Tetralogy of Fallot (TOF) is the most common form of cyanotic heart disease (1). Prior to surgical repair, which usually occurs within the first 6 months of life, affected infants have pressure overload on the right ventricle of the heart and can have episodic or persistent hypoxia. The resulting hypoxic and pressure-induced stress may have lasting effects on the structure and function of the heart. After surgical repair, which involves closing a ventricular septal defect and widening the right ventricular outflow tract to the pulmonary artery, the hypoxia is relieved and the pressure dramatically reduced. Unfortunately, the widened outflow tract leads to leakage of ejected blood back into the right ventricle. Over time, this pulmonary insufficiency causes progressive ventricular dysfunction that will eventually require placement of a competent valve between the right ventricle and the pulmonary artery (2). The rate at which this dysfunction progresses can vary from one patient to the next, and clinical determination of how to time valve replacement to preserve ventricular function and exercise tolerance has been challenging (3). The variable and often unpredictable clinical course suggests that individual differences in how patients with TOF respond to their heart condition or the surgical repair may be important in determining when valve replacement will be necessary and how effective the surgery will be in improving a patient’s clinical condition.
Therefore, in their paper “Genetic determinants of right ventricular remodeling after tetralogy of Fallot repair,” Jeewa et al. (4) have made an important contribution to our understanding of what some of those individual differences may be and provide insight into why the progress of the right ventricular dysfunction seems to vary between patients. Given the importance of Hypoxia Inducible Factor, 1 alpha (HIF1A), a hypoxia-inducible transcription factor, in regulating the expression of a broad range of downstream genes in response to hypoxia (5,6), the study team examined the correlation between genetic markers associated with enhanced HIF1A expression and (i) the degree of fibrosis at the time of surgical repair and (ii) the right ventricular structure and function during postoperative follow-up. They noted that low-expression HIF1A variants were associated with less fibrosis at the time of surgery but enhanced adverse ventricular remodeling after surgical repair. This suggests that individual differences in genetic pathways that govern the hypoxic stress response may have an important role in determining clinical course. Although additional studies will need to be performed to confirm this finding, it raises the important possibility that clinicians may be able, using focused genetic tests, to identify patients who are at risk for more rapid development of irreversible ventricular dysfunction and treat them patients according to their risk.