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1.
Artigo em Inglês | MEDLINE | ID: mdl-31923049

RESUMO

Longstanding aspirin is the cornerstone to prevent recurrence of thrombotic events in patients with ischemic heart disease. However, clopidogrel, a more potent antiplatelet agent, is preferred over aspirin in targeted populations including those with high risk of gastrointestinal bleeding. In addition, clopidogrel offers superior oral-tolerance and it may reduce the rates of intracranial hemorrhages as compared to aspirin. On the other hand, an extensive inhibition of coagulation cascade appears to be reasonable to minimize thrombotic events in such patients. After several failed exploratory investigations in the past with vitamin K antagonists, the newest direct oral anticoagulants may represent an alternative. In order to counterbalance bleeding complications, a low dose of these agents should be considered. Few publications have already showed promising results with the combination of clopidogrel and low-dose DOACs. Further investigations should be addressed to elucidate whether or not this is the downfall of the aspirin era for secondary prevention of atherosclerotic cardiovascular events.

3.
4.
Int J Mol Sci ; 20(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277431

RESUMO

The sodium-glucose cotransporter (SGLT) inhibitors represent a new alternative for treating patients with diabetes mellitus. They act primarily by inhibiting glucose reabsorption in the renal tubule and therefore, decreasing blood glucose levels. While little is yet known about SGLT subtype 1, SGLT2 inhibitors have demonstrated to significantly reduce cardiovascular mortality and heart failure hospitalizations. This cardioprotective benefit seems to be independent of their glucose-lowering properties; however, the underlying mechanism(s) remains still unclear and numerous hypotheses have been postulated to date. Moreover, preclinical research has suggested an important role of SGLT1 receptors on myocardial ischemia. Following acute phase of cardiac injury there is an increased activity of SGLT1 cotransport that ensures adequate energy supply to the cardiac cells. Nonetheless, a long-term upregulation of this receptor may not be that beneficial and whether its inhibition is positive or not should be further addressed. This review aims to present the most cutting-edge insights into SGLT receptors.


Assuntos
Miocárdio/metabolismo , Proteínas de Transporte de Sódio-Glucose/antagonistas & inibidores , Animais , Metabolismo Energético , Humanos , Modelos Biológicos , Resultado do Tratamento
5.
J Am Coll Cardiol ; 73(15): 1931-1944, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30999996

RESUMO

BACKGROUND: Empagliflozin cardiac benefits in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial cannot be explained exclusively by its antihyperglycemic activity. OBJECTIVES: The hypothesis was that empagliflozin's cardiac benefits are mediated by switching myocardial fuel metabolism away from glucose toward ketone bodies (KB), which improves myocardial energy production. METHODS: Heart failure was induced in nondiabetic pigs (n = 14) by 2-h balloon occlusion of the proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Animals were evaluated with cardiac magnetic resonance imaging and 3-dimensional echocardiography. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus. Myocardial samples were obtained for molecular evaluation. Nonmyocardial infarction animals served as comparison. RESULTS: Despite similar initial ischemic myocardial injury in both groups, the empagliflozin group showed amelioration of adverse remodeling at 2 months (lower left ventricular [LV] mass, reduced LV dilatation, less LV sphericity) versus the control group. LV systolic function (LV ejection fraction and echocardiography-derived strains) was improved, as was neurohormonal activation. Compared with nonmyocardial infarction, control animals increased myocardial glucose consumption mainly through anaerobic glycolysis while reducing utilization of free fatty acid (FFA) and branched-chain amino acid (BCAA). Empagliflozin-treated pigs did not consume glucose (reduction in myocardial glucose uptake, and glucose-related enzymes) but instead switched toward utilization of KB, FFA, and BCAA (increased myocardial uptake of these 3 metabolites, and enhanced expression/activity of the enzymes implicated in the metabolism of KB/FFA/BCAA). Empagliflozin increased myocardial ATP content and enhanced myocardial work efficiency. CONCLUSIONS: Empagliflozin ameliorates adverse cardiac remodeling and heart failure in a nondiabetic porcine model. Empagliflozin switches myocardial fuel utilization away from glucose toward KB, FFA, and BCAA, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling.

7.
Expert Opin Drug Metab Toxicol ; 15(4): 275-285, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30822172

RESUMO

INTRODUCTION: Cardiac metabolism represents a complex network of numerous pathways responsible for an adequate supply of ATP to the incessant contractile apparatus. Impairments of such pathways are associated with myocardial dysfunction. The newest antidiabetic drugs, the SGLT2 inhibitors, have been demonstrated to reduce cardiovascular mortality and heart failure hospitalizations. The mechanisms underlying these benefits are still uncertain; however, they may play a decisive role in restoring energy efficiency to the damaged heart. Areas covered: This article reviews normal cardiac metabolism and contribution of different substrates to fuel supply. Specific attention is devoted to alterations of these pathways and their association with myocardial dysfunction. In addition, the impact of the novel SGLT2 inhibitors on cardiac mortality and heart failure hospitalizations is discussed. Various postulated mechanisms responsible for such benefits are also discussed. Expert opinion: Metabolic alterations seem to play a crucial role in etiology and progression of heart failure. The cardiovascular benefits of the novel SGLT2 inhibitors have attracted more attention to this field. With effects beyond lowering glucose levels, these agents have been reported to induce changes in cardiac metabolism and to exert anti-inflammatory properties that may contribute to their large cardiovascular beneficial effects by improving contractile bioenergetics. Therefore, SGLT2 inhibitors may become an alternative drug to treat heart failure patients, regardless of diabetic status.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus/tratamento farmacológico , Progressão da Doença , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hospitalização/estatística & dados numéricos , Humanos , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
8.
Cardiovasc Drugs Ther ; 33(1): 87-95, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30675708

RESUMO

The SGLT2 inhibitor empagliflozin reduced cardiovascular mortality by 38% and heart failure (HF) hospitalizations by 35% in diabetic patients. We have recently demonstrated the efficacy of empagliflozin in ameliorating HF and improving cardiac function in a non-diabetic porcine model of HF mediated via a switch in myocardial metabolism that enhances cardiac energetics. Therefore, we hypothesized that the cardiac benefits of empagliflozin can also be extended to non-diabetic HF patients. The EMPA-TROPISM clinical trial is a randomized, double-blind, parallel group, placebo-controlled, trial comparing the efficacy of and safety of empagliflozin in non-diabetic HF patients. Eighty patients with stable HF for over 3 months, LVEF < 50%, and New York Heart Association functional class II to IV symptoms will be randomized to empagliflozin 10 mg for 6 months or placebo. All patients will undergo cardiac magnetic resonance (CMR), cardiopulmonary exercise test (CPET), 6-min walk test, and quality of life questionnaires. The primary outcome is the change in left ventricular end-diastolic volume measured by CMR. Secondary end-points include change in peak VO2 (CPET); change in LV mass, in LVEF, in myocardial mechanics (strains), in left atrium volumes, in RV function and volumes, in interstitial myocardial fibrosis, and in epicardial adipose tissue (CMR); change in the distance in the 6-min walk test; and changes in quality of life (Kansas Cardiomyopathy questionnaire [KCCQ-12] and the 36-Item Short Form Survey [SF-36]). Safety issues (e.g., hypoglycemia, urinary infections, ketoacidosis,…) will also be monitored. In summary, EMPA-TROPISM clinical trial will determine whether the SGLT2 inhibitor empagliflozin improves cardiac function and heart failure parameters in non-diabetic HF patients (EMPA-TROPISM [ATRU-4]: Are the "cardiac benefits" of Empagliflozin independent of its hypoglycemic activity; NCT 03485222).


Assuntos
Compostos Benzidrílicos/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Glucosídeos/efeitos adversos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Cidade de Nova Iorque , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , Teste de Caminhada
11.
Expert Opin Drug Metab Toxicol ; 14(12): 1287-1302, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30463454

RESUMO

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder associated with high cardiovascular (CV) risk. Some of the therapeutic strategies are contraindicated in patients with concomitant heart disease. However, the newest antidiabetic medications, sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown to significantly reduce CV mortality and heart failure (HF) hospitalizations. The mechanism behind these surprising cardiac benefits remains unclear. Areas covered: This article reviews the pharmacokinetic, pharmacodynamics, efficacy, and safety data for the different SGLT2 inhibitors. Specific attention is devoted to the postulated mechanisms of action for their benefit. The therapeutic efficacy and potential use in different indications outside T2DM such as HF, T1DM, and renal disease are also discussed. Expert opinion: SGLT2 inhibitors have an excellent pharmacokinetic and pharmacodynamic profile. Importantly, SGLT2 inhibitors are a safe and efficacious treatment option for T2DM. Given their cardiac benefits (reduction in HF and death) and the low incidence of adverse events, SGLT2 inhibitors are being currently studied as a treatment for HF also in nondiabetic individuals. These agents seem to represent a shift in the treatment of HF patients regardless their glycemic profile.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Hospitalização/estatística & dados numéricos , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
12.
Methods Mol Biol ; 1816: 161-171, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29987818

RESUMO

The Badimon perfusion chamber is an ex vivo model of thrombosis that assesses the thrombogenicity of blood in humans and large animals. It works with native blood thereby excluding any interfering effects of anticoagulants unavoidable with the majority of platelet function testing methodologies. Each variable of the Virchow's triad (blood, blood flow, and endothelial wall) that modulates blood-vessel wall interaction and thrombus formation is incorporated in this perfusion model. These features make this device a valuable tool for the assessment of thrombogenic potential of various diseases and also gauging the efficacy of antithrombotic (anticoagulant and antiplatelet) treatments.


Assuntos
Aorta/patologia , Plaquetas/patologia , Perfusão/métodos , Trombose/patologia , Animais , Anticoagulantes/farmacologia , Aorta/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo , Plaquetas/efeitos dos fármacos , Desenho de Equipamento , Humanos , Processamento de Imagem Assistida por Computador/métodos , Microscopia/métodos , Microtomia/métodos , Perfusão/instrumentação , Inibidores da Agregação de Plaquetas/farmacologia , Coloração e Rotulagem/métodos , Suínos , Trombose/tratamento farmacológico , Inclusão do Tecido/métodos
14.
Cardiovasc Drugs Ther ; 32(2): 213-222, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29679303

RESUMO

Type 2 diabetes mellitus (T2DM) is one of the most common chronic health conditions in the USA; it affects approximately 10% of adults with up to one-quarter being undiagnosed. T2DM is associated with substantial cardiovascular (CV) morbidity and mortality. T2DM is a pathological condition characterized by elevated levels of glucose and associated with high CV risk. Traditional hypoglycemic drugs have demonstrated their capability for effective and maintained management of high glucose levels, but they have not significantly impacted on the incidence of CV events. Recently, a new class of hypoglycemic agents, SGLT-2 receptor inhibitors, has been developed. The EMPA-OUTCOME trial involving empagliflozin (a SGLT-2 receptor inhibitor) has shown significant reductions in major adverse cardiac events (MACEs), cardiovascular mortality, and hospitalization for heart failure (HF) when administered on top of standard-of-care therapy for T2DM patients at high CV risk. The dramatic change driving the superiority of the primary composite outcome (major adverse CV events) was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35 and 32% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively. These effects are even more important given the difficulties for treating concomitant HF in T2DM patients. These surprising results have been also corroborated by another agent of this class, canagliflozin, and the CANVAS trial. The magnitude of these somehow surprising cardiac benefits attained in the absence of major differences in glycemic, lipid, or blood pressure (BP) control has led to several groups to suggest that these benefits may be independent of its hypoglycemic activity and whether this new class could be considered a "cardiac" drug. The objective of this review has been to review the different hypotheses proposed to explain the cardiac benefits of this new class of antidiabetic drugs.


Assuntos
Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
15.
Int J Cardiovasc Imaging ; 34(2): 171-175, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28735413

RESUMO

The diagnostic role of echocardiographic and hemodynamic assessment in acute mitral regurgitation (AMR) remains unclear. The central question of this study was to determine if echocardiographic and hemodynamic parameters can predict early clinical events in AMR. AMR was induced by percutaneously severing the mitral valve chordae tendineae in 39 Yorkshire pigs. Immediately after AMR induction, echocardiographic and hemodynamic exams were performed, and compared between those who died and those who survived within 30-days of the procedure. Echocardiographic indices of MR severity as well as the left atrial pressure showed significant differences between survivors and non-survivors in univariate analysis. Multi-variate logistic regression analysis revealed that echocardiography-derived regurgitant fraction and vena contracta as well as mean left atrial pressure could be used to segment the cohort into survivors and non-survivors. Our study demonstrated, for the first time, that echocardiographic and hemodynamic assessment of AMR provides predictive information on early clinical events in a clinically relevant animal model of AMR.


Assuntos
Ecocardiografia Doppler em Cores , Hemodinâmica , Insuficiência da Valva Mitral/diagnóstico por imagem , Valva Mitral/diagnóstico por imagem , Doença Aguda , Animais , Função do Átrio Esquerdo , Pressão Atrial , Modelos Animais de Doenças , Progressão da Doença , Feminino , Modelos Logísticos , Masculino , Valva Mitral/fisiopatologia , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/fisiopatologia , Análise Multivariada , Razão de Chances , Valor Preditivo dos Testes , Prognóstico , Índice de Gravidade de Doença , Volume Sistólico , Sus scrofa , Fatores de Tempo , Função Ventricular Esquerda
16.
Atherosclerosis ; 266: 81-86, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28992468

RESUMO

BACKGROUND AND AIMS: Dronedarone reduced the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF) in the ATHENA trial. This cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms. This study aimed to investigate any direct effect of dronedarone on blood thrombogenicity, independent of its antiarrhythmic effects. METHODS: Blood samples from patients with cardiovascular disease (n = 30) taking no anticoagulant or antiplatelet medication except aspirin were incubated with dronedarone's active metabolite (SR35021A) at 66 ng/ml (am-L) and 119 ng/ml (am-H), i.e., minimum and maximum mean Cmax reported after repeated 400 mg BID dosing. A third aliquot of blood was incubated with vehicle (Control). Antithrombotic effects of dronedarone were assessed using Coagulation Time (CT), Clot Formation Rate (CFR) and Maximum Clot Firmness (MCF) in ThromboElastoMetry and whole blood platelet aggregation in response to ADP, collagen and TRAP. RESULTS: Compared to Control, mean CT was prolonged by am-L and am-H (164 ± 25 s vs. 180 ± 22 and 182 ± 32 s, respectively, p<0.01 for both). Small but statistically significant reductions were observed in CFR (am-L and am-H) and MCF (am-H). Platelet aggregation induced by ADP and TRAP was also reduced (p<0.05 for both) by am-H. CONCLUSIONS: Dronedarone exerts direct anticoagulant and antiplatelet effects on human blood in vitro that are independent of its antiarrhythmic actions. This suggests the reductions in ischemic events reported with dronedarone may not be due to amelioration of AF itself. Additional clinical studies are required to further improve understanding of the mechanisms involved.


Assuntos
Amiodarona/análogos & derivados , Antiarrítmicos/farmacologia , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Idoso , Amiodarona/farmacologia , Testes de Coagulação Sanguínea , Doenças Cardiovasculares/sangue , Dronedarona , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Plaquetária
18.
J Am Heart Assoc ; 6(8)2017 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754654

RESUMO

BACKGROUND: Extracorporeal membrane oxygenation following cardiac surgery safeguards end-organ oxygenation but unfavorably alters cardiac hemodynamics. Along with the detrimental effects of cardiac surgery to the right heart, this might impact outcome, particularly in patients with preexisting right ventricular (RV) dysfunction. We sought to determine the prognostic impact of RV function and to improve established risk-prediction models in this vulnerable patient cohort. METHODS AND RESULTS: Of 240 patients undergoing extracorporeal membrane oxygenation support following cardiac surgery, 111 had echocardiographic examinations at our institution before implantation of extracorporeal membrane oxygenation and were thus included. Median age was 67 years (interquartile range 60-74), and 74 patients were male. During a median follow-up of 27 months (interquartile range 16-63), 75 patients died. Fifty-one patients died within 30 days, 75 during long-term follow-up (median follow-up 27 months, minimum 5 months, maximum 125 months). Metrics of RV function were the strongest predictors of outcome, even stronger than left ventricular function (P<0.001 for receiver operating characteristics comparisons). Specifically, RV free-wall strain was a powerful predictor univariately and after adjustment for clinical variables, Simplified Acute Physiology Score-3, tricuspid regurgitation, surgery type and duration with adjusted hazard ratios of 0.41 (95%CI 0.24-0.68; P=0.001) for 30-day mortality and 0.48 (95%CI 0.33-0.71; P<0.001) for long-term mortality for a 1-SD (SD=-6%) change in RV free-wall strain. Combined assessment of the additive EuroSCORE and RV free-wall strain improved risk classification by a net reclassification improvement of 57% for 30-day mortality (P=0.01) and 56% for long-term mortality (P=0.02) compared with the additive EuroSCORE alone. CONCLUSIONS: RV function is strongly linked to mortality, even after adjustment for baseline variables and clinical risk scores. RV performance improves established risk prediction models for short- and long-term mortality.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Disfunção Ventricular Direita/etiologia , Função Ventricular Direita , Idoso , Área Sob a Curva , Procedimentos Cirúrgicos Cardíacos/mortalidade , Ecocardiografia , Oxigenação por Membrana Extracorpórea/mortalidade , Feminino , Hemodinâmica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Curva ROC , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/mortalidade , Disfunção Ventricular Direita/fisiopatologia , Função Ventricular Esquerda
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