Preterm (PT) birth is defined as being born at less than 37 weeks gestation.
Although the incidence of PT birth has decreased in recent years, as of 2014, 9.6%
infants were born PT.1 Additionally, 1.4% of all live births in the U.S. are very low
birth weight (VLBW < 1500g).2 PT infants are at a higher risk of infant death
compared to healthy term born peers, with PT birth accounting for 1/3 of infant
mortality.1,3 Survivors of PT birth face a number of short and long-term
consequences including respiratory, neurodevelopmental, and cardiovascular
complications, in addition to increased mortality.3
Adults born PT have been shown to have higher incidence of hypertension
(HTN) and mortality due to cardiovascular disease (CVD) risk when compared with
healthy term born peers.4,5 This relationship may be partly attributable to the fetal
origins of adult disease (FOAD) hypothesis, which proposes that adverse events
during key developmental windows alter organ system structure and function that
promotes survival in the short-term, but may be detrimental in the long-term,
leading to higher risk for developing chronic diseases such as hypertension,
cardiovascular disease, and diabetes later in life.6,7
The kidney is one organ system that may be affected, and is especially
important in terms of blood pressure (BP) regulation. Nephrogenesis begins by 9
weeks gestation, however kidney formation is not complete until around 32-36
weeks.8 Both animal and human studies indicate that PT birth is associated with
reduced nephron number, which may lead to hypertension.8,9 There is growing
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evidence that the renin angiotensin system (RAS), another key component of BP
control, may also be affected by both PT birth, as well as kidney development.10–13 In
RAS, Angiotensin II (Ang II) acts as a vasoconstrictor, ultimately raising BP, whereas
Angiotensin 1-7 (Ang 1-7) acts as a vasodilator and lowers BP.14,15 High levels of
Ang II is associated with higher blood pressure, and chronic diseases such as CVD
and diabetes; on the other hand Ang 1-7 has been shown to have cardio protective
effects.16 When compared with healthy term born peers, adults born PT and/or
VLBW have been shown to have elevated levels of plasma Ang II, in addition to
elevated levels of angiotensin converting enzyme (ACE; the enzyme that converts
ANGI to AngII), ultimately implicating RAS as having a role in developing HTN
within this population.10,11,13
Preterm birth has also been associated with reduced cardiorespiratory
fitness as well as participation in physical activity (PA).17,18 It is well established
that individuals who participate in more PA, or have higher aerobic fitness, are at
lower risk of developing hypertension and other cardio metabolic diseases.19–22
Consequently, lower PA and aerobic fitness may put this predisposed population at
even greater risk for developing HTN and other diseases.17,23–25
Little research has been done examining the influence of PA and fitness on
RAS, with no studies examining these relationships in PT populations. A metaanalysis
examining the effects of exercise on RAS found lower plasma renin activity
post aerobic training.26 Additionally, one animal model demonstrated that rats
exposed to a 16 week PA program had lower levels of ACE, Ang II, and BP when
compared to rats that did not participate in PA.27 If this same relationship exists in
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humans, then adults born PT who participate in PA and have higher cardio
respiratory fitness (CRF) may have more favorable RAS, and subsequently lower BP
and HTN risk.
In summary, there is some evidence that being born PT and/or VLBW is
associated with higher ACE and Ang II levels10,11,13 which in turn has been associated
with hypertension and other cardiometabolic diseases. There is evidence that
PT/VLBW persons have lower PA and fitness, which is also associated with higher
BP and other chronic diseases.19,20,23,24 Lastly, there is evidence in animal models
that PA may decrease the ACE/Ang II levels.27 However, to date no study has
examined the influence of PT birth on RAS and the role that fitness and PA may have
on its association.
Therefore, the aims of this study are to examine RAS in PT/VLBW
adolescents compared to their term-born peers, and the potential mediating
influence of PA and fitness on the association between PT birth and RAS.
Understanding this relationship may help to determine preventative or therapeutic
strategies for this at risk population.