Therapeutic aproaches in PAH with beneficial effects on right ventricular function - preclinical studies

Introdução: A hipertensão pulmonar (PH) é uma condição progressiva que afeta a vasculatura pulmonar, mas cujo principal fator de prognóstico é a função ventricular direita. É definida como uma elevação da pressão média da artéria pulmonar acima de 20 mmHg em repouso. A PH grupo 1 - hipertensão arterial pulmonar (PAH) - é um tipo de PH que beneficia primariamente de tratamento dirigido. Vários modelos de ratinho e rato são usados na investigação da PAH, mas a translação para ensaios clínicos geralmente falha. Recentemente, cada vez mais estudos têm usado também o modelo de ligação da artéria pulmonar (PAB) - um modelo de disfunção/insuficiência ventricular direita sem PH. Esta revisão visa descrever os principais achados de estudos que testam intervenções em modelos de PH e PAB, simultaneamente. Métodos: os artigos foram pesquisados nas seguintes bases de dados: Scopus, Web of Science e Pubmed, sem restrições de tempo ou linguagem. Os critérios de inclusão consistiram em intervenções farmacológicas com intuito terapêutico testadas num grupo de animais PAB e, pelo menos, num modelo de PH. Critérios de exclusão foram intervenções agudas; modelos genéticos e estudos sem dados para os grupos PAB e, pelo menos, outro modelo de PH. Resultados: vários fármacos melhoraram tanto a hemodinâmica pulmonar em modelos de PH como atenuaram a disfunção e hipertrofia do ventrículo direito resultante de PAB, em ratinhos e ratos. De uma forma geral, os modelos de PH e PAB concordaram na maioria dos resultados (concordância de 73,1%) para fármacos que não antagonistas dos recetores da endotelina e inibidores da fosfodiesterase 5. A pressão sistólica no ventrículo direito (RVSP) foi o parâmetro com mais discordâncias entre os dois tipos de modelos. Apenas o dicloroacetato melhorou a RVSP em animais sujeitos a PAB, enquanto 14 em 19 fármacos reduziram a RVSP em modelos de PAH. Os resultados da fibrose do ventrículo direito, pelo contrário, foram no mesmo sentido com todos os 12 fármacos. O macitentan, sildenafil e tadalafil melhoraram a maioria dos parâmetros avaliados em modelos de PAH, mas quase nenhum em modelos de PAB: o macitentan foi a exceção, melhorando dois - o índice de Fulton e a TAPSE. A dapaglifozina foi o único fármaco que não mostrou melhorias em nenhum dos parâmetros selecionados. Conclusão: esta revisão mostrou que vários fármacos em investigação para PAH exercem cardioproteção em modelos animais - pelo que têm potencial para também a exercerem em seres humanos - tal como oferecem benefícios na hemodinâmica e remodelagem da circulação pulmonar. Contudo, os resultados de estudos isolados devem ser interpretados com cuidado, já que pequenas diferenças na metodologia podem resultar em importantes diferenças nos resultados. Desta forma, para melhorar o potencial de translação de fármacos nesta área, os investigadores deverão testá-los em vários modelos, incluindo PAB, e otimizar a indução dos modelos para que estes se assemelhem com a doença humana.Introduction : Pulmonary hypertension (PH) is a progressive condition that affects pulmonary vessels, but its main prognostic factor is right ventricle (RV) function. It is defined as an elevation of mean pulmonary arterial pressure above 20 mmHg at rest. PH group 1 - pulmonary arterial hypertension (PAH) - is a type of disease that primarily benefits from targeted treatment. Many mice/rat models are used for research in PAH, but results fail to translate in clinical trials. Recently, more and more studies are also using pulmonary arterial banding (PAB) - a model of RV disfunction/failure without PH. This review aims to summarize studies that test interventions on PAB and other PH models concomitantly. Methods: articles were searched in Scopus, Web of Science and PubMed, without time or language limitation. Inclusion criteria consisted of pharmacological therapeutical interventions, tested on a PAB and in a PAH animal model. Exclusion criteria were acute interventions, genetic models, and studies without data for PAB group and, at least, one other PH model. Results: multiple tested drugs both improved pulmonary vascular haemodynamics on PH models and ameliorated RV structure and function after PAB, in rats and mice. PH models and PAB frequently exhibited similar results (73,1% concordance) with drugs other than ERA and PDE5i. RV systolic pressure (RVSP) accounted for most differences between PH models and PAB. Only dichloroacetate improved it in PAB animals, whereas 14 out of 19 drugs/combination of drugs improved RVSP in PH models. Results on RV fibrosis, on the other hand, all agreed (12 drugs). Macitentan, sildenafil and tadalafil improved most parameters in PH models, but almost none in PAB animals: only macitentan ameliorated two - Fulton index and TAPSE. Dapagliflozin was the only drug that improved no parameters. Conclusion: this review showed that many drugs currently under research for PAH have a cardioprotective effect on animals that may translate to humans, as well as pulmonary vascular hemodynamics and remodelling benefits. However, results of isolated studies should be interpreted with caution, as small differences in the methodology can lead to noticeable changes in the results. To improve the translational potential of drugs in this field, researchers should test them in multiple models, including PAB, while optimizing induction methods for human disease translation

Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension

This open access book focuses on the molecular mechanism of congenital heart disease and pulmonary hypertension, offering new insights into the development of pulmonary circulation and the ductus arteriosus. It describes in detail the molecular mechanisms involved in the development and morphogenesis of the heart, lungs and ductus arteriosus, covering a range of topics such as gene functions, growth factors, transcription factors and cellular interactions, as well as stem cell engineering technologies. The book also presents recent advances in our understanding of the molecular mechanism of lung development, pulmonary hypertension and molecular regulation of the ductus arteriosus. As such, it is an ideal resource for physicians, scientists and investigators interested in the latest findings on the origins of congenital heart disease and potential future therapies involving pulmonary circulation/hypertension and the ductus arteriosus

Active ingredients of traditional Chinese medicine inhibit NOD-like receptor protein 3 inflammasome: a novel strategy for preventing and treating heart failure

Heart failure (HF) has emerged as a significant global public health challenge owing to its high rates of morbidity and mortality. Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is regarded as a pivotal factor in the onset and progression of HF. Therefore, inhibiting the activation of the NLRP3 inflammasome may represent a promising therapeutic approach for preventing and treating HF. The active ingredients serve as the foundation for the therapeutic effects of traditional Chinese medicine (TCM). Recent research has revealed significant advantages of TCM active ingredients in inhibiting the activation of the NLRP3 inflammasome and enhancing cardiac structure and function in HF. The study aimed to explore the impact of NLRP3 inflammasome activation on the onset and progression of HF, and to review the current advancements in utilizing TCM active ingredients to inhibit the NLRP3 inflammasome for preventing and treating HF. This provides a novel perspective for the future development of precise intervention strategies targeting the NLRP3 inflammasome to prevent and treat HF

A Systematic Review and Meta-Analysis of the Incidence of Injury in Professional Female Soccer

The epidemiology of injury in male professional football is well documented and has been used as a basis to monitor injury trends and implement injury prevention strategies. There are no systematic reviews that have investigated injury incidence in women’s professional football. Therefore, the extent of injury burden in women’s professional football remains unknown. PURPOSE: The primary aim of this study was to calculate an overall incidence rate of injury in senior female professional soccer. The secondary aims were to provide an incidence rate for training and match play. METHODS: PubMed, Discover, EBSCO, Embase and ScienceDirect electronic databases were searched from inception to September 2018. Two reviewers independently assessed study quality using the Strengthening the Reporting of Observational Studies in Epidemiology statement using a 22-item STROBE checklist. Seven prospective studies (n=1137 professional players) were combined in a pooled analysis of injury incidence using a mixed effects model. Heterogeneity was evaluated using the Cochrane Q statistic and I2. RESULTS: The epidemiological incidence proportion over one season was 0.62 (95% CI 0.59 - 0.64). Mean total incidence of injury was 3.15 (95% CI 1.54 - 4.75) injuries per 1000 hours. The mean incidence of injury during match play was 10.72 (95% CI 9.11 - 12.33) and during training was 2.21 (95% CI 0.96 - 3.45). Data analysis found a significant level of heterogeneity (total Incidence, X2 = 16.57 P < 0.05; I2 = 63.8%) and during subsequent sub group analyses in those studies reviewed (match incidence, X2 = 76.4 (d.f. = 7), P <0.05; I2 = 90.8%, training incidence, X2 = 16.97 (d.f. = 7), P < 0.05; I2 = 58.8%). Appraisal of the study methodologies revealed inconsistency in the use of injury terminology, data collection procedures and calculation of exposure by researchers. Such inconsistencies likely contribute to the large variance in the incidence and prevalence of injury reported. CONCLUSIONS: The estimated risk of sustaining at least one injury over one football season is 62%. Continued reporting of heterogeneous results in population samples limits meaningful comparison of studies. Standardising the criteria used to attribute injury and activity coupled with more accurate methods of calculating exposure will overcome such limitations