Appraising the Preclinical Evidence of the Role of the Renin-Angiotensin-Aldosterone System in Antenatal Programming of Maternal and Offspring Cardiovascular Health Across the Life Course: Moving the Field Forward: A Scientific Statement From the American Heart Association

Abstract

There is increasing interest in the long-term cardiovascular health of women with complicated pregnancies and their affected offspring. Emerging antenatal risk factors such as preeclampsia appear to increase the risk of hypertension and cardiovascular disease across the life course in both the offspring and women after pregnancy. However, the antenatal programming mechanisms responsible are complex and incompletely understood, with roots in alterations in the development, structure, and function of the kidney, heart, vasculature, and brain. The renin-angiotensin-aldosterone system is a major regulator of maternal-fetal health through the placental interface, as well as kidney and cardiovascular tissue development and function. Renin-angiotensin-aldosterone system dysregulation plays a critical role in the development of pregnancy complications such as preeclampsia and programming of long-term adverse cardiovascular health in both the mother and the offspring. An improved understanding of antenatal renin-angiotensin-aldosterone system programming is crucial to identify at-risk individuals and to facilitate development of novel therapies to prevent and treat disease across the life course. Given the inherent complexities of the renin-angiotensin-aldosterone system, it is imperative that preclinical and translational research studies adhere to best practices to accurately and rigorously measure components of the renin-angiotensin-aldosterone system. This comprehensive synthesis of preclinical and translational scientific evidence of the mechanistic role of the renin-angiotensin-aldosterone system in antenatal programming of hypertension and cardiovascular disease will help (1) to ensure that future research uses best research practices, (2) to identify pressing needs, and (3) to guide future investigations to maximize potential outcomes. This will facilitate more rapid and efficient translation to clinical care and improve health outcomes.

Keywords: AHA Scientific Statements; aldosterone; angiotensin-converting enzyme 2; hypertension; pre-eclampsia; pregnancy; renin-angiotensin system.

Figure 1.. Physiological roles of the RAAS in healthy and pathological pregnancies.

A, Expression and actions of the major RAAS components during healthy pregnancy. B, Expression and actions of the major RAAS components during pathological pregnancies, including preeclampsia and placental insufficiency. Ang indicates angiotensin; ACE, angiotensin-converting enzyme; AT₁R, angiotensin type 1 receptor; AT₂R, angiotensin type 2 receptor; AT₁R-AA, angiotensin II type 1 receptor autoantibody; BP, blood pressure; HTN, hypertension; PlGF, placental growth factor; PRA, plasma renin activity; RAAS, renin-angiotensin-aldosterone system; sFlt-1, soluble fms-like tyrosine kinase 1; and VEGF, vascular endothelial growth factor.

Figure 2.. Conceptual causal model of representative antenatal exposures and their effects on various tissue programming mechanisms.

Directed acyclic graph with exposures noted as green ovals with black triangles and outcome as blue oval with black vertical bar. Intermediate mechanisms as mediators on the causal path are noted as blue ovals; causal paths are noted as green arrows. White ovals are unmeasured factors; black arrows are noncausal and nonbiasing paths. HPA indicates hypothalamic-pituitary axis; LV, left ventricular; and RAAS, renin-angiotensin-aldosterone system. Figure created with www.dagitty.net.