‘Stiffening the sinews of the heart’

Predisposition to chronic disease by adverse conditions experienced during fetal and neonatal development is firmly enshrined in the concept of developmental programming. The earliest clinical examples of programming were in studies on the origins of life course cardiovascular disease (CVD) by the Southampton research group led by David Barker and the Harvard Nurses study. Both showed that susceptibility to later life CVD is related to birth weight (Osmond & Barker, 2000).

Inadequate fetal nutrient supply results in intrauterine growth restriction (IUGR), defined as reduced fetal mass compared to normal growth. IUGR animal models include hypoxia, induced placental insufficiency (PI) or maternal nutrient restriction (MNR) of protein or overall calories. IUGR involves a complex sequence of epigenetic changes and altered signalling and metabolic processes that favour survival of organs/systems critical for fetal development and postnatal life, while sacrificing functional capabilities of those less critical to survival. In both reduced maternal consumption and placental insufficiency placental nutrient transport is reduced, inhibiting liver, pancreas, skeletal muscle and kidney development while maintaining relatively normal cerebral and cardiac function. In early sheep MNR studies both heart ventricles scaled with body size in IUGR and controls (Vonnahme et al. 2003). Later the same group showed that several myocardial cDNA clones, related to cardiac hypertrophy and myocardial remodelling, were up‐regulated in MNR fetuses (Han et al. 2004). In a sheep fetal PI model, basal myocardial blood oxygen content, plasma glucose concentration and insulin concentrations were lower than in control fetuses (Limesand et al. 2007).

The study by Darby et al. (2018) in this issue of The Journal of Physiology extends our understanding of intercellular pathways by which MNR remodels fetal cardiac structure by evaluating insulin‐like growth factors (IGFs), key growth factors involved in heart development. Studies were conducted on right ventricular (RV) tissue from fetuses of undernourished ewes fed 50% of the global intake of control ewes over 30 days in late gestation. Fetal plasma glucose was reduced while fetuses were normoxaemic. Cardiac expression of insulin‐like growth factor 2 (IGF2) and its receptor (IGF2R) negatively correlated with plasma glucose. This study also presented evidence of decreased cardiac muscle contractile power in fetuses of undernourished ewes. The protein abundance of phosphorylated phospholamban B was higher and phosphorylated troponin I lower in the fetal RV of undernourished compared to well‐nourished ewes. One significant feature of this study is that it shows that a short duration of MNR is associated with hypoglycaemia and stimulates adverse programming processes. Further studies of both short and long term nutritional challenges are needed.

Importantly, Darby et al. (2018) found that RV fibrosis increased in undernourished fetuses. Expression of COL1A was inversely correlated with fetal plasma glucose and diffuse myocardial fibrosis increased collagen in MNR fetal myocardium. Unfortunately, the study was not able to determine sexually dimorphic differences. A study of left ventricular (LV) myocardial tissue in IUGR fetuses of baboons fed 70% of control diet found that in males, but not females, LV fibrosis inversely correlated with birth weight (Muralimanoharan et al. 2017). It found differences in expression of fetal myocardial microRNAs (miRNAs) between male and female fetuses within both control and IUGR baboon groups. The Akt pathway was one of the most affected pathways in males and females of undernourished baboons. The mechanistic relationship between growth factors, Akt and myocardial fibrosis is complex and incompletely defined. One model posits that decreases in the anti‐fibrogenic histone demethylase, PHF8, coupled to increased activity in the profibrogenic Akt/mTOR pathway leads to development of cardiac fibrosis (Ghosh et al. 2017). In support of this view, miR‐133a improves cardiac function and reduces fibrosis by inhibiting Akt in a rat heart failure model (Sang et al. 2015).

Much can be learned from comparative studies regarding challenges that programme cardiac fibrosis. One rat study compared adverse cardiac structural outcomes in offspring of mothers maintained in an ambient environment of 12% oxygen from 15 days of pregnancy and another group to a diet of 40% of global diet‐fed controls (Xu et al. 2006). Effects on cardiac structural proteins, especially increased collagen 1 were apparent by age 4 months in offspring of hypoxic mothers but only by 7 months in offspring of underfed mothers, indicating interesting similarities and differences in structural remodelling in hypoxic and nutritional challenges.

One major challenge in all studies addressing programming is to distinguish processes responsible for persistent damage from compensatory and secondary responses that play no role in the programming. The timing of data collection following the challenge is also of importance in that emergence is another major principle of programming. The immediate responses shown here should be followed up.

At age ∼9 years (∼35 human years equivalent), IUGR baboons had smaller hindlimb but not brachial or common carotid arteries than controls and increased carotid blood flow velocity (Kuo et al. 2018). Overall these data indicate that region specific vascular and haemodynamic changes that occur with IUGR persist postnatally to and likely contribute to later life cardiac dysfunction. The nature of these postnatal changes fit with the fibrosis demonstrated in the article reviewed here and Muralimanoharan et al. (2017). The pattern of vascular distribution observed in IUGR offspring is reminiscent of the changes that occur in fetuses challenged by hypoxia or undernutrition (Cohn et al. 1974; Kuo et al. 2018). Further studies are needed to determine the life course progression of the consequences of these programmed structural alterations. While targeting the factors responsible for fibrosis in fetal tissues presents many difficulties, these observations will aid clinical management by suggesting molecular pathways in fibrosis and growth factor function to target as potential interventions to reverse the emergence of further fibrosis in later life.

Additional information

Competing interests

None declared.

Author contributions

Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

Funding

This work was supported by NIH grant no. HD 21350 to P.W.N.