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,1
* Departments of Obstetrics/Gynecology and Physiology, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada; and
Physiology, Centre for the Early Origins of Adult Health, School of Molecular and Biomedical Science, University of Adelaide, South Australia, Australia
2Correspondence: 232 HMRC, Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail: sandra.davidge{at}ualberta.ca
SPECIFIC AIMS
A series of epidemiological studies have demonstrated that intrauterine growth restriction (IUGR) is associated with an increased risk of developing cardiovascular disease in adult offspring. The etiology of clinical IUGR is variable; however, in the majority of instances fetal growth is ultimately constrained by a limitation of oxygen and/or nutrient delivery. The mechanisms that underlie the association between prenatal growth and adult cardiovascular health must be defined before therapeutic approaches to reduce the cardiovascular risk associated with IUGR can be developed. Currently, the impact of IUGR on the structure and function of the adult heart is unclear. The aim of this study was to determine the effects of reduced oxygen and/or nutrient supply during late gestation on ultrastructural components of the adult heart, and further, to determine whether such changes are associated with increased cardiac susceptibility to ischemia/reperfusion injury.
PRINCIPAL FINDINGS
1. Left ventricular hypertrophy occurred in male adult offspring where IUGR resulted from maternal hypoxia but not from maternal undernutrition
In this study, fetal substrate supply was decreased by reducing maternal inspired oxygen to 12% during the last week of pregnancy (IUGR-H) in rats. Exposure to hypoxia also decreased food intake in pregnant rats. Therefore, in order to assess whether the cardiac effects of IUGR due to prenatal hypoxia combined with reduced food intake (undernutrition) were distinct from the effects of undernutrition alone, we also assessed the cardiac effects of equivalent maternal undernutrition (IUGR-NR) alone. While left ventricular hypertrophy was observed in IUGR-H offspring at 4 and 7 mo, the ratio of left ventricular wt: body wt in IUGR-NR offspring was not different from controls at either 4 or 7 mo. Interestingly, these results were consistent with our previous observations in neonatal rat offspring, where maternal hypoxia, but not nutrient restriction, during pregnancy increased relative neonatal heart weight. The present results therefore further suggest that there is a specific impact of prenatal hypoxia, or the combination of hypoxia and undernutrition, on adult heart mass compared to nutrient restriction alone.
2. The cardiac expression of structural proteins implicated in pathological left ventricular remodeling was greater in IUGR offspring
When the ultrastructural composition of cardiac tissue was assessed, the left ventricular expression of structural proteins that have been implicated in pathological cardiac remodeling was increased by IUGR in a remarkably consistent pattern. At 4 mo, the ratio of ßbeta; to 
myosin heavy chain (MHC) protein (Fig. 1
) and the expression of collagen I and III were all increased in only IUGR-H offspring. At 7 mo, however, the expression of all three proteins was increased in both IUGR-H and IUGR-NR offspring relative to control offspring. When fibrillar collagen structure was assessed by scanning electron microscopy, the collagen weave matrix also demonstrated thickened fibrillar strands, increased density and increased intrafibrillar connections in only IUGR-H offspring at 4 mo, but in both IUGR-H and IUGR-NR offspring at 7 mo. These results suggest that whether fetal growth is restricted by a combined reduction in oxygen and nutrition, or reduced nutrition alone, the adult heart of IUGR offspring undergoes pathological remodeling.
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3. The cardiac expression of matrix metalloproteinase-2 was reduced in IUGR offspring
Consistent with the observed changes in structural protein expression, the expression of matrix metalloproteinase-2 (MMP-2) was lower only in IUGR-H offspring at 4 mo, while at 7 mo, MMP-2 expression was lower in both IUGR-H and IUGR-NR offspring relative to control. A reduction in MMP activity is consistent with the observed accumulation of collagen.
4. IUGR resulted in diastolic dysfunction in hearts from adult offspring consistent with left ventricular stiffening
The functional cardiac consequences of impaired prenatal development were assessed using a working heart preparation. At 4 mo, IUGR-H offspring exhibited diastolic dysfunction, indicated by decreased –dp/dt and increased left ventricular end diastolic pressure (LVEDP), which was consistent with left ventricular stiffening. By 7 mo, diastolic dysfunction was observed in both IUGR-H and IUGR-NR offspring relative to control. The impairments in baseline cardiac function in the IUGR groups are consistent and corroborate with the observed pathological structural remodeling in the left ventricular wall.
5. IUGR impaired functional recovery from global ischemia in a manner consistent with the observed remodeling in left ventricular tissue
Functional recovery from 20 min global ischemia was impaired in only hearts from IUGR-H offspring at 4 mo relative to control or IUGR-NR at this age (Fig. 2
A, B). Similar to the structural and functional differences observed at 7 mo, recovery from ischemia was impaired in hearts from both IUGR-H and IUGR-NR offspring relative to control (Figure 2A
).
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CONCLUSIONS AND SIGNIFICANCE
The significant and novel findings of this study were that the restriction of fetal substrate supply during development resulted in pathological ultrastructural changes in left ventricular cardiac tissue. Furthermore, the changes in cardiac structure observed in all instances were associated functionally with increased left ventricular stiffness consistent with diastolic dysfunction and increased sensitivity to ischemia/reperfusion injury.
In this study, comparison of the effects of reduced oxygen combined with reduced nutrition vs. nutrient restriction alone allowed further investigation into how the etiology of fetal growth restriction may influence the adult cardiovascular outcomes. The clinical causes of IUGR are diverse; however, ultimately growth restriction occurs in the majority of cases through a limitation of either fetal oxygen and nutrient delivery, or nutrient delivery alone. While the time course of pathological cardiac remodeling differed in IUGR-H and IUGR-NR offspring, in this study, both protocols led to a similar degree of cardiac impairment by 7 mo of age. These data therefore indicate that whether IUGR results from a reduction in fetal oxygen and nutrient availability, as occurs during placental insufficiency, or from reduced maternal nutrient supply alone, the structure and function of the adult heart is impaired later in life (Fig. 3
). Remodeling may therefore represent a central pathway in the pathogenesis of impaired diastolic function and increased cardiac ischemia/reperfusion injury susceptibility following IUGR. Further studies are required, however, to identify the pathways that initiate cardiac remodeling when prenatal growth is impaired, and to define how these pathways may interact with the normal processes of aging.
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Hypertrophy and remodeling
We have previously reported that, at birth, relative heart weight was increased in IUGR-H pups compared to control or IUGR-NR pups. Consistent with this observation, relative left ventricle weight was increased in only IUGR-H offspring, at both ages studied, which may further suggest a specific effect of prenatal hypoxia on heart development. Interestingly, however, pathological left ventricular remodeling occurred in both IUGR-H and IUGR-NR offspring, although hypertrophy was observed only after prenatal hypoxia. Moreover, fetal growth restriction results in changes in the ßbeta;/ myosin heavy chain ratio in left ventricular tissue of adult offspring. Although MHC- expression predominates in healthy rat cardiac tissue, a transition to greater MHC-ßbeta; expression occurs during pathological remodeling. This is associated with a change in cardiac functional characteristics, including slower and less efficient contraction. The increased collagen deposition and increased fibrosis observed within left ventricular tissue from IUGR offspring may have further increased ventricular stiffness, and thus impaired diastolic heart function. The ability of the heart to respond to mechanical and chemical stimuli is influenced by the delicate balance between synthesis and degradation of extracellular structural components of extracellular matrix, which therefore has a significant impact on cardiac function. As we observed increased collagen deposition, fibrosis, and reduced MMP-2 expression in both IUGR-H and IUGR-NR offspring, our data suggest that this balance may be perturbed by a reduced oxygen and/or nutrient supply in utero such that inappropriate cardiac remodeling is favored.
Heart function and recovery from ischemia/reperfusion injury
The reduced –dp/dt, and higher left ventricular end diastolic pressures observed in IUGR-H offspring at both ages, and IUGR-NR offspring at 7 mo were consistent with increased left ventricular stiffness, and therefore corroborate well with the pattern of ultrastructural changes observed in each group. In addition, in both IUGR-H and IUGR-NR offspring, cardiac remodeling and diastolic dysfunction were associated with impaired functional recovery from ischemia/reperfusion injury, as well as greater tissue damage. To our knowledge, these data are the first to describe the impact of undernutrition during pregnancy on adult heart function, or sensitivity to ischemia-reperfusion injury. The progressive diastolic dysfunction observed in IUGR-H and IUGR-NR offspring in this study suggests that specific structural remodeling in the left ventricle following impaired prenatal development resulted in the diastolic functional changes observed, and likely contributed to the sensitization toward ischemic tissue injury.
Regression of cardiac remodeling improves the prognosis of patients with cardiovascular disease. These results have therefore identified a potentially modifiable mechanism, whereby impaired growth in utero may increase the susceptibility to adverse cardiovascular events in adult life. Further, this mechanism is relevant whether impaired fetal growth is the consequence of reduced oxygen and nutrient supply, as occurs in placental insufficiency, or maternal malnutrition alone, and therefore is relevant to the majority of cases of intrauterine growth restriction. Importantly, the prevention or regression of left ventricular hypertrophy and remodeling may reduce the risk of later cardiovascular disease in individuals whose growth was restricted in utero, and therefore represent one therapeutic approach to reduce the cardiovascular risk associated with IUGR.
FOOTNOTES
1 These authors contributed equally to this work 
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-4917fje
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