Congenital Heart Disease: An Immunological Perspective

Abstract

Congenital heart disease (CHD) poses a significant global health and economic burden-despite advances in treating CHD reducing the mortality risk, globally CHD accounts for approximately 300,000 deaths yearly. Children with CHD experience both acute and chronic cardiac complications, and though treatment options have improved, some remain extremely invasive. A challenge in addressing these morbidity and mortality risks is that little is known regarding the cause of many CHDs and current evidence suggests a multifactorial etiology. Some studies implicate an immune contribution to CHD development; however, the role of the immune system is not well-understood. Defining the role of the immune and inflammatory responses in CHD therefore holds promise in elucidating mechanisms underlying these disorders and improving upon current diagnostic and treatment options. In this review, we address the current knowledge coinciding CHDs with immune and inflammatory associations, emphasizing conditions where this understanding would provide clinical benefit, and challenges in studying these mechanisms.

Keywords: congenital heart disease; immune response; inflammation; models of CHD; primary immunodeficiency.

Figure 1

Overview of congenital structural heart defects associated with immune or inflammatory reactions. Congenital heart diseases are conditions present at birth and are mainly comprised of abnormalities in the development of the heart chambers, valves, or the conduction system, or the persistence of congenital structures that typically involute after birth. The heart defects depicted here are examples of those associated with an immune cause or reactive inflammatory changes, many of which are associated with genetic and immune syndromes.

Figure 2

Immune mechanisms causing congenital heart disease. autoimmune and infectious causes have been identified as factors in the development of some CHDs, including congenital heart block (CHB) and congenital rubella syndrome. (A) In CHB, maternal autoantibodies target fetal cardiac proteins, causing conductive tissue damage. (B) In congenital rubella syndrome, the virus can target endothelial cells during cardiogenesis, preventing normal developmental processes and creating structural defects.

Figure 3

Genetic syndromes associated with CHDs and altered immune responses. Though many genetic syndromes are associated with both immune deficiencies and CHDs, they are not linked directly. (A) In DiGeorge Syndrome, the abnormal development of the pharyngeal arches, the precursor structure for both the heart and thymus, leads to mature T-cell deficiency and cardiac defects. (B) Down Syndrome is commonly associated with cardiac septal defects and an increased propensity for infections in childhood. Though the associations are unclear, the alterations in immune response are evidenced by the greater prevalence of immune cell malignancies. (C) In Turner Syndrome, children can have CHDs, including bicuspid aortic valve and aortic damage, as well as immune complications, such as autoimmune disease. A connection between the cardiac and immune systems is seen in the inflammatory complications of the bicuspid valves, which undergo premature immune-mediated calcification, and induce a systemic pro-inflammatory state.