The contribution of cell generation to physiological heart growth and maintenance in humans has been difficult to establish and has remained controversial. We report that the full complement of cardiomyocytes is established perinataly and remains stable over the human lifespan, whereas the numbers of both endothelial and mesenchymal cells increase substantially from birth to early adulthood. Analysis of the integration of nuclear bomb test-derived (14)C revealed a high turnover rate of endothelial cells throughout life (>15% per year) and more limited renewal of mesenchymal cells (<4% per year in adulthood). Cardiomyocyte exchange is highest in early childhood and decreases gradually throughout life to <1% per year in adulthood, with similar turnover rates in the major subdivisions of the myocardium. We provide an integrated model of cell generation and turnover in the human heart.

Restriction of maternal protein intake during rat pregnancy produces offspring that are hypertensive in adulthood, but the mechanisms are not well understood. Our purpose was to determine whether this adult hypertension could be programmed during development by suppression of the fetal/newborn reninangiotensin system (RAS) and a consequent reduction in nephron number. Pregnant rats were fed a normal protein (19%, NP) or low-protein (8.5%, LP) diet throughout gestation. Birth weight was reduced by 13% (p Ͻ 0.0005), and the kidney/body weight ratio was reduced in LP pups. Renal renin mRNA levels were significantly reduced in newborn LP pups; renal renin concentration and renin immunostaining were suppressed. Renal tissue angiotensin II levels were also suppressed in newborn LP (0.079 Ϯ 0.002 ng/mg, LP versus 0.146 Ϯ 0.016 ng/mg, NP, p Ͻ 0.01). Mean arterial pressure in conscious, chronically instrumented adult offspring (21 wk) was higher in LP (135 Ϯ 1 mm Hg, LP versus 126 Ϯ 1 mm Hg, NP, p Ͻ 0.00007), and GFR normalized to kidney weight was reduced in LP (p Ͻ 0.04). The number of glomeruli per kidney was lower in adult LP offspring (21,567 Ϯ 1,694, LP versus 28,917 Ϯ 2,342, NP, p Ͻ 0.03), and individual glomerular volume was higher (1.81 Ϯ 0.16 10 6 m 3 , LP versus 1.11 Ϯ 0.10 10 6 m 3 , NP, p Ͻ 0.005); the total volume of all glomeruli per kidney was not significantly different. Thus, perinatal protein restriction in the rat suppresses the newborn intrarenal RAS and leads to a reduced number of glomeruli, glomerular enlargement, and hypertension in the adult. Abbreviations RAS, renin-angiotensin system ERPF, effective renal plasma flow NP, normal protein (19%) diet LP, low-protein (8.5%) diet ANGII, angiotensin II PAH, para-amino hippurate A decade ago, Barker et al. first reported an inverse relationship between birth weight and death from cardiovascular disease in adulthood (1). Subsequently, a number of epidemiologic studies in different parts of the world have found a relationship between early growth patterns and the risk of cardiovascular disease in adulthood (2-8). Although these findings remain somewhat controversial (9), the majority of evidence indicates that even within the "normal" range of birth weights, babies that are born smaller have a higher risk of death from cardiovascular disease when they reach adulthood. This indicates that some factor or factors in the perinatal environment, probably related at least in part to maternal nutrition, can "program" the individual for increased cardiovascular risk later in life. However, the precise physiologic and molecular mechanisms by which this programming occurs are unknown.Recently, a rat model of perinatal protein restriction has been identified that has several features in common with the observations in humans, suggesting that this may be a good animal model of the human condition. In particular, offspring ABSTRACT460

The number and size of glomeruli in normal, mature human kidneys were estimated by a direct and unbiased stereological method, the fractionator. The number was 617,000 on average, and the mean size 6.0 M microns3. Both glomerular number and size showed significant negative correlation to age and significant positive correlation to kidney weight. Apparently, humans loose glomeruli with age. Body surface area correlated positively to kidney weight and total glomerular volume but not to number of glomeruli. Body surface area correlates significantly with metabolic rate (Robertson and Reid, Lancet, 1: 940-943, 1952). Thus, intraspecies adaptation of kidney filtration capacity to the metabolic demand is performed by changing the size of glomeruli, i.e., the number of glomeruli in individuals of a given species is independent of the metabolic rate.

Vasodilation and increased blood flow are characteristic early vascular responses to acute hyperglycemia and tissue hypoxia. In hypoxic tissues these vascular changes are linked to metabolic imbalances associated with impaired oxidation of NADH to NAD+ and the resulting increased ratio of NADH/NAD+. In hyperglycemic tissues these vascular changes also are linked to an increased ratio of NADH/NAD+, in this case because of an increased rate of reduction of NAD+ to NADH. Several lines of evidence support the likelihood that the increased cytosolic ratio of free NADH/NAD+ caused by hyperglycemia, referred to as pseudohypoxia because tissue partial pressure oxygen is normal, is a characteristic feature of poorly controlled diabetes that mimics the effects of true hypoxia on vascular and neural function and plays an important role in the pathogenesis of diabetic complications. These effects of hypoxia and hyperglycemia-induced pseudohypoxia on vascular and neural function are mediated by a branching cascade of imbalances in lipid metabolism, increased production of superoxide anion, and possibly increased nitric oxide formation.