Cardiopulmonary-vascular disorders in Down syndrome research: a long overlocked issue.

Individuals with Down syndrome (DS) are at greater risk of developing pulmonary arterial hypertension (PAH) (1), a devastating and life-threatening condition. However, the management and development of PAH as a comorbidity in DS individuals is majorly overlooked (2), specifically in preclinical research. The increased incidence of PAH in the context of DS is mainly due to upper airway obstruction, congenital cardiac disorders, alveolar hypoventilation, hypoplasia of the pulmonary vascular bed and chronic infections (1). Anatomical anomalies result in an increased incidence of obstructive sleep apnea (OSA) of 30-50%, which in turn leads to chronic hypoxia, respiratory acidosis and eventually pulmonary hypertension (PH). In addition, 40 to 50% of newborns with DS suffer from congenital heart defects (CHD) (3). Exposure to this increased left-to-right shunt flow increases shear stress and induces irreversible remodeling of pulmonary arteries in individuals with DS. This is mediated through lower production of vasodilators such as prostacyclin and nitric oxide, and higher production of vasoconstrictors like endothelin-1 and thromboxane. This altered balance between vasodilators and vasoconstrictors further induces remodeling of the pulmonary arterial wall, resulting in underdevelopment of alveoli (4). Our collaborators Bush and colleagues evidenced by retrospective histological analysis that children with DS had impaired lung alveolar and vascular development, resulting in the development of PH (5). In addition, respiratory disorders account for 75% of mortality and morbidity in individuals with DS (6). For children with DS aged <3 years, respiratory illnesses (pneumonia, aspiration and bronchiolitis), are identified as the most significant health problem in children with DS and occur 50 times more frequently as compared to the general population (6–8). A respiratory syncytial virus (RSV) infection is known to be the most common cause of pneumonia or bronchiolitis. These overwhelming numbers stand in sharp contrast with the very limited evidence on the development of DS focussed on heart and pulmonary vascular tree along with lack of evidence regarding the management and evolution of respiratory tract infections in DS. Pre-clinical studies evaluating the development of PH in a model of DS are completely missing. Indeed, there is no single animal model of DS properly characterized in terms of immunology, lung function or analysis of RV and vascular hypertrophy to resemble the human pulmonary pathologies. Considering the impact of cardiopulmonary and respiratory diseases and the incidence of PH in the DS population, our aim is to understand and evaluate development of heart and lung (vascular) system in a pre-clinical animal model of DS. We hypothesize that the Ts65Dn mice will present typical PH clinical features and that an inflammatory insult induced by a respiratory infection may further exacerbate the PH phenotype. In addition, increasing insight in the DS upregulated molecular pathways we expect to gain a view on the pathways that may drive the development of PH in the DS population. Using a Ts65Dn mouse model, which is widely used for DS research, our preliminary data showsindeed that trisomic mice have right ventricular hypertrophy after 7 months indicating development of PAH, a lower percentage of T and B-lymphocytes and increased non-aerated lung volumes on microcomputed tomography (µCT), which may indicate potential lung pathologies against a background of altered immune status. This project will provide for the first time, detailed insight into the lung pathophysiology of DS and occurrence of PH in a pre-clinical setting. Our research will fill a significant knowledge gap, not only for the DS community, but also for research into PAH and in the context of lung diseases in general. Our research group has the required experience to capitalize pre-clinical investigations towards unravelling the pathophysiology of PAH and develop novel therapeutic strategies. While the focus of this project will be on the Ts65Dn model, the methods developed herewith can be easily applied and transferred to other existing DS mouse models including the Dp16 model in collaboration with Dr. C. Galambos (university of Colorado). This research is relevant for both the PAH and DS population since potential DS modulatory agents can be assessed. Furthermore, the effect and use of PAH-specific therapies in a DS individual is unexplored but important for the management of this specific subpopulation of PH-patients.