Influence of Genetic Polymorphisms on Ventricular Structure and Function in Patients With Single Ventricle Anatomy

In the United States, approximately 30,000 children are born with congenital heart disease every year. Between 1000 and 2000 of these children have some form of functional single ventricle anatomy, with variants of hypoplastic left heart syndrome (HLHS) comprising about half. Patients with functional single ventricle anatomy are born with a malformation that renders one of their ventricles unusable and surgically unrecoverable. In HLHS, for example, either the mitral or aortic valve can be absent or significantly stenotic, which is generally associated with marked hypoplasia of the left ventricle and the ascending aorta. Other common variants of single ventricle anatomy are tricuspid or pulmonary atresia, often associated with some degree of right ventricular hypoplasia, unbalanced atrioventricular defects, in which either ventricle can be unusable due to malposition of the interventricular septum, and the heterotaxy syndromes. All of these congenital cardiac anomalies, as well as several other less common variants, can be treated with a multi-stage surgical palliation that usually requires three surgical procedures during the first three years of life. At the completion of this series of palliative procedures the children are left with their single functional ventricle driving blood flow to the systemic circulation while their pulmonary circulation is derived from passive drainage of the systemic venous return into and through the pulmonary vasculature. This arrangement, the so-called "Fontan physiology", can provide an excellent quality of life as these children grow and enter young adulthood; however, it is by no means a normal hemodynamic arrangement and a significant percentage of children with single ventricle anatomy will fail either during the early palliative steps or at some point after they achieve final Fontan palliation.

Failure of single ventricle patients to progress through the multi-stage palliation or late failure of patients after the Fontan procedure can result from a myriad of causes. While ventricular dysfunction is a common finding in failing single ventricle patients, an anatomic reason for their clinical failure, such as myocardial ischemia or ventricular outflow obstruction, often cannot be identified. Many of these patients subsequently die or require cardiac transplantation when their single ventricle fails. Because patient outcomes are highly variable despite similar anatomy and hemodynamics, it has been suggested that genetic variability may play a role in the ability of patients to tolerate long-term single ventricle palliation.

The interaction between genetic variability and outcomes has been well documented for adult patients with cardiovascular disease. Genetic polymorphisms in the renin-angiotensin system (RAS) in particular have been well studied. The active final product of the RAS is angiotensin-II, which is produced by the sequential cleavage of angiotensinogen (AGT) by renin and angiotensin-converting enzyme (ACE). Several steps in this series of enzymatic reactions have been evaluated as candidate genes of influence for cardiovascular disorders.

Polymorphisms in the AGT gene have been associated with essential hypertension, however, a subsequent study failed to demonstrate any influence of these polymorphisms on outcome in patients with idiopathic dilated cardiomyopathy. A polymorphism in the ACE gene involving a 287-base pair insertion (I) or deletion (D) has been evaluated in several studies. The DD genotype is associated with higher serum levels of ACE and angiotensin II, increased incidence of sudden death in patients with hypertrophic cardiomyopathy, increased mortality in patients with idiopathic heart failure, and decreased exercise tolerance in patients with congestive heart failure. Meanwhile, a genetic variant in the Angiotensin II type 2-receptor (AT2-R) has been shown to influence left ventricular structure and function in young men with hypertension.

Another potentially important contributor to ventricular function that has been studied with regard to genetic polymorphism related variability is the Beta1-adrenergic receptor (Beta1-AR). The Beta1-AR is the primary myocardial receptor for the catecholamines epinephrine and norepinephrine, which increase myocardial contractility and blood pressure. Several polymorphisms in the Beta1-AR gene have been associated with an increased risk for congestive heart failure and with exercise capacity in patients with ischemic or idiopathic cardiomyopathy.

A final area of interest is the opposing system of vasodilators and vasoconstrictors that control systemic vascular tone. Two major contributors to vasomotor tone in humans are the endothelium derived vasodilator nitric oxide (NO) and the powerful vasoconstrictor endothelin-1. Endothelial NO is produced by the enzyme endothelial nitric oxide synthase (eNOS). A single base-pair polymorphism (G894T) is associated with an increased risk of vasospastic angina pectoris and with increased vascular responsiveness to phenylephrine in patients on cardiopulmonary bypass. Meanwhile, a single base-pair polymorphism in the preproendothelin-1 (pp-ET1) gene (G5665T) has been shown to increase vasomotor reactivity in human mammary arteries. This polymorphism is also associated with hypertension in overweight patients with the T allele.

While there is very little data available regarding the causes of failure in children with single ventricle anatomy, it is clear that genetic factors which influence ventricular function and the development of heart failure in adults with two ventricles could play a role in the failure of patients with one ventricle. We propose a combined retrospective and prospective evaluation of each of the candidate gene polymorphisms discussed above for potential linkage to poor outcome in children with single ventricle anatomy. Poor outcome for these children would be defined as a multi-endpoint variable including death, evaluation for heart transplantation, or the development of severe single ventricle dysfunction by echocardiographic or cardiac catheterization criteria. Identification of high-risk combinations of genetic alleles could guide therapy for patients with poor predicted outcome, possibly steering such patients towards early transplantation rather than attempted staged palliation.