History of Our Understanding of the Causes of Congenital Heart Disease.

Because the dawning of the era in which interventions for congenital heart disease (CHD) became possible, the primary intellectual framework undergirding pediatric cardiology and cardiothoracic surgery has been based on morphology and hemodynamics (henceforth, the M/H model). This model has been wildly successful, enabling practitioners to devise creative interventions for even the most complex forms of CHD. Today, we are confronting new challenges as we have awakened to the realization that longer-term outcomes for CHD, both cardiac and extracardiac, are well below earlier expectations. Relying on the M/H model that has permitted us to discover the unnatural history of CHD, our field is bringing scientific rigor to examining those outcomes and developing interventions to improve them. Although this M/H model–based approach to improving outcomes is eminently reasonable, sole reliance on it is ultimately limiting. Use of a model based on causes might enable us to envision other therapies for CHD. For example, the principal risk associated with bicuspid aortic valve is valve calcification in later adulthood. Using the M/H model, we have attributed bicuspid aortic valve–associated valve calcification to hemodynamic stresses and used surveillance of valve function to determine the timing of surgical intervention. Operating under the causation model, it was discovered that a small percentage of patients with bicuspid aortic valve harbor NOTCH1 mutations, which are associated with early valve calcification. Aside from improving prognostication, the cause-based understanding of this form of bicuspid aortic valve suggests that therapies altering NOTCH signaling might prevent the deterioration of aortic valve function. The causation model once occupied a larger role among CHD thought leaders. This period preceded the development of heart surgery and catheterization, when the only viable route seemed to be preventative strategies. Early thinkers emphasized environmental factors and, less importantly, heredity. Today, we still point to those 2 factors but think that their relative importance is reversed. Of note, the widespread belief in the role of genetics for CHD causation arose despite the facts that CHD usually arises sporadically and specific genetic defects can be identified for few affected individuals. In this review, I will explore the history of the causation model of CHD, emphasizing how we arrived at our current understanding, particularly with respect to genetics. I will then discuss how the causation model might contribute to CHD care in the future.