RESUMO
Although the development of therapies and tools for the improved management of heart failure (HF) continues apace, day-to-day management in clinical practice is often far from ideal. A Cardiovascular Round Table workshop was convened by the European Society of Cardiology (ESC) to identify barriers to the optimal implementation of therapies and guidelines and to consider mitigation strategies to improve patient outcomes in the future. Key challenges identified included the complexity of HF itself and its treatment, financial constraints and the perception of HF treatments as costly, failure to meet the needs of patients, suboptimal outpatient management, and the fragmented nature of healthcare systems. It was discussed that ongoing initiatives may help to address some of these barriers, such as changes incorporated into the 2021 ESC HF guideline, ESC Heart Failure Association quality indicators, quality improvement registries (e.g. EuroHeart), new ESC guidelines for patients, and the universal definition of HF. Additional priority action points discussed to promote further improvements included revised definitions of HF 'phenotypes' based on trial data, the development of implementation strategies, improved affordability, greater regulator/payer involvement, increased patient education, further development of patient-reported outcomes, better incorporation of guidelines into primary care systems, and targeted education for primary care practitioners. Finally, it was concluded that overarching changes are needed to improve current HF care models, such as the development of a standardized pathway, with a common adaptable digital backbone, decision-making support, and data integration, to ensure that the model 'learns' as the management of HF continues to evolve.
Assuntos
Cardiologia , Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/terapiaRESUMO
Many biomarkers that could be used to assess ejection fraction, heart failure, or myocardial infarction fail to translate into clinical practice because they lack essential performance characteristics or fail to meet regulatory standards for approval. Despite their potential, new technologies have added to the complexities of successful translation into clinical practice. Biomarker discovery and implementation require a standardized approach that includes: identification of a clinical need; identification of a valid surrogate biomarker; stepwise assay refinement, demonstration of superiority over current standard-of-care; development and understanding of a clinical pathway; and demonstration of real-world performance. Successful biomarkers should improve efficacy or safety of treatment, while being practical at a realistic cost. Everyone involved in cardiovascular healthcare, including researchers, clinicians, and industry partners, are important stakeholders in facilitating the development and implementation of biomarkers. This article provides suggestions for a development pathway for new biomarkers, discusses regulatory issues and challenges, and suggestions for accelerating the pathway to improve patient outcomes. Real-life examples of successful biomarkers-high-sensitivity cardiac troponin, T2* cardiovascular magnetic resonance imaging, and echocardiography-are used to illustrate the value of a standardized development pathway in the translation of concepts into routine clinical practice.
Assuntos
Pesquisa Biomédica , Cardiologia , Doenças Cardiovasculares/diagnóstico , Ecocardiografia , Imageamento por Ressonância Magnética , Troponina T/sangue , Função Ventricular Esquerda , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/terapia , Humanos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos TestesRESUMO
Regulator of G-protein signalling (RGS) proteins form a superfamily of at least 25 proteins, which are highly diverse in structure, expression patterns, and function. They share a 120 amino acid homology domain (RGS domain), which exhibits GTPase accelerating activity for alpha-subunits of heterotrimeric G-proteins, and thus, are negative regulators of G-protein-mediated signalling. Based on the organisation of the Rgs genes, structural similarities, and differences in functions, they can be divided into at least six subfamilies of RGS proteins and three more families of RGS-like proteins. Many of these proteins regulate signalling processes within cells, not only via interaction with G-protein alpha-subunits, but are G-protein-regulated effectors, Gbetagamma scavenger, or scaffolding proteins in signal transduction complexes as well. The expression of at least 16 different RGS proteins in the mammalian or human myocardium have been described. A subgroup of at least eight was detected in a single atrial myocyte. The exact functions of these proteins remain mostly elusive, but RGS proteins such as RGS4 are involved in the regulation of G(i)-protein betagamma-subunit-gated K(+) channels. An up-regulation of RGS4 expression has been consistently found in human heart failure and some animal models. Evidence is increasing that the enhanced RGS4 expression counter-regulates the G(q/11)-induced signalling caused by hypertrophic stimuli. In the vascular system, RGS5 seems to be an important signalling regulator. It is expressed in vascular endothelial cells, but not in cultured smooth muscle cells. Its down-regulation, both in a model of capillary morphogenesis and in an animal model of stroke, render it a candidate gene, which may be involved in the regulation of capillary growth, angiogenesis, and in the pathophysiology of stroke.
Assuntos
Sistema Cardiovascular/metabolismo , Proteínas RGS , Transdução de Sinais/fisiologia , Animais , Humanos , Miocárdio/metabolismo , Proteínas RGS/classificação , Proteínas RGS/genética , Proteínas RGS/fisiologiaRESUMO
OBJECTIVE: Endotoxin (LPS)-induced acute cardiac failure during sepsis is associated with alterations in G protein mediated signal transduction. We therefore examined the expression of the G proteins G(i), G(q), and G(s) and of four 'regulators of G protein signaling' (RGS) proteins, RGS1, RGS4, RGS5, and RGS16 in rat hearts. METHODS: For in vivo experiments, Wistar rats were treated with 600 microg/day E. coli LPS, intravenously) and hearts were excised after 6, 24 and 72 h. Cultured neonatal rat cardiomyocytes were treated with 4 microg/ml LPS for 24 and 72 h. Isolated membrane proteins were used for Western blot analysis and for evaluation of phospholipase C (PLC) activity. RGS16 mRNA was detected by RNAse protection. RESULTS: LPS induced G(i) protein 1.4-fold 72 h after in vivo administration of LPS, whereas expression of G(s) and G(q) was unaltered. After 6 h of LPS treatment, RGS16 mRNA was transiently up-regulated 3.7-fold, followed by transient protein induction (24 h: 2.5-fold; 72 h: 1.5-fold). Similarly, RGS4 protein was transiently induced (24 h: 3.1-fold; 72 h: 1.5-fold), whereas expression of RGS1 and RGS5 was not altered. Similar to the LPS-treated rat hearts, RGS16 expression was transiently induced by LPS in cultured neonatal rat cardiomyocytes (24 h: 1.6-fold, 72 h: 0.9-fold). To determine the functional consequences of the RGS protein induction phospholipase C (PLC) activity was analyzed in membranes obtained from solvent and LPS-treated hearts. Basal and endothelin-1-stimulated PLC activity was transiently repressed by LPS with a maximum after 24 h although no apparent changes in PLCbeta1 or endothelin receptor expression could be detected. CONCLUSION: These data suggest that the rapid up-regulation of cardiac RGS4 and RGS16 is associated with a desensitization of endothelin-1 receptor signaling. Up-regulation of these RGS proteins may thus be involved in the early onset of cardiac failure during sepsis.
Assuntos
Insuficiência Cardíaca/metabolismo , Lipopolissacarídeos/farmacologia , Miocárdio/metabolismo , Proteínas RGS/metabolismo , Receptores de Endotelina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Células Cultivadas , Proteínas de Ligação ao GTP/metabolismo , Masculino , Proteínas/genética , Proteínas/metabolismo , Proteínas RGS/genética , RNA Mensageiro/análise , Ratos , Ratos Wistar , Fosfolipases Tipo C/análise , Fosfolipases Tipo C/metabolismoRESUMO
OBJECTIVE: RGS proteins (regulators of G protein signalling) negatively regulate G protein function as GTPase activating proteins. By controlling heterotrimeric G proteins they may regulate myocardial hypertrophy and contractility. We investigated the expression of RGS proteins in the human heart and whether they take part in the pathophysiological changes of heart failure. METHODS AND RESULTS: Using RNase protection assays (RPAs) RGS2, 3L, 3S, 4, 5 and 6 were identified in the myocardium from terminally failing human hearts with dilated (DCM, n=22) or ischemic (ICM, n=18) cardiomyopathy and from nonfailing donor hearts (NF, n=9). With reverse transcriptase polymerase chain reaction in addition mRNA of RGS1, 9, 12, 14 and 16 were detectable. Compared to NF in failing LV myocardium RGS4 mRNA and protein was upregulated 2-3-fold (mRNA, 10(-21) mol/microg+/-S.E.M.: NF: 22+/-5, DCM: 51+/-10*, ICM: 37+/-8; P<0.05 vs. DCM+ICM, *P<0.05 vs. NF, P<0.05 vs. DCM+ICM; protein, % of NF+/-S.E.M.: NF: 100+/-35, DCM 266+/-60*, ICM: 205+/-64, n=5, *P<0.05 vs. NF). In contrast, RGS2, 3L, 3S, 5, 6, and 16 protein and mRNA levels did not vary between failing and NF hearts. In order to investigate the impact of RGS4 on Gq/11 mediated signalling, PLC activity was measured in human LV membranes. Recombinant RGS4 blunted the endothelin-1 (ET-1) stimulated PLC activity. When overexpressed by adenoviral mediated gene transfer in rabbit ventricular myocytes RGS4 abolished the inotropic effect of ET-1. CONCLUSION: The upregulation of RGS4 in failing human myocardium diminishes Gq/11-mediated signalling and can be involved in the desensitization of Gq/11-mediated positive inotropic effects.
Assuntos
Proteínas de Ligação ao GTP , Proteínas Ativadoras de GTPase , Regulação da Expressão Gênica , Insuficiência Cardíaca/metabolismo , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Proteínas RGS/genética , Animais , Western Blotting , Estudos de Casos e Controles , Feminino , Expressão Gênica , Ventrículos do Coração , Humanos , Pessoa de Meia-Idade , Miocárdio/química , Proteínas/análise , Proteínas RGS/análise , Proteínas RGS/metabolismo , RNA Mensageiro/análise , Coelhos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Muscarinic acetylcholine receptors (mAChRs) mediate their main cardiac effects via pertussis toxin-sensitive G-proteins. Physiological effects differ considerably between atrium and ventricle, and it is unknown to which extent these differences derive from selective receptor-G-protein coupling or further downstream events. We have characterized specific coupling between mAChRs and Gi/Go-protein isoforms in atrial and ventricular myocardium by agonist-dependent photoaffinity labeling with [(32)P]azidoanilido GTP (aaGTP) and immunoprecipitation in sarcolemmal membranes from terminally failing human hearts. The total amount of mAChRs, as determined by specific binding of [(3)H]QNB, was significantly higher in right-atrial (RA +/- SEM, 959 +/- 68 fmol/mg, n = 4) than in left-ventricular membranes (LV, 582 +/- 53 fmol/mg, n = 6). Standardized immunoblots revealed that Gialpha-2 was the predominant subtype in both regions. A 40-kDa splice variant of Goalpha (Goalpha-1 and/or Goalpha-3) was almost exclusively detectable in RA. Levels of Gialpha-3 and a 39-kDa splice variant of Goalpha (Goalpha-2) were also higher in RA. Basal aaGTP binding was higher in RA than in LV for all Gialpha/Goalpha subtypes. The carbachol (10 micromol/l)-induced increase in aaGTP binding was significantly higher in RA than in LV for Goalpha-1/3 (336 +/- 95% of LV, n = 4) and for Gialpha-3 (211 +/- 83%), lower for Gialpha-2 (42 +/- 5%), and was similar in both regions for Goalpha-2 (130 +/- 62%). The differential coupling of mAChRs in human RA and LV suggests that the initiation of different physiological responses to mAChR stimulation starts with signal sorting at the receptor-G-protein level.
Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química , Miocárdio/patologia , Receptores Muscarínicos/metabolismo , Acetilcolina/metabolismo , Difosfato de Adenosina/metabolismo , Adenosina Difosfato Ribose/metabolismo , Adulto , Carbacol/farmacologia , Membrana Celular/metabolismo , Relação Dose-Resposta a Droga , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Guanosina Trifosfato/metabolismo , Humanos , Immunoblotting , Luz , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Toxina Pertussis/metabolismo , Toxina Pertussis/farmacologia , Testes de Precipitina , RNA Mensageiro/metabolismo , Fatores de Tempo , Distribuição TecidualRESUMO
A dysregulated metabolism of oxygen-derived free radicals, nitric oxide and endothelin-1(ET-1) in conditions such as hypercholesterolaemia or hypertension may promote the development of atherosclerosis. We therefore subjected cultured human umbilical vein endothelial cells and coronary artery smooth muscle cells to oxidative stress induced by xanthine oxidase or hydrogen peroxide and observed alterations in ET-1 metabolism. Incubation with oxygen-derived free radicals increased preproET-1 promoter activity, ET-1 mRNA synthesis and big ET-1 concentrations in both cell types. This interaction of oxidative stress and ET-1 expression may be relevant in atherogenic conditions such as hypercholesterolaemia and hypertension since our data indicate that oxidative stress further aggravates the injurious effects attributed to ET-1.