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1.
J Am Coll Cardiol ; 76(15): 1777-1794, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33032740

RESUMO

Viral respiratory infections are risk factors for cardiovascular disease (CVD). Underlying CVD is also associated with an increased risk of complications following viral respiratory infections, including increased morbidity, mortality, and health care utilization. Globally, these phenomena are observed with seasonal influenza and with the current coronavirus disease 2019 (COVID-19) pandemic. Persons with CVD represent an important target population for respiratory virus vaccines, with capacity developed within 3 large ongoing influenza vaccine cardiovascular outcomes trials to determine the potential cardioprotective effects of influenza vaccines. In the context of COVID-19, these international trial networks may be uniquely positioned to redeploy infrastructure to study therapies for primary and secondary prevention of COVID-19. Here, we describe mechanistic links between influenza and COVID-19 infection and the risk of acute cardiovascular events, summarize the data to date on the potential cardioprotective effects of influenza vaccines, and describe the ongoing influenza vaccine cardiovascular outcomes trials, highlighting important lessons learned that are applicable to COVID-19.


Assuntos
Doenças Cardiovasculares , Infecções por Coronavirus , Vacinas contra Influenza/farmacologia , Influenza Humana , Pandemias , Pneumonia Viral , Betacoronavirus , Cardiotônicos/farmacologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Humanos , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Saúde Pública , Fatores de Risco , Vacinação/métodos
2.
Int J Nanomedicine ; 15: 4859-4876, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764923

RESUMO

Introduction: CoenzymeQ10 (CoQ10) is a well-known antioxidant and anti-inflammatory agent with cardioprotective properties. However, clinical trials based on its oral administration have failed to provide significant effect on cardiac functionality. The main limitation of CoQ10 is based on its very low oral bioavailability and instability that limit dramatically its effects as a cardioprotective agent. Herein, we loaded CoQ10 in high bioavailable nano-emulsions (NEs) coated with chitosan or chitosan and hyaluronic acid in order to improve its performance. Methods: We tested cardioprotective and hepatoprotective effects of CoQ10-loaded nano-carriers against Doxorubicin and Trastuzumab toxicities in cardiomyocytes and liver cells through analysis of cell viability, lipid peroxidation, expression of leukotrienes, p65/NF-kB and pro-inflammatory cytokines involved in anticancer-induced cardio and hepatotoxicity. Results: Nano-carriers showed high stability and loading ability and increased cell viability both in hepatocytes and cardiomyocytes during anticancer treatments. We observed that these effects are mediated by the inhibition of lipid peroxidation and reduction of the inflammation. CoQ10-loaded nano-emulsions showed also strong anti-inflammatory effects reducing leukotriene B4 and p65/NF-κB expression and Interleukin 1ß and 6 production during anticancer treatments. Discussion: Anthracyclines and Human epidermal growth factor receptor (HER2) inhibitors have shown significant anticancer effects in clinical practice but their use is characterized by cardiotoxicity and hepatotoxicity. Nano-carriers loaded with CoQ10 showed cardio and hepatoprotective properties mediated by reduction of oxidative damages and pro-inflammatory mediators. These results set the stage for preclinical studies of cardio and hepatoprotection in HER2+ breast cancer-bearing mice treated with Doxorubicin and Trastuzumab.


Assuntos
Antraciclinas/efeitos adversos , Fígado/citologia , Miócitos Cardíacos/efeitos dos fármacos , Nanoestruturas/química , Trastuzumab/efeitos adversos , Ubiquinona/análogos & derivados , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Cápsulas , Cardiotônicos/química , Cardiotônicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Feminino , Hepatócitos/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Ubiquinona/química , Ubiquinona/farmacologia
3.
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
4.
Med Hypotheses ; 143: 110112, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32721806

RESUMO

In coronavirus disease-19 (COVID-19), four major factors have been correlated with worse prognosis: aging, hypertension, obesity, and exposure to androgen hormones. Angiotensin-converting enzyme-2 (ACE2) receptor, regulation of the renin-angiotensin-aldosterone system (RAAS), and transmembrane serine protease 2 (TMPRSS2) action are critical for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry and infectivity. ACE2 expression and RAAS are abnormal in hypertension and obesity, while TMPRSS2 is overexpressed when exposed to androgens, which may justify why these factors are overrepresented in COVID-19. Among therapeutic targets for SARS-CoV-2, we hypothesized that spironolactone, a long used and safe mineralocorticoid and androgen receptors antagonist, with effective anti-hypertensive, cardioprotective, nephroprotective, and anti-androgenic properties may offer pleiotropic actions in different sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balances membrane-attached and free circulating ACE2 and between angiotensin II and Angiotensin-(1-7) (Ang-(1-7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may provide protection from SARS-CoV-2, and has sufficient plausibility to be clinically tested, particularly in the early stages of COVID-19.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Androgênios/fisiologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Espironolactona/uso terapêutico , Antagonistas de Androgênios/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Indução Enzimática/efeitos dos fármacos , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Obesidade/complicações , Obesidade/fisiopatologia , Peptidil Dipeptidase A/biossíntese , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Prognóstico , Receptores Virais/efeitos dos fármacos , Fatores de Risco , Serina Endopeptidases/efeitos dos fármacos , Distribuição por Sexo , Espironolactona/farmacologia , Internalização do Vírus/efeitos dos fármacos
5.
Ann Biol Clin (Paris) ; 78(3): 253-260, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32420888

RESUMO

Elevated circulating leptin levels have been associated with an increased cardiovascular risk in humans. However, recent meta-analyses show that certain epidemiological studies did not find this association, suggesting distinct effects of leptin depending on the pathophysiological context. Studies performed in mice deficient in leptin or in leptin receptors are often contradictory, showing both protective and deleterious effects of leptin. These effects appear to vary depending on the genetic background of the animal and the doses of leptin administered, making interpretation of the results difficult. In humans, elevated adiponectinemia is associated with a favourable cardiovascular risk profile. Adiponectin exerts protective effects at all stages of development of atherosclerotic plaque. However, our knowledge of the pathophysiological mechanisms involved in these protective effects has been established from cellular models, which do not necessarily reproduce the pathology in all its complexity. In addition, mouse models have a very different lipoprotein metabolism from humans, which does not always allow extrapolation of results to humans. Finally, epidemiological studies evaluating adiponectin as a marker of cardiovascular risk show paradoxical results since a high serum adiponectin concentration has not been associated with a reduction in the number of cardiovascular events but with an increase of cardiovascular and all causes mortality in healthy subjects and coronary patients. These observations illustrate the paradox of adipokines actions and show the complexity to use these biomarkers in cardiovascular diseases. Resistance to the action of these adipokines is one of the hypotheses put forward to explain these discrepancies.


Assuntos
Adiponectina/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Leptina/farmacologia , Adiponectina/fisiologia , Animais , Biomarcadores/sangue , Cardiotônicos/farmacologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Sistema Cardiovascular/fisiopatologia , Humanos , Leptina/fisiologia , Camundongos , Fatores de Risco
6.
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
7.
Life Sci ; 254: 117759, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32389830

RESUMO

OBJECTIVE: Metformin, introduced in 1957, is widely used as an anti-diabetic drug and has considerable benefits in cardiovascular disease reportedly, dependent or independent on its glucose-lowering effects. Aim of this study was to investigate the effect of metformin on gap junction and the inducibility of AF. METHODS: Beagle dogs were subjected to acute or chronic pacing at right atrial appendage by a pacemaker to develop an AF model and electrophysiological parameters were measured. In vitro study, a cell fast pacing model was developed by CardioExcyte 96. We performed Western blot, histology immunohistochemical staining and electron microscopy to detect the effect of metformin. RESULTS: In chronic AF model, the inducibility and duration of AF increased obviously after pacing for 6 weeks compared with sham-operated group (Inducibility, 3.33 ±â€¯5.77 vs. 85.33 ±â€¯7.89%, P<0.0001; Duration, 0.8 ±â€¯0.84 vs. 11 ±â€¯2.67 ms, P<0.0001). Effective refractory periods (ERP) decreased at left and right left atrium and atrial appendages compared with sham-operated group (123.95 ±â€¯6.57 vs. 89.96 ±â€¯7.39 ms P<0.0001). Metformin attenuated the pacing-induced increase in EPR (89.96 ±â€¯7.39 vs. 105.83 ±â€¯7.45 ms, P<0.05), AF inducibility and AF duration (Inducibility, 85.33 ±â€¯7.89 vs. 64.17 ±â€¯7.36%, Duration, 11 ±â€¯2.67 vs. 8.62 ±â€¯1.15 ms, P<0.05). The expression of Cx43 shows a significant downregulation(about 38%, P<0.001) after chronic pacing and treating with metformin could alleviate this decrease(P<0.01). However, the effect of metformin in acute pacing model is limited. The immunohistochemical staining of cardiac tissue also shown that there is more lateralized Cx43 under pacing condition (87.67 ±â€¯2.52 vs. 60.8 ±â€¯9.13%, P<0.005). These pacing-induced lateralize Cx43 could be alleviated by the metformin (48.4 ±â€¯8.62 vs. 60.8 ±â€¯9.13%, P<0.05). Additionally, metformin could affect the interactions of ZO-1 with p-Src/Cx43 via decrease the abnormal cAMP level after pacing (84.04 ±â€¯4.58 vs. 69.34 ±â€¯4.5 nmol/L, P<0.001). CONCLUSIONS: Metformin could alleviate the vulnerability of AF and attenuate the downregulation of gap junction under pacing condition via AMPK pathway and decreasing the P-Src level.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Cardiotônicos/metabolismo , Metformina/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Estimulação Cardíaca Artificial/métodos , Cardiotônicos/farmacologia , Conexina 43/metabolismo , Modelos Animais de Doenças , Cães , Junções Comunicantes/efeitos dos fármacos , Átrios do Coração/metabolismo , Masculino , Taquicardia/fisiopatologia
8.
Toxicol Appl Pharmacol ; 399: 115038, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32417440

RESUMO

The cardiotoxicity caused by doxorubicin and extravasation injury caused by anthracyclines is reduced by the clinically approved bisdioxopiperazine drug dexrazoxane. Dexrazoxane is a rings-closed analog of EDTA and is hydrolyzed in vivo to a form that strongly binds iron. Its protective effects were originally thought to be due to the ability of its metabolite to remove iron from the iron-doxorubicin complex, thereby preventing oxygen radical damage to cellular components. More recently it has been suggested that dexrazoxane may exert its protective effects by inhibiting topoisomerase IIß in the heart and inducing a reduction in its protein levels through induction of proteasomal degradation. The ability of dexrazoxane, other bisdioxopiperazines, and mitindomide to protect against doxorubicin-induced damage was determined in primary neonatal rat myocytes. This QSAR study showed that the protection that a series of bisdioxopiperazine analogs of dexrazoxane and the bisimide mitindomide offered against doxorubicin-induced myocyte damage was highly correlated with the ability of these compounds to catalytically inhibit the decatenation activity of topoisomerase II. The structural features of the dexrazoxane analogs that contribute to the binding and inhibition of topoisomerase II have been identified. These results suggest that the inhibition of topoisomerase II in myocytes by dexrazoxane is central to its role in its activity as an anthracycline cardioprotective agent. Additionally, sequence identity analysis of the amino acids surrounding the dexrazoxane binding site showed extremely high identity, not only between both invertebrate topoisomerase II isoforms, but also with yeast topoisomerase II as well.


Assuntos
Cardiotônicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Dexrazoxano/farmacologia , Doxorrubicina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Antraciclinas/farmacologia , Feminino , Isoindóis/farmacologia , Masculino , Miócitos Cardíacos/metabolismo , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Sprague-Dawley
9.
J Cardiothorac Surg ; 15(1): 108, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448319

RESUMO

BACKGROUND: Patients with moderate-severe systolic dysfunction undergoing coronary artery bypass graft have a higher incidence of postoperative low cardiac output. Preconditioning with levosimendan may be a useful strategy to prevent this complication. In this context, design cost-effective strategies like preconditioning with levosimendan may become necessary. METHODS: In a sequential assignment of patients with Left Ventricle Ejection Fraction less than 40%, two strategies were compared in terms of cost-effectiveness: standard care (n = 41) versus preconditioning with Levosimendan (n = 13). The adverse effects studied included: postoperative new-onset atrial fibrillation, low cardiac output, renal failure and prolonged mechanical ventilation. The costs were evaluated using deterministic and probabilistic sensitivity analysis, and Monte Carlo simulations were performed. RESULTS: Preconditioning with levosimendan in moderate to severe systolic dysfunction (Left Ventricle Ejection Fraction < 40%), was associated with a lower incidence of postoperative low cardiac output in elective coronary artery bypass graft surgery 2(15.4%) vs 25(61%) (P < 0.01) and lesser intensive care unit length of stay 2(1-4) vs 4(3-6) days (P = 0.03). Average cost on levosimendan group was 14,792€ while the average cost per patient without levosimendan was 17,007€. Patients with no complications represented 53.8% of the total in the levosimendan arm, as compared to 31.7% in the non-levosimendan arm. In all Montecarlo simulations for sensitivity analysis, use of levosimendan was less expensive and more effective. CONCLUSIONS: Preconditioning with levosimendan, is a cost-effective strategy preventing postoperative low cardiac output in patients with moderate-severe left ventricular systolic dysfunction undergoing elective coronary artery bypass graft surgery.


Assuntos
Baixo Débito Cardíaco/prevenção & controle , Ponte de Artéria Coronária/efeitos adversos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Simendana/farmacologia , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Idoso , Baixo Débito Cardíaco/epidemiologia , Baixo Débito Cardíaco/etiologia , Cardiotônicos/farmacologia , Ponte de Artéria Coronária/economia , Doença da Artéria Coronariana/cirurgia , Análise Custo-Benefício , Feminino , Humanos , Incidência , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Espanha/epidemiologia , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
10.
Medicine (Baltimore) ; 99(20): e20135, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443326

RESUMO

BACKGROUND: Although patients with coronary artery disease (CAD) rely increasingly upon percutaneous coronary intervention (PCI), this therapy causes subsequent the complications of myocardial injury. Acupuncture safely protects the heart from ischemic injury; however, the efficacy of acupuncture for periprocedural myocardial injury after PCI remains unclear. METHODS: Seven databases in English and Chinese including PubMed, Web of Science, Cochrane Library, Embase, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, and Wanfang Database will be searched. Randomized controlled trials (RCTs) that use acupuncture to treat PCI-related myocardial injury in patients with CAD, regardless of blinding. The crossover randomized trials will be included, but only the pre-crossover data will be analyzed to avoid carryover effects. We will exclude non-RCTs, qualitative studies, uncontrolled clinical trials, and laboratory studies. The measurement of concentration of cardiac troponin (T or I) and MB isoenzyme of creatine kinase will be used as primary outcome. Postprocedural cardiac function and the major adverse cardiac/cerebrovascular event rate will be assessed as secondary outcome. Relevant data were collected independently by 2 reviewers and the third reviewer was responsible for resolving discrepancies through discussion. The Review Manager V.5.3.3 s will be used to perform the data synthesis and subgroup analysis. DISCUSSION: This systematic review and meta-analysis would provide convincing evidence of various types of acupuncture that specifically focuses on cardioprotective effect of acupuncture on PCI-related myocardial injury. REGISTRATION: Open Science Framework (OSF) registries (osf.io/n2e6t) with the registration DOI: 10.17605/OSF.IO/79H2E.


Assuntos
Terapia por Acupuntura/métodos , Doença da Artéria Coronariana/terapia , Isquemia Miocárdica/terapia , Intervenção Coronária Percutânea/efeitos adversos , Terapia por Acupuntura/estatística & dados numéricos , Cardiotônicos/farmacologia , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/patologia , Creatina Quinase Forma MB/sangue , Humanos , Isquemia Miocárdica/sangue , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/prevenção & controle , Intervenção Coronária Percutânea/métodos , Período Perioperatório , Ensaios Clínicos Controlados Aleatórios como Assunto , Sensibilidade e Especificidade , Troponina/sangue
11.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276406

RESUMO

Ramelteon is a Melatonin 1 (MT1)-and Melatonin 2 (MT2)-receptor agonist conferring cardioprotection by pharmacologic preconditioning. While activation of mitochondrial calcium-sensitive potassium (mKCa)-channels is involved in this protective mechanism, the specific upstream signaling pathway of Ramelteon-induced cardioprotection is unknown. In the present study, we (1) investigated whether Ramelteon-induced cardioprotection involves activation of protein kinase G (PKG) and/or protein kinase B (Akt) and (2) determined the precise sequence of PKG and Akt in the signal transduction pathway of Ramelteon-induced preconditioning. Hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia, hearts were perfused with Ramelteon (Ram) with or without the PKG or Akt inhibitor KT5823 and MK2206, respectively (KT5823 + Ram, KT5823, MK2206 + Ram, MK2206). To determine the precise signaling sequence, subsequent experiments were conducted with the guanylate cyclase activator BAY60-2770 and the mKCa-channel activator NS1619. Infarct size was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Ramelteon-induced infarct size reduction was completely blocked by KT5823 (p = 0.0012) and MK2206 (p = 0.0005). MK2206 with Ramelteon combined with BAY60-2770 reduced infarct size significantly (p = 0.0014) indicating that PKG activation takes place after Akt. Ramelteon and KT5823 (p = 0.0063) or MK2206 (p = 0.006) respectively combined with NS1619 also significantly reduced infarct size, indicating that PKG and Akt are located upstream of mKCa-channels. This study shows for the first time that Ramelteon-induced preconditioning (1) involves activation of PKG and Akt; (2) PKG is located downstream of Akt and (3) both enzymes are located upstream of mKCa-channels in the signal transduction pathway.


Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Coração/efeitos dos fármacos , Indenos/farmacologia , Precondicionamento Isquêmico Miocárdico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Cardiotônicos/farmacologia , Masculino , Infarto do Miocárdio , Miocárdio/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais
12.
Basic Res Cardiol ; 115(3): 24, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32140789

RESUMO

Intramyocardial hemorrhage is an independent predictor of adverse outcomes in ST-segment elevation myocardial infarction (STEMI). Iron deposition resulting from ischemia-reperfusion injury (I/R) is pro-inflammatory and has been associated with adverse remodeling. The role of iron chelation in hemorrhagic acute myocardial infarction (AMI) has never been explored. The purpose of this study was to investigate the cardioprotection offered by the iron-chelating agent deferiprone (DFP) in a porcine AMI model by evaluating hemorrhage neutralization and subsequent cardiac remodeling. Two groups of animals underwent a reperfused AMI procedure: control and DFP treated (N = 7 each). A comprehensive MRI examination was performed in healthy state and up to week 4 post-AMI, followed by histological assessment. Infarct size was not significantly different between the two groups; however, the DFP group demonstrated earlier resolution of hemorrhage (by T2* imaging) and edema (by T2 imaging). Additionally, ventricular enlargement and myocardial hypertrophy (wall thickness and mass) were significantly smaller with DFP, suggesting reduced adverse remodeling, compared to control. The histologic results were consistent with the MRI findings. To date, there is no effective targeted therapy for reperfusion hemorrhage. Our proof-of-concept study is the first to identify hemorrhage-derived iron as a therapeutic target in I/R and exploit the cardioprotective properties of an iron-chelating drug candidate in the setting of AMI. Iron chelation could potentially serve as an adjunctive therapy in hemorrhagic AMI.


Assuntos
Cardiotônicos/farmacologia , Deferiprona/uso terapêutico , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Quelantes de Ferro/uso terapêutico , Infarto do Miocárdio/complicações , Miocárdio/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Cardiotônicos/farmacocinética , Cardiotônicos/uso terapêutico , Deferiprona/farmacocinética , Deferiprona/farmacologia , Modelos Animais de Doenças , Feminino , Hemorragia/patologia , Quelantes de Ferro/farmacocinética , Quelantes de Ferro/farmacologia , Infarto do Miocárdio/patologia , Suínos
13.
Adv Clin Chem ; 95: 219-243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32122524

RESUMO

The main function of blood platelets is to form hemostatic plugs and enable thrombosis. These properties, however, can be greatly influenced by dietary components which may inhibit certain steps of platelet activation, including platelet aggregation. Such inhibition can play a role in the prophylaxis and treatment of cardiovascular diseases associated with blood platelet hyperactivation. In fact, plant and fish oils have been identified and specifically used for this purpose. Numerous in vivo and in vitro experiments have explored the potential use of these oils to inhibit platelet activation as well as their role in reducing oxidative stress and blood pressure, and lowering triglyceride and cholesterol. This chapter presents and compares the anti-platelet effects of fish and plant oils and their constituents, especially fatty acids. Studies on healthy subjects and patients with various cardiovascular diseases are also examined. Findings indicate that both fish and plant oils contain protective components with anti-platelet activity having clearly defined mechanisms of action. Although both are excellent sources of omega fatty acids and vitamins, plant oils contain components with cardioprotective benefit in hypercholesterolemics, i.e., phytosterols. Plant oils may hence play a key role in strategies for preventing and treating cardiovascular diseases associated with platelet hyperactivation. Further studies are clearly needed to determine the precise dose of these components needed for effective prophylaxis and treatment.


Assuntos
Plaquetas/efeitos dos fármacos , Cardiotônicos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Óleos Vegetais/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Animais , Humanos
14.
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
15.
Adv Pharmacol ; 87: 179-203, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089233

RESUMO

Icariin (ICA) is a principal active component from traditional Chinese medicine Epimedium grandiflorum. To explain its traditional medical usages by modern science, a variety of pharmacological effects have been studied for ICA. In this review, we summarized the pharmacokinetics of ICA as well as its pharmacological mechanisms in neurodegenerative disease, cardiovascular disease, anti-osteoporosis, anti-inflammation, anti-oxidative stress, anti-depression and anti-tumors.


Assuntos
Flavonoides/farmacologia , Animais , Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Flavonoides/química , Flavonoides/farmacocinética , Flavonoides/uso terapêutico , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos
16.
Open Vet J ; 9(4): 375-383, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32042661

RESUMO

Background: Left atrial (LA) function is an important determinant of the left ventricular (LV) filling, playing a key role in maintaining optimal cardiac performance. Pimobendan is a phosphodiesterase III inhibitor with positive inotropic and vasodilator effects. The present study aims to investigate the effects of pimobendan on LA function in dogs with stage B2 myxomatous mitral valve disease (MMVD). Aim: The aim of this investigation was to study the effects of pimobendan on LA function in dogs with preclinical MMVD. Methods: Twenty-seven dogs with stage B2 MMVD were retrospectively included. LA function was assessed before and 1-6 months following pimobendan initiation. For each dog, two-dimensional (2D) echocardiography was performed to assess LA diameter and volume for each phase of the LA cycle and to assess complete, passive, and active LA function. Pulsed-wave tissue Doppler imaging (TDI) of the left ventricular longitudinal myocardial velocity associated with atrial contraction (A'), both at the level of the interventricular septum and the LV free wall, was also used as an indicator of LA function. Results: There were no significant differences in any of the left atrial variables pre- and posttreatment. Conclusion: Echocardiographic estimates of LA function by 2D diameters and volumes and TDI A' in dogs with MMVD do not change after treatment with pimobendan.


Assuntos
Função do Átrio Esquerdo/efeitos dos fármacos , Doenças do Cão/tratamento farmacológico , Doenças das Valvas Cardíacas/veterinária , Piridazinas/farmacologia , Vasodilatadores/farmacologia , Animais , Cardiotônicos/farmacologia , Cães , Feminino , Doenças das Valvas Cardíacas/tratamento farmacológico , Masculino , Inibidores de Fosfodiesterase/farmacologia
17.
Int J Nanomedicine ; 15: 1101-1115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110010

RESUMO

Background: The clinical use of doxorubicin (DOX) is severely limited due to its cardiotoxicity. Thus, there is a need for prophylactic and treatment strategies against DOX-induced cardiotoxicity. Purpose: The purpose of this study was to develop a liquiritigenin-loaded submicron emulsion (Lq-SE) with enhanced oral bioavailability and to explore its efficacy against DOX-induced cardiotoxicity. Methods: Lq-SE was prepared using high-pressure homogenization and characterized using several analytical techniques. The formulation was optimized by central composite design response surface methodology (CCD-RSM). In vivo pharmacokinetic studies, biochemical analyses, reactive oxygen species (ROS) assays, histopathologic assays, and Western blot analyses were performed. Results: Each Lq-SE droplet had a mean particle size of 221.7 ± 5.80 nm, a polydispersity index (PDI) of 0.106 ± 0.068 and a zeta potential of -28.23 ± 0.42 mV. The area under the curve (AUC) of Lq-SE was 595% higher than that of liquiritigenin (Lq). Lq-SE decreased the release of serum cardiac enzymes and ameliorated histopathological changes in the hearts of DOX-challenged mice. Lq-SE significantly reduced oxidative stress by adjusting the levels of ROS, increasing the activity of antioxidative enzymes and inhibiting the protein expression of NOX4 and NOX2. Furthermore, Lq-SE significantly improved the inflammatory response through the mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signalling pathway and induced cardiomyocyte apoptosis. Conclusion: Lq-SE could be used as an effective cardioprotective agent against DOX in chemotherapy to enable better treatment outcomes.


Assuntos
Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Emulsões/química , Flavanonas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Cardiotônicos/farmacologia , Cardiotoxicidade/metabolismo , Emulsões/administração & dosagem , Feminino , Flavanonas/administração & dosagem , Flavanonas/farmacocinética , Coração/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
18.
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
19.
Mol Immunol ; 120: 61-66, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32078859

RESUMO

Myocardial infarction (MI) or heart attack is a deadly event with high prevalence. In the present study, we investigated the effects of the polypeptide copolymer glatiramer acetate (GA) in H9c2 rat cardiomyocytes exposed to oxygen-glucose deprivation/reperfusion injury. Immediately following MI, an acute inflammatory response is triggered that causes activation of various proinflammatory cytokines, infiltration of immune cells, and neovascularization. This response is largely mediated by some genes such as TNF-α, IL-6, ICAM-1, and VEGF. Additionally, the rapid influx of oxidants, such as reactive oxygen species (ROS), leads to a harmful state of oxidative stress. Here, we found that GA could reduce OGD/R-induced inflammation and oxidative stress by inhibiting the expression of TNF-α, IL-6, ICAM-1, and VEGF, and suppressing the production of ROS via reduced NADPH oxidase 1 (NOX1) expression. To elucidate the pathways involved in these promising results, we took a close look at the impact of the endothelial growth response-1 (Egr-1), a transcriptional factor recognized as a mediator of MI-related inflammation and cellular injury. Using siRNA for Egr-1, we found that GA could reduce the expression of ICAM-1 and VEGF by inhibiting Egr-1 expression. Together, our findings indicate a novel therapeutic potential of GA in the treatment of MI.


Assuntos
Cardiotônicos/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Acetato de Glatiramer/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Animais , Linhagem Celular , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Glucose/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
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