/tratamento farmacológico , Paenibacillus/enzimologia , Peptidil Dipeptidase A/genética , Angiotensina II/metabolismo , Animais , Cardiomegalia/patologia , Modelos Animais de Doenças , Fibrose/patologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Hipertensão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptidil Dipeptidase A/metabolismo , Proteínas Recombinantes/farmacologia
17.
Mol Pharmacol ; 97(4): 250-258, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32015008

RESUMO

Phenytoin is a hydantoin derivative that is used clinically for the treatment of epilepsy and has been reported to have antiarrhythmic actions on the heart. In a failing heart, the elevated diastolic Ca2+ leak from the sarcoplasmic reticulum can be normalized by the cardiac ryanodine receptor 2 (RyR2) inhibitor, dantrolene, without inhibiting Ca2+ release during systole or affecting Ca2+ release in normal healthy hearts. Unfortunately, dantrolene is hepatotoxic and unsuitable for chronic long-term administration. Because phenytoin and dantrolene belong to the hydantoin class of compounds, we test the hypothesis that dantrolene and phenytoin have similar inhibitory effects on RyR2 using a single-channel recording of RyR2 activity in artificial lipid bilayers. Phenytoin produced a reversible inhibition of RyR2 channels from sheep and human failing hearts. It followed a hyperbolic dose response with maximal inhibition of ∼50%, Hill coefficient ∼1, and IC50 ranging from 10 to 20 µM. It caused inhibition at diastolic cytoplasmic [Ca2+] but not at Ca2+ levels in the dyadic cleft during systole. Notably, phenytoin inhibits RyR2 from failing human heart but not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans. We conclude that phenytoin could effectively inhibit RyR2-mediated release of Ca2+ in a manner paralleling that of dantrolene. Moreover, the IC50 of phenytoin in RyR2 is at least threefold lower than for other ion channels and clinically used serum levels, pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrythmias. SIGNIFICANCE STATEMENT: We show that phenytoin, a Na channel blocker used clinically for treatment of epilepsy, is a diastolic inhibitor of cardiac calcium release channels [cardiac ryanodine receptor 2 (RyR2)] at doses threefold lower than its current therapeutic levels. Phenytoin inhibits RyR2 from failing human heart and not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans and pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrhythmias.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Cardiotônicos/farmacologia , Insuficiência Cardíaca/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Fenitoína/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/patologia , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cardiotônicos/uso terapêutico , Dantroleno/farmacologia , Dantroleno/uso terapêutico , Relação Dose-Resposta a Droga , Vesículas Extracelulares , Insuficiência Cardíaca/patologia , Humanos , Bicamadas Lipídicas , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fenitoína/uso terapêutico , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Ovinos
18.
Circ Res ; 126(4): 533-551, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32078451

RESUMO

During aging, deterioration in cardiac structure and function leads to increased susceptibility to heart failure. The need for interventions to combat this age-related cardiac decline is becoming increasingly urgent as the elderly population continues to grow. Our understanding of cardiac aging, and aging in general, is limited. However, recent studies of age-related decline and its prevention through interventions like exercise have revealed novel pathological and cardioprotective pathways. In this review, we summarize recent findings concerning the molecular mechanisms of age-related heart failure and highlight exercise as a valuable experimental platform for the discovery of much-needed novel therapeutic targets in this chronic disease.


Assuntos
Envelhecimento/fisiologia , Exercício Físico/fisiologia , Insuficiência Cardíaca/fisiopatologia , Coração/fisiopatologia , Miocárdio/metabolismo , Transdução de Sinais/fisiologia , Idoso , Envelhecimento/genética , Envelhecimento/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/prevenção & controle , Humanos , MicroRNAs/genética , Transdução de Sinais/genética
19.
BMC Cardiovasc Disord ; 20(1): 61, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024471

RESUMO

BACKGROUND: The relative importance of lifestyle, medical and psychosocial factors on the risk of recurrent major cardiovascular (CV) events (MACE) in coronary patients' needs to be identified. The main objective of this study is to estimate the association between potentially preventable factors on MACE in an outpatient coronary population from routine clinical practice. METHODS: This prospective follow-up study of recurrent MACE, determine the predictive impact of risk factors and a wide range of relevant co-factors recorded at baseline. The baseline study included 1127 consecutive patients 2-36 months after myocardial infarction (MI) and/or revascularization procedure. The primary composite endpoint of recurrent MACE defined as CV death, hospitalization due to MI, revascularization, stroke/transitory ischemic attacks or heart failure was obtained from hospital records. Data were analysed using cox proportional hazard regression, stratified by prior coronary events before the index event. RESULTS: During a mean follow-up of 4.2 years from study inclusion (mean time from index event to end of study 5.7 years), 364 MACE occurred in 240 patients (21, 95% confidence interval: 19 to 24%), of which 39 were CV deaths. In multi-adjusted analyses, the strongest predictor of MACE was not taking statins (Relative risk [RR] 2.13), succeeded by physical inactivity (RR 1.73), peripheral artery disease (RR 1.73), chronic kidney failure (RR 1.52), former smoking (RR 1.46) and higher Hospital Anxiety and Depression Scale-Depression subscale score (RR 1.04 per unit increase). Preventable and potentially modifiable factors addressed accounted for 66% (95% confidence interval: 49 to 77%) of the risk for recurrent events. The major contributions were smoking, low physical activity, not taking statins, not participating in cardiac rehabilitation and diabetes. CONCLUSIONS: Coronary patients were at high risk of recurrent MACE. Potentially preventable clinical and psychosocial factors predicted two out of three MACE, which is why these factors should be targeted in coronary populations. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT02309255. Registered at December 5th, 2014, registered retrospectively.


Assuntos
Infarto do Miocárdio/terapia , Revascularização Miocárdica , Prevenção Secundária , Idoso , Progressão da Doença , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Humanos , Ataque Isquêmico Transitório/mortalidade , Ataque Isquêmico Transitório/prevenção & controle , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/psicologia , Revascularização Miocárdica/efeitos adversos , Revascularização Miocárdica/mortalidade , Noruega/epidemiologia , Readmissão do Paciente , Estudos Prospectivos , Recidiva , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Fatores de Tempo , Resultado do Tratamento
20.
Rev Mal Respir ; 37(3): 257-266, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-32088063

RESUMO

Cor pulmonale is a disease of the heart characterised by dilatation of the right ventricle and paradoxical movement of the interventricular septum. The diagnosis depends on echocardiography even if pulmonary artery catheterisation suggests it. It is secondary to pulmonary disease or a disorder of the pulmonary circulation. These two mechanisms, which are often connected, involve pulmonary hypertension as the origin of a systolic and diastolic overload of the right ventricle, which then leads to the alterations of its structure and performance. Acute cor pulmonale is usually secondary to an acute respiratory distress syndrome or to a pulmonary embolism but it can also be seen in primary lactic acidosis, a vaso-occlusive crisis in a patient with sickle cell anaemia, severe acute asthma, and entry of air or injected crushed tablets into the circulation. Chronic cor pulmonale is the terminal stage of pulmonary hypertension. Clinically these patients are dyspnoeic with signs of chronic right heart failure. They should have an echocardiogram confirming the cardiac involvement. Certain precipitating factors, such as infection of any origin, have been reported, leading to acute on chronic cor pulmonale that has a particularly high mortality.


Assuntos
Doença Cardiopulmonar/etiologia , Disfunção Ventricular Direita/complicações , Doença Crônica , Diagnóstico Diferencial , Ecocardiografia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/terapia , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/etiologia , Embolia Pulmonar/terapia , Doença Cardiopulmonar/diagnóstico , Doença Cardiopulmonar/terapia , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/terapia , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/terapia
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