It Takes Three to Tango

The risk factors of cardiovascular disease (CVD) are thought to be well known, but the relative importance of nature versus nurture continues to be debated. Although sex, family history, and genetic susceptibility are recognized as playing a major role, most attention has focused on lifestyle risk factors because of the substantial clinical benefits achievable—and achieved—by preventing or treating hypercholesterolemia, diabetes mellitus, hypertension, obesity, and smoking. In addition to genetically determined and postnatal risk factors, during the past 2 decades, developmental programming has emerged as a potential determinant of CVD. The concept that adult CVD is influenced by the conditions encountered by the developing fetus in utero originated largely from the observation by Barker and colleagues1 that low birth weight was associated with increased CVD. This prompted a flurry of epidemiological studies, the majority of which supported the association of birth weight with CVD and hypertension,2,3 whereas the association with type 2 diabetes mellitus remains more controversial.4,–,6 Later studies highlighted the need to differentiate low birth weight resulting from premature birth from true intrauterine growth restriction and established that the CVD risk is in fact associated with birth weight adjusted for gestational length.7Article see p 2792Unfortunately, the original Barker hypothesis has yielded only limited mechanistic insights and no translational benefits as of yet. The difficulty in identifying the underlying mechanisms stems largely from the fact that birth weight is an outcome of pregnancy and does not result from a uniform pathogenic condition in utero. Epidemiological studies of populations born during prolonged hunger periods established undernutrition as a cause of low birth weight,8 but many other pathogenetically diverse factors can result in low birth weight, such as severely protein-deficient diets, mechanical obstructions of the uterine artery, corticosteroid treatment, and …