Mechanisms linking preterm birth to onset of cardiovascular disease later in adulthood

Abstract

Cardiovascular disease (CVD) rates in adulthood are high in premature infants; unfortunately, the underlying mechanisms are not well defined. In this review, we discuss potential pathways that could lead to CVD in premature babies. Studies show intense oxidant stress and inflammation at tissue levels in these neonates. Alterations in lipid profile, foetal epigenomics, and gut microbiota in these infants may also underlie the development of CVD. Recently, probiotic bacteria, such as the mucin-degrading bacterium Akkermansia muciniphila have been shown to reduce inflammation and prevent heart disease in animal models. All this information might enable scientists and clinicians to target pathways to act early to curtail the adverse effects of prematurity on the cardiovascular system. This could lead to primary and secondary prevention of CVD and improve survival among preterm neonates later in adult life.

Keywords: Cardiovascular disease; Dyslipidaemia; Inflammation; Microbiome; Prematurity; Renin–angiotensin system.

Take home figure

Mechanisms linking preterm birth and cardiovascular disease in a nutshell.

Figure 1

Interplay and crosstalk between elevated oxidative stress, an immature immune response, and altered renin–angiotensin–aldosterone system responses that can prime a preterm infant for development of cardiovascular disease later in life. Oxidative stress results in formation of ox-LDL which is taken up by macrophages which develop into foam cells. These cells release large amounts of reactive oxygen species and growth factors such as angiotensin II; the latter stimulates Type 1 receptor AT1R on endothelial cells and smooth muscle cells. Reactive oxygen species and AT1R activation repress endothelial nitric oxides synthase activity, resulting in reduced constitutive NO production and vasoconstriction. The immature immune response results in an imbalance of pro-inflammatory and anti-inflammatory cytokines, with enhancing effects on oxidative stress and vasoconstriction. Inflammatory cells under the influence of pro-inflammatory cytokines activate iNOS resulting in formation of large amounts of NO which can have a tissue injurious effect. Direct and possible long-term effects are listed at the bottom of the figure.

Figure 2

Abnormalities in the gut microbiome are associated with various conditions that increase the risk of cardiovascular disease, including a decrease in short-chain fatty acid-producing bacteria, increased inflammation, and reduced H2S production. Changes in oral flora can result in less NO production. For several of these associations cause and effect are still obscure, with the exception of increased trimethylamine-producing bacteria. Trimethylamine results from bacterial digestion of dietary quaternary amines (choline or carnitine). In preterm infant, increased levels of trimethylamine-producers result in higher trimethylamine-N-oxide production in the liver. This increases the risk of cardiovascular disease via conditions indicated on the left. Abnormalities in the gut microbiome are associated with various conditions that increase the risk of cardiovascular disease, including a decrease in short-chain fatty acid producing bacteria, increased inflammation, and reduced H2S production. Changes in oral flora can result in less NO production. For several of these associations cause and effect are still obscure, with the exception of increased trimethylamine producing bacteria. Trimethylamine results from bacterial digestion of dietary quaternary amines (choline or carnitine). In preterm infant, increased levels of trimethylamine producers result in higher trimethylamine-N-oxide production in the liver. This increases the risk of cardiovascular disease via conditions indicated on the left.