Impact of prematurity on lifelong cardiovascular health: structural and functional considerations

The aetiology of preterm cardiovascular disease formation appears different from that of traditional population. Within the ‘ traditional ’ population cardiovascular disease formation is driven by functional stressors (e


Preterm trajectory of disease
Preterm birth is a complex and multifactorial phenomenon that can result from a combination of biological, environmental, and socioeconomic factors.In terms of biological factors, preterm birth can occur due to maternal medical conditions such as pre-eclampsia, infection, or cervical incompetence 5 .Additionally, genetic, and epigenetic factors can also play a role in preterm birth [15][16][17] .Furthermore, environmental factors such as socio-economic factors, poor nutrition, stress, exposure to pollutants, and substance abuse can also increase this risk of preterm birth 5 .
Preventive strategies for preterm birth include reducing risk factors such as maternal smoking and substance abuse, improving access to prenatal care, and promoting healthy behaviours such as good nutrition and stress management.However, preterm birth can have significant consequences for the infant, including an increased risk of neonatal morbidity and mortality, as well as long-term health consequences such as respiratory problems, cognitive and developmental delays, and an increased risk of chronic diseases in later life.
In recent years, prenatal impacts have been recognised as determinants of health and illness in later life, namely hypertension, ischaemic heart disease and heart failure [18][19][20] .Several epidemiological studies have demonstrated that prenatal and early childhood events may affect body composition and metabolism, thereby increasing the prevalence of several adult illnesses, including hypertension 21,22 , Type 2 diabetes 23,24 , and CVD 13,25 .Barker hypothesised that lower prenatal and postnatal growth may be associated with a higher risk of CVD in adulthood 26 .In addition, infants exposed to the Dutch Hunger Winter in early pregnancy during World War II were shown to have a higher incidence of obesity and cardiovascular disease later in life 27 .Following this, other studies established a definite association between preterm birth and CVD risk markers such as raised systolic and diastolic blood pressures 21,28 , impaired glucose tolerance and increased insulin resistance 23,[29][30][31] , hypertriglyceridemia and low highdensity lipoprotein levels in the blood 32,33 .Eriksson et al. 34 looked at 4630 men born at Helsinki Hospital and found that men with a low ponderal index (the ratio of body weight to height) and slow weight gain in the first year of life had a greater risk of developing coronary heart disease later in life.Researchers found that premature babies were observed to experience 'catch-up' growth and had their body mass index go up between the ages of 1 and 12 were more likely to develop CVD 34 .However, this effect was only seen in children who had a ponderal index of 26 at birth 34 .Others have shown that low birth weight is a predictor of heart disease.However, low birthweight is an imprecise measure of growth in the womb and is not always caused by being born too early.Further research on preterm neonates has found that gestational age is a factor in the development of CVD 13,19,35,36 .In one study, men born preterm were shown to have greater quantities of total cholesterol, LDL-C, and apolipoprotein B than females 33 .Even after birthweight correction, these sexually dimorphic disparities in prematurely-born adolescents persisted 33 .When compared to full-termborn individuals, preterm birth was associated with higher LDL-C levels and elevated systolic and diastolic blood pressure 33 .Twin studies with dizygotic and monozygotic groups discovered that genetic and intrauterine environmental influences played a role in the development of CVD later in life 17,37 .Even though preterm birth is associated with a higher risk of developing CVD, the underlying processes or mechanisms that explain these correlations are not entirely known.
What is apparent is that this correlation with an elevated CVD risk profile is set from birth [38][39][40][41] .The capacity to adapt to the extrauterine environment determines survival in the immediate neonatal period, which has also been shown to have sexually dimorphic effects 42,43 .Male infants are born preterm at greater rates, exhibit more clinical complications during the neonatal period and are more likely to be readmitted following discharge than their female counterparts 43,44 .The cause of this discrepancy while unknown is likely multifactorial, with hormonal, genetic, and inflammatory factors playing key roles 44 .While more stable in the neonatal period, females born preterm exhibit an elevated risk profile throughout life with decompensation observable in adolescence 33 .While changes in neonatal care have significantly improved preterm survival, few improvements have eased the neonatal transition as much as the implementation of antenatal corticosteroids 45 .Indeed, while many infants now survive into adulthood without major comorbidities, all those born preterm carry a CVD risk inversely proportional to their gestational age 13,20,46 .
In addition to both maternal 5 and neonatal factors 28,34 , antenatal corticosteroid (glucorticoid) treatments are increasingly associated with long-term disease outcomes 47,48 .Antenatal glucocorticoids have been routinely used since their introduction in the 1970's to induce rapid lung maturation prior to birth 45,47 .While this treatment has become a mainstay treatment for prematurityparticularly at gestations <34 weeks (See Roberts et al. 49 ) -the immediate effects on systemic growth may contribute to long-term cardiac, renal and insulin sensitivity 47,50,51 .Given the heterogeneity of the population, the long-term effects of antenatal corticosteroids remain conflicting, with late-preterm-and postnatal-administration appearing to add more controversy to this topic [52][53][54] .

Infancy
At birth, foetal proliferation and development of the heart and arteries abruptly slows, interrupting the normal process of cardiomyocyte differentiation in preparation for postnatal life 55 .Animal studies have demonstrated smaller hearts with reduced number of binucleated myocytes following preterm birth 56 (Table 1).Foetal hyperplastic cardiomyocyte growth of cardiac tissue is ceased by the transition to neonatal life, potentially limiting the lifelong myocyte size and number 38,48 .This phenomena impacts both the left and right ventricle, contributing to altered geometry of the heart, as well as affecting the heart's contractile function and overall performance 20,57 .Additionally, mechanistic studies of the preterm ovine heart have demonstrated diffuse collagen deposition seven times greater than in term hearts 38,58 , and studies in mice have shown that the presence of short, disorganised myofibrils that fail to align in the myocardium in preterm models 59 .These structural changes incurred because of preterm birth persist beyond infancy and ultimately determine a greater risk of CVD during later life 20,60 .
The functional complications associated with premature transition pose a more immediate clinical significance during the neonatal period 61,62 .Studies of piglets have demonstrated altered adrenoceptor profile in the neonatal period 63 , which when combined with excess sympathetic tone [64][65][66] and altered circulating catecholamines [67][68][69] , contributes to impaired cardiac output and cardiovascular instability 70,71 .Instability which is further exacerbated by alterations in both pulmonary and systemic vasculature.Persistent pulmonary hypertension is three times more common among preterms, impairing right ventricle ejection fraction 57,72 .Growth arrest and increased stiffness of the aorta increases afterload on the heart, further impairing cardiac function 39,73,74 (Table 1).Patent ductus arteriosus (PDA) in many preterm neonates (perhaps as many as 50% 75 ) also impedes attempts to improve cardiovascular stability in the neonatal period 76 .Furthermore, microvascular networks of preterm infants are rarefied and disorganised 76,77 , and are typically maximally dilated at rest 42,62,[78][79][80][81] .These complications pose significant problems for the clinician as inotropes can prove fickle in rectifying circulatory failure (40% fail to respond to dopamine or dobutamine 71 ).
Reactivity tests including exposure to 4% CO 2 , hypoxia, and thermal or orthostatic stress have elicited responses that are contradictory, but importantly, consistently altered from that of term-born infants [82][83][84][85] (Table 1).These altered responses to stress may be a symptom of the heterogeneity of the preterm condition at different gestational ages and under different levels of clinical severity.However, they may also provide critical insight into cardiovascular stability in the neonatal period.As demonstrated by Stark et al. 62 , microvascular perfusion in the immediate postnatal period correlates with both cardiovascular stability and mortality within 72 h of birth.Preterm infants with greater vascular flexibility, and thereby improved stability, tend to have reduced clinical severity and better outcomes.As such, while many structural alterations are present within the neonatal period (e.g., PDA, reduced heart and artery size), the functional responses to neonatal life, and therefore the functional complications, appear to be of greater significance to neonatal morbidity and mortality (Fig. 1).

Effects of preterm birth on cardiovascular health throughout life
By childhood, the shortened gestation becomes apparent in the structure of the cardiovascular system.Whereas cardiovascular control appears comparable between term and preterm infants 64 , increased circulating catecholamines 88 , alongside narrowed arteries 73,89 and reduced microvascular density 90 , results in elevated blood pressure (BP) 88,90 and altered stress responses in children born preterm [91][92][93] .These structural and functional cardiovascular alterations seldom reach clinical significance, particularly following moderate-to-late preterm birth, but may be early markers of future disease present in childhood 36,94,95 .
Both left and right heart geometry remain altered in childhood, impacting cardiac contractility 36,94,95 .Using echocardiography with extremely preterm-born children, Mohlkert et al. 94 demonstrated significantly smaller left ventricles and impaired ventricular function, which is associated with a 4-fold higher risk of heart failure in children and adolescents born between 28 and 31 weeks' gestation and 17-fold increase with gestations below 28 weeks 36 .Investigating the right heart, Mohlkert et al. 95 also demonstrated increased right ventricle thickness and altered geometry alongside increased pulmonary vascular resistance.While unable to parse out differences between functional versus structural causation, the alterations in the preterm right ventricle are likely due to a combination of reduced or immature pulmonary vessels, and the resultant increase in pulmonary pressure 96 .A similar mechanism is likely at play in the systemic circulation.Certainly, a history of pulmonary neonatal diseases is associated with an elevated risk of pulmonary hypertension by adulthood 72,97 .In the systemic circulation, preterm-born children show reduced aortic, coronary and carotid artery diameters 73,89 , though this is significantly affected by the length of gestation.At later gestations carotid artery size appears comparable to term-born children 98 , indicating a threshold effect to arterial compromise in childhood.Combining the work of Szpinda [99][100][101] , Zhong et al. 102 , and Schubert et al. 39 , the aorta grows linearly in utero with elasticity increasing significantly from 31 weeks' gestation (remaining similar between 20 and 31 weeks' 102 ), but aortic growth abruptly slows at birth.Impaired growth of carotid and coronary arteries has also been observed in extremely preterm-born children 73,89,98 , suggesting that growth cessation is common among major vessels.
While elastin accumulation is maximal in the perinatal period 103 , its synthesis in the aorta is significantly impacted by intrauterine growth restriction 104,105 and presumably also by prematurity 74 .Furthermore, as collagen and elastin content remains almost constant from infancy up to 3 years 106,107 , failure to synthesise adequate amounts of elastin due to premature birth may permanently impact arterial compliance 103,106,108 .Indeed, Odri Komazec et al. 108 identified decreased elasticity and increased stiffness in aorta of preterm-born children (<32 weeks' GA), and these characteristics have been similarly observed in adolescence and adulthood following gestations of 30-34 weeks' [109][110][111] (discussed further below).The altered compliance in the major arteries of preterm children is only exacerbated by reduced arterial diameters and microvascular rarefaction 90 .This is likely the cause of elevated blood pressure observed by Bonamy et al. 90 .The elevations in BP, while minor in childhood ( ~4 mmHg), further drive cardiac maladaptation and the propensity for disease formation.
The persistence of altered cardiovascular structure presents clinically and epidemiologically in adulthood.Studies by Lewandowski and colleagues 57,112 show that the morphometric changes observed in preterm infants and children persist into young adulthood, with magnetic resonance imaging revealing significant differences in both left and right ventricular structure.Functionally, in two meta-analyses of preterm-born young adults, preterm birth was associated with 4.2 mmHg 113 and 3.4 mmHg 114 elevations in systolic BP, respectively, with both analyses noting stronger effects in women.Additionally, a recent large-scale study by Crump 13 , identified an adjusted hazard ratio of 1.28 and 2.45 for new-onset hypertension in preterm-and extremely preterm-born adults (18-29 y/o), respectively.Similarly, Risnes et al. 115 observed a 1.4-fold and 1.2-fold increase in mortality in early and late preterm born individuals between 15 and 50 years.Supporting this, Crump et al. 28 observed a significant relationship between preterm birth and prescription of antihypertensive medications in young adults (25-37 y/o).Preterm birth has been further linked with heart failure 36,116 , ischaemic heart disease 117,118 , and pulmonary vascular disease 97 , though this risk is strongly-and inversely-related to gestation 6,13 .In a register-based cohort study, Carr et al. 116 observed a 17-fold increased risk of heart failure in those born extremely preterm (<28 wks' GA), with this reducing to 3.6-fold in those born very preterm (28-32 wks' GA).In terms of ischaemic heart disease, Crump's register-based cohort study observed a 53% increased relative risk of developing ischaemic heart disease in preterm born individuals aged 30-43 years 117 .Such findings in those born preterm are perhaps unsurprising given the continuity of cardiovascular dysfunction from infancy, adolescence, and adulthood.
A clear trajectory of decompensation can be observed through adolescence and adulthood, precipitated by persistent structural alterations in the heart and vasculature of preterm-born children.The structural limitations, such as altered cardiac geometry, narrowed and rarefied vasculature become more pronounced by adolescence (Table 1).The hearts and arteries of preterm-born adolescents are smaller (LV 55,119 ; RV 55 ; aorta [119][120][121] ), resulting in greater vascular resistance 121 and elevated BP 33,109,[121][122][123][124] .Many studies, though not all 98 , have also observed greater arterial stiffness and intimamedia thickness; however, the causal mechanisms remain unknown.While data is sparse in adolescents, the elevated BP and vascular resistance do not appear to impair cardiac output (LV function 55,119 ) or vascular function 10,122 and no signs of concentric hypertrophy can be observed at this age 55 .However, by adulthood, those born preterm exhibit hypertrophic and functionally impaired hearts, narrowed and stiffened arteries, vascular dysfunction and rarefaction (Table 1).While much of the evidence is observed at gestations below 29 weeks, structural and functional alterations consistent with the overarching pathology are observable at later gestations (~34 weeks).Indeed, the conventional risk factors for CVD in young adults born preterm are often present across the spectrum of prematurity 13,108 .This unique aetiology of preterm-related CVD has driven calls for clinical recognition 14,18 , and potentially a new cardiomyopathy 36 .

Stress reactivity
Stress tests are frequently employed to expose underlying cardiovascular dysfunction that is obscured at rest.Indeed, cardiopulmonary exercise testing is commonly used in the diagnosis of CVD.In populations with known risks of CVD, an impaired capacity to respond toor recover fromthe stressor may be indicative of early disease states.Stress testing may then provide useful prognostic insights into the preterm risk of CVD.Studies of those born preterm, from infancy through adulthood, have demonstrated persistent abnormal reactivity to a wide range of stressors, though there is ample room for expansion in these studies.
Autonomic and cardiovascular maturity has been examined in preterm infants using inotrope reactivity, hypercapnia, orthostasis and hypoxia (Table 1) [82][83][84][85] .Inotropes are routinely administered-with mixed efficacyto improve cardiovascular compromise in hypotensive infants 125,126 .Mechanistic studies of preterm piglets have demonstrated reduced reactivity to both dopamine and dobutamine, with this possibly explained by immature cardiac and vascular adrenoceptor profiles (namely low abundance of cardiac ß 1 -adrenoceptors 63 and vascular α-adrenoceptors 71,84,127,128 .As a result of immature neural control, preterm infants place greater reliance on circulating catecholamines; as demonstrated in the altered hypercapnic and orthostatic stress responses 82,83 , as well as hypoxic responses in preterm piglets 84 .Cohen et al. observed a 3-to 4-fold greater BP response compared to term-born counterparts with almost absent HR response when exposed to orthostatic stress 83 .Similarly, in response to hypoxia Eiby et al. 84  compensation.Together these studies demonstrate immature baro-and chemo-reflexes, particularly in the cardiac component of these reflexes.Notably, despite appearing stable at discharge from the hospital, these altered responses do not appear to resolve by term equivalent age 82 . Childhood appears to be a deflection point in cardiovascular dysfunction when observed across the lifespan.Structural differences can be observed, but these appear to have a limited impact on function (Table 1).Exercise stress testing in children indicates a reduced exercise capacity, but due to a focus on respiratory function, limited inferences can be made to cardiovascular function 91,92 .One study in extremely preterm children exposed to acetylcholine challenge demonstrated elevated microvascular reactivity in children born appropriate for gestational age, though this only achieved significance compared to intrauterine growth-restricted preterm children and not term-born children 93 .Further studies in this age group would elucidate the impact of altered cardiovascular architecture and may prove beneficial for identifying early markers of disease.
By early adulthood, the structural limitations in the preterm cardiovascular system begin to produce pronounced dysfunction during stress testing.Using stress echocardiography, Huckstep et al. 129 demonstrated progressive impairment in left ventricular ejection fraction and cardiac output during graded exercise, with this likely due to altered cardiac geometry exhibited at rest 112,129 .In a similar study, Macdonald et al. 130 demonstrated impaired stroke volume augmentation and impaired right heart kinetics during exercise.This resulted in increased cardiac work for comparable stroke volumes and an increased reliance on heart rate response 130 .Importantly, these significant changes exhibited under stress were not present at rest 130 .Furthermore, examination of the vasculature during stress testing has shown increased stiffness in the form of increased pulse wave velocity, systolic blood pressure and pulse pressure in the brachial artery 131 .Increased vascular stiffness has been shown to increase afterload, and increase cardiac work for a given stress 132 , though the changes in preterm vasculature do not necessarily reach clinical significance 133 .This may explain the hypertrophic changes in both left and right ventricles 57,112,134 .Recovery, too, is impaired with preterm adolescents and adults exhibiting impaired heart rate recovery following graded exercise 135,136 .Heart rate recovery following exercise is primarily due to parasympathetic activation and sympathetic withdrawal 137 , and its impairment has been shown to be a predictor of cardiovascular disease 135,137 .Finally, in a cohort of preterm-born adults a 16 week exercise training intervention improved aerobic capacity and power, but not ambulatory systolic or diastolic blood pressure, a major risk factor for CVD 138 .
Collectively, the above studies demonstrate a trajectory of dysfunction as a result of persistently altered cardiovascular structure.The alterations in structure become progressively deleterious with age such that by early adulthood the altered cardiac structure exhibited at rest produces functional impairment under stress.Such studies demonstrate both the efficacy of stress testing in the preterm population as well as the value of stress testing as a prognostic test.While there are indications of system-wide dysfunction at rest, in the form of altered cardiac structure and vascular diameter and stiffness, the effects of these alterations appear dysfunctional under stress.

Current and future directions
As discussed in the outset, calls have been made for preterm birth to be recognised as a non-modifiable risk factor for cardiovascular disease for over 20 years now 9,12,36,139 .As a non-modifiable risk factor, short of preventing preterm birth, the root cause cannot be treated.Furthermore, the pathophysiological mechanisms contributing to CVD in preterm-born adults remains undetermined 36,139 .It appears, however, that structural insuffiencies strongly contribute to CVD risk (Fig. 1, Table 1), with contributing factors across multiple systems 140 .For graduates of neonatal intensive care, many are discharged from neonatal follow-up programmes early on, which consist mainly of neurodevelopmental milestones 14 .However, given the weight of evidence supporting lifelong risk of chronic disease includingbut not limited to -CVD, and the absence of treatments, a sustained cardiometabolic follow-up programme offers a cost-effective and practical solution 139,140 .In 'traditional' CVD populations, acknowledging non-modifiable risk factors (e.g., family history), educating patients, and advising lifestyle interventions (e.g., diet, exercise, smoking cessation) are proven treatment optionsused alone or in combination with pharmacological interventions to treat CVD [141][142][143][144] .Indeed, a recent questionnaire by Girard-Bock et al. 14 , found that many of the preterm-born adults were not even aware of their heightened CVD risk.They concluded that it is essential that long-term consequences of preterm birth are effectively communicated to preterm-born populations 14 .They, among others, noted that preventative strategies would be an effective treatment in the preterm population 14,139,140 .Current guidelines for BP management call for non-pharmacological management in patients with systolic BP of 120-139 mmHg 140,144 .While pharmacological treatment has been demonstrated to be effective in patients with systolic BP between 130-139 mmHg, it has not been recommended for young adults 140,144 .Elevated BP can be detected in the preterm population from childhood 90,93,145 , with dysfunctional traits manifesting in early adulthood (Fig. 1, Table 1).Jones et al. 140 , recommended heightened monitoring, including at-home BP measurement and early counselling on lifestyle interventions, with pharmacotherapy an option in high-risk patients.Given the efficacy of preventative strategies in other populations, such an approach will certainly save more in the long-run than waiting for the disease to manifest.

Conclusion
Events that alter the normal trajectory of early life development have profound implications for life-course health and wellbeing extending decades beyond the insult.Those born preterm are a heterogenous group in terms of sex, gestation, and neonatal morbidity.However, two things are clear: 1) preterm birth produces permanent structural changes to the heart and vasculature; and 2) preterm birth is associated with long-term risk of CVD.
Here, we have put forward the hypothesis, that the structural limitations incurred at birth produce adverse functional cardiovascular changes which, across the lifespan, drive maladaptive remodelling (e.g., concentric cardiac hypertrophy, arterial fibrosis) and CVD (Fig. 1).Such changes are pivotal stages in 'traditional' CVD aetiology.The key difference between the 'traditional' and preterm populations is that those born preterm require no further insult (e.g., poor diet, smoking, stress) to drive CVD, as the persistent structural changes drive hypertension, impaired cardiac output, and endothelial dysfunction.

Table 1 (
continued) | Systematic review of preterm cardiovascular changes in comparison to term cohorts from infancy through to adulthood npj Cardiovascular Health | (2024) 1:2

Table 1 (
continued) | Systematic review of preterm cardiovascular changes in comparison to term cohorts from infancy through to adulthood The gestational age range of other species expressed as equivalent human weeks (denoted by 'E.').For methodology underlying systematic search of publications related to Table1, refer to the Supplementary File.