Genetic and Environmental Factors Contributing to Cardiovascular Malformation: A Unified Approach to Risk

I n the late 19th century, William Osler notoriously quipped that treating infants with cardiac defects was futile, thereby encouraging Maude Abbott to pursue her rigorous studies of pathologic heart specimens. Ultimately, this work resulted in The Atlas of Congenital Cardiac Disease, which is widely regarded as the first systematic catalogue of cardiovascular malformation (CVM) and therefore the first classification system for clinical pediatric cardiology. Organizing malformations requires consideration of cause. The investigations of the etiology of CVM, also known as congenital heart disease (CHD), has advanced on 2 largely independent lines of thought: environmental or genetic. During the same time, the advent and rapid evolution of surgical intervention for these conditions defined an exquisite clinical taxonomy that was based on anatomy and physiology. Only recently have there been efforts to reconcile environmental and genetic factors in a clinically meaningful manner and integrate this information into the existing classification scheme. Classification schemes for CVM continue to present significant challenges for both clinicians and researchers. When considering cause, it is important to group lesions appropriately and avoid misclassification that may confound interpretation. To this end, classification paradigms have been developed that account for the developmental relationships of lesions, in addition to the anatomic relationships previously described, to increase confidence in grouping. The National Birth Defects Prevention Study developed an exhaustive taxonomy that organizes CVM in multiple ways, including the most specific definition of a single defect (eg, hypoplastic left heart syndrome—the so-called “splitting” approach), the most broad groupings (eg, left sided outflow tract obstruction lesions—the “clumping” approach), and an intermediate level that allows flexibility with the analysis of common associations (eg, aortic stenosis and coarctation of the aorta). Overall, a classification system that incorporates etiologic factors as well as deep phenotyping is necessary for clinical and research advances alike. In this issue of JAHA: Journal of the American Heart Association, Fung et al have made an important step toward unifying the analysis of environmental and genetic risk factors for CVM. Importantly, they have called for increased surveillance that includes a more rigorous ascertainment of risk factors in general and comprehensive integration of different types of CVM risk in particular. An important strength of the study is the use of the International Nomenclature for Congenital Heart Surgery that utilizes developmentally informed splitting and clumping approaches. This study reports both genetic risk factors (family history, genetic testing results, and the presence of extra-cardiac anomalies) and environmental risk factors (maternal health, maternal exposures, and pregnancy complications) in over 2300 pediatric patients with CVM in the present era. This approach combines exhaustive information from divergent perspectives, as opposed to an assessment of only one or the other, and analyzes genetic and environmental risk factors together, recognizing that elucidating the genetic basis of CVM will require a thoughtful assessment of environmental factors that can influence disease causation. In the age of genetics, environmental factors often are not acknowledged or recognized, or are viewed as noncontributory or secondary. However, the Baltimore Washington Infant Study (BWIS) and others have reported clear associations between CVM and a variety of environmental factors, including diabetes and retinoic acid. Prenatal risk factors are broadly defined as something that increases the chances of developing a disease. Risk factors contribute to the manifestation of disease; they may or may not cause disease. In the context of this study, clinical risk factors for CVM have been grouped as maternal health (age, prepregnancy BMI, type 1 diabetes status), maternal exposures (smoking, medications, chemicals), and complications of pregnancy The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From The Heart Institute, Division of Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH. Correspondence to: Robert B. Hinton, MD, the Heart Institute, Division of Cardiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 2003, Cincinnati OH 45229. E-mail: [email protected] J Am Heart Assoc. 2013;2:e000292 doi: 10.1161/JAHA.113.000292. a 2013 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.