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1.
Life Sci ; 266: 118888, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310031

RESUMO

AIMS: Peroxisome proliferator-activated receptor (PPAR) α, a key regulator of lipid metabolism, plays a role in maintaining the homeostasis of myocardial energy metabolism. Both hypoxia and obesity inhibit the expression of PPARα in the myocardium. In this study, we verified the inhibitory effects of hypoxia and obesity on PPARα and examined whether WY14643 (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid), an agonist of PPARα, ameliorates myocardial mitochondrial dysfunction and protects cardiac function in obese rats under chronic persistent hypoxia. MAIN METHODS: Sprague-Dawley rats were randomly divided into six groups: a control group (normal chow diet, normal oxygen), a high-fat diet (HFD) group (normal oxygen), a chronic persistent hypoxia normal chow diet group, a chronic persistent hypoxia HFD group, a chronic persistent hypoxia HFD group with WY14643 treatment, and a chronic persistent hypoxia HFD group with vehicle treatment. KEY FINDINGS: Hypoxia and obesity increased myocardial lipid accumulation, mitochondrial dysfunction, and left ventricular systolic dysfunction. Myocardial lipid metabolism-related genes, including those encoding PPARα, PPARγ coactivator 1α (PGC1α), and carnitine palmitoyl transferase 1α (CPT1α), were downregulated, while acetyl-CoA carboxylase 2 (ACC2) was upregulated under a combination of hypoxia and obesity. WY14643 upregulated PPARα, PGC1α, and CPT1α, and downregulated ACC2. WY14643 alleviated hypoxia- and obesity-induced myocardial lipid accumulation and improved mitochondrial and left ventricular systolic functions. SIGNIFICANCE: WY14643 improved myocardial mitochondrial and left ventricular systolic functions in obese rats under chronic persistent hypoxia. Thus, WY14643 possibly exerts its effects by regulating the PPARα pathway and shows potential as a therapeutic target for cardiovascular diseases associated with obesity and hypoxia.


Assuntos
Hipóxia/fisiopatologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Obesidade/fisiopatologia , PPAR alfa/agonistas , Pirimidinas/farmacologia , Sístole/efeitos dos fármacos , Disfunção Ventricular Esquerda/tratamento farmacológico , Animais , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Volume Sistólico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/patologia
4.
Nat Commun ; 11(1): 5209, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060602

RESUMO

Chronic high-thoracic and cervical spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, including impaired left ventricular (LV) contractility. Here, we aim to determine whether such dysfunction manifests immediately post-injury, and if so, whether correcting impaired contractility can improve spinal cord oxygenation (SCO2), blood flow (SCBF) and metabolism. Using a porcine model of T2 SCI, we assess LV end-systolic elastance (contractility) via invasive pressure-volume catheterization, monitor intraparenchymal SCO2 and SCBF with fiberoptic oxygen sensors and laser-Doppler flowmetry, respectively, and quantify spinal cord metabolites with microdialysis. We demonstrate that high-thoracic SCI acutely impairs cardiac contractility and substantially reduces SCO2 and SCBF within the first hours post-injury. Utilizing the same model, we next show that augmenting LV contractility with the ß-agonist dobutamine increases SCO2 and SCBF more effectively than vasopressor therapy, whilst also mitigating increased anaerobic metabolism and hemorrhage in the injured cord. Finally, in pigs with T2 SCI survived for 12 weeks post-injury, we confirm that acute hemodynamic management with dobutamine appears to preserve cardiac function and improve hemodynamic outcomes in the chronic setting. Our data support that cardio-centric hemodynamic management represents an advantageous alternative to the current clinical standard of vasopressor therapy for acute traumatic SCI.


Assuntos
Coração/fisiopatologia , Hemodinâmica/fisiologia , Hemorragia/fisiopatologia , Fenômenos Fisiológicos Respiratórios , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Modelos Animais de Doenças , Dobutamina/farmacologia , Feminino , Fluxometria por Laser-Doppler , Chaperonas Moleculares/metabolismo , Norepinefrina/farmacologia , Fluxo Sanguíneo Regional/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Suínos , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/fisiopatologia
5.
Isr Med Assoc J ; 7(22): 375-379, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32692500

RESUMO

BACKGROUND: Heart failure (HF) patients with reduced ejection fraction (HFrEF) are frequently treated with sub-optimal doses of angiotensin converting enzyme-inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and beta blockers (BBs). OBJECTIVES: To determine factors associated with attaining upper-range doses in patients with HFrEF. METHODS: We examined treatment in patients with left ventricular ejection fraction (LVEF) ≤ 40% in a community-based, dedicated heart-failure clinic. Upper-range doses were defined as ≥ 75% of target recommended doses by heart failure society guidelines. RESULTS: The majority of the 215 patients were men (82%); median age at presentation 73 years (interquartile range [IQR] 65-78) and LVEF of 30% (IQR 25-35%). Following the up-titration program, 41% and 35% of patients achieved upper-range doses of ACE-Is/ARBs and BBs, respectively. Higher body mass index (BMI) was the only parameter found to be associated with achieving upper-range doses of ACE-I/ARBs (odds ratio [OR] 1.13, 95% confidence interval [95%CI] 1.05-1.22, P = 0.001). More patients achieved this target as BMI increased, with a sharp decline in the highest obesity category (BMI ≥ 40 m2/kg). Attaining upper-range doses of BBs was associated with pre-existing diabetes mellitus (DM) (OR 2.6, 95%CI 1.34-5.19, P = 0.005); women were associated with attaining lower BBs doses (OR 0.34, 95%CI 0.13-0.90, P = 0.031). CONCLUSIONS: Achieving upper-range doses of ACE-Is/ARBs and BBs in HFrEF outpatients in a treatment up-titration program were associated with greater BMI and DM, respectively. These findings may serve as benchmarks for up-titration programs.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Disfunção Ventricular Esquerda/tratamento farmacológico , Idoso , Benchmarking , Índice de Massa Corporal , Diabetes Mellitus/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/efeitos dos fármacos
6.
Expert Rev Cardiovasc Ther ; 18(7): 405-414, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32546023

RESUMO

INTRODUCTION: The European Society of Cardiology (ESC), Canadian Cardiovascular Society, and the American College of Cardiology Heart Failure (HF) guidelines all currently recommend the use of Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs) and Beta Blockers (BB) in the treatment of HF with a reduced ejection fraction (HFrEF). Newer medications targeting combining an ARB with a neprilysin inhibitor (ARNI) sacubitril/valsartan have shown benefits in mortality and can be used in place of an ACE inhibitor or an ARB. Additionally, dapagliflozin, a medication targeting the sodium-glucose cotransporter 2 (SGLT2) can be used in addition to current therapies. AREAS COVERED: This review provides a comprehensive analysis of the evidence around the new pharmacotherapies for HFrEF, specifically, sacubitril/valsartan and dapagliflozin. A comprehensive review of the literature using keywords such as heart failure with reduced ejection fraction, angiotensin receptor, neprilysin inhibitor, and sodium glucose transporter was conducted within the National Centre for Biotechnology Information (NCBI) and Google Scholar databases. The reference sections of articles were also examined to find additional articles. EXPERT OPINION: Sacubitril/valsartan and dapagliflozin both show marked benefits on mortality in HFrEF patients. More research needs to be conducted on the mechanisms of action on disease modification.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Disfunção Ventricular Esquerda/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Humanos , Neprilisina/antagonistas & inibidores , Volume Sistólico , Resultado do Tratamento
7.
Cardiovasc Drugs Ther ; 34(5): 723-735, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32564304

RESUMO

After an episode of myocardial infarction (MI), patients remain at risk for recurrent ischemic events, heart failure (HF), and sudden death. Post-MI patients with left ventricular systolic dysfunction (LVSD) have an even greater risk of mortality and morbidity. Randomized clinical trials that included post-MI patients with LVSD have demonstrated that pharmacologic therapies aimed at preventing post-MI remodeling with neurohormonal antagonists can significantly improve short- and long-term outcomes, including death, reinfarction, and worsening HF. Recent trials have also demonstrated benefits in terms of cardiovascular event reduction with effective antithrombotic therapies and cholesterol-lowering agents in post-MI setting, especially in patients at very high risk such as those with LVSD. This paper reviews clinical trials that included post-MI patients with LVSD, with or without signs and symptoms of HF, assessing the efficacy of established and emerging pharmacological therapies.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/complicações , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Fármacos Cardiovasculares/efeitos adversos , Medicina Baseada em Evidências , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Recuperação de Função Fisiológica , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
9.
Circ Heart Fail ; 13(5): e006597, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32354280

RESUMO

BACKGROUND: Loop diuretics are used for congestion relief, and dose adaptations are usually a consequence of the clinicians' clinical judgement about the congestive status of the patient. In EPHESUS (Eplerenone in Patients With Systolic Dysfunction After Myocardial Infarction), many patients required diuretics for congestion relief. We thus hypothesized that blinded allocation to eplerenone would lead clinicians to reduce loop diuretics, as a consequence of the improvement in patients' status. METHODS: Cox and mixed-effects models were used over a median follow-up of 1.3 years in 6632 patients. RESULTS: A total of 6632 patients were included; at baseline, 3352 (50.5%) did not have diuretics, 2195 (33.1%) had diuretic doses between 1 and 40 mg/day, and 1085 (16.4%) had diuretic doses >40 mg/day. Patients with higher furosemide equivalent doses had a worse clinical status. Both baseline and follow-up incremental loop diuretic doses were associated with worse prognosis. Eplerenone treatment was associated with lower prescribed loop diuretic doses throughout the follow-up; lower doses were observed at 90 days and decreased further at 180 days and beyond. Eplerenone treatment led to a mean furosemide equivalent dose reduction of -2.2 mg/day (-2.9 to -1.6) throughout the follow-up. Eplerenone was effective in reducing morbidity and mortality regardless of the baseline loop diuretic dose used: hazard ratio for the outcome of cardiovascular death or heart failure hospitalization was 0.83 ([95% CI, 0.75-0.92]; P for interaction, 0.54). CONCLUSIONS: Eplerenone treatment led to a loop diuretic dose reduction during follow-up without evidence of treatment effect modification by loop diuretics. These findings suggest that eplerenone reduces congestive signs and symptoms, which enables clinicians to reduce loop diuretic doses.


Assuntos
Eplerenona/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Infarto do Miocárdio/complicações , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Eplerenona/efeitos adversos , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Recuperação de Função Fisiológica , Inibidores de Simportadores de Cloreto de Sódio e Potássio/efeitos adversos , Sístole , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/fisiopatologia
10.
Cardiovasc Drugs Ther ; 34(4): 487-501, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32377826

RESUMO

BACKGROUND: Previous studies have demonstrated that a high-carbohydrate intake could induce metabolic syndrome (MetS) in male rats with marked cardiac functional abnormalities. In addition, studies mentioned some benefits of insulin application on these complications, but there are considerable disagreements among their findings. Therefore, we aimed to extend our knowledge on the in-vitro influence of insulin on left ventricular dysfunction and also in the isolated cardiomyocytes from MetS rats. RESULTS: At the organ function level, an acute insulin application (100-nM) provided an important beneficial effect on the left ventricular developed pressure in MetS rats. Furthermore, to treat the freshly isolated cardiomyocytes from MetS rats with insulin provided marked recoveries in elevated resting intracellular Ca2+-level, as well as significant prevention of prolonged action potential through an augmentation in depressed K+-channel currents. Insulin also normalized the cellular levels of increased ROS and phosphorylation of PKCα, together with normalizations of apoptotic markers in MetS cardiomyocytes through the insulin-mediated regulation of phospho-Akt. Since not only elevated PKCα-activity but also reductions in phospho-Akt are key modulators of titin-based cardiomyocyte stiffening in hyperglycemia, insulin treatment of the cardiomyocytes prevented the activation of titin via the above pathways. Furthermore, CK2α-activation and NOS-phosphorylation could be prevented with insulin treatment. Mechanistically, we found that impaired insulin signaling and elevated PKCα and CK2α activities, as well as depressed Akt phosphorylation, are key modulators of titin-based cardiomyocyte stiffening in MetS rats. CONCLUSION: We propose that restoring normal kinase activities and also increases in phospho-Akt by insulin can contribute marked recoveries in MetS heart function, indicating a promising approach to modulate titin-associated factors in heart dysfunction associated with type-2 diabetes mellitus. Graphical Abstract.


Assuntos
Caseína Quinase II/metabolismo , Conectina/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Insulina/farmacologia , Síndrome Metabólica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Modelos Animais de Doenças , Preparação de Coração Isolado , Masculino , Síndrome Metabólica/enzimologia , Síndrome Metabólica/fisiopatologia , Miócitos Cardíacos/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/fisiopatologia , Pressão Ventricular/efeitos dos fármacos
11.
Circ Heart Fail ; 13(5): e006609, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32418479

RESUMO

BACKGROUND: Low myocardial cGMP-PKG (cyclic guanosine monophosphate-protein kinase G) activity has been associated with increased cardiomyocyte diastolic stiffness in heart failure with preserved ejection fraction. Cyclic guanosine monophosphate is mainly hydrolyzed by PDE (phosphodiesterases) 5a and 9a. Importantly, PDE9a expression has been reported to be upregulated in human heart failure with preserved ejection fraction myocardium and chronic administration of a PDE9a inhibitor reverses preestablished cardiac hypertrophy and systolic dysfunction in mice subjected to transverse aortic constriction (TAC). We hypothesized that inhibiting PDE9a activity ameliorates diastolic dysfunction. METHODS: To examine the effect of chronic PDE9a inhibition, 2 diastolic dysfunction mouse models were studied: (1) TAC-deoxycorticosterone acetate and (2) Leprdb/db. PDE9a inhibitor (5 and 8 mg/kg per day) was administered to the mice via subcutaneously implanted osmotic minipumps for 28 days. The effect of acute PDE9a inhibition was investigated in intact cardiomyocytes isolated from TAC-deoxycorticosterone acetate mice. Atrial natriuretic peptide together with PDE9a inhibitor were administered to the isolated intact cardiomyocytes through the cell perfusate. RESULTS: For acute inhibition, no cellular stiffness reduction was found, whereas chronic PDE9a inhibition resulted in reduced left ventricular chamber stiffness in TAC-deoxycorticosterone acetate, but not in Leprdb/db mice. Passive cardiomyocyte stiffness was reduced by chronic PDE9a inhibition, with no differences in myocardial fibrosis or cardiac morphometry. PDE9a inhibition increased the ventricular-arterial coupling ratio, reflecting impaired systolic function. CONCLUSIONS: Chronic PDE9a inhibition lowers left ventricular chamber stiffness in TAC-deoxycorticosterone acetate mice. However, the usefulness of PDE9a inhibition to treat high-diastolic stiffness may be limited as the required PDE9a inhibitor dose also impairs systolic function, observed as a decline in ventricular-arterial coordination, in this model.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Diástole , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/enzimologia , Inibidores de Fosfodiesterase/toxicidade , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/fisiopatologia
12.
Sci Rep ; 10(1): 6665, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313194

RESUMO

The aim of this study was to evaluate the effects of Sacubitril/Valsartan (S/V) on clinical, laboratory and echocardiographic parameters and outcomes in a real-world population with heart failure with reduced ejection fraction (HFrEF). This was a prospective observational study enrolling patients with HFrEF undergoing treatment with S/V. The primary outcome was the composite of cardiac death and HF rehospitalization at 12 months follow-up; secondary outcomes were all-cause death, cardiac death and the occurrence of rehospitalization for worsening HF. The clinical outcome was compared with a retrospective cohort of 90 HFrEF patients treated with standard medical therapy. The study included 90 patients (66.1 ± 11.7 years) treated with S/V. The adjusted regression analysis showed a significantly lower risk for the primary outcome (HR:0.31; 95%CI, 0.11-0.83; p = 0.019) and for HF rehospitalization (HR:0.27; 95%CI, 0.08-0.94; p = 0.039) in S/V patients as compared to the control group. A significant improvement in NYHA class, left ventricular ejection fraction, left ventricular end systolic volume and systolic pulmonary arterial pressure was observed up to 6 months. S/V did not affect negatively renal function and was associated with a significantly lower dose of furosemide dose prescribed at 6- and 12-month follow-up. In this study, S/V reduced the risk of HF rehospitalization and cardiac death at 1 year in patients with HFrEF. S/V improved NYHA class, echocardiographic parameters and need of furosemide, and preserved renal function.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Tetrazóis/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Idoso , Pressão Arterial/efeitos dos fármacos , Estudos de Casos e Controles , Diuréticos/uso terapêutico , Combinação de Medicamentos , Ecocardiografia , Feminino , Furosemida/uso terapêutico , Coração/diagnóstico por imagem , Coração/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Análise de Regressão , Estudos Retrospectivos , Volume Sistólico/efeitos dos fármacos , Análise de Sobrevida , Resultado do Tratamento , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
13.
Adv Exp Med Biol ; 1177: 269-295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32246448

RESUMO

Heart failure (HF) is defined as a clinical syndrome resulting from structural or functional impairment of ventricular fillings or ejections of blood. Currently, HF is divided into three groups which include HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF) and HF with midrange EF (HFmrEF). Even though major advances have been made in treating HFrEF during the past decades, heart failure is a fatal disease. In this review, we briefly summarize the current advances in pharmaceutical managements for heart failure, which includes drugs used in acute heart failure as well as those that prevent heart failure progression, in each category major clinical trials are also described. In addition, information about some of potential new drugs are also mentioned. Traditional Chinese medicine also shows its potential in treating HF, and we are still lack of medicine to treat HFpEF.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Progressão da Doença , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/fisiopatologia
14.
Cardiovasc Drugs Ther ; 34(2): 153-164, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32146638

RESUMO

PURPOSE: Vepoloxamer (VEPO), a rheologic agent, repairs damaged cell membranes, thus inhibiting unregulated Ca2+ entry into cardiomyocytes. This study examined the effects of i.v. infusion of VEPO on LV function in dogs with coronary microembolization-induced heart failure (HF) (LV ejection fraction, EF ~ 30%). METHODS: Thirty-five HF dogs were studied. Study 1: 21 of 35 dogs were randomized to 2-h infusion of VEPO at dose of 450 mg/kg (n = 7) or VEPO at 225 mg/kg (n = 7) or normal saline (control, n = 7). Hemodynamics were measured at 2 h, 24 h, 1 week, and 2 weeks after infusion. Study 2: 14 HF dogs were randomized to 2-h infusions of VEPO (450 mg/kg, n = 7) or normal saline (control, n = 7). Each dog received 2 infusions of VEPO or saline (pulsed therapy) 3 weeks apart and hemodynamics measured at 24 h, and 1, 2, and 3 weeks after each infusion. In both studies, the change between pre-infusion measures and measures at other time points (treatment effect, Δ) was calculated. RESULTS: Study 1: compared to pre-infusion, high dose VEPO increased LVEF by 11 ± 2% at 2 h, 8 ± 2% at 24 h (p < 0.05), 8 ± 2% at 1 week (p < 0.05), and 4 ± 2% at 2 weeks. LV EF also increased with low-dose VEPO but not with saline. Study 2: VEPO but not saline significantly increased LVEF by 6.0 ± 0.7% at 2 h (p < 0.05); 7.0 ± 0.7%% at 1 week (p < 0.05); 1.0 ± 0.6% at 3 weeks; 6.0 ± 1.3% at 4 weeks (p < 0.05); and 5.9 ± 1.3% at 6 weeks (p < 0.05). CONCLUSIONS: Intravenous VEPO improves LV function for at least 1 week after infusion. The benefits can be extended with pulsed VEPO therapy. The results support development of VEPO for treating patients with acute on chronic HF.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Poloxâmero/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Infusões Intravenosas , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia
15.
Cardiovasc Drugs Ther ; 34(3): 311-321, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32185580

RESUMO

BACKGROUND: The use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) is currently expanding to cardiovascular risk reduction in non-diabetic subjects, but renal (side-)effects are less well studied in this setting. METHODS: Male non-diabetic Sprague Dawley rats underwent permanent coronary artery ligation to induce MI, or sham surgery. Rats received chow containing empagliflozin (EMPA) (30 mg/kg/day) or control chow. Renal function and electrolyte balance were measured in metabolic cages. Histological and molecular markers of kidney injury, parameters of phosphate homeostasis and bone resorption were also assessed. RESULTS: EMPA resulted in a twofold increase in diuresis, without evidence for plasma volume contraction or impediments in renal function in both sham and MI animals. EMPA increased plasma magnesium levels, while the levels of glucose and other major electrolytes were comparable among the groups. Urinary protein excretion was similar in all treatment groups and no histomorphological alterations were identified in the kidney. Accordingly, molecular markers for cellular injury, fibrosis, inflammation and oxidative stress in renal tissue were comparable between groups. EMPA resulted in a slight increase in circulating phosphate and PTH levels without activating FGF23-Klotho axis in the kidney and bone mineral resorption, measured with CTX-1, was not increased. CONCLUSIONS: EMPA exerts profound diuretic effects without compromising renal structure and function or causing significant electrolyte imbalance in a non-diabetic setting. The slight increase in circulating phosphate and PTH after EMPA treatment was not associated with evidence for increased bone mineral resorption suggesting that EMPA does not affect bone health.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Rim/efeitos dos fármacos , Infarto do Miocárdio/complicações , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Compostos Benzidrílicos/toxicidade , Biomarcadores/sangue , Biomarcadores/urina , Modelos Animais de Doenças , Diurese/efeitos dos fármacos , Glucosídeos/toxicidade , Rim/patologia , Rim/fisiopatologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Ratos Sprague-Dawley , Inibidores do Transportador 2 de Sódio-Glicose/toxicidade , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
16.
JAMA ; 323(14): 1353-1368, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32219386

RESUMO

Importance: Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes. Objective: To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. Design, Setting, and Participants: Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy. Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%. Results: Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes. Conclusions and Relevance: In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Compostos Benzidrílicos/efeitos adversos , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Feminino , Glucosídeos/efeitos adversos , Hemoglobina A Glicada/análise , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Placebos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/tratamento farmacológico
17.
N Engl J Med ; 382(20): 1883-1893, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32222134

RESUMO

BACKGROUND: The effect of vericiguat, a novel oral soluble guanylate cyclase stimulator, in patients with heart failure and reduced ejection fraction who had recently been hospitalized or had received intravenous diuretic therapy is unclear. METHODS: In this phase 3, randomized, double-blind, placebo-controlled trial, we assigned 5050 patients with chronic heart failure (New York Heart Association class II, III, or IV) and an ejection fraction of less than 45% to receive vericiguat (target dose, 10 mg once daily) or placebo, in addition to guideline-based medical therapy. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure. RESULTS: Over a median of 10.8 months, a primary-outcome event occurred in 897 of 2526 patients (35.5%) in the vericiguat group and in 972 of 2524 patients (38.5%) in the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P = 0.02). A total of 691 patients (27.4%) in the vericiguat group and 747 patients (29.6%) in the placebo group were hospitalized for heart failure (hazard ratio, 0.90; 95% CI, 0.81 to 1.00). Death from cardiovascular causes occurred in 414 patients (16.4%) in the vericiguat group and in 441 patients (17.5%) in the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06). The composite of death from any cause or hospitalization for heart failure occurred in 957 patients (37.9%) in the vericiguat group and in 1032 patients (40.9%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P = 0.02). Symptomatic hypotension occurred in 9.1% of the patients in the vericiguat group and in 7.9% of the patients in the placebo group (P = 0.12), and syncope occurred in 4.0% of the patients in the vericiguat group and in 3.5% of the patients in the placebo group (P = 0.30). CONCLUSIONS: Among patients with high-risk heart failure, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower among those who received vericiguat than among those who received placebo. (Funded by Merck Sharp & Dohme [a subsidiary of Merck] and Bayer; VICTORIA ClinicalTrials.gov number, NCT02861534.).


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Pirimidinas/uso terapêutico , Administração Oral , Idoso , Doenças Cardiovasculares/mortalidade , Doença Crônica , Método Duplo-Cego , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Compostos Heterocíclicos com 2 Anéis/efeitos adversos , Hospitalização/estatística & dados numéricos , Humanos , Hipotensão/induzido quimicamente , Incidência , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Guanilil Ciclase Solúvel/metabolismo , Volume Sistólico , Síncope/induzido quimicamente , Disfunção Ventricular Esquerda/tratamento farmacológico
18.
Int J Mol Sci ; 21(4)2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32098266

RESUMO

An increased incidence of myocardial infarction (MI) has recently emerged as the cause of cardiovascular morbidity and mortality worldwide. In this study, cardiac function was investigated in a rat myocardial ischemia/reperfusion (I/R) model using echocardiography. Metformin administration significantly increased ejection fraction and fractional shortening values on Days 3 and 7 when MI occurred, indicating that metformin improved left ventricular systolic function. In the Sham + MET and MI + MET groups, the E' value was significantly different up to Day 3 but not at Day 7. This may mean that left ventricular diastolic function was effectively restored to some extent by Day 7 when metformin was administered. These results suggest that diastolic dysfunction, assessed by echocardiography, does not recover in the early phase of ischemic reperfusion injury in the rat myocardial I/R model. However, administering metformin resulted in recovery in the early phase of ischemic reperfusion injury in this model. Further gene expression profiling of left ventricle tissues revealed that the metformin-treated group had notably attenuated immune and inflammatory profiles. To sum up, a rat myocardial I/R injury model and ultrasound-based assessment of left ventricular systolic and diastolic function can be used in translational research and for the development of new heart failure-related drugs, in addition to evaluating the potential of metformin to improve left ventricular (LV) diastolic function.


Assuntos
Ecocardiografia , Regulação da Expressão Gênica/efeitos dos fármacos , Metformina/farmacologia , Traumatismo por Reperfusão Miocárdica , Disfunção Ventricular Esquerda , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/metabolismo
19.
Cardiovasc Diabetol ; 19(1): 10, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969144

RESUMO

BACKGROUND: Although a variety of antidiabetic drugs have significant protective action on the cardiovascular system, it is still unclear which antidiabetic drugs can improve ventricular remodeling and fundamentally delay the process of heart failure. The purpose of this network meta-analysis is to compare the efficacy of sodium glucose cotransporter type 2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, metformin (MET), sulfonylurea (SU) and thiazolidinediones (TZDs) in improving left ventricular (LV) remodeling in patients with type 2 diabetes (T2DM) and/or cardiovascular disease (CVD). METHODS: We searched articles published before October 18, 2019, regardless of language or data, in 4 electronic databases: PubMed, EMBASE, Cochrane Library and Web of Science. We included randomized controlled trials in this network meta-analysis, as well as a small number of cohort studies. The differences in the mean changes in left ventricular echocardiographic parameters between the treatment group and control group were evaluated. RESULTS: The difference in the mean change in LV ejection fraction (LVEF) between GLP-1 agonists and placebo in treatment effect was greater than zero (MD = 2.04% [0.64%, 3.43%]); similar results were observed for the difference in the mean change in LV end-diastolic diameter (LVEDD) between SGLT-2 inhibitors and placebo (MD = - 3.3 mm [5.31, - 5.29]), the difference in the mean change in LV end-systolic volume (LVESV) between GLP-1 agonists and placebo (MD = - 4.39 ml [- 8.09, - 0.7]); the difference in the mean change in E/e' between GLP-1 agonists and placebo (MD = - 1.05[- 1.78, - 0.32]); and the difference in the mean change in E/e' between SGLT-2 inhibitors and placebo (MD = - 1.91[- 3.39, - 0.43]). CONCLUSIONS: GLP-1 agonists are more significantly associated with improved LVEF, LVESV and E/e', SGLT-2 inhibitors are more significantly associated with improved LVEDD and E/e', and DPP-4 inhibitors are more strongly associated with a negative impact on LV end-diastolic volume (LVEDV) than are placebos. SGLT-2 inhibitors are superior to other drugs in pairwise comparisons.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Incretinas/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Adulto , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Feminino , Humanos , Incretinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/fisiopatologia
20.
Rev Med Interne ; 41(2): 143-144, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-31928796
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