The Role of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Heart Failure, Regardless of Diabetes Status: Focus on Cardiovascular Disease.

OBJECTIVE: To provide clinical guidance and an overview of the available data on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with reduced ejection fraction (HFrEF), regardless of the presence of type 2 diabetes mellitus (T2DM). DATA SOURCES: We searched the MEDLINE database via PubMed (from January 2015 to November 2020) for the following key terms: SGLT2 inhibitors, sodium-glucose co-transporter-2 inhibitors, SGLT2i, heart failure, and heart failure with reduced ejection fraction. STUDY SELECTION AND DATA EXTRACTION: To be included in the review, the articles needed to assess the effects of SGLT2 inhibitors in the heart failure (HF) scenario. DATA SYNTHESIS: There is consistent evidence that SGLT2 inhibitors reduce the risk of major adverse cardiovascular (CV) events and hospitalization in patients with HFrEF, even in the absence of T2DM. On May 5, 2020, the U.S. Food and Drug Administration approved dapagliflozin for adults with HFrEF, regardless of the presence of T2DM, even in those patients on standard therapy, including an angiotensin receptor/neprilysin inhibitor. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The SGLT2 inhibitors are well tolerated, and their once-daily dosing without the need for adjustments is convenient. These drugs can be considered a major breakthrough in pharmacotherapy for HF, providing physicians with a new treatment approach to reduce major clinical outcomes. CONCLUSIONS: SGLT2 inhibitor therapy reduces CV death and hospitalizations in HFrEF patients regardless of T2DM. The decision to prescribe this class of drugs should not be determined by glycemic status.

Intradialytic training in patients with end-stage renal disease: a systematic review and meta-analysis of randomized clinical trials assessing the effects of five different training interventions.

OBJECTIVE: Patients with end-stage renal disease (ESRD) undergoing hemodialysis may have reduced dialysis adequacy (Kt/V), low cardiorespiratory fitness, and worse prognosis. Different types of intradialytic training (IDT) may serve as an adjunct therapy for the management of the ESRD. This systematic review and meta-analysis aimed to assess the impact of different types of IDT on clinical outcomes and functional parameters in ESRD. METHODS: PubMed, Embase, CINAHL, Cochrane CENTRAL, Scopus, SPORTDiscus, and Google Scholar were searched for randomized clinical trials in adult patients with ESRD which compared IDT with usual care (UC), without language restrictions and published up to July 2019; a handsearch of references was also performed. Certainty of evidence was assessed using GRADE, and risk of bias in primary studies with the RoB 1.0 tool. RESULTS: Fifty studies were included (n = 1757). Compared to UC, aerobic IDT improved Kt/V (WMD = 0.08), VO2peak (WMD = 2.07 mL/kg/min), 6-minute walk test (6MWT) distance (64.98 m), reduced systolic blood pressure (- 10.07 mmHg) and C-reactive protein (- 3.28 mg/L). Resistance training increased 6MWT distance (68.50 m). Combined training increased VO2peak (5.41 mL/kg/min) and reduced diastolic blood pressure (- 5.76 mmHg). Functional electrostimulation (FES) and inspiratory muscle training (IMT) improved 6MWT distance (54.14 m and 117.62 m, respectively). There was no impact on total cholesterol, interleukin-6, or hemoglobin levels. There was no difference in incidence of adverse events between the IDT and control groups. The certainty of evidence was variable according to the GRADE scale, with most outcomes rated very low certainty. The risk of bias assessment of primary studies showed unclear risk in most. CONCLUSIONS: Aerobic, resistance, and combined training during hemodialysis, as well as FES and IMT, demonstrated to be effective for the treatment of the patient with ESRD. Our data should be interpreted in light of the unclear risk of bias of most evaluated articles and the low to very low certainty of evidence for evaluated outcomes. PROSPERO REGISTRATION ID: CRD42017081338. DATA SHARING REPOSITORY: https://osf.io/fpj54/.

Biochemical and Molecular Mechanisms of Glucose Uptake Stimulated by Physical Exercise in Insulin Resistance State: Role of Inflammation / Mecanismos Bioquímicos e Moleculares da Captação da Glicose Estimulada pelo Exercício Físico no Estado de Resistência à Insulina: Papel da Inflamação

Abstract Obesity associated with systemic inflammation induces insulin resistance (IR), with consequent chronic hyperglycemia. A series of reactions are involved in this process, including increased release of proinflammatory cytokines, and activation of c-Jun N-terminal kinase (JNK), nuclear factor-kappa B (NF-κB) and toll-like receptor 4 (TLR4) receptors. Among the therapeutic tools available nowadays, physical exercise (PE) has a known hypoglycemic effect explained by complex molecular mechanisms, including an increase in insulin receptor phosphorylation, in AMP-activated protein kinase (AMPK) activity, in the Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) pathway, with subsequent activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), Rac1, TBC1 domain family member 1 and 4 (TBC1D1 and TBC1D4), in addition to a variety of signaling molecules, such as GTPases, Rab and soluble N-ethylmaleimide-sensitive factor attached protein receptor (SNARE) proteins. These pathways promote greater translocation of GLUT4 and consequent glucose uptake by the skeletal muscle. Phosphoinositide-dependent kinase (PDK), atypical protein kinase C (aPKC) and some of its isoforms, such as PKC-iota/lambda also seem to play a fundamental role in the transport of glucose. In this sense, the association between autophagy and exercise has also demonstrated a relevant role in the uptake of muscle glucose. Insulin, in turn, uses a phosphoinositide 3-kinase (PI3K)-dependent mechanism, while exercise signal may be triggered by the release of calcium from the sarcoplasmic reticulum. The objective of this review is to describe the main molecular mechanisms of IR and the relationship between PE and glucose uptake.

Resumo A obesidade associada à inflamação sistêmica induz resistência à insulina (RI), com consequente hiperglicemia crônica. Este processo envolve o aumento na liberação de citocinas pró-inflamatórias, ativação da enzima c-Jun N-terminal cinase (JNK), do fator nuclear kappa-B (NF-κB) e dos receptores do tipo Toll 4 (TLR4). Dentre as ferramentas terapêuticas disponíveis, o exercício físico (EF) tem efeito hipoglicemiante conhecido, explicado por mecanismos moleculares complexos. Dentre eles, ocorre aumento na fosforilação do receptor da insulina, na atividade da proteína quinase ativada por AMP (AMPK), na via da proteína cinase cinase dependente de Ca+2/calmodulina (CaMKK), com posterior ativação do coativador-1α do receptor ativado por proliferador do peroxissoma (PGC-1α), proteínas Rac1, TBC1 membro das famílias de domínio 1 e 4 (TBC1D1 e TBC1D4), além de uma variedade de moléculas de sinalização, como as proteínas GTPases, Rab e proteína solúvel de fusão sensível a N-etil-maleimida (SNARE); estas vias promovem maior translocação de transportador de glicose do tipo 4 (GLUT4) e consequente captação de glicose pelo músculo esquelético. A cinase fosfatidilinositol-dependente (PDK), proteína quinase C atípica (aPKC) e algumas das suas isoformas, como a PKC-iota/lambda também parecem desempenhar papel fundamental no transporte de glicose. Nesse sentido, a associação entre autofagia e EF também tem demonstrado papel relevante na captação de glicose muscular. A insulina, por sua vez, utiliza um mecanismo dependente da fosfatidilinositol-3-quinase (PI3K), enquanto que o sinal do EF pode ter início mediante liberação de cálcio pelo retículo sarcoplasmático e concomitante ativação da AMPK. O objetivo desta revisão é descrever os principais mecanismos moleculares da RI e da relação entre o EF e a captação de glicose.

Biochemical and Molecular Mechanisms of Glucose Uptake Stimulated by Physical Exercise in Insulin Resistance State: Role of Inflammation.

Obesity associated with systemic inflammation induces insulin resistance (IR), with consequent chronic hyperglycemia. A series of reactions are involved in this process, including increased release of proinflammatory cytokines, and activation of c-Jun N-terminal kinase (JNK), nuclear factor-kappa B (NF-κB) and toll-like receptor 4 (TLR4) receptors. Among the therapeutic tools available nowadays, physical exercise (PE) has a known hypoglycemic effect explained by complex molecular mechanisms, including an increase in insulin receptor phosphorylation, in AMP-activated protein kinase (AMPK) activity, in the Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) pathway, with subsequent activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), Rac1, TBC1 domain family member 1 and 4 (TBC1D1 and TBC1D4), in addition to a variety of signaling molecules, such as GTPases, Rab and soluble N-ethylmaleimide-sensitive factor attached protein receptor (SNARE) proteins. These pathways promote greater translocation of GLUT4 and consequent glucose uptake by the skeletal muscle. Phosphoinositide-dependent kinase (PDK), atypical protein kinase C (aPKC) and some of its isoforms, such as PKC-iota/lambda also seem to play a fundamental role in the transport of glucose. In this sense, the association between autophagy and exercise has also demonstrated a relevant role in the uptake of muscle glucose. Insulin, in turn, uses a phosphoinositide 3-kinase (PI3K)-dependent mechanism, while exercise signal may be triggered by the release of calcium from the sarcoplasmic reticulum. The objective of this review is to describe the main molecular mechanisms of IR and the relationship between PE and glucose uptake.

PCSK9 Inhibitors: Clinical Relevance, Molecular Mechanisms, and Safety in Clinical Practice / Inibidores de PCSK9: Importância Clínica, Mecanismos Moleculares, e Segurança na Prática Clínica

Abstract Coronary artery disease (CAD) is one of the leading causes of mortality. High circulating levels of low-density lipoprotein (LDL) in the blood are associated with cardiovascular mortality, whether through an etiological role or through its association with the progression of CAD per se. Randomized clinical trials have shown that, when LDL levels are reduced, cardiovascular risk is also reduced, which reinforces this association. The first major trial involving a hypolipidemic agent of the statin family, the Scandinavian Simvastatin Survival Study (4S), was published in 1994 and found a significant reduction in mortality in patients at high cardiovascular risk. However, even in subsequent studies with different statins, a residual risk persisted, and this seems not to have changed over time; it is speculated that this risk may be due to statin intolerance. In this scenario, the potential exists for novel hypolipidemic agents to drive a true revolution in the therapy of dyslipidemia. The recent discovery of PCSK9 inhibitors (PCSK9i), a class of hypolipidemic monoclonal antibodies, is extremely promising. PCSK9 inhibition is capable of promoting a mean LDL reduction of up to 60%, with potential for very significant clinical repercussions, as every 38 mg/dL reduction in LDL appears to be associated with a 22% reduction in cardiovascular risk. This review addresses a brief history of PCSK9i, major trials of these drugs, cardiovascular outcomes, and aspects related to their efficacy and safety. Finally, the molecular mechanisms and possible pleiotropic effects of PCSK9i are also discussed.

Resumo A doença arterial coronariana (DAC) é uma das principais causas de mortalidade. Níveis circulantes elevados de lipoproteína de baixa densidade (LDL) no sangue estão associados com mortalidade cardiovascular, seja por um papel etiológico ou por sua associação com a progressão da DAC em si. Estudos clínicos randomizados mostram que, quando os níveis de LDL são reduzidos, o risco cardiovascular também é reduzido, o que reforça tal associação. O primeiro ensaio importante envolvendo um agente hipolipemiante da família da estatina, o estudo Scandinavian Simvastatin Survival Study (4S), foi publicado em 1994 e encontrou uma redução significativa na mortalidade de pacientes com risco cardiovascular elevado. Contudo, mesmo em estudos subsequentes com diferentes estatinas, observou-se um risco residual persistente, o qual aparentemente não mudou ao longo dos anos. Especula-se que esse risco se deve à intolerância às estatinas. Nesse cenário, existe um potencial para novos agentes hipolipemiantes que levem a uma verdadeira revolução no tratamento das dislipidemias. A descoberta recente dos inibidores de PCSK9 (PCSK9i), uma classe de anticorpos monoclonais, é extremamente promissora. A inibição da PCSK9 é capaz de promover uma redução média nos níveis de LDL de até 60%, com potencial para repercussões clínicas muito significativas, já que para cada redução de 38 mg/dL, parece haver uma redução de 22% no risco cardiovascular. Esta revisão aborda uma breve história dos PCSK9i, os principais ensaios envolvendo esses medicamentos, desfechos cardiovasculares, e aspectos relacionados a sua eficácia e segurança. Finalmente, os mecanismos moleculares e possíveis efeitos pleiotrópicos dos PCSK9i são também discutidos.

PCSK9 Inhibitors: Clinical Relevance, Molecular Mechanisms, and Safety in Clinical Practice.

Coronary artery disease (CAD) is one of the leading causes of mortality. High circulating levels of low-density lipoprotein (LDL) in the blood are associated with cardiovascular mortality, whether through an etiological role or through its association with the progression of CAD per se. Randomized clinical trials have shown that, when LDL levels are reduced, cardiovascular risk is also reduced, which reinforces this association. The first major trial involving a hypolipidemic agent of the statin family, the Scandinavian Simvastatin Survival Study (4S), was published in 1994 and found a significant reduction in mortality in patients at high cardiovascular risk. However, even in subsequent studies with different statins, a residual risk persisted, and this seems not to have changed over time; it is speculated that this risk may be due to statin intolerance. In this scenario, the potential exists for novel hypolipidemic agents to drive a true revolution in the therapy of dyslipidemia. The recent discovery of PCSK9 inhibitors (PCSK9i), a class of hypolipidemic monoclonal antibodies, is extremely promising. PCSK9 inhibition is capable of promoting a mean LDL reduction of up to 60%, with potential for very significant clinical repercussions, as every 38 mg/dL reduction in LDL appears to be associated with a 22% reduction in cardiovascular risk. This review addresses a brief history of PCSK9i, major trials of these drugs, cardiovascular outcomes, and aspects related to their efficacy and safety. Finally, the molecular mechanisms and possible pleiotropic effects of PCSK9i are also discussed.

Adiponectina, doença cardiovascular e suas relações com o exercício físico: revisão narrativa / Adiponectin, cardiovascular disease and its relationship with physical exercise: a narrative review

Há uma estreita relação entre os níveis circulantes de adiponectina, resistência à insulina e risco cardiovascular. As evidências disponíveis que avaliaram a relação entre adiponectina e exercício físico apresentam algumas controvérsias. Estudos recentes mostraram que o treinamento aeróbico não altera os níveis de adiponectina sem que haja redução significativa no peso corporal; outros estudos mostram que uma modesta perda de peso, em conjunto com treinamento aeróbico, melhora de forma importante os níveis dessa proteína ­ inclusive se não houver alteração no peso. Por outro lado, foi documentado que o treinamento aeróbico aumenta níveis de adiponectina até mesmo se houver ganho de peso. Motivado por tais discordâncias, o objetivo desta revisão narrativa foi apresentar e discutir a relação entre adiponectina e doenças cardiovasculares, bem como a possível influência do exercício físico nas concentrações sanguíneas de adiponectina e a sua associação com a melhora do estado glicêmico

There is a close relationship between circulating levels of adiponectin, insulin resistance and cardiovascular risk. The available evidence that evaluated the relationship between adiponectin levels and physical exercise is somewhat controversial. Recent studies have shown that aerobic training does not alter adiponectin levels without significant reduction in body weight; other studies show that modest weight loss, along with aerobic training, significantly improves the levels of this protein ­ even if there is no change in weight. On the other hand, it has been documented that aerobic training increases levels of adiponectin even if there is weight gain. Motivated by such inconsistencies, the purpose of this narrative review was to present and discuss the relationship between adiponectin and cardiovascular diseases, as well as the possible influence of physical exercise on blood concentrations of adiponectin and its association with improved glycemic status

Exercício físico em indivíduos em hemodiálise: benefícios e melhores indicações - revisão sistemática / Physical exercise in individuals in hemodialysis: benefits and best indications - systematic review

INTRODUÇÃO: Cresce o número de indivíduos com doença renal crônica (DRC) submetidos à hemodiálise (HD). No Brasil, em 2012, o número de pacientes em HD era de 97.586, com taxa de mortalidade de 19%. O exercício físico (EF) é uma terapia adjuvante capaz de promover controle glicêmico, pressórico e outros ganhos relevantes para o controle da DRC. OBJETIVO: Descrever os benefícios sobre a qualidade de vida, os cuidados e os protocolos mais efetivos de exercício físico para indivíduos em hemodiálise. MÉTODOS: Estudo de revisão sistemática. Consultados artigos dos bancos de dados SciELO e PubMed entre 2005 e 2016, sobre os efeitos fisiológicos do exercício e qualidade de vida de indivíduos em hemodiálise. Os descritores em cruzamento utilizados foram: "hemodialysis" AND "exercises", "haemodialysis" AND "exercises" e "intradialytic" AND "exercises". RESULTADOS: Foram selecionados 23 artigos com diferentes programas de EF 8 aeróbios, 6 resistidos, 5 compostos pela associação de ambos e 1 de comparação entre aeróbio e resistido. A amostra variou entre 6 a 103 pacientes. Tempo de intervenção de 2 a 4 meses. Todos os programas aeróbios confirmaram melhorias em um ou mais parâmetros: capacidade funcional, redução da inflamação, melhora da complacência arterial dentre outros. Nos EF resistidos, um dos estudos reportou efeitos deletérios para os pacientes, já aqueles com EF resistido e aeróbico, apontaram benefícios. CONCLUSÃO: O EF foi capaz de prevenir o estresse oxidativo, reduzir a pressão arterial e a glicemia, aumentar o volume e a força muscular, além de ganhos na qualidade de vida, entretanto não houve unanimidade sobre o melhor protocolo. [AU]

INTRODUCTION: The number of patients with chronic chronic disease (CKD) on hemodialysis (HD) has increased. In Brazil, in 2012, the number of patients in HD was 97,586, with a mortality rate of 19%. Physical exercise (PE) is an adjuvant therapy capable of promoting glycemic control, blood pressure and other gains relevant to CKD control. OBJECTIVE: To describe the benefits of quality of life, care and the most effective protocols of physical exercise for the individual on hemodialysis. METHODS: Systematic review study. Consultations of the SciELO and PubMed databases between 2005 and 2016 on the physiological effects of exercise and the quality of life of the individual on hemodialysis. The cross-over descriptors used were: "hemodialysis" and "exercises", "hemodialysis" and "exercises" and "intradialitic" and "exercises". RESULTS: 23 articles were selected with different EF programs, 8 exercises, 6 resisted, 5 composed by the association of both, and 1 of a comparison between aerobic and resisted. A sample ranged from 6 to 103 patients. Intervention time of 2 to 4 months. All programs should be improved in relation to functional capacity, reduction of inflammation, improvement of arterial compliance and others. In resisted PE, one of the studies reported deleterious effects for the patients, while those with resisted and aerobic PE showed benefits. CONCLUSION: EF was able to prevent oxidative stress, reduce blood pressure and increase blood glucose, increase muscle volume and strength, and gain quality in life, but there was no agreement on the best protocol. [AU]

Adiponectina: caracterização, ação metabólica e cardiovascular / Adiponectin: characterization, metabolic and cardiovascular action

Nas últimas duas décadas, o entendimento da biologia do tecido adiposo sofreu mudanças revolucionárias, passando de principal sítio de armazenamento energético a importante órgão endócrino responsável pela produçãoe secreção de proteínas, peptídeos e não peptídeos bioativos. Dentre as proteínas secretadas pelos adipócitos, aadiponectina (APN) é a mais abundante, apresentando ações fisiológicas importantes no sistema cardiovasculare endócrino, envolvendo a sensibilização da ação insulínica e regulação do metabolismo energético corporal, incluindo o coração. Esta revisão tem por objetivo descrever a ação da APN sobre o sistema cardiovascular. Foramincluídos artigos originais realizados com animais ou humanos. Consultadas as bases de dados Pubmed e Medlineentre os anos de 1994 e 2013. Não foram incluídos relatos de caso, estudos-piloto ou estudos de revisão. Utilizou-se como palavras-chave os descritores em ciências da saúde e MeSH específico para o Medline. Oscruzamentos realizados foram: Adiponectin AND Obesity, Adiponectin AND Metabolism e Adiponectin AND Cardiovascular Disease. Encontrados 303 artigos, excluídos 204 e selecionados 31 artigos que compuseram esteestudo. No contexto geral desta revisão a APN apresenta efeitos anti-inflamatórios e ateroprotetores no tecidovascular e ainda ação sensibilizadora para a insulina nos tecidos envolvidos nos metabolismos glicídico e lipídico. Assim, é considerado biomarcador importante para o desenvolvimento de doenças cardiovasculares.

In the last two decades, the understanding of adipose tissue biology underwent revolutionary changes, from a major energy storage site to an important endocrine organ responsible for the production and secretion of proteins, peptides and non-bioactive peptides. Among the proteins secreted by adipocytes, adiponectin (APN) is the most abundant, with important physiological actions in the cardiovascular and endocrine system, involving the sensitization of insulin action and regulation of body energy metabolism, including the heart. This review aims to describe the action of APN on the cardiovascular system. It includes original manuscripts with humans or animals. The databases PubMed and Medline, from years 1994 to 2013, were searched. Case reports, pilot studies or review studies have not been included. The health science descriptors and MeSH specific for Medline were used as keywords. The following cross searches were carried out: Adiponectin AND Obesity, Adiponectin AND Metabolism and Adiponectin AND Cardiovascular Disease. We found 303 manuscripts, excluded 204 and selected 31 manuscripts that were included this study. Inthe general context of this review, APN presents anti-inflammatory and ateroprotector effects in the vascular tissue and an insulin sensitizing action in tissues involved in glucose and lipid metabolism. It is thus considered an important biomarker for the developmentof cardiovascular diseases.