Several studies have been designed to determine whether adults that were undergrown as fetuses have persistently impaired endothelial function. Using forearm plethysmography techniques, Leeson et al3
and Goodfellow et al4
both found deficits in endothelial function using similar techniques in young adults. McAllister et al5
found evidence of endothelial injury in adults that were undergrown at birth based upon increased plasma von Willebrand factor, but did not find a deficit in the vasodilatory acetylcholine response. Hermann et al6
found a reduced insulin stimulated glucose uptake in the forearms of 20 year olds that were born small. Studies in adult rats have also shown endothelial dysfunction associated with either maternal protein restriction7
or reduced uterine blood flow during prenatal life.8
In summary, these studies suggest that global endothelial function is compromised in humans and animals that were stressed during fetal life or under grown at birth. It is well known that compromised endothelial function may lead to increased risk for coronary disease.9,10
However, it has not yet been shown that fetal undergrowth or nutritional deprivation lead to coronary endothelial dysfunction as a precursor to adult onset coronary disease.
During embryonic and fetal life, many different conditions including a small placenta can lead to diastolic or systolic pressure loading of the heart. The immature myocardium is able to respond to changes in loading condition. Applying a moderate (Pinson et al11
) or severe (Barbera et al12
) pressure load to the right ventricle (RV) of the sheep fetus leads to right ventricular thickening and improves right ventricular function considerably. For example, an acute 20 mm Hg increase in pulmonary arterial (PA) pressure will reduce the stroke volume of the normal fetal right ventricle by about 50%. However, after 7–10 days of increased mean PA pressure by 10 mm Hg pressure, the stroke volume will be reduced by only ~10% with the same 20 mm Hg increase. Is there a long term cost associated with such accommodation?
Ordinarily, the ventricular myocardium grows by hyperplastic growth (cell replication with relatively constant cardiomyocyte volume) from the time that the embryonic heart is formed until the myocardium reaches a stage of maturity where cardiomyocytes exit the cell cycle (so called “terminal differentiation”). In sheep, rats, and mice this phase is accompanied by the formation of a second nucleus in each cell (binucleation). We now know that mononucleated cells are able to proliferate but are not able to enlarge to any great degree.13,14
On the other hand, binucleated cardiomyocytes are not able to divide but can enlarge. Thus, as the population of cells within the myocardium becomes binucleated, the generative potential of the myocardium decreases. Loading leads to a dramatic increase in the portion of cardiomyocytes carrying two nuclei indicating a net reduction in the portion of cardiomyocytes that can divide. These findings raise the question of whether the total number of cardiomyocytes will be reduced for life.