What people with Down Syndrome can teach us about cardiopulmonary disease

Abstract

Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with cognitive impairment, congenital malformations (particularly cardiovascular) and dysmorphic features. Immune disturbances in Down syndrome account for an enormous disease burden ranging from quality-of-life issues (autoimmune alopecia) to more serious health issues (autoimmune thyroiditis) and life-threatening issues (leukaemia, respiratory tract infections and pulmonary hypertension). Cardiovascular and pulmonary diseases account for ∼75% of the mortality seen in persons with Down syndrome. This review summarises the cardiovascular, respiratory and immune challenges faced by individuals with Down syndrome, and the genetic underpinnings of their pathobiology. We strongly advocate increased comparative studies of cardiopulmonary disease in persons with and without Down syndrome, as we believe these will lead to new strategies to prevent and treat diseases affecting millions of people worldwide.

FIGURE 1

Heart and lung diseases are the leading causes of death for persons with Down syndrome. Pneumonia and infectious lung disease, congenital heart defect (CHD) and circulatory disease (vascular diseases not including CHD or ischaemic heart disease) account for ∼75% of all deaths in persons with Down syndrome. Interestingly, ischaemic cardiovascular disease accounts for only ∼7% of deaths in Down syndrome, compared to the typical population mortality rate of ∼30% (not shown). Reproduced and modified from [38] with permission from the publisher.

FIGURE 2

Research and cardiopulmonary disease in Down syndrome: opportunities for therapeutic leverage. A number of Hsa21-encoded genes affect organ homeostasis. Persons with Down syndrome have low rates of cardiovascular disease (CVD), despite elevated risk factors. In contrast, congenital heart disease (CHD) is highly prevalent in Down syndrome. Pulmonary infectious disease is the leading cause of mortality in Down syndrome, caused by both intrinsic (morphological factors) and extrinsic (immune dysfunction) factors. Listed in each organ cartoon are genes implicated in disturbed heart, lung and immune function. Research into the mechanisms of resistance to development of coronary artery disease and solid tumours inherent in persons with Down syndrome will undoubtedly benefit the larger population (i.e. therapeutic leverage). MI/CAD: myocardial infarction/coronary artery disease; AVSD: atrioventricular septal defect; RSV: respiratory syncytial virus.