Developmental Origins of Cardiovascular Dysfunction – Doomed From Birth? –
論文ID: CJ-16-0207
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論文ID: CJ-16-0207
One of the most intriguing medical findings in the past 30 years was the observation by Barker and colleagues that one’s birth weight can dictate future ischemic heart disease.1 This finding suggests that one may not have complete control over one’s health; rather, it is influenced and possibly preprogrammed by a likely combination of parental genetics2 and the intrauterine environment. Barker’s findings also gave rise to a broad new field of medical research into the developmental origins of health and disease (DOHaD). Researchers have explored the hypothesis that fetal programming/intrauterine environment influences the long-term development of multiple pathological conditions, including renal disease, cancer, neurological disorders, diabetes, obesity, metabolic syndrome, and cardiovascular diseases.3 These studies are beginning to provide a framework to better understand the effect of early life events on disease risk and to guide the search for early interventions in order to delay or prevent chronic disease.
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Small for gestational age (SGA) is defined clinically in the USA as having a birth weight below the 10th percentile for gestational age. Risk factors for SGA include fetal infection, multiple gestation, and genetic abnormalities, as well as maternal medical conditions and/or exposures, which can have a significant effect on the fetal environment. Thus, being SGA itself provides an indirect view of the adequacy of the fetal environment and how a “hostile” environment may affect both the short- and long-term health of the newborn. Barker and his colleagues showed that impaired fetal growth led to increased adult mortality from cardiovascular disease,4,5 as well as an increased risk for adult hypertension.6 Although the effect of poor nutrition in utero alters fetal metabolism and likely plays a key role in programming risk for cardiovascular disease, it is also postulated that being SGA can lead to rapid, neonatal weight gain (known as catch-up growth), resulting in disordered metabolism in the early postnatal period (reviewed by Kerkhof et al7). Indeed, a Danish cohort showed that weight gain during the first 3 months of life in SGA infants positively correlated with indices of insulin resistance, lipid levels and systolic blood pressure during adolescence.8 Even normal weight children who were SGA had elevated indices of insulin resistance and markers of oxidative stress as compared to non-SGA children.9
Although the long-term risk of cardiovascular-related morbidity and mortality in adults previously SGA is now clear (Figure), the underlying mechanisms for this phenomenon are only just beginning to emerge. In this issue of the Journal, Faienza et al10 explore changes in cardiovascular function in a cohort of Italian children (mean age, 10 years) who were previously severely SGA (birth weight and/or length <3rd percentile) and who had similar catch-up growth. They reported impairments in carotid intima-media thickness (IMT), flow-mediated dilation, cardiac dysfunction (increased LV ejection fraction (EF), LV and RV TEI indices, and left and right E/A ratio; decreased TAPSE and E/e’) and HOMA-IR, an index of insulin resistance. It is interesting to note that mild cardiac dysfunction at this mid-childhood time point was suggested by increased LV and RV TEI indices, which are load- and heart-rate sensitive measures of global cardiac function.11 This was coupled with pseudonormal diastolic filling in the presence of slightly improved, albeit normal, EF. Faienza’s data also suggest potentially important differences between right and left ventricular dysfunction; although both appear to have mild diastolic dysfunction (E/A, E/e’), RV systolic function may be slightly impaired whereas LV systolic function is slightly improved, but within normal limits. As the authors appropriately point out, because of its ability to detect early subtle changes in cardiac dysfunction, the future use of speckle tracking for the assessment of myocardial strain may help resolve these differences in both SGA patients and patients who were previously SGA.
Summary of how the study by Faienza et al fits into current SGA-associated cardiovascular disease literature. Severe SGA is associated with early cardiovascular structure-function impairments and possibly long-term risk of cardiovascular disease (CVD) and mortality from CVD. The developmental origins of health and disease (DOHaD) model proposes earlier intervention that may further mitigate cardiovascular risk. SGA, small for gestational age.
Though early cardiovascular pathophysiology, including increased IMT12 and cardiac dysfunction,13,14 has been previously reported in infants and young adults born SGA, the current study by Faienza et al is the first to look in detail at cardiovascular changes in SGA children as they approach adolescence. Whether these specific childhood cardiovascular alterations are transient or fully persist into adulthood to account for increased mortality remains to be fully determined. Based on the current study and recent literature, one might speculate that these changes start early and do persist unresolved into adulthood and, in a sense, prime an individual to have exacerbated responses to other environmental exposures such as an unhealthy diet. One other important issue is the degree of SGA severity. Although some studies use <10th percentile as the clinical standard for SGA, the current and other studies incorporated data from previously SGA patients who were <3rd percentile for body weight/length. This naturally begs the question, “Does SGA severity influence cardiovascular structure-function relationships and mortality?” The next logical step of investigation may be to determine the links among SGA severity, the temporal assessment of cardiovascular pathophysiology, and long-term risks that lead to poor cardiovascular outcomes and mortality.
Although the long-term risk of being SGA is clear, the future holds hope that someone who is SGA is not inextricably doomed from birth. Several studies have already shown a benefit of exercise training in reversing the long-term implications of being SGA. This is particularly evident in studies showing that the inverse relationship between birth weight and insulin resistance in a group of low-activity adolescents was attenuated in the high-activity adolescents.15 Continuing studies such as this will help to determine the extent that lifestyle choices can affect SGA-associated cardiovascular risk. Thus it is reasonable to anticipate that both pharmacological and nonpharmacological therapies directed at improving metabolism or reducing oxidative stress may mitigate SGA-associated cardiovascular risk (Figure). Furthering the work presented here by Faienza and colleagues through implementation of such therapies will help usher in a new area of preventative medicine, one that includes both prenatal and postnatal risk assessments.
This work was supported by the American Heart Association (15GRNT2579003 to A.J.T.), the National Institutes of Health (K99/R00HL116769 to A.J.T.), and Nationwide Children’s Hospital (to M.D.T. and A.J.T.). The authors thank Dr Mary J. Cismowski for her assistance with this manuscript.
None.
NIH/NHLBI K99/R00 Pathway to Independence Award (to A.J.T.). AHA Grant-in-Aid (to A.J.T.). Nationwide Children’s Hospital (to M.D.T. and A.J.T.).
