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1.
JAMA ; 324(5): 488-504, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32749493

RESUMO

Importance: Worldwide, the burden of heart failure has increased to an estimated 23 million people, and approximately 50% of cases are HF with reduced ejection fraction (HFrEF). Observations: Heart failure is a clinical syndrome characterized by dyspnea or exertional limitation due to impairment of ventricular filling or ejection of blood or both. HFrEF occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodeling. Assessment for heart failure begins with obtaining a medical history and physical examination. Also central to diagnosis are elevated natriuretic peptides above age- and context-specific thresholds and identification of left ventricular systolic dysfunction with LVEF of 40% or less as measured by echocardiography. Treatment strategies include the use of diuretics to relieve symptoms and application of an expanding armamentarium of disease-modifying drug and device therapies. Unless there are specific contraindications, patients with HFrEF should be treated with a ß-blocker and one of an angiotensin receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker as foundational therapy, with addition of a mineralocorticoid receptor antagonist in patients with persistent symptoms. Ivabradine and hydralazine/isosorbide dinitrate also have a role in the care of certain patients with HFrEF. More recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors have further improved disease outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status, and vericiguat, a soluble guanylate cyclase stimulator, reduces heart failure hospitalization in high-risk patients with HFrEF. Device therapies may be beneficial in specific subpopulations, such as cardiac resynchronization therapy in patients with interventricular dyssynchrony, transcatheter mitral valve repair in patients with severe secondary mitral regurgitation, and implantable cardiac defibrillators in patients with more severe left ventricular dysfunction particularly of ischemic etiology. Conclusions and Relevance: HFrEF is a major public health concern with substantial morbidity and mortality. The management of HFrEF has seen significant scientific breakthrough in recent decades, and the ability to alter the natural history of the disease has never been better. Recent developments include SGLT2 inhibitors, vericiguat, and transcatheter mitral valve repair, all of which incrementally improve prognosis beyond foundational neurohormonal therapies. Disease morbidity and mortality remain high, with a 5-year survival rate of 25% after hospitalization for HFrEF.


Assuntos
Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/terapia , Volume Sistólico , Reabilitação Cardíaca , Cardiotônicos/administração & dosagem , Desfibriladores Implantáveis , Diuréticos/uso terapêutico , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Humanos , Prognóstico
2.
Medicine (Baltimore) ; 99(28): e20934, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664090

RESUMO

This study aimed to investigate the myocardial protective effect of liquid sodium phosphocreatine cardiac arrest in extracorporeal circulation surgery treating infants with atrial septal defects.Eighty-four infants with atrial septal defects who required extracorporeal circulation surgery treatment at our hospital from January 2016 to June 2018 were divided into an observation group and a control group through a digitally randomized method, with 42 cases in each group. The control group adopted the conventional modified St Thomas II high potassium cold liquid crystal cardiac arrest, while the observation group adopted the liquid sodium phosphocreatine cardiac arrest.The myocardial enzyme indexes of the 2 groups 3, 6, 12, and 24 hours postoperatively were higher than before establishing the cardiopulmonary bypass and the enzyme indexes of the control group at the same time were higher than that of the observation group; adenosine triphosphate, adenosine diphosphate, and other energy levels and the postoperative recovery rate energy levels of the observation group were higher than those in the control group, the difference was statistically significant (P < .05).Liquid sodium phosphocreatine cardiac arrest used in extracorporeal circulation surgery treating infants with atrial septal defects can reduce myocardial ischemia-reperfusion injury, maintain energy supply during ischemia, strengthen the St Thomas II effect, and aid postoperative cardiac function recovery of high potassium cold liquid crystal cardiac arrest used in infants with atrial septal defects and treated with extracorporeal circulation surgery.


Assuntos
Ponte Cardiopulmonar/métodos , Cardiotônicos/farmacologia , Parada Cardíaca Induzida/métodos , Comunicação Interatrial/cirurgia , Fosfocreatina/farmacologia , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Cardiotônicos/administração & dosagem , Estudos de Casos e Controles , Pré-Escolar , Circulação Extracorpórea/métodos , Feminino , Parada Cardíaca/induzido quimicamente , Comunicação Interatrial/diagnóstico , Comunicação Interatrial/tratamento farmacológico , Humanos , Lactente , Masculino , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/química , Miocárdio/enzimologia , Preservação de Órgãos/métodos , Fosfocreatina/administração & dosagem , Período Pós-Operatório , Cloreto de Potássio/administração & dosagem , Cloreto de Potássio/farmacologia , Substâncias Protetoras/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos
3.
Anesth Analg ; 131(2): 527-536, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32371741

RESUMO

BACKGROUND: Catecholamine inotropes are frequently used after cardiopulmonary bypass (CPB) but may have undesirable effects. The aim was to identify whether the routine use of inhaled pulmonary vasodilators might reduce the requirement for inotrope drugs after cardiac surgery. METHODS: Retrospective cohort study of sequential patients undergoing cardiac surgery at the Royal Melbourne Hospital performed by a single surgeon and anesthesia care team, within 14 months before and after routine implementation of inhaled pulmonary vasodilators, August 2017. Milrinone 4 mg and iloprost 20 µg were inhaled using a vibrating mesh nebulizer (Aerogen) before initiation of CPB and at chest closure. Other aspects of clinical management were unaltered over the time period. Two investigators blinded to each other extracted data from electronic and written medical records. The primary outcome was any use of inotropes in the perioperative period; a Fisher exact test was used to analyze any differences between the 2 groups. Demographic data, hemodynamic data, and use of inotropes and vasopressors were collected from induction of anesthesia to 36 hours postoperative in the intensive care unit (ICU). Hospital and ICU length of stay, cost, and complications were collected. RESULTS: Any use of inotropes was significantly lower with inhaled pulmonary dilators (62.5% vs 86.8%, odds ratio [95% confidence interval {CI}], 0.253 (0.083-0.764); P = .011), including intraoperative inotrope use (37.5% vs 86.8%, odds ratio [95% CI], 0.091 (0.03-0.275); P < .001). ICU length of stay was significantly lower with inhaled pulmonary dilators (45 hours, interquartile range [IQR], 27-65 vs 50 hours, IQR, 45-74; P = .026). There were no significant differences among major postoperative complications or costs between groups. CONCLUSIONS: Routine use of inhaled milrinone 4 mg and iloprost 20 µg before and after CPB is associated with reduced postoperative inotrope use.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Iloprosta/administração & dosagem , Complicações Intraoperatórias/prevenção & controle , Milrinona/administração & dosagem , Contração Miocárdica/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Administração por Inalação , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiotônicos/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Cuidados Intraoperatórios/métodos , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/etiologia , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Projetos Piloto , Estudos Retrospectivos
4.
Life Sci ; 256: 117855, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32473245

RESUMO

OBJECTIVE: Subjects with type 2 diabetes (T2D) have lower circulating hydrogen sulfide (H2S) levels following myocardial ischemia and a higher risk of mortality. The aim of this study was to determine the dose-dependent favorable effects of sodium hydrosulfide (NaSH) on myocardial ischemia-reperfusion (IR) injury in rats with T2D. METHODS: T2D was induced using a high-fat diet (HFD) and low-dose of streptozotocin. Rats were divided into control, T2D, and T2D + NaSH groups. NaSH (0.28, 0.56, 1.6, 2.8, and 5.6 mg/kg) was administered intraperitoneally for 9 weeks. At the end of the study, heart from all rats were isolated and left ventricular developed pressure (LVDP) and the peak rates of positive and negative changes in LV pressure (±dp/dt) were recorded during baseline and following myocardial IR injury. In addition, infarct size as well as mRNA expression of H2S- and nitric oxide (NO)-producing enzymes were measured. RESULTS: In diabetic rats, NaSH only at doses of 0.56 and 1.6 mg/kg increased recovery of LVDP (16% and 42%), +dp/dt (25% and 35%) and -dp/dt (23% and 32%) as well as decreased infarct size (44% and 35%). At these doses, NaSH increased expressions of cystathionine γ-lyase (CSE) (440% and 271%) and endothelial NO synthase (eNOS) (232% and 148%) but it decreased the expressions of inducible NOS (iNOS) (55% and 71%). NaSH at 0.28, 2.8 and 5.6 mg/kg had no significant effects on these parameters. CONCLUSION: NaSH had a bell-shaped cardioprotective effect against myocardial IR injury in rats with T2D. Higher tolerance to IR injury in heart isolated from type 2 diabetic rats treated with intermediate doses of NaSH is associated with higher CSE-derived H2S and eNOS-derived NO as well as lower iNOS-derived NO.


Assuntos
Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Sulfetos/farmacologia , Animais , Cardiotônicos/administração & dosagem , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Sulfeto de Hidrogênio/metabolismo , Masculino , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/complicações , Ratos , Ratos Wistar , Estreptozocina , Sulfetos/administração & dosagem
5.
J Card Surg ; 35(6): 1253-1257, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32333432

RESUMO

BACKGROUND: del Nido (DN) cardioplegia is commonly used during robotic mitral valve surgery. Poor venous drainage during surgery may result in venous backpressure and washout of this one-shot cardioplegia, limiting its cardioprotective effects. METHODS: One hundred eighty-seven patients undergoing isolated robotic mitral valve surgery, from January 2015 to July 2017, were retrospectively reviewed. Intraoperative central venous pressure (CVP) tracings were reviewed and venous drainage was categorized as good or poor and the relationship of the quality of venous drainage to postoperative ventricular dysfunction (operationalized as the need for inotropic support during and after weaning from cardiopulmonary bypass [CPB]) was assessed. RESULTS: Drainage was judged to be good in 107 patients and poor in 79 patients. On univariate analysis, 23 patients (41%) with good drainage required inotropic support whereas 33 patients (59%) with poor drainage required inotropic support (P = .0025). On multivariable analysis, poor venous drainage remained significantly associated with inotropic use even after adjusting for cross-clamp and CPB time. Inotrope use was associated with significantly longer intensive care unit length of stay (P = .027). CONCLUSION: Maintenance of excellent venous drainage, as assessed by CVP monitoring, should be a high priority in isolated robotic mitral valve surgery undertaken with DN cardioplegia.


Assuntos
Drenagem , Parada Cardíaca Induzida/métodos , Valva Mitral/cirurgia , Monitorização Intraoperatória/métodos , Complicações Pós-Operatórias , Procedimentos Cirúrgicos Robóticos/métodos , Disfunção Ventricular , Adulto , Idoso , Ponte Cardiopulmonar , Cardiotônicos/administração & dosagem , Pressão Venosa Central , Feminino , Parada Cardíaca Induzida/efeitos adversos , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
J Card Surg ; 35(6): 1228-1236, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32333454

RESUMO

BACKGROUND: Cardiac surgery using cardiopulmonary bypass is a well-established procedure. However, up to 20% to 30% of patients require high dose vasopressor or inotropic support following surgery, enhancing the risk of organ dysfunction and impacting mortality. Nonalcoholic fatty liver disease (NAFLD) is a frequent finding in these patients and may be involved in the pathophysiology of vasoplegia and cardiac failure. METHODS: Retrospective analysis of 463 patients undergoing elective cardiac surgery in 2014 at our institution. NAFLD was defined using the NAFLD fibrosis score and the vasoactive-inotropy score was used to determine postoperative vasopressor and inotropic dependency. RESULTS: Patients with NAFLD more often presented with high vasopressor or inotropic support compared to patients without NAFLD, resulting in significant differences after 6 hours (n = 20 [27.0%] of 74 patients), 12 hours (n = 20 [27.0%] of 74 patients), and on the first postoperative day (n = 12 [16.4%] of 73 patients) of intensive care unit (ICU) treatment. Multivariate analysis revealed time of catecholamine application (P = .001), preoperative left ventricular ejection fraction (P = .001), type of surgery (P = .001), model of endstage liver disease on hospital admission (P = .002), pre-existing pulmonary hypertension (P = .004) and NAFLD-time interaction (P = .05) as independent predictors of high vasopressor and inotropic support. Patients with NAFLD had higher degrees of extrahepatic organ dysfunction, were more dependent on hemodialysis, spent more days in the ICU and within the hospital. Patients with NAFLD and high catecholamine support had the highest mortality rates among the study population. CONCLUSIONS: NAFLD is a common finding in elective cardiac surgery patients. Anesthesiologists and intensivists should be sensitive for the specific risk profile of this population.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Ponte Cardiopulmonar , Catecolaminas/administração & dosagem , Catecolaminas/efeitos adversos , Hepatopatias/etiologia , Complicações Pós-Operatórias/etiologia , Vasoconstritores/administração & dosagem , Vasoconstritores/efeitos adversos , Idoso , Procedimentos Cirúrgicos Cardíacos/mortalidade , Cardiotônicos/administração & dosagem , Cardiotônicos/efeitos adversos , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Período Pós-Operatório , Estudos Retrospectivos , Risco , Volume Sistólico , Vasoplegia/etiologia , Função Ventricular Esquerda
7.
Int Heart J ; 61(2): 384-389, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32132321

RESUMO

Tachycardia and supraventricular tachyarrhythmias often impair cardiovascular capacity in patients with decompensated heart failure (dHF) treated with inotropes. Normalization of heart rhythm or rate typically improves diastolic filling and stroke volume (SV). Thus, isochronal administration of an ultra-short-acting and highly selective ß1-blockers, such as landiolol, along with inotropic calcium-sensitizer medications, such as levosimendan, could benefit patients with dHF.We present a case series of three patients with severe dHF and low ejection fraction who were successfully treated with a combination of landiolol and levosimendan. The co-administration of landiolol and levosimendan was well tolerated, improved cardiac function, normalized SV, and enabled the reduction of norepinephrine dosing in all patients. Additionally, the combination improved the vectorcardiographic spatial QRS-T angle and decreased the corrected QT interval. All patients were successfully discharged from the intensive care unit (ICU).A combination of levosimendan and landiolol was safe and well-tolerated. This combination may be a new option for successful treatment of patients with acute dHF complicated by sinus or supraventricular tachycardias.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Cardiotônicos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Morfolinas/administração & dosagem , Simendana/administração & dosagem , Taquicardia/tratamento farmacológico , Ureia/análogos & derivados , Idoso , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/complicações , Humanos , Masculino , Taquicardia/etiologia , Ureia/administração & dosagem
8.
Life Sci ; 249: 117476, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32119962

RESUMO

Mangiferin is a well-known xanthone extracted from mango leaves (Mangifera indica Linn). Mangiferin is widely distributed in the bark, peel, leaf, seed, stalk, and kernel of mango and higher plants. The pharmacological properties of mangiferin, including its antioxidant, anticancer, antiaging, antiviral, hepatoprotective, analgesic, and immunomodulatory activities, have been described in several studies. We investigated the effect of mangiferin on isoproterenol-induced apoptosis. Experimental heart failure was induced in rats by intraperitoneal administration of isoproterenol (5 mg/kg) for 7 consecutive days. Rats were divided into five groups: group I (sham rats), group II (isoproterenol alone control), group III (isoproterenol + 25 mg/kg mangiferin), group IV (isoproterenol + 50 mg/kg mangiferin), and group V (isoproterenol + 0.0225 mg/kg digitalis as a positive control). Hemodynamic parameters and body weight, heart weight and liver weight, apoptosis induction, and caspase-3, Bax, and Bcl-2 protein levels were measured, and a histopathological analysis of cardiomyocytes was performed. In addition, apoptosis and protein expression of caspase-3, cleaved caspase-3, Bax, and Bcl-2 were measured in cardiac H9c2 cells. Mangiferin supplementation significantly increased heart rate and improved the maximum rate of decrease in left ventricular (LV) pressure, the maximum rate of increase in LV pressure, and LV systolic pressure. Mangiferin reduced inflammatory cell infiltration and the number of broken myocardial fibers, and decreased apoptosis in cardiomyocytes by reducing proteins levels of caspase-3 and Bax and increasing those of Bcl-2. Our findings suggest that mangiferin has a cardioprotective effect against isoproterenol-induced apoptosis in cardiomyocytes.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Insuficiência Cardíaca/induzido quimicamente , Coração/efeitos dos fármacos , Xantonas/farmacologia , Animais , Cardiotônicos/administração & dosagem , Injeções Intraperitoneais , Isoproterenol/administração & dosagem , Isoproterenol/farmacologia , Ratos
9.
Food Funct ; 11(1): 32-44, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31942892

RESUMO

Cardiovascular disease is a leading cause of death in the United States and much of the developed world, costing billions of dollars in lost work time, lower productivity and high health care expenditures. Research on foods and bioactive food components that have cardioprotective benefits may provide new insights as to how modest changes in one's diet may result in a reduced risk of vascular disease. In intervention trials, the consumption of strawberries, either fresh or freeze-dried, has been reported to improve select markers of cardiovascular health, including improved lipid profiles, microvascular function, and platelet reactivity. Consistent with the above, epidemiological studies suggest beneficial effects of strawberries on vascular function. Preliminary studies on the effects of freeze-dried strawberry powder on vascular health are reviewed in the current paper.


Assuntos
Cardiotônicos/administração & dosagem , Sistema Cardiovascular , Frutas , Lipídeos/sangue , Adolescente , Biomarcadores , Doenças Cardiovasculares/prevenção & controle , Dieta , Fragaria , Liofilização , Humanos , Masculino , Pós , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Am J Med ; 133(7): 857-864, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31883773

RESUMO

BACKGROUND: Milrinone infusion is one of a few select "non-device" therapies for patients with New York Heart Association (NYHA) class IV, stage D heart failure, which has been associated with an increase in ventricular tachyarrhythmia and atrial fibrillation. Milrinone improves hemodynamics and provides symptomatic relief. Many patients with end-stage heart failure die from cardiac pump failure, and the impact of ventricular tachyarrhythmia and atrial fibrillation on their mortality is unclear. METHODS: This is a retrospective study of 98 consecutive patients receiving outpatient milrinone in a single center from 2008 to 2016. The primary endpoint of the study was overall survival on milrinone. Secondary endpoints were incidence of post-milrinone implantable cardioverter defibrillator (ICD) shocks and development of ventricular tachyarrhythmia or atrial fibrillation. RESULTS: Median survival was 581 ± 96 days with no difference between those with prior ventricular tachyarrhythmia and those without at 1 month (92% vs 97%, P = 0.34), 6 months (67% vs 73%, P = 0.75), and 12 months (67% vs 61%, P = 0.88). Seven out of 12 (58%) patients with prior ventricular tachyarrhythmia had ICD shocks, as compared to 5 out of 78 (6.4%) (P <0.001). Thirty-five patients had atrial fibrillation prior to starting milrinone, which decreased to 72% (P <0.05) by the third follow-up time period (7-9 months). Amiodarone use was protective against new onset atrial fibrillation. CONCLUSIONS: Patients with stage D heart failure with a history of ventricular tachyarrhythmia have similar survival on outpatient milrinone compared to those without. However, those with prior ventricular tachyarrhythmia received more ICD shocks for more ventricular tachyarrhythmias. Milrinone remains a viable therapy for patients with stage D heart failure with limited therapeutic options.


Assuntos
Fibrilação Atrial/complicações , Desfibriladores Implantáveis , Insuficiência Cardíaca/terapia , Milrinona/administração & dosagem , Taquicardia Ventricular/complicações , Idoso , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Cardiotônicos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Humanos , Infusões Intravenosas , Masculino , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/terapia
11.
Eur Rev Med Pharmacol Sci ; 23(23): 10541-10548, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31841210

RESUMO

OBJECTIVE: To explore the influence of butorphanol on myocardial ischemia/reperfusion (I/R) injury in rats through the mitogen-activated protein kinase (MAPK) signaling pathway. MATERIALS AND METHODS: The I/R model in Sprague-Dawley rats was established. The rats were randomly divided into normal group (n=20), myocardial I/R model group (model group, n=20), and butorphanol treatment group (treatment group, n=20). Next, the liver function indicators such as alkaline phosphatase (ALP), alanine aminotransferase (ALT), and the myocardial function index creatine kinase (CK) in rats were detected. ELISA was carried out to measure the relative levels of tumor necrosis factor-gamma (TNF-γ), interleukin-6 (IL-6), and IL-1α in serum samples of rats. The cardiac function indexes were examined via magnetic resonance imaging (MRI) and echocardiography (ECG). Besides, the pathological changes of the myocardial tissues were detected through hematoxylin-eosin (HE) staining. The quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blotting were performed to measure the mRNA and protein expression levels of the relative genes in the MAPK signaling pathway in the rat myocardial tissues. RESULTS: The serum levels of ALP, ALT, and CK in I/R model group were significantly higher than those in the normal group. In I/R model group, the relative levels of TNF-γ, IL-6, and IL-1α, as well as left ventricular end-diastolic diameter (LVEDd) and left ventricular end-systolic diameter (LVESd), were remarkably higher, while the fractional shortening (FS, %) and the ejection fraction (EF, %) were lower in comparison with those in the normal group. The HE staining results showed that the myocardial tissues in the I/R model group exhibited severe injury. The expression levels of Caspase3, MAPK, and c-Jun N-terminal kinase (JNK) were clearly higher in the I/R model group than those in the treatment group (p<0.05), while the expression level of extracellular regulated protein kinase 1 (ERK1) was remarkably lower (p<0.05). The protein level of MAPK in the treatment group was overtly reduced compared with that in the I/R model group (p<0.05). CONCLUSIONS: Butorphanol can modulate the recovery of the myocardial injury in the rats after the myocardial I/R by inhibiting the MAPK signaling pathway.


Assuntos
Butorfanol/administração & dosagem , Cardiotônicos/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Humanos , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
12.
Parasit Vectors ; 12(1): 532, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31706334

RESUMO

BACKGROUND: Trypanosoma cruzi is the causative agent of Chagas disease, which is endemic to subtropical and tropical Americas. The disease treatment remains partially ineffective, involving therapies directed to the parasite as well as palliative strategies for the clinical manifestations. Therefore, novel candidates for disease control are necessary. Additionally, strategies based on parasite inhibition via specific targets and application of compounds which improve the immune response against the disease is welcomed. Ghrelin is a peptide hormone pointed as a substance with important cardioprotective, vasodilatory, anti-apoptotic, anti-oxidative and immune modulatory functions. The aims of this study were to evaluate the immunomodulatory effects of ghrelin in male Wistar rats infected with the Y strain of T. cruzi. METHODS: In order to delineate an immune response against T. cruzi mediated by ghrelin, we evaluated the following parameters: quantification of blood and cardiac parasites; analysis of cell markers (CD3+, CD8+, NK, NKT, CD45RA+, macrophage and RT1B+); nitric oxide (NO) production; lymphoproliferation assays; splenocyte apoptosis; and INF-γ, IL-12 and IL-6 quantification in sera. RESULTS: The animals infected with T. cruzi and supplemented with ghrelin demonstrated an upregulated pattern in macrophage and NO production, whereas an anti-inflammatory response was observed in T cells and cytokines. The low response against T. cruzi mediated by T cells probably contributed to a higher colonization of the cardiac tissue, when compared to infected groups. On the other side, the peptide decreased the inflammatory infiltration in cardiac tissue infected with T. cruzi. CONCLUSIONS: Ghrelin demonstrated a dual function in animals infected with T. cruzi. Further studies, especially related to the decrease of cardiac tissue inflammation, are needed in order to determine the advantages of ghrelin supplementation in Chagas disease, mostly for populations from endemic areas.


Assuntos
Cardiotônicos/administração & dosagem , Doença de Chagas/tratamento farmacológico , Grelina/administração & dosagem , Fatores Imunológicos/administração & dosagem , Animais , Proliferação de Células , Doença de Chagas/patologia , Citocinas/análise , Modelos Animais de Doenças , Injeções Subcutâneas , Linfócitos/imunologia , Macrófagos/imunologia , Masculino , Miocárdio/patologia , Carga Parasitária , Ratos Wistar , Resultado do Tratamento
13.
EMBO Mol Med ; 11(11): e10469, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31609086

RESUMO

Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health-promoting and longevity-extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4-dimethoxychalcone (3,4-DC), among a library of polyphenols. When added to several different human cell lines, 3,4-DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well-characterized CRMs, 3,4-DC, however, required transcription factor EB (TFEB)- and E3 (TFE3)-dependent gene transcription and mRNA translation to trigger autophagy. 3,4-DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4-DC induced autophagy in vitro and in mouse organs, mediated autophagy-dependent cardioprotective effects, and improved the efficacy of anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4-DC is a novel CRM with a previously unrecognized mode of action.


Assuntos
Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Cardiotônicos/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos , Acetilação , Estruturas Animais/patologia , Animais , Cardiotônicos/administração & dosagem , Linhagem Celular , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Processamento de Proteína Pós-Traducional , Transporte Proteico
14.
Drug Dev Ind Pharm ; 45(12): 1889-1895, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31549866

RESUMO

Rhizomes of the plant Curcuma longa has been traditionally used in medicine and culinary practices in India. It possesses various pharmacological effect, namely, antioxidant, hepatoprotective, anti-inflammatory, anti-thrombosis, and anti-apoptotic. The study was undertaken to assess the effect of curcumin and curcumin loaded mesoporous silica nanoparticles (MSNs) against doxorubicin (DOX)-induced myocardial toxicity in rats. Furthermore, the study also included the bioavailability estimation of curcumin delivered alone and delivered via mesoporous technology. Cardiotoxicity was produced by cumulative administration of DOX (2.5 mg/kg for two weeks). Curcumin and curcumin loaded mesoporous nanoparticles (MSNs) each 200 mg/kg, po was administered as pretreatment for two weeks and then for two alternate weeks with DOX. The repeated administration of DOX induced cardiomyopathy associated with an antioxidant deficit and increased level of cardiotoxic biomarkers. Pretreatment with curcumin (alone and via MSNs) significantly protected myocardium from the toxic effects of DOX by significantly decreased the elevated level of malondialdehyde and increased the reduced level of reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in cardiac tissue. MSNs based delivery was found superior compared to curcumin delivered alone. Moreover, the results of bioavailability assessment in rats clearly indicated higher Cmax and AUC values in rats when curcumin was administered via MSNs indicating superior bioavailability. The bioavailability of curcumin loaded MSNs, biochemical and histopathology reports support the good cardioprotective effect of curcumin which could be attributed to its increased bioavaibility lead to good antioxidant and anti-inflammatory activity.


Assuntos
Cardiotônicos/farmacocinética , Cardiotoxicidade/prevenção & controle , Curcumina/farmacocinética , Portadores de Fármacos/química , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Disponibilidade Biológica , Cardiotônicos/administração & dosagem , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Curcuma/química , Curcumina/administração & dosagem , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Miocárdio/patologia , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Ratos , Dióxido de Silício/química
15.
Biochimie ; 167: 119-134, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31557503

RESUMO

Protocatechuic acid (PCA), the natural phenolic antioxidant, reportedly exhibited hypoglycemic and insulin-like effects. Recent studies have reported its cardioprotective effect in glucocorticoid (GC)-induced hypertensive rats. Nevertheless, its beneficial role has not been investigated in the setting of GCs excess-induced insulin resistance. This study aimed to investigate the possible protective potential and the plausible mechanisms of pretreatment with PCA against GCs-induced insulin resistance, liver steatosis and vascular dysfunction. Insulin resistance was induced in male Wistar rats by a 7-day treatment with dexamethasone (DEX) (1 mg/kg/day, i.p.). PCA (50, 100 mg/kg/day, orally) was started 7 days before DEX administration and continued during the test period. PCA significantly and dose-dependently attenuated DEX-induced a) glucose intolerance (↓ AUCOGTT), b) hyperglycemia (↓ fasting blood glucose), c) impaired insulin sensitivity [↓fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR) index)] and d) dyslipidemia (↓total cholesterol, triglycerides, low-density lipoprotein-cholesterol and very low-density lipoprotein-cholesterol). PCA mitigated DEX-induced liver steatosis with associated reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Moreover, PCA ameliorated DEX-induced vascular dysfunction and enhanced ACh-induced relaxation in aortic rings. The metabolic ameliorating effects of PCA might be attributed to the enhanced insulin signaling in soleus muscles (↑AKT phosphorylation) and mitigating gluconeogenesis (↓ hepatic mRNA expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). The vasculoprotective effect of PCA might be related to its ability to restore normal mRNA expression of [endothelial nitric oxide synthase (eNOS) and NADPH Oxidase 4 (NOX4)]. PCA restored normal oxidative balance [↓ oxidant species, malondialdehyde (MDA) and (↑ antioxidant superoxide dismutase (SOD)]. The findings herein reveal for the first time that PCA may be taken as a supplement with GCs to limit their metabolic and vascular side effects through its hypoglycemic, insulin-sensitizing, hypolipidemic and antioxidant effects.


Assuntos
Antioxidantes , Cardiotônicos , Hidroxibenzoatos , Hipoglicemiantes , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Suplementos Nutricionais , Modelos Animais de Doenças , Dislipidemias/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Intolerância à Glucose/tratamento farmacológico , Hidroxibenzoatos/administração & dosagem , Hidroxibenzoatos/farmacologia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Resistência à Insulina , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
16.
Food Funct ; 10(9): 5587-5604, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31432062

RESUMO

Doxorubicin is a powerful anticancer agent used to treat a variety of human neoplasms. However, the clinical use of doxorubicin is hampered by cardiotoxicity and effective cardioprotective adjuvants do not exist. Dietary zinc, an essential nutrient, is required to maintain steady-state tissue zinc levels and intestinal homeostasis and may yield therapeutic benefits in diseases associated with zinc dysregulation or gut dysbiosis. Here, we investigated the effects of dietary Zn(ii)-curcumin (ZnCM) solid dispersions on gut dysbiosis and zinc dyshomeostasis during doxorubicin-induced cardiotoxicity in rats. Rats were injected with multiple low doses of doxorubicin and orally administered ZnCM daily over four weeks. Daily administration of ZnCM not only alleviated Dox-induced gut dysbiosis-as indicated by the increased Firmicutes-to-Bacteroidetes ratio and the maintenance of the relative abundances of major beneficial bacteria including Clostridium_XIVa, Clostridium_IV, Roseburia, Butyricicoccus and Akkermansia-but also maintained intestinal barrier integrity and decreased the lipopolysaccharide (LPS) contents of feces and plasma. ZnCM also significantly attenuated doxorubicin-induced zinc dyshomeostasis, which was mirrored by preservation of zinc levels and expression of zinc-related transporters. Furthermore, ZnCM significantly improved heart function and reduced cardiomyocyte apoptosis and myocardial injury in doxorubicin-treated rats. Notably, the regulation of zinc homeostasis and cardioprotective and microbiota-modulating effects of ZnCM were transmissible through horizontal feces transfer from ZnCM-treated rats to normal rats. Thus, ZnCM supplementation has potential as an effective therapeutic strategy to alleviate gut dysbiosis and zinc dyshomeostasis during doxorubicin-induced cardiotoxicity.


Assuntos
Antineoplásicos/toxicidade , Cardiotoxicidade/tratamento farmacológico , Curcumina/administração & dosagem , Doxorrubicina/toxicidade , Disbiose/tratamento farmacológico , Zinco/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Cardiotônicos/administração & dosagem , Cardiotoxicidade/etiologia , Cardiotoxicidade/microbiologia , Cardiotoxicidade/fisiopatologia , Suplementos Nutricionais/análise , Disbiose/etiologia , Disbiose/microbiologia , Fezes/microbiologia , Homeostase/efeitos dos fármacos , Humanos , Masculino , Miocárdio/citologia , Ratos , Ratos Sprague-Dawley
17.
Can J Physiol Pharmacol ; 97(10): 989-998, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31464528

RESUMO

The current study was carried out to evaluate the effect of pretreatment and co-treatment with a newly synthesized coumarin hydrazone, (E)-4-hydroxy-N'-(1-(3-oxo-3H-benzo[f]chromen-2-yl)ethylidene)benzohydrazide (hereinafter EK6), against isoproterenol-induced myocardial infarction in rats. Changes in biochemistry, cardiac biomarkers, electrocardiography, and histopathology after treatment with EK6 or acenocoumarol (Sintrom) were studied. Animals were randomly divided into 4 groups: vehicle control (C), isoproterenol + Sintrom (ISO + Sin), isoproterenol + EK6 (ISO + EK6), and isoproterenol (ISO). Myocardial infarction was induced by subcutaneous ISO administration at a dose of 85 mg·kg-1·day-1 with a drug-free interval of 24 h on days 6 and 7. Treatment with ISO led to significant elevation (p < 0.05) in serum levels of cardiac injury biomarkers, namely cardiac troponin-T, lactate dehydrogenase, creatine kinase-MB, alanine aminotransferase, and aspartate aminotransferase compared with levels in the vehicle control. A change in the lipid profile was also observed as a significant increase in total cholesterol and triglycerides. Furthermore, ISO caused significant alterations in the electrocardiogram pattern, including significant ST-segment elevation, significant decreased R wave amplitude, and significant increase in heart rate (16%) as well as marked changes in the histopathology of the heart tissue. Pretreatment and co-treatment with newly synthesized coumarin hydrazone restored all ISO-induced biochemical, lipid, cardiac, and histopathological changes in rats with myocardial infarction.


Assuntos
Benzopiranos/administração & dosagem , Cardiotônicos/administração & dosagem , Cumarínicos/administração & dosagem , Hidrazonas/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Animais , Benzopiranos/síntese química , Biomarcadores/análise , Cardiotônicos/síntese química , Cumarínicos/síntese química , Modelos Animais de Doenças , Eletrocardiografia , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidrazonas/síntese química , Isoproterenol/toxicidade , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/diagnóstico , Miocárdio/patologia , Ratos , Ratos Wistar , Resultado do Tratamento
18.
Br J Anaesth ; 123(4): 439-449, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31383364

RESUMO

BACKGROUND: Nerve growth factor (NGF) has been implicated in hyperalgesia by sensitising nociceptors. A role for NGF in modulating myocardial injury through ischaemic nociceptive signalling is plausible. We examined whether inhibition of spinal NGF attenuates myocardial ischaemia-reperfusion injury and explored the underlying mechanisms. METHODS: In adult rats, lentivirus-mediated short-hairpin RNA targeted at reducing NGF gene expression (NGF-shRNA) or a transient receptor potential vanilloid 1 (TRPV1) antagonist (capsazepine) was injected intrathecally before myocardial ischaemia-reperfusion. Infarct size (expressed as the ratio of area at risk) and risk of arrhythmias were quantified. Whole-cell clamp patch electrophysiology was used to record capsaicin currents in primary dorsal root ganglion neurones. The co-expression of substance P (SP) and calcitonin gene-related peptide (CGRP), plus activation of TRPV1, protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also quantified. RESULTS: NGF levels increased by 2.95 (0.34)-fold in dorsal root ganglion and 2.12 (0.27)-fold in spinal cord after myocardial ischaemia-reperfusion injury. Intrathecal injection of NGF-shRNA reduced infarct area at risk from 0.58 (0.02) to 0.37 (0.02) (P<0.01) and reduced arrhythmia score from 3.67 (0.33) to 1.67 (0.33) (P<0.01). Intrathecal capsazepine was similarly cardioprotective. NGF-shRNA suppressed expression of SP/CGRP and activation of Akt/ERK and TRPV1 in spinal cord. NGF increased capsaicin current amplitude from 144 (42) to 840 (132) pA (P<0.05), which was blocked by the TRPV1 antagonist 5'-iodoresiniferatoxin. Exogenous NGF enhanced capsaicin-induced Akt/ERK and TRPV1 activation in PC12 neuroendocrine tumour cells in culture. CONCLUSIONS: Spinal NGF contributes to myocardial ischaemia-reperfusion injury by mediating nociceptive signal transmission.


Assuntos
Terapia Genética/métodos , Lentivirus/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fator de Crescimento Neural/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Animais , Arritmias Cardíacas/prevenção & controle , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Cardiotônicos/administração & dosagem , Cardiotônicos/uso terapêutico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Injeções Espinhais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/prevenção & controle , Fator de Crescimento Neural/biossíntese , Células PC12 , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
19.
J Am Coll Cardiol ; 74(5): 617-627, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31370952

RESUMO

BACKGROUND: The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. OBJECTIVES: The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. METHODS: Of the 11,900 hospitalized patients with HFrEF (EF ≤45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. RESULTS: Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778). CONCLUSIONS: Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes.


Assuntos
Digoxina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Sistema de Registros , Volume Sistólico/fisiologia , Idoso , Cardiotônicos/administração & dosagem , Causas de Morte , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pacientes Ambulatoriais , Readmissão do Paciente/tendências , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Resultado do Tratamento , Estados Unidos/epidemiologia , Suspensão de Tratamento
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