Cardiovascular disease continues to be the leading cause of global morbidity and mortality. Traditional risk factors account for only part of the attributable risk. The origins of atherosclerosis are in early life, a potential albeit largely unrecognized window of opportunity for early detection and treatment of subclinical cardiovascular disease. There are robust epidemiological data indicating that poor intrauterine growth and/or prematurity, and perinatal factors such as maternal hypercholesterolaemia, smoking, diabetes and obesity, are associated with adverse cardiovascular intermediate phenotypes in childhood and adulthood. Many of these early-life risk factors result in a heightened inflammatory state. Inflammation is a central mechanism in the development of atherosclerosis and cardiovascular disease, but few studies have investigated the role of overt perinatal infection and inflammation (chorioamnionitis) as a potential contributor to cardiovascular risk. Limited evidence from human and experimental models suggests an association between chorioamnionitis and cardiac and vascular dysfunction. Early life inflammatory events may be an important mechanism in the early development of cardiovascular risk and may provide insights into the associations between perinatal factors and adult cardiovascular disease. This review aims to summarise current data on the early life origins of atherosclerosis and cardiovascular disease, with particular focus on perinatal inflammation.

INTRODUCTION

Traditional risk factors for CVD (cardiovascular disease), e.g. hypertension, obesity, diabetes and hypercholesterolaemia, only partially explain the growing population at risk [1]. There is increasing epidemiological evidence to suggest that risk trajectories that lead to adult CVD, like many other non-communicable diseases, may already be present at birth or in the early postnatal period. Thus early life represents a window of opportunity for detection of subclinical cardiovascular risk, whether in the form of early atherosclerosis, impaired endothelial dysfunction or altered cardiac structure and cardiopulmonary haemodynamics. Accordingly, there is now substantial focus on the developmental origins of CVD and the early determinants of cardiovascular risk.

The immune system is a key mediator of the development of atherosclerosis and CVD. Inflammation is central to the pathogenesis of CVD and partly mediates the effects of traditional risk factors [2,3]. Conditions characterized by chronic inflammation, including diabetes, rheumatoid arthritis, Crohn's disease and systemic lupus erythematosus, are associated with accelerated atherosclerosis and increased CVD mortality [46]. Patients with acute coronary syndromes also have raised levels of inflammatory markers [5]. Furthermore, the development of atherosclerotic disease and cardiovascular events is driven by a chronic subclinical inflammatory response that involves both the innate and adaptive arms of the immune system [7]. These observations reflect the central role of host inflammation in all stages of CVD pathogenesis.

Despite the broad consensus that atherosclerosis is a chronic inflammatory condition and that cardiovascular pathology starts in early life, there are relatively few investigations into the possible contributory role of perinatal infection and inflammation to cardiovascular risk and pathogenesis. Exposure to infection and/or inflammation within the uterus during pregnancy (chorioamnionitis), or in the first few months after birth, may have pervasive effects on developing organs, including the heart and blood vessels [8]. Given the key role of inflammation in atherosclerosis development, and the clinical associations of heightened inflammation with CVD, early life inflammatory events may be important in programming for later CVD susceptibility. Therefore inflammation may contribute to the causal pathways that underpin the epidemiological associations between perinatal factors, such as poor intrauterine growth and preterm birth, and adult CVD (Figure 1).

Potential inflammatory links between intrauterine factors and later development of CVD

Figure 1
Potential inflammatory links between intrauterine factors and later development of CVD

Poor intrauterine growth, preterm birth and exposure to maternal cardiovascular risk profiles are important perinatal factors in programming cardiovascular disease susceptibility; they have been associated with adverse cardiovascular intermediate phenotypes in early life and traditional CVD risk factors, which culminate in an increased risk of CVD in adulthood. Furthermore, these maternal and intrauterine factors, as well as the majority of the cardiovascular risk factors illustrated, have been associated with heightened inflammation (as highlighted in red). Intrauterine inflammation (chorioamnionitis) may be a risk factor for CVD, as there is evidence demonstrating that preterm fetuses and those exposed to poor intrauterine growth are at an increased risk of chorioamnionitis. Whether early-life inflammatory events such as chorioamnionitis may contribute to increased cardiovascular risk and disease in later life is yet to be comprehensively investigated.

Figure 1
Potential inflammatory links between intrauterine factors and later development of CVD

Poor intrauterine growth, preterm birth and exposure to maternal cardiovascular risk profiles are important perinatal factors in programming cardiovascular disease susceptibility; they have been associated with adverse cardiovascular intermediate phenotypes in early life and traditional CVD risk factors, which culminate in an increased risk of CVD in adulthood. Furthermore, these maternal and intrauterine factors, as well as the majority of the cardiovascular risk factors illustrated, have been associated with heightened inflammation (as highlighted in red). Intrauterine inflammation (chorioamnionitis) may be a risk factor for CVD, as there is evidence demonstrating that preterm fetuses and those exposed to poor intrauterine growth are at an increased risk of chorioamnionitis. Whether early-life inflammatory events such as chorioamnionitis may contribute to increased cardiovascular risk and disease in later life is yet to be comprehensively investigated.

The present review outlines evidence on the early-life origins of atherosclerosis and CVD, focusing particularly on perinatal inflammation and its possible effects on the early development of cardiovascular risk.

PRENATAL INFLAMMATION: CHORIOAMNIONITIS

Definitions and pathophysiology

A perinatal inflammatory exposure most commonly manifests as intrauterine inflammation, usually referred to as chorioamnionitis [9]. Chorioamnionitis is inflammation of the fetal membranes (chorion and amnion) and the chorionic plate of the placenta, and may occur with or without membrane rupture [8]. Commonly asymptomatic, the diagnosis of chorioamnionitis can only reliably be made by placental histology, which allows for semi-quantification of severity of inflammation and determination of maternal and/or fetal involvement [1012].

Microbes most frequently cause chorioamnionitis by retrograde or ascending infection arising from the cervix and vagina [8]. Many cases of chorioamnionitis are sterile on microbial culture, suggesting causative organisms that are difficult to grow under standard conditions (e.g. Mycoplasma hominis and Ureaplasma urealyticum) and/or placental inflammation resulting from bacterial ligands, such as Toll-like receptor agonists [13,14]. The microbes and/or microbial products trigger a maternal and fetal inflammatory response with increased local and systemic mediators of inflammation, including interleukins, TNF (tumour necrosis factor), matrix metalloproteinases and CRP (C-reactive protein) [8]. This inflammatory response may result in prostaglandin release, cervical ripening, membrane rupture and onset of labour before term [8]. Consequently, the inflammatory cascade triggered by chorioamnionitis is strongly associated with preterm birth and prematurity-associated disease [15]. There is a strong negative correlation between gestational age at birth and the risk of chorioamnionitis; approximately 15% of term births and up to 70% of preterm births are complicated by histological chorioamnionitis [8,16].

FIRS (fetal inflammatory response syndrome) and related morbidity

In addition to direct fetal infection and postnatal sepsis, chorioamnionitis may contribute to FIRS, which is characterized by activation of the fetal immune system, funisitis and increased pro-inflammatory cytokine levels in umbilical cord blood [17]. FIRS may result in brain injury, which has been associated with subsequent chronic neurobehavioural disorders, including cerebral palsy, autism and schizophrenia [16,1820]. Chorioamnionitis with fetal inflammation is associated with a number of adverse outcomes common in preterm infants, including bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and both systemic and pulmonary hypertension [15,17,21]. Chorioamnionitis also modulates the risk of early- and late-onset neonatal sepsis in premature newborns; it increases the risk of early neonatal sepsis, which is caused by the same organisms that may result in chorioamnionitis, but decreases the risk of nosocomial late-onset sepsis by promoting-probably transiently-innate immune responses at weeks 2–3 of life [17,22]. The immunological effects of chorioamnionitis may also be pervasive; it is associated with a higher frequency of childhood infections such as recurrent otitis media [23], lower respiratory tract infection and other infectious diseases [8], as well as asthma and allergy [24,25].

Therefore perinatal inflammation has significant and pervasive effects on a number of organ systems [15], but at present, surprisingly little is known regarding long term inflammation and cardiometabolic risk among those with a history of perinatal inflammation.

PERINATAL INFLAMMATION AND CARDIOVASCULAR DISEASE

Animal studies of perinatal inflammation and related pregnancy complications

Animal models of chorioamnionitis most frequently involve the injection of pro-inflammatory ligands or live organisms into the amniotic fluid, which induces intrauterine and fetal cytokine production [26]. Numerous other (usually systemic) pro-inflammatory exposures during pregnancy have also been studied in experimental animals. However, their effects mimic the clinical scenarios of overt maternal systemic infectious illness or symptomatic clinical chorioamnionitis, as opposed to histological chorioamnionitis, which is the most common manifestation of intrauterine inflammation in human pregnancies.

Models of chorioamnionitis have been developed in sheep, non-human primates, rodents and rabbits [15,26,27]. The majority of animal data relating to cardiovascular injury following chorioamnionitis have investigated changes in haemodynamics; fewer studies have looked at structural alteration to the heart and vessels. To date, no study has investigated the effects of perinatal inflammation on development of vascular injury and atherosclerosis.

Newborn rats exposed to chorioamnionitis induced by intracervical LPS (lipopolysaccharide) show haemodynamic disturbances and depressed cardiac function [27]. Intra-amniotic LPS in fetal mice results in increased inflammatory cytokine expression in the fetal myocardium and impaired myocardial contractility and relaxation [28]. Maternal exposure to LPS also increases cardiac afterload and reduces cardiac output in fetal mice [29]. These effects may be long-lasting; mice exposed to systemic maternal inflammation in utero and subsequently to neonatal hyperoxia display more marked abnormalities in cardiac structure and function at 8 weeks of age, compared with those exposed to neonatal hyperoxia alone [30]. In the lungs of preterm lambs, intrauterine inflammation attenuates vascular growth and results in remodelling in resistance arterioles and alterations in pulmonary arteriole development, leading to pulmonary and systemic hypertension [31,32]. In the hearts of fetal sheep, intrauterine inflammation suppresses ventricular contractility, reduces cardiomyocyte numbers and enhances responsiveness to stress [33].

Animal models of maternal obesity, maternal undernutrition (calorie and protein restriction) and placental insufficiency (uterine artery ligation, umbilical arterial embolism or carunclectomy) [3436] further complement the picture of perinatal inflammation as a predictor for postnatal cardiometabolic abnormalities. Maternal obesity is associated with a state of chronic low-grade inflammation [37], which may include the placenta [38]. Fetal inflammation is characteristic of various animal models of maternal obesity (in mice, rats, sheep and non-human primates), which progresses to a metabolic syndrome-like phenotype by promoting offspring cardiovascular risk factors among other multi-organ effects [39,40]. A maternal obesogenic diet in c57BL/6J mice results in increased adiposity, resistance artery endothelial dysfunction, hypertension and insulin resistance in offspring 3 and 6 months after birth [41]. In rats, maternal obesity induced by overfeeding results in offspring with increased fat mass, and higher serum insulin and leptin levels, even when reared by lean surrogate dams, suggesting that maternal obesity exerts a developmental programming effect on the fetus [42]. Ovine maternal obesity models similarly demonstrate impaired fetal cardiac contractile function [43], and increased fetal and adult offspring plasma glucose and insulin concentrations [43,44], thereby potentially contributing to cardiovascular risk.

Maternal malnutrition is a major determinant of poor fetal growth and LBW (low birth weight). In turn, these adverse factors are associated with placental inflammation, aberrant immune responses and detrimental development of primary and secondary lymphoid organs, which can affect the risk of both obesity-induced cardiometabolic dysfunction and chronic inflammatory diseases in later life [4547]. Rat models of maternal dietary restriction induce hypertension, obesity, abnormal endothelial and smooth muscle reactivity, resistance artery wall stiffness and inflammatory profiles in adult offspring [39,48] that are reversible with interventions such as neonatal leptin administration [49], dietary cofactor supplementation [50,51], and pre-weaning growth hormone treatment [45,52].

Pre-eclampsia and IUGR (intrauterine growth restriction) in humans is associated with up-regulated expression of genes of pro-inflammatory mediators in the placenta, as well as alterations in angiogenesis and metabolism-related genes [35,53,54]. Placental insufficiency in sheep and rodents may result in fetal hypoxaemia, hypercapnia and mild acidaemia (as seen in human IUGR), as well as reduced growth of the developing heart [35]. A model of pre-eclampsia, induced by a reduction in uterine artery perfusion, has demonstrated increased blood pressure, BMI (body mass index) and serum lipids, cardiac and vascular functional and structural changes, altered glucose metabolism, and altered sympatho-adrenal function in offspring [36].

In vitro studies

Panaro et al. [55] demonstrated that 10-day-old chick embryonic cardiomyocytes stimulated with LPS produce NO (nitric oxide) and TNF, inflammatory mediators that depress cardiac function [55]. These LPS-treated cardiomyocytes undergo significantly increased cell death that is reversible with pharmacological inhibition of nitric oxide synthase or its regulators [56]. These in vitro studies therefore provide some support for a relationship between inflammatory exposures in utero and impaired cardiovascular development and function in offspring.

Human studies

Human fetuses exposed to intra-amniotic infection have increased left ventricular dilatation [57], and newborns have reduced mean and diastolic blood pressure [58]. These changes in cardiopulmonary haemodynamics in the fetus and preterm newborn persist and are probably due to vascular remodelling [31,59]. Preterm infants exposed to histological chorioamnionitis are also at increased risk of PPHN (persistent pulmonary hypertension of the newborn [21], discussed subsequently), consistent with the developmental effects observed in animal experiments [31,32].

ADM (adrenomedullin) is a biomarker of atherosclerosis, pulmonary hypertension and CVD [60,61]; however, its diagnostic utility is limited by its short half-life. MR-proADM (mid-regional proadrenomedullin) is a stable inactive peptide derived from the adrenomedullin precursor, proadrenomedullin, and is produced by vascular endothelial cells and other cell types [62]. Increased levels of MR-proADM are reported in arterial hypertension, heart failure and acute coronary syndrome in adults [62]. Admaty et al. [62] measured MR-proADM levels in arterial and venous cord blood in a cohort of 270 newborns. Plasma concentrations of MR-proADM were elevated in infants born following histological or clinical chorioamnionitis and were inversely associated with gestational age at birth [62]. These relationships support the concept that intrauterine infection and inflammation impair fetal microvasculature development, potentially increasing susceptibility to future cardiovascular pathology (Table 1).

Table 1
Cardiovascular outcomes following inflammation in human and animal models
ExperimentalmodelRoute of perinatal inflammationCardiovascular outcomes of perinatal inflammationReference(s)
Rat Intracervical LPS Haemodynamic disturbances and depressed neonatal cardiac function [27
Mouse Intra-amniotic LPS ↑ Inflammatory cytokines in fetal myocardium; impaired myocardial contractility and relaxation [28
 Intraperitoneal LPS ↑ Fetal cardiac afterload; ↓ cardiac output [29
 Intraperitoneal LPS and 85% O2 for 14 days (hyperoxia) Altered cardiac structure and function in offspring (compared with neonatal hyperoxia alone) [30
Sheep Intra-amniotic LPS ↓ Vascular growth, remodelled resistance arterioles and altered pulmonary arteriole development in preterm lungs, causing pulmonary and systemic hypertension [31,32
  ↓ Ventricular contractility, ↓ cardiomyocyte numbers, ↑ stress response in fetal hearts [33
In vitro LPS stimulation Embryonic cardiomyocytes produced NO and TNF, and underwent significant cell death that is reversible with pharmacological inhibition of nitric oxide synthase or its regulators [55,56
Humans Histological chorioamnionitis ↑ Left ventricular dilatation in fetuses [57
  ↓ Mean and diastolic blood pressure in premature newborns [58
  ↑ Risk of PPHN in preterm infants [21
  ↑ MR-proADM levels in infants; levels are inversely associated with gestational age at birth [62
ExperimentalmodelRoute of perinatal inflammationCardiovascular outcomes of perinatal inflammationReference(s)
Rat Intracervical LPS Haemodynamic disturbances and depressed neonatal cardiac function [27
Mouse Intra-amniotic LPS ↑ Inflammatory cytokines in fetal myocardium; impaired myocardial contractility and relaxation [28
 Intraperitoneal LPS ↑ Fetal cardiac afterload; ↓ cardiac output [29
 Intraperitoneal LPS and 85% O2 for 14 days (hyperoxia) Altered cardiac structure and function in offspring (compared with neonatal hyperoxia alone) [30
Sheep Intra-amniotic LPS ↓ Vascular growth, remodelled resistance arterioles and altered pulmonary arteriole development in preterm lungs, causing pulmonary and systemic hypertension [31,32
  ↓ Ventricular contractility, ↓ cardiomyocyte numbers, ↑ stress response in fetal hearts [33
In vitro LPS stimulation Embryonic cardiomyocytes produced NO and TNF, and underwent significant cell death that is reversible with pharmacological inhibition of nitric oxide synthase or its regulators [55,56
Humans Histological chorioamnionitis ↑ Left ventricular dilatation in fetuses [57
  ↓ Mean and diastolic blood pressure in premature newborns [58
  ↑ Risk of PPHN in preterm infants [21
  ↑ MR-proADM levels in infants; levels are inversely associated with gestational age at birth [62

CONTRIBUTION OF PERINATAL FACTORS TO EARLY AND LATER CARDIOVASCULAR DISEASE

LBW, IUGR and prematurity are established risk factors for short- and long-term cardiovascular risk and possibly CVD [63,64], but the underlying mechanisms are largely unknown. In this section, we discuss whether early-life inflammation is a common contributory mechanism that links poor intrauterine growth to later cardiovascular risk.

Perinatal growth and nutrition: the ‘Barker hypothesis’

The ‘Barker hypothesis’ arose from observations of a British population of men [65] and women [66] in whom, as birth weight decreased, mortality rates from adult CVD increased. David Barker's seminal work introduced the concept that poor growth in utero was associated with coronary artery disease and with thrombotic and haemorrhagic stroke in adulthood [67]. This work gave rise to the DOHaD (developmental origins of health and disease) paradigm, which postulates that perinatal environmental factors can alter development and influence susceptibility to adult non-communicable diseases [68]. Notably, newborns with LBW have adverse intermediate cardiovascular phenotypes at birth [increased aortic IMT (intima–media thickness)], as well as elevated blood pressure and impaired endothelial function in adulthood [69,70].

The association between LBW and CVD has subsequently been reported in many large population studies of ischaemic heart disease [7173], stroke [71,74], elevated systolic blood pressure [75] and diabetes [76,77]. Some of these findings and their interpretation are controversial [78] and alternative explanations have been suggested. These include the fetal insulin hypothesis, which proposes that the association between LBW and adult insulin resistance is predominantly genetically mediated [79]. Other parameters suggestive of adverse intrauterine development, including increased ponderal index and reduced placental dimensions, have also been associated with adverse cardiovascular outcomes in adulthood [80,81]. Interestingly, high birth weight (>4 kg) has been associated with greater risk of diabetes in later life [82].

Poor intrauterine growth and reduced gestational age

The terminology regarding birth weight and gestational age is often confusing. Although terms such as ‘low birth weight’ (LBW), ‘intrauterine growth restriction’ (IUGR) and ‘small for gestational age’ (SGA) are sometimes used interchangeably, they refer to related, but distinct, entities that may carry different risks. The World Health Organization defines LBW as a birth weight at term of <2500 g [83]. Birth weight is determined by two main factors; the duration of gestation and the rate of fetal growth [84]. Infants born preterm (<37 weeks of gestational age) are part of the LBW spectrum and have an increased risk of perinatal morbidity and mortality [8].

A fetus or newborn may be of LBW if they are born small for gestational age (SGA; birth weight less than the 10th percentile of a reference birth weight distribution for gestational age) [85]. Being SGA may result from IUGR, which complicates approximately 5–10% of all pregnancies and is associated with a higher risk of perinatal complications and long-term morbidity [86]. Although the terms SGA and IUGR are often used interchangeably, they are not always equivalent. Some SGA infants may be constitutionally small and not growth-restricted, and some growth-restricted infants do not meet the criteria for SGA. In low- and middle-income countries, SGA is often considered a proxy for IUGR, as they often occur together [85].

Perinatal inflammation, preterm birth and low birth weight

Infection and inflammation are established risk factors for prematurity [85]. Of all the proposed causes of preterm labour and delivery, infection and/or inflammation is the only pathological process for which both a causal link with preterm birth has been established and a molecular pathophysiology defined [11]. The prevalence of intrauterine inflammation increases markedly with decreasing gestational age, with up to 70% of extremely preterm births associated with histological chorioamnionitis [22]. Considering that preterm birth accounts for 75% of perinatal mortality and >50% of long-term disability [87], the direct and indirect contribution of chorioamnionitis to adverse outcomes is substantial.

Inflammation is also common in pregnancies complicated by poor intrauterine growth. In such cases, the inflammation can persist after birth, although the causal pathway is less clear than for preterm birth. IUGR fetuses and SGA newborns have raised levels of CRP and pro-inflammatory cytokines in amniotic fluid and umbilical cord blood [88,89]. LBW is also associated with higher CRP levels in adulthood [90] and reduced IGF-1 (insulin-like growth factor 1) concentration [91,92], which itself is associated with chronic inflammation [93]. Analyses of the 1966 Northern Finland Birth Cohort found that a 1 kg reduction in birth weight was associated with a 12% increase in CRP levels in adulthood [90].

Preterm birth, IUGR and LBW are therefore all associated with an inflammatory state that may persist beyond an acute intrauterine response into postnatal life and even adulthood [8890]. As inflammation plays a principal role in both the pathogenesis of preterm delivery and a pathological state following poor intrauterine growth, inflammation may potentially link preterm birth and poor intrauterine growth to the cardiopulmonary and metabolic sequelae that may manifest after birth.

Preterm birth, poor intrauterine growth and cardiovascular outcomes

Preterm birth is a risk factor for systemic hypertension, diabetes and adult CVD. However, the varied aetiologies and different effects and interactions of preterm birth, SGA and IUGR on cardiovascular and cardiopulmonary outcomes remain largely unknown and data are inconsistent with respect to the degree of risk [9496]. In regard to cardiovascular risk, it is likely that IUGR, rather than LBW, influences vascular programming and subsequent risk of adult CVD [97]. For the purposes of the present review, the effects of both prematurity and IUGR are described.

LBW and/or prematurity may significantly disadvantage the newborn. Both are associated with a myriad of cardiovascular repercussions, including cardiac and endothelial dysfunction, increased blood pressure, subclinical atherosclerosis and the development of early cardiometabolic risk factors such as hypertension and insulin resistance [63,98100]. The mechanisms underlying these robust epidemiological associations are largely unknown. As a significant proportion of these newborns would have been exposed to intrauterine infection and/or inflammation, it is plausible that there is a pathological relationship between the inflammatory intrauterine environment and the possible adverse cardiovascular consequences. However, to date, most data are circumstantial. In the following section, we discuss the relationships between poor intrauterine growth and prematurity, vascular perinatal risk factors and cardiovascular outcomes. Where data are available, we highlight the potential for a more direct contribution of perinatal inflammation to cardiovascular risk.

PPHN (persistent pulmonary hypertension of the newborn)

Failure of the pulmonary circulation to vasodilate at birth leads to pulmonary hypertension in newborns, characterized by a sustained elevation in pulmonary vascular resistance, frequently with low systemic vascular resistance and reduced cardiac output [101,102]. Experimental models of chronic pulmonary hypertension demonstrate impaired endothelial release of NO and increased vasoconstrictive mediators such as endothelin-1 [103].

There is growing evidence that the perinatal environment plays a key role in PPHN [102]. Risk factors for PPHN include maternal obesity, diabetes, smoking, prolonged rupture of the fetal membranes, maternal fever and colonization with Group B streptococcus [101,102]. In preterm infants with IUGR, bronchopulmonary dysplasia with subsequent severe pulmonary hypertension is increasingly recognized [101]. In fetal sheep, attenuated development of the pulmonary vasculature is a consequence of intrauterine inflammation and results in abnormal pulmonary vascular function before and after birth [59,104]. Preterm complications therefore increase the incidence of PPHN and may increase CVD risk.

Cardiac dysfunction

Cardiac dysfunction is a recognized pathophysiological feature of IUGR [86]. In utero, the right ventricle is the dominant chamber which at the birth transition, yields to left ventricle dominance to maintain cardiac output. However, IUGR fetuses redistribute their fetal cardiac output to favour the left ventricle, with lower ventricular ejection forces, tricuspid regurgitation, cardiomegaly, and systolic and diastolic dysfunction due to direct myocardial compromise [105]. Term-born SGA infants display abnormal cardiac structure (dilated left atrium) and functional impairment (reduced cardiac output and decreased relaxation) during the early postnatal period, compared with term ‘appropriate for gestational age’ infants [86]. Infants with bronchopulmonary dysplasia, which is itself associated with perinatal inflammation [15] and is a common sequela of preterm birth [106], are also at greater risk of left ventricular dysfunction [107]. These adverse cardiovascular changes appear to be persistent; adults born with IUGR have changes in cardiac shape, decreased stroke volume, increased heart rate, and decreased systolic mitral and tricuspid ring displacement [108].

B-type (BNP) and atrial (ANP) natriuretic peptide are expressed by the heart in response to cardiac volume and pressure overload and are useful biochemical markers of subclinical myocardial cell injury [109]. In a study of over 300 newborns, BNP levels in umbilical venous cord blood and amniotic fluid were significantly increased in infants with hypotension and cardiac dysfunction [110]. Elevated umbilical cord and amniotic fluid BNP were found in preterm, LBW and SGA infants [110], whereas IUGR newborns had raised BNP and ANP concentrations in the umbilical artery, as well as evidence of left ventricular dysfunction on ultrasonography [109].

Interestingly, BNP levels also correlate with infection and inflammation. In newborns, chorioamnionitis is an independent predictor of umbilical cord blood BNP levels [110]. Adult patients with severe sepsis and septic shock have increased plasma BNP levels [111,112], equivalent to those seen in acute heart failure [112]. Increasing evidence from clinical, animal and in vitro studies demonstrate that endotoxin and inflammatory mediators correlate with elevated production and secretion of natriuretic peptides [113116], supporting the concept that inflammation and cardiac injury may be mechanistically linked, in early life as well as in adulthood.

Endothelial dysfunction

Human studies predominantly show a positive association between fetal growth restriction and persistent endothelial dysfunction [98]. LBW correlates with endothelial dysfunction measured biochemically [117], by flow-mediated dilation [118,119], and by acetylcholine-induced vasodilation [120]. The effect of LBW on the vascular endothelium is of the same order of magnitude as that induced by smoking [121].

Endothelial dysfunction is closely related to inflammation; CRP induces the expression of adhesion molecules by human endothelial cells, which reflects endothelial damage [122,123]. Early inflammatory processes associated with endothelial dysfunction and LBW may contribute to the cardiovascular risks that accompany endothelial dysfunction.

Early preclinical changes in endothelial dysfunction have clinical prognostic relevance through adolescence and early adulthood [64,118,120]. These intermediate phenotypes are predictive of cardiovascular morbidity [120,124]. In adults, endothelial dysfunction is linked to hypertension, hyperglycaemia, dyslipidaemia and smoking [98,123]. Endothelial dysfunction is considered to be an early pathophysiological event in the development of atherosclerosis [99,123]. In patients with coronary heart disease, the degree of endothelial dysfunction predicts the severity of atherosclerotic lesions and prognosis [98].

Hypertension

Arterial stiffness is evident in some studies of very preterm or SGA infants [86,125127]; however, the association between IUGR and long-term aortic and carotid stiffness is unclear [98]. Given that increased and accelerated aortic stiffening is an independent risk factor for coronary heart disease and stroke in hypertensive patients [128,129], early loss of arterial elasticity in the arteries of newborn infants may predict later CVD. A recent review supports a link between inflammatory biomarkers and arterial stiffness, and highlights the association between increased arterial stiffness and inflammation in patients with chronic inflammatory diseases [130].

Impaired systolic and diastolic function are present in mildly IUGR term infants [131] and LBW is associated with increased blood pressure in young children [108,132]. A meta-analysis of 27 studies found that adults born preterm had significantly higher systolic and diastolic blood pressure and a pro-atherogenic lipid profile [133]. Lowering blood pressure by 2 mmHg can reduce the prevalence of hypertension by 17%, ischaemic heart disease by 6% and stroke by 15% [134]. As such, differences between preterm and term-born adults are likely to be clinically significant.

Atherosclerosis and arterial intima–media thickness

Although atherosclerotic lesions manifest clinically in adulthood, early lesions have been detected in the arteries of newborns, infants and young children [69,135]. These early lesions manifest as increased arterial IMT and fatty streaks in the initial stages of atherosclerosis, characterized by the accumulation of LDL (low-density lipoprotein) and lipid-laden macrophages (‘foam cells’) in the intima of the arterial wall [136]. Arterial IMT is the most feasible non-invasive marker of subclinical atherosclerosis currently available and can be measured from birth onwards [137]. More advanced atherosclerotic lesions such as early fibroatheroma, indicative of a degree of permanent damage to the arterial wall, may be evident by the end of puberty [138] and eventually progress to advanced atheroma and thrombus formation in adulthood [136].

Atherosclerosis is considered to be a chronic inflammatory disease [7,139,140]. Both CRP levels and serum levels of CD40 ligand (an innate immunity marker, which stimulates pro-inflammatory and pro-thrombotic responses) are positively correlated with carotid IMT in young human subjects [2,141]. In young adults, high-sensitive CRP levels are highly predictive of maximum carotid artery IMT, independent of type 1 diabetes, sex, BMI, diastolic blood pressure or age [142]. Low-grade inflammation may therefore be a risk factor for the development of early atherosclerotic lesions, and their presence in fetuses and newborns may reflect vascular damage arising during the perinatal period, from which early atherosclerosis and CVD may develop.

Skilton et al. [69] was the first to report an inverse relationship between IUGR and aortic IMT in infants [69]. Follow-up studies support the finding that carotid and aortic IMT are increased in IUGR infants [92,98], and this association may persist into childhood [118,125,143] and adulthood [70,144,145]. In adults, carotid IMT is an early sign of subclinical atherosclerosis that is strongly predictive of later cardiovascular risk [146,147]. Traditional cardiovascular risk factors in childhood, such as dyslipidaemia, hypertension and increased BMI, are also associated with an increased IMT in adulthood [98].

Maternal cardiovascular risk factors, risk in offspring and the role of perinatal inflammation

Perinatal risk factors such as maternal hypercholesterolaemia, smoking, diabetes and obesity may influence the risk of atherosclerosis and CVD in early life and adulthood. These factors are also associated with an increased inflammatory environment in utero, which may induce fetal vascular remodelling and underlie the predisposition to adverse cardiovascular outcomes. Intrauterine inflammation may therefore be a link between fetal insult and the manifestation of atherosclerotic and cardiovascular pathology in adulthood.

Maternal hypercholesterolaemia

Maternal hypercholesterolaemia is a well-established determinant of atherosclerosis development in the offspring. Studies in rabbits [148] and mice [149] confirm that diet-induced maternal hypercholesterolaemia is sufficient to enhance fetal atherosclerotic lesion formation. Furthermore, lipid-lowering agents administered to hypercholesterolaemic animals during pregnancy decrease offspring lesion formation and result in a sustained reduction in cardiovascular risk in adulthood [148,150].

Napoli et al. [151,152] reported the formation of fatty streaks in the aortas of premature human fetuses in a systematic analysis of autopsy specimens; these fatty streaks were prevalent in all fetuses, and maternal hypercholesterolaemia significantly increased lesion number and size. Fatty streaks, albeit to a lesser extent, were also found in the common carotid, intracranial and extracranial arteries of human fetuses [153,154]. In the FELIC (Fate of Early Lesions in Children) study, post-mortem analysis of fetuses and children showed that aortic lesion size increased linearly with age, and that progression was greatly enhanced in children of hypercholesterolaemic mothers, even when the children themselves were normocholesterolaemic [155,156]. It is therefore suggested that fatty streak formation and smooth muscle proliferation can begin in the perinatal period and continue after birth, and that these events may form the basis of atherosclerosis in adulthood [157].

Maternal hypercholesterolaemia correlates with raised maternal CRP levels, indicative of inflammation [158]. This maternal inflammation may contribute to an inflammatory intrauterine environment and the early fetal atherosclerotic lesions associated with maternal hypercholesterolaemia. In hypercholesterolaemic mothers, maternal CRP is significantly associated with increased atherosclerosis in the offspring, although the association was weaker than for maternal cholesterol [158].

Maternal smoking

Tobacco triggers a systemic low-grade inflammatory response, alters mediators of lipid metabolism [159], and increases the risk of preterm birth over 2-fold [87] and also of IUGR [160]. Although the exact mechanism of atherosclerosis in smokers is unknown, increased circulating levels of inflammatory mediators and endothelial dysfunction are reported [3]. In experimental models of maternal smoking, rodent offspring develop impaired endothelial relaxation, abnormal cyclo-oxygenase-2 and endothelial nitric oxide synthase responsiveness and increased neonatal mortality [161,162].

In humans, maternal smoking in pregnancy correlates with significantly increased neonatal aortic IMT and LBW, with trends towards decreased serum IGF-1 and IGF-binding protein-3 in infants, suggesting increased inflammation [160]. In the FELIC study, elevated maternal CRP levels correlated with maternal smoking and aortic atherosclerosis in children [158]. Furthermore, pre-atherosclerotic changes in the coronary arteries are detectable in stillborn fetuses from smoking mothers [163]. Similar vascular lesions are seen in sudden and unexpected death in infants whose parents smoked [164]. In a cohort of healthy teenagers and young adults, endothelial flow-mediated dilatation was significantly reduced and inversely related to the intensity of exposure to passive smoking [159]. A 27-year follow-up study showed that children of mothers who smoked during pregnancy had increased total cholesterol levels and a more adverse lipoprotein profile [165].

Maternal obesity

The World Health Organization identifies obesity as a critical global public health crisis, affecting more than 1.4 billion adults and posing a major risk for cardiovascular morbidity and mortality ([37] and http://www.who.int/nutrition/topics/obesity/en/). Recent reviews have synthesized the broad evidence base suggesting that chronic low-grade inflammation plays a role in maternal obesity-induced postnatal disease, including CVD [2,166168]. Adipose tissue stimulates macrophage accumulation and the production of pro-inflammatory mediators, generating a local and systemic inflammatory state and accelerating endothelial dysfunction and atherosclerosis [2].

Obesity in pregnancy leads to immune dysregulation in the mother and infant [37]. Women who are obese antenatally are more likely to develop wound, chest, abdominal wall and urinary tract infections [169171], sepsis [172] and chorioamnionitis [173]. Children born to obese mothers have markedly raised CRP levels [174]. This inflammatory state may play a crucial mechanistic role in programming fetal and early-life development of an adverse cardiovascular phenotype. Maternal obesity may predispose infants to long-term consequences, including proportionally high body fat, greater risk of insulin resistance, diabetes and CVD in adulthood [168].

Maternal diabetes

Diabetes in pregnancy is broadly divided into pre-existing diabetes (Types 1 and 2) and GDM (gestational diabetes mellitus), defined as the onset of glucose intolerance during pregnancy [175]. Gestational diabetes complicates approximately 8% of all pregnancies worldwide [176]. Whereas the majority of cases of maternal diabetes arise from GDM (~80%), pregnancies affected by pre-existing diabetes are increasing [175] and carry a higher risk of adverse maternal and neonatal outcomes [176].

A feature of diabetes in pregnancy is an inflammatory intrauterine environment, indicated by alterations in the placental transcriptome, predominantly in genes regulating inflammation and endothelial function [177,178]. Children of diabetic mothers have raised levels of CRP, IL (interleukin)-6 and ICAM (intercellular adhesion molecule)-1 in umbilical cord plasma [177]. This early inflammatory state may contribute to the development of the cardiometabolic diseases in offspring of diabetic mothers.

In maternal diabetes, maternal hyperglycaemia results in fetal hyperglycaemia, stimulating fetal insulin production and excessive intrauterine growth [92,100]. As a result, fetuses exposed to maternal diabetes frequently develop macrosomia (fetal overgrowth resulting in excessive birth weight). Macrosomia increases the risk of adverse perinatal outcomes. This risk is compounded by maternal diabetes [179] and precedes an increased risk of glucose intolerance, obesity and early onset CVD in adulthood [178]. There is a higher incidence of congenital anomalies in newborns from pre-gestational diabetic mothers, including cardiac malformations [179]. Other outcomes of maternal diabetes include IUGR, preterm birth, stillbirth and hypertrophic cardiomyopathy in infants [179]. Maternal diabetes is also associated with increased aortic IMT in macrosomic newborns [92,180] and with significant alterations in the lipid profile in infants and children [181,182].

Children born following maternal diabetes also have a worse cardiovascular risk profile, including a high prevalence of childhood overweight and obesity, diabetes, increased systolic blood pressure, endothelial dysfunction and increased circulating markers associated with early atherosclerosis [183186].

Potential molecular mechanisms: a role for epigenetics?

Accumulating evidence supports a role for epigenetic processes in atherosclerosis, diabetes mellitus and CVD [187]. Although the specific genes affected by these modifications are largely unknown, it is likely that epigenetic regulation is important in the modulation of inflammation in atherogenesis [188]. DNA methylation, the most widely studied epigenetic mark, is altered in single-loci studies and genome-wide profiles of atherosclerotic lesions [187] and of peripheral blood leucocyte DNA from patients with CVD [189,190]. Changes in DNA methylation precede the appearance of histological lesions in experimental models of atherosclerosis and are associated with CVD predisposition [191].

Epigenetics is similarly widely implicated in intrauterine programming of disease [192]. Differential DNA methylation has been detected in placental tissue and cord blood from infants with increased or LBW, IUGR or SGA and from infants of mothers with adiposity, glucose intolerance, and smoking, although the implications for later cardiometabolic disease risk require further exploration [192]. Although in-depth discussion on these potential mechanisms is beyond the scope of this review, perinatal inflammatory events such as chorioamnionitis may result in a change in epigenetic marks at specific regulatory sites of genes important in the development of CVD. Identifying epigenetic changes induced by perinatal inflammation and their associations with CVD may lead to new insights into the developmental origins of CVD and provide a platform for the development of early interventions [188].

SUMMARY

Despite the current paucity of research on the effects of intrauterine and perinatal inflammation on cardiovascular outcomes, there is evidence for a relationship between chorioamnionitis and altered cardiopulmonary haemodynamics, cardiac structure and function, blood pressure and endothelial dysfunction. Indirect effects of perinatal inflammation have been observed in studies of perinatal cardiovascular structure and function as a result of prematurity, LBW and maternal cardiometabolic diseases. Manifestations of these perinatal factors include cardiac and endothelial dysfunction, arterial stiffness and hypertension, pre-clinical atherosclerosis and increased cardiovascular risk in adulthood.

A common feature of the diverse perinatal factors contributing to early cardiovascular risk is inflammation. Although it is apparent that chronic inflammation in the fetus in response to chorioamnionitis may result in the development of cardiovascular injury, potentially predisposing the infant to adult CVD, further mechanistic studies are required to fully elucidate the impact of an early inflammatory exposure on life-long cardiovascular health and to establish whether there is an association with adult CVD. Studies exploring the molecular factors underlying chronic inflammation may present novel pharmacological targets in those at increased risk and provide a basis for potential early-life interventions.

FUNDING

Our work is funded by the National Health and Medical Research Council (NHMRC) and the National Heart Foundation (NHF) of Australia, and the Victorian Government's Operational Infrastructure Support Program.

Abbreviations

     
  • ADM

    adrenomedullin

  •  
  • ANP

    atrial natriuretic peptide

  •  
  • BMI

    body mass index

  •  
  • BNP

    B-type natriuretic peptide

  •  
  • CRP

    C-reactive protein

  •  
  • CVD

    cardiovascular disease

  •  
  • FELIC

    Fate of Early Lesions in Children

  •  
  • FIRS

    fetal inflammatory response syndrome

  •  
  • GDM

    gestational diabetes mellitus

  •  
  • IGF

    insulin-like growth factor

  •  
  • IMT

    intima–media thickness

  •  
  • IUGR

    intrauterine growth restriction

  •  
  • LBW

    low birth weight

  •  
  • LPS

    lipopolysaccharide

  •  
  • MR-proADM

    mid-regional proadrenomedullin

  •  
  • PPHN

    persistent pulmonary hypertension of the newborn

  •  
  • SGA

    small for gestational age

  •  
  • TNF

    tumour necrosis factor

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Author notes

1

These authors are equal first authors.

2

These authors are equal senior authors.