Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of... Show moreCardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task. In particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and co-morbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models cannot provide a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on a organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and improved current animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction and refinement (3R) as a guiding concept. Show less
Cozijnsen, L.; Plomp, A.S.; Post, J.G.; Pals, G.; Bogunovic, N.; Yeung, K.K.; ... ; Micha, D. 2019
Background Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD.... Show moreBackground Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD. Methods Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation. Results The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for pathogenicity was found by the predicted damaging effect of this mutation and the co-segregation in the family. Functional analysis with myogenic transdifferentiation of dermal fibroblasts to smooth muscle-like cells, revealed increased myogenic differentiation in patient cells with the TGFBR1 mutation, shown by a higher expression of myogenic markers ACTA2, MYH11 and CNN1 compared to cells from healthy controls. Conclusion Our findings confirm the pathogenic effect of the TGFBR1 mutation in causing TAAD in Loeys-Dietz syndrome and show increased myogenic differentiation of patient fibroblasts. Show less
Introduction The pathophysiology and natural course of abdominal aortic aneurysms (AAAs) are insufficiently understood. In order to improve our understanding, it is imperative to carry out... Show moreIntroduction The pathophysiology and natural course of abdominal aortic aneurysms (AAAs) are insufficiently understood. In order to improve our understanding, it is imperative to carry out longitudinal research that combines biomarkers with clinical and imaging data measured over multiple time points. Therefore, a multicentre biobank, databank and imagebank has been established in the Netherlands: the 'Pearl Abdominal Aortic Aneurysm' (AAA bank).Methods and analysis The AAA bank is a prospective multicentre observational biobank, databank and imagebank of patients with an AAA. It is embedded within the framework of the Parelsnoer Institute, which facilitates uniform biobanking in all university medical centres (UMCs) in the Netherlands. The AAA bank has been initiated by the two UMCs of Amsterdam UMC and by Leiden University Medical Center. Participants will be followed during AAA follow-up. Clinical data are collected every patient contact. Three types of biomaterials are collected at baseline and during follow-up: blood (including DNA and RNA), urine and AAA tissue if open surgical repair is performed. Imaging data that are obtained as part of clinical care are stored in the imagebank. All data and biomaterials are processed and stored in a standardised manner. AAA growth will be based on multiple measurements and will be analysed with a repeated measures analysis. Potential associations between AAA growth and risk factors that are also measured on multiple time points can be assessed with multivariable mixed-effects models, while potential associations between AAA rupture and risk factors can be tested with a conditional dynamic prediction model with landmarking or with joint models in which linear mixed-effects models are combined with Cox regression.Ethics and dissemination The AAA bank is approved by the Medical Ethics Board of the Amsterdam UMC (University of Amsterdam).Trial registration number NCT03320408. Show less
Overwater, E.; Marsili, L.; Baars, M.J.H.; Baas, A.F.; Beek, I. van de; Dulfer, E.; ... ; Maugeri, A. 2018
