SAN FRANCISCO – The renin-angiotensin system (RAS) is out of balance in adolescents born prematurely, according to investigators from Wake Forest School of Medicine in Winston-Salem, N.C.
Among other findings, the amount of circulating angiotensin 1-7, a vasodilator that counteracts the vasoconstrictive and other effects of angiotensin II, was lower relative to angiotensin II in 175 subjects born preterm and assessed at age 14 years, compared with 51 controls born at term.
The findings suggest a possible explanation for why people born prematurely have an increased risk for hypertension and cardiovascular disease, which has been a mystery. If the findings pan out with additional research, they also suggest potential therapeutic targets to attenuate the risk, namely upregulating angiotensin 1-7 and blocking angiotensin II, either at birth or later.
Dr. Andrew South
“If you could give medications to shift the balance in the RAS back to what it should be, then maybe you could prevent some of the changes that we see at age 14. With the current treatments, that’s difficult; ACE inhibitors and angiotensin II receptor blockers are (generally) not used in the neonatal period because they can precipitate acute kidney injury.” For older patients, “there’s no indication to use these medications in a subtle situation like we have here,” Dr. South said in an interview at a hypertension science meeting jointly sponsored by the American Heart Association and the American Society of Hypertension.
The direct manipulation of angiotensin 1-7 remains, for now, largely in the realm of clinical research.
The preterm subjects had lower plasma angiotensin II and lower angiotensin 1-7 concentrations, compared with their term peers, but an overall increase in the angiotensin II/angiotensin 1-7 ratio (4.2 vs. 2.4). Preterm subjects also had increased urinary excretion of angiotensin 1-7. The findings were statistically significant, and adjusted for potential confounders.
The differences were exaggerated in obese subjects, about a third in both groups. Obesity is known to be associated with increased angiotensin II activity.
The drop in angiotensin 1-7 was greater in preterm girls than in boys, which was curious because female sex is normally associated with decreased angiotensin II activity, and estrogen normally upregulates angiotensin 1-7; perhaps in prematurity, there’s a breakdown in the normal response to estrogen, Dr. South said.
Whatever the case, it’s possible the risk of hypertension and cardiovascular disease from preterm birth might be especially high in obese patients and women, he said.
The preterm group had a mean gestational age of 28 weeks, and a mean birth weight of 1.1 kg. The term group was born at a mean of 40 weeks, with a mean birth weight of 3.5 kg. At age 14 years, preterm subjects were shorter and weighed less than their peers.
Mean systolic and diastolic blood pressures were higher in the preterm group, and 21 preterm subjects (12%) had blood pressures at or above 120/80 mm Hg, vs. one subject (2%) in the term group.
Maternal hypertension and smoking during pregnancy, and C-section delivery, were far more common in the preterm group, as was Medicaid use at age 14 years. There were slightly more girls than boys in both groups, and just over 40% of the subjects in each were black.
The Wake Forest team continues to follow their preterm subjects, who are now in their mid-twenties. “If we can correlate what we found at age 14 with” early development of disease, “it will give us more of an indication that this is actually true causation, not just an association,” Dr. South said.
The investigators had no industry disclosures. The work was funded in part by the National Institutes of Health.