Programming and the barker hypothesis

Over the past half century, cardiovascular disease has been thought to arise more from abnormal genes and poor lifestyle choices than from underlying environmental-induced vulnerability. However, studies in the field of programming suggest a different view. Barker and colleagues demonstrated that the underpinnings of cardiovascular disease such as hypertension, type 2 diabetes and obesity are the direct result of inadequate growth during the formative stages of development or from exposure to stressors including hypoxemia and/or cortisol. It is now known that there are definite stages of embryonic and fetal development when the heart and blood vessels are especially vulnerable to these stressors. The pre-septation heart of the embryo is sensitive to a long list of stressors with hypoxia, hyperglycemia and altered sheer and stretch forces. Exposure to these stressors leads to structural and epigenetic changes that underlie heart defects and/or vulnerabilities for abnormal growth thereafter. The near term stage, when cardiomyocytes are undergoing terminal differentiation represents another critical period during which exposures to hormonal, nutritional or hypoxic episodes change the number of cardiomyocytes and coronary microvessels for life and lead for vulnerability to heart failure and coronary disease. In the later stages of heart development hypoxia leads to a suppression of cardiomyocyte hyperplasia and hearts are born endowed with fewer working cells that are larger than normal and hearts are more vulnerable to ischemic damage for life. Glucocorticoids are steroid hormones that are required for normal development of the cardiovascular system but when present in excess before term can lead to programming effects in the hearts of offspring. Abused drugs like cocaine and ethanol also have specific effects on the developing myocardium. In addition, the mechanisms that protect against ischemic damage such as PKC epsilon are suppressed in males through the methylation of specific sites on the promoter. Thus, epigenetic mechanisms, including DNA methylation and histone protein modifications are key to understanding the link between the intrauterine environment and later cardiovascular vulnerability. DNA methylation plays a critical role in gene repression. Methylated cytosines recruit methyl-binding proteins that restrict binding of transcription factors to promoter regions. Histone protein modifications regulate access of transcription machinery for selected genes. Histone proteins are modified by acetylation of lysine residues via histone acetyltransferases, deacetylation of lysine residues via histone deacetylases and methylation of lysine 4 on histone H3 is generally associated with transcriptional active promoters while multiple methylation of histone restricts transcription. Thus, vulnerability for cardiovascular disease has its primary roots in prenatal life. A growing number of underlying mechanisms have been identified. However, the field is in urgent need of investigation.