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Preterm Birth Contributes to Increased Vascular Resistance and Higher Blood Pressure in Adolescent Girls
Abstract
Preterm birth might induce permanent changes in vascular structure and function as well as in blood pressure. To elucidate this hypothesis and underlying mechanisms in girls born before term, the authors correlated neonatal data, including estradiol levels, with vascular function and structure and with blood pressure after puberty. In a case-control study design, 34 girls born before term and 32 gender- and age-matched control infants born at term were included. Pulse wave analysis was used to determine aortic pressure profiles and overall arterial compliance. Stiffness of the carotid artery and abdominal aorta was measured with ultrasonography. Pulse wave velocity in the forearm was measured with photoplethysmography. A laser Doppler technique was used to determine skin perfusion before and after transdermal delivery of acetylcholine, an endothelium-dependent vasodilator. It was found that preterm girls had significantly higher brachial and aortic blood pressure, a narrower but less stiff abdominal aorta, and lower peripheral skin blood flow than did control infants. Augmentation index, carotid stiffness, pulse wave velocity, endothelium-dependent vasodilatation, and heart rate were similar in the two groups. In the preterm group, blood pressure and vascular functions showed no association with intrauterine growth retardation or neonatal estradiol levels. In conclusion, preterm girls have higher blood pressure and an increased resistance in the vascular tree after puberty. These findings may have implications for future cardiovascular risk in the growing adult population surviving preterm birth.
... [1][2][3] Biomarkers of cardiovascular disease, such as increased blood pressure and aortic stiffness, have been observed already in childhood and adolescence after preterm birth and low birth weight. 4,5 However, improvements in perinatal management have decreased peri-and neonatal mortality and morbidity, [6][7][8][9][10] and recent studies show normal blood pressure and arterial stiffness in young children born extremely preterm. [11][12][13] These recent studies show no additive effect of birth weight deviation as a marker of fetal growth restriction (FGR) to that of preterm birth on blood pressure and arterial stiffness. ...
... This is in contrast to earlier studies indicating increased arterial stiffness after either preterm birth or low birth weight. 4,5,40,41 Whether low birth weight due to FGR exacerbates the effect of preterm birth is not clear from these earlier studies. Contrary to Cheung et al., 41 the current study showed no differences in arterial stiffness between groups and thus no additive effect of FGR to that of very preterm birth. ...
... Increased arterial stiffness has previously been shown in adolescent girls born very or extremely preterm with no additional effect of low birth weight for gestational age to that of preterm birth. 5 In contrast to that previous study, however, the current study population had normal blood pressure, possibly indicating improved cardiovascular outcome in this more recent study population. ...
Background
Although preterm birth predisposes for cardiovascular disease, recent studies in children indicate normal blood pressure and arterial stiffness. This prospective cohort study therefore assessed blood pressure and arterial stiffness in adolescents born very preterm due to verified fetal growth restriction (FGR).
Methods
Adolescents (14 (13–17) years; 52% girls) born very preterm with FGR (preterm FGR; n = 24) and two control groups born with appropriate birth weight (AGA), one in similar gestation (preterm AGA; n = 27) and one at term (term AGA; n = 28) were included. 24-hour ambulatory blood pressure and aortic pulse wave velocity (PWV) and distensibility by magnetic resonance imaging were acquired.
Results
There were no group differences in prevalence of hypertension or in arterial stiffness (all p ≥ 0.1). In boys, diastolic and mean arterial blood pressures increased from term AGA to preterm AGA to preterm FGR with higher daytime and 24-hour mean arterial blood pressures in the preterm FGR as compared to the term AGA group. In girls, no group differences were observed (all p ≥ 0.1).
Conclusions
Very preterm birth due to FGR is associated with higher, yet normal blood pressure in adolescent boys, suggesting an existing but limited impact of very preterm birth on cardiovascular risk in adolescence, enhanced by male sex and FGR.
Impact
Very preterm birth due to fetal growth restriction was associated with higher, yet normal blood pressure in adolescent boys.
In adolescence, very preterm birth due to fetal growth restriction was not associated with increased thoracic aortic stiffness.
In adolescence, very preterm birth in itself showed an existing but limited effect on blood pressure and thoracic aortic stiffness.
Male sex and fetal growth restriction enhanced the effect of preterm birth on blood pressure in adolescence.
Male sex and fetal growth restriction should be considered as additional risk factors to that of preterm birth in cardiovascular risk stratification.
... L ow birthweight and prematurity are predisposing factors for cardiovascular morbidity and mortality in adulthood [1][2][3][4]. Vascular abnormalities may be evident by adolescence or early adult life, including an elevated pulse wave velocity (PWV) [5,6], increased carotid arterial intima-media thickness (cIMT) [6,7], smaller aortic dimensions [5,8,9], and impaired microvascular function [7,9,10]. ...
... L ow birthweight and prematurity are predisposing factors for cardiovascular morbidity and mortality in adulthood [1][2][3][4]. Vascular abnormalities may be evident by adolescence or early adult life, including an elevated pulse wave velocity (PWV) [5,6], increased carotid arterial intima-media thickness (cIMT) [6,7], smaller aortic dimensions [5,8,9], and impaired microvascular function [7,9,10]. ...
... The more prominent early backward waves in the aortic arch may be related to attenuated aortic growth in expreterm participants compared with controls, as described in our previous study, and thus leading to a potential impedance mismatch in the systemic arterial circulation [14]. A reduced aortic diameter in ex-preterm adolescents has also been reported in AGA or SGA ex-preterm adolescent girls [5], and the smaller diameter of other major arteries, such as the brachial artery in adolescents [10] and the common carotid artery in infants [37], suggests that a generalized growth impairment of systemic arterial vasculature accompanies preterm birth. ...
Objective:
To evaluate the wave reflection characteristics in the aortic arch and common carotid artery of ex-preterm adolescents and assess their relationship to central blood pressure in a cohort followed prospectively since birth.
Methods:
Central blood pressures, pulse wave velocity, augmentation index, microvascular reactive hyperemia, arterial distensibility, compliance and stiffness index, and also aortic and carotid wave intensity were measured in 18-year-olds born extremely preterm at below 28 weeks' gestation (n = 76) and term-born controls (n = 42).
Results:
Compared with controls, ex-preterm adolescents had higher central systolic (111 ± 11 vs. 105 ± 10 mmHg; P < 0.001) and diastolic blood pressures (73 ± 7 vs. 67 ± 7 mmHg; P < 0.001). Although conventional measures of arterial function and biomechanics such as pulse wave velocity and augmentation index were no different between groups, wave intensity analysis revealed elevated backward compression wave area (-0.39 ± 0.21 vs. -0.29 ± 0.17 W/m/s × 10; P = 0.03), backward compression wave pressure change (9.0 ± 3.5 vs. 6.6 ± 2.5 mmHg; P = 0.001) and reflection index (0.44 ± 0.15 vs. 0.32 ± 0.08; P < 0.001) in the aorta of ex-preterm adolescents compared with controls. These changes were less pronounced in the carotid artery. On multivariable analysis, forward and backward compression wave areas were the only biomechanical variables associated with central systolic pressure.
Conclusions:
Ex-preterm adolescents demonstrate elevated wave reflection indices in the aortic arch, which correlate with central systolic pressure. Wave intensity analysis may provide a sensitive novel marker of evolving vascular dysfunction in ex-preterm survivors.
... Other studies reported values that demonstrate similar but non-significant trends in the aorta of low birth weight pre-adolescents (7-11 years) (Martin et al. 2000) and newborns (Akira & Yoshiyuki, 2006;Mori et al. 2006), as well as positive correlation between adult common femoral artery diameter and birth weight (mean age = 36 years) (te Velde et al. 2004). One complicating factor in some human studies is the inclusion of subjects from both term and pre-term births since gestational age is associated with differences in aorta diameter (Bonamy et al. 2005;Schubert et al. 2011;Ciccone et al. 2013). The change in large artery size with IUGR has not been consistently demonstrated across animal models, and may be partially attributable to both variation in the method of IUGR induction and inter-species difference. ...
... The lack of association between low birth weight and brachial artery diameter has been documented in human children (8-13 years) (Franco et al. 2006), adolescents (13-19 years) (Singhal et al. 2001;Brodszki et al. 2005), and young adults (20-28 years) (Goodfellow et al. 1998;Leeson et al. 2001). Likewise, in most studies of IUGR humans, a difference in common carotid artery dimension has not been found (Martin et al. 2000;Bonamy et al. 2005;Brodszki et al. 2005;Mori et al. 2006). It has been hypothesized that the differential effects of IUGR on vessel size may be due to the relative sensitivity of elastic artery growth to IUGR compared to muscular arteries (Karatza & Varvarigou, 2013). ...
... Interestingly, we did not observe vascular stiffening in the carotid arteries. In line with our results, increase in carotid stiffness is either not seen in IUGR children (Bonamy et al. 2005;Brodszki et al. 2005) or only present in a sub-group of the subjects with increased aortic stiffness (Mori et al. 2006). Possibly related to this finding, when regional arterial stiffness is assessed across the carotid-radial segment, no difference is seen between IUGR and control adolescents (Rossi et al. 2011). ...
Key points:
Intrauterine growth restriction (IUGR) increases offspring risk of chronic diseases later in life, including cardiovascular dysfunction. Our prior studies suggest biventricular cardiac dysfunction and vascular impairment in baboons who were IUGR at birth because of moderate maternal nutrient reduction. The current study reveals changes in artery sizes, distensibility, and blood flow pattern in young adult IUGR baboons, which may contribute to cardiac stress. The pattern of abnormality observed suggests that vascular redistribution seen with IUGR in fetal life may continue into adulthood.
Abstract:
Maternal nutrient reduction induces intrauterine growth restriction (IUGR), increasing risks of chronic diseases later in life, including cardiovascular dysfunction. Using ultrasound, we determined regional blood flow, blood vessel sizes, and distensibility in IUGR baboons (8 males, 8 females, 8.8 years, similar to 35 human years) and controls (12 males, 12 females, 9.5 years). The measured blood vessels were larger in size in the males compared to females before but not after normalization to body surface area. Smaller IUGR normalized blood vessel sizes were observed in the femoral and external iliac arteries but not the brachial or common carotid arteries and not correlated significantly with birth weight. Mild decrease in distensibility in the IUGR group was seen in the iliac but not the carotid arteries without between-sex differences. In IUGR baboons there was increased carotid arterial blood flow velocity during late systole and diastole. Overall, our findings support the conclusion that region specific vascular and haemodynamic changes occur with IUGR, which may contribute to the occurrence of later life cardiac dysfunction. The pattern of alteration observed suggests vascular redistribution efforts in response to challenges in the perinatal period may persist into adulthood. Further studies are needed to determine the life course progression of these changes.
... In general, multiple risk factors predisposing to a later development of cardiovascular diseases have been identified in preterm-born individuals. These risk factors involve increased peripheral and central systolic (SBP) and/or diastolic (DBP) blood pressures , higher heart rate (HR) [4,22,23], higher fat mass [21], lower functional skin capillary density [4], lower peripheral skin blood flow [24], abnormal retinal vascularization (both structure and function) [1,3,17], increased sympathoadrenal activity together with higher levels of urine catecholamines [22], kidney hypoplasia, incomplete nephrogenesis (reduced number of nephrons) and impaired renal function (decreased glomerular filtration rate, microalbuminuria) [20,[25][26][27][28], worsened respiratory parameters usually as a consequence of bronchopulmonary dysplasia (BPD) [19,29,30], impaired exercise capacity [19,30], elevated fasting glucose and cholesterol levels [10], higher serum levels of insulin 2 h after the glucose load [31], decreased insulin sensitivity [32][33][34][35][36], or even higher incidence of systolic or diastolic prehypertension/hypertension [13,25,[37][38][39][40], chronic kidney disease [13,25], lipid disorders [39,41], type 1 diabetes mellitus [39,[42][43][44][45][46], metabolic syndrome [38], and asthma [29,[47][48][49]. ...
... Smaller left ventricles [9,12,50], smaller right atria [51], smaller right ventricles [51,52], greater right and left ventricular mass [50,52], smaller ascending aorta diameter [9,18], and higher relative wall thickness [51] were observed in children, adolescents, and young adults born preterm. In addition, narrower abdominal aortas and lower abdominal aortic stiffness were detected together with higher brachial and aortic blood pressures [24]. Besides, lower left ventricular longitudinal shortening and systolic tissue velocity [12], higher transversal shortening fraction [12], lower atrial emptying velocities [12], higher right ventricular myocardial performance index (RVmpi') [51], elevated aortic wave reflection [14], decreased carotid and brachial distensibility [18], and higher estimated pulmonary vascular resistance (PVR) [51] were found in children, adolescents, and young preterm-born adults. ...
(1) Background: Preterm-born children have an increased cardiovascular risk with the first clinical manifestation during childhood and/or adolescence. (2) Methods: The occurrence of overweight/obesity, prehypertension/hypertension, valve problems or heart defects, and postnatal microRNA expression profiles were examined in preterm-born children at the age of 3 to 11 years descending from preterm prelabor rupture of membranes (PPROM) and spontaneous preterm birth (PTB) pregnancies. The whole peripheral blood gene expression of 29 selected microRNAs associated with cardiovascular diseases was the subject of our interest. (3) Results: Nearly one-third of preterm-born children (32.43%) had valve problems and/or heart defects. The occurrence of systolic and diastolic prehypertension/hypertension was also inconsiderable in a group of preterm-born children (27.03% and 18.92%). The vast majority of children descending from either PPROM (85.45%) or PTB pregnancies (85.71%) had also significantly altered microRNA expression profiles at 90.0% specificity. (4) Conclusions: Postnatal microRNA expression profiles were significantly influenced by antenatal and early postnatal factors (gestational age at delivery, birth weight of newborns, and condition of newborns at the moment of birth). These findings may contribute to the explanation of increased cardiovascular risk in preterm-born children. These findings strongly support the belief that preterm-born children should be dispensarized for a long time to have access to specialized medical care.
... Preterm birth itself is associated with neonatal acute kidney injury due to possible insults like decreased kidney perfusion (patent ductus, resuscitation, sepsis) or nephrotoxic medications. The resulting kidney damage is associated with renal pathology later in life such as hypertension, proteinuria and a decreased glomerular filtration rate [3][4][5][6][7][8][9][10]. ...
... In humans preterm birth exacts a toll on many organ systems, especially the lung, brain and kidney. This results in an increased morbidity later in life with obstructive lung pathology, impaired neurocognitive outcomes and chronic renal disease with hypertension [3][4][5][6][7][8][9][10], but the pathophysiological background is still not entirely known. This is in part due to the lack of data from human subjects, because of ethical concerns and a large developmental variability [19], which forces researchers to rely on animal studies. ...
Recent advances in neonatal care have improved the survival rate of those born premature. But prenatal conditions, premature birth and clinical interventions can lead to transient and permanent problems in these fragile patients. Premature birth (<36 gestational weeks) occurs during critical renal development and maturation. Some consequences have been observed but the exact pathophysiology is still not entirely known. This experimental animal study aims to investigate the effect of premature birth on postnatal nephrogenesis in premature neonatal rabbits compared to term rabbits of the same corrected age. We analyzed renal morphology, glomerular maturity and functional parameters (proteinuria and protein/creatinine ratio) in three cohorts of rabbit pups: preterm (G28), preterm at day 7 of life (G28+7) and term at day 4 of life (G31+4). We found no significant differences in kidney volume and weight, and relative kidney volume between the cohorts. Nephrogenic zone width increased significantly over time when comparing G31 + 4 to G28. The renal corpuscle surface area, in the inner cortex and outer cortex, tended to decrease significantly after birth in both preterm and term groups. With regard to glomerular maturity, we found that the kidneys in the preterm cohorts were still in an immature state (presence of vesicles and capillary loop stage). Importantly, significant differences in proteinuria and protein/creatinine ratio were found. G28 + 7 showed increased proteinuria ( p = 0.019) and an increased protein/creatinine ratio ( p = 0.023) in comparison to G31 +4. In conclusion, these results suggest that the preterm rabbit kidney tends to linger in the immature glomerular stages and shows signs of a reduced renal functionality compared to the kidney born at term, which could in time lead to short- and long-term health consequences.
... In several studies in young adults born extremely preterm, the lumen of the ascending, thoracic, and abdominal aorta was shown to be smaller ( Figure 4). 19,32,33 For the thoracic and abdominal aorta, these differences appear to remain even after taking into account body size. 34 Data on other major arteries, such as the carotid and brachial arteries, are less consistent, with studies showing no differences or smaller internal diameters. ...
... Furthermore, skin microvascular perfusion and density have been shown to be reduced and to correlate with higher blood pressure and circulating antiangiogenic factors. 32,48 Reduced systemic angiogenic capacity could underlie impaired vascular growth. Neonatal exposure to high oxygen, which mimics preterm birth-related physiological conditions, reduced in vitro angiogenic capacity and systemic microvascular density in adult rats. ...
... In several studies in young adults born extremely preterm, the lumen of the ascending, thoracic, and abdominal aorta was shown to be smaller ( Figure 4). 19,32,33 For the thoracic and abdominal aorta, these differences appear to remain even after taking into account body size. 34 Data on other major arteries, such as the carotid and brachial arteries, are less consistent, with studies showing no differences or smaller internal diameters. ...
... Furthermore, skin microvascular perfusion and density have been shown to be reduced and to correlate with higher blood pressure and circulating antiangiogenic factors. 32,48 Reduced systemic angiogenic capacity could underlie impaired vascular growth. Neonatal exposure to high oxygen, which mimics preterm birth-related physiological conditions, reduced in vitro angiogenic capacity and systemic microvascular density in adult rats. ...
Preterm birth accounts for over 15 million global births per year. Perinatal interventions introduced since the early 1980s, such as antenatal glucocorticoids, surfactant, and invasive ventilation strategies, have dramatically improved survival of even the smallest, most vulnerable neonates. As a result, a new generation of preterm-born individuals has now reached early adulthood, and they are at increased risk of cardiovascular diseases. To better understand the sequelae of preterm birth, cardiovascular follow-up studies in adolescents and young adults born preterm have focused on characterizing changes in cardiac, vascular, and pulmonary structure and function. Being born preterm associates with a reduced cardiac reserve and smaller left and right ventricular volumes, as well as decreased vascularity, increased vascular stiffness, and higher pressure of both the pulmonary and systemic vasculature. The purpose of this review is to present major epidemiological evidence linking preterm birth with cardiovascular disease; to discuss findings from clinical studies showing a long-term impact of preterm birth on cardiac remodeling, as well as the systemic and pulmonary vascular systems; to discuss differences across gestational ages; and to consider possible driving mechanisms and therapeutic approaches for reducing cardiovascular burden in individuals born preterm.
... Bonami AK, et al. [30] Relationship among preterm birth, increased vascular resistance, and high blood pressure. ...
... Indeed, a decrease in arterial compliance has been detected in preterm babies since their birth [29]. Again, the presence of a persistent increase in BP, pulse pressure, and vascular resistance has been reported in preterm girls after puberty [30]. An unfavourable trend has also been demonstrated, with systolic BP in childhood being related to an increased BP in adolescents born extremely preterm (<28 weeks) [27,31,32]. ...
Subjects formerly born preterm subsequently develop arterial - particularly isolated systolic- hypertension more frequently than their peers born at term.
Numerous factors may influence this predisposition, including an incomplete nephrogenesis, implying the presence of kidneys with a reduced number of nephrons and consequent reduction in haematic filtration, increased sodium absorption and activation of renin-angiotensin-aldosterone system, increased arterial rigidity produced by an elastin deficiency previously observed in anatomic specimens of human immature aorta, and reduced endothelial nitric oxide excretion, due to high blood levels of ADMA, a strong direct inhibitor of nitric oxide that exerts a vasoconstrictor effect.
Other possible factors (i.e. excretion of neuroendocrine compounds) may also be implicated. The aim of this paper was to review all possible mechanisms involved in the observed increase in blood pressure in individuals who had been born preterm and/or with intrauterine growth restriction. The outlook for new and promising laboratory techniques capable of identifying alterations in the metabolic pathways regulating blood pressure levels, such as metabolomics, is also provided.
... One systematic review found that preterm birth was associated with a significantly higher systolic and diastolic blood pressure [56], potentially owing to factors such as reduced total nephron number [57]. However, the evidence for other markers of cardiovascular health is less consistent: some studies showed changes in intima-media thickness (an early sign of atheroma formation, and a risk for later atherosclerosis) [56] in preterm infants, while others showed no difference in features such as arterial stiffness [58], another risk factor for cardiovascular disease. Evidence for an association between preterm birth and long-term changes in glucose and insulin metabolism is again inconsistent. ...
... Evidence for an association between preterm birth and long-term changes in glucose and insulin metabolism is again inconsistent. One large review [58] reported an association in early childhood between reduced insulin sensitivity (a risk factor for Type 2 diabetes) and preterm birth, but a reduction of the strength of this association in later childhood and adulthood. For adiposity, a meta-analysis identified a significant increase in low-density lipoprotein in infants born preterm [56], but no significant difference in adult BMI. ...
Preterm birth is a significant public health problem worldwide, leading to substantial mortality in the newborn period, and a considerable burden of complications longer term, for affected infants and their carers. The fact that it is so common, and rates vary between different populations, raising the question of whether in some circumstances it might be an adaptive trait. In this review, we outline some of the evolutionary explanations put forward for preterm birth. We specifically address the hypothesis of the predictive adaptive response, setting it in the context of the Developmental Origins of Health and Disease, and explore the predictions that this hypothesis makes for the potential causes and consequences of preterm birth. We describe how preterm birth can be triggered by a range of adverse environmental factors, including nutrition, stress and relative socioeconomic status. Examining the literature for any associated longer-term phenotypic changes, we find no strong evidence for a marked temporal shift in the reproductive life-history trajectory, but more persuasive evidence for a re-programming of the cardiovascular and endocrine system, and a range of effects on neurodevelopment. Distinguishing between preterm birth as a predictive, rather than immediate adaptive response will depend on the demonstration of a positive effect of these alterations in developmental trajectories on reproductive fitness.
This article is part of the theme issue ‘Developing differences: early-life effects and evolutionary medicine'.
... Today, survival is 70% to 80%, and a majority of these infants are free from disability in later life. [3][4][5][6] There are indications that development of the cardiovascular, renal, and autonomic nervous systems may be affected by preterm birth, [7][8][9][10][11][12] and risks of stroke and death from cardiovascular disease are increased in some 13,14 but not all 15 cohorts of adults who were born preterm. Earlier studies showed that blood pressure (BP) is already elevated in adolescence and adulthood after preterm birth. ...
... 19,29 In adolescence and at young adult age, however, several studies including a systematic review reported up to 2-to 4-mm Hg higher SBP and DBP in people who were born preterm. 7,11,16,18,[30][31][32] Although this increase in BP may seem small at an individual level, increasing the mean BP in a population by 2 to 5 mm Hg may have significant effects on the numbers who will have hypertension 33 and later stroke or ischemic heart disease. [34][35][36] Given that a dose-response relationship exists with gestational age 18,32,33 and that the association between preterm birth and elevated BP has been found to be independent of shared familial factors 18 and intrauterine growth restriction, 30,31,37 there may be a causal relationship. ...
Background
Advances in perinatal medicine have increased infant survival after very preterm birth. Although this progress is welcome, there is increasing concern that preterm birth is an emerging risk factor for hypertension at young age, with implications for the lifetime risk of cardiovascular disease.
Methods and Results
We measured casual blood pressures (BPs) in a population‐based cohort of 6‐year‐old survivors of extremely preterm birth (<27 gestational weeks; n=171) and in age‐ and sex‐matched controls born at term (n=172). Measured BP did not differ, but sex, age‐, and height‐adjusted median z scores were 0.14 SD higher (P=0.02) for systolic BP and 0.10 SD higher (P=0.01) for diastolic BP in children born extremely preterm than in controls. Among children born extremely preterm, shorter gestation, higher body mass index, and higher heart rate at follow‐up were all independently associated with higher BP at 6 years of age, whereas preeclampsia, smoking in pregnancy, neonatal morbidity, and perinatal corticosteroid therapy were not. In multivariate regression analyses, systolic BP decreased by 0.10 SD (P=0.08) and diastolic BP by 0.09 SD (P=0.02) for each week‐longer gestation.
Conclusions
Six‐year‐old children born extremely preterm have normal but slightly higher BP than their peers born at term. Although this finding is reassuring for children born preterm and their families, follow‐up at older age is warranted.
... Children born preterm are at higher risk of cardiometabolic diseases (8), such as increased vascular resistance and blood pressure (12), alterations in fat distribution (13), and impaired glucose regulation (14). Understanding the exercise capacity of children born preterm and the systems limiting exercise capacity improves our understanding of deterrents to partaking in physical activity. ...
Objectives
The long-term cardiopulmonary outcomes following preterm birth during the surfactant era remain unclear. Respiratory symptoms, particularly exertional symptoms, are common in preterm children. Therefore, cardiopulmonary exercise testing may provide insights into the pathophysiology driving exertional respiratory symptoms in those born preterm. This review aims to outline the current knowledge of cardiopulmonary exercise testing in the assessment of children born preterm in the surfactant era.
Design
This study is a narrative literature review.
Methods
Published manuscripts concerning the assessment of pulmonary outcomes using cardiopulmonary exercise testing in preterm children (aged <18 years) were reviewed. Search terms related to preterm birth, bronchopulmonary dysplasia, and exercise were entered into electronic databases, including Medline, PubMed, and Google Scholar. Reference lists from included studies were scanned for additional manuscripts.
Results
Preterm children have disrupted lung development with significant structural and functional lung disease and increased respiratory symptoms. The association between these (resting) assessments of respiratory health and exercise capacity is unclear; however, expiratory flow limitation and an altered ventilatory response (rapid, shallow breathing) are seen during exercise. Due to the heterogeneity of participants, treatments, and exercise protocols, the effect of the aforementioned limitations on exercise capacity in children born preterm is conflicting and poorly understood.
Conclusion
Risk factors for reduced exercise capacity in those born preterm remain poorly understood; however, utilizing cardiopulmonary exercise testing to its full potential, the pathophysiology of exercise limitation in survivors of preterm birth will enhance our understanding of the role exercise may play. The role of exercise interventions in mitigating the risk of chronic disease and premature death following preterm birth has yet to be fully realized and should be a focus of future robust randomized controlled trials.
... It may therefore be speculated that female participants recruited using the present criteria would also demonstrate similar responses to a well-matched control group, under the assumption that the potential for blunted physiological responsiveness is reduced in relation to prematurely born males. However, evidence of long-term cardiovascular sequelae specific to prematurely born girls also exists (Bonamy et al., 2005), so further work to elucidate potential sex-related different consequences of prematurity is undoubtedly warranted. ...
Pre‐term birth is associated with physiological sequelae that persist into adulthood. In particular, modulated ventilatory responsiveness to hypoxia and hypercapnia has been observed in this population. Whether pre‐term birth per se causes these effects remains unclear. Therefore, we aimed to assess pulmonary ventilation and blood gases under various environmental conditions, comparing 17 healthy prematurely born individuals (mean ± SD; gestational age, 28 ± 2 weeks; age, 21 ± 4 years; peak oxygen uptake, 48.1 ± 11.2 ml kg ⁻¹ min ⁻¹ ) with 16 well‐matched adults born at term (gestational age, 40 ± 1 weeks; age, 22 ± 2 years; peak oxygen uptake, 51.2 ± 7.7 ml kg ⁻¹ min ⁻¹ ). Participants were exposed to seven combinations of hypoxia/hypobaria (equivalent to ∼3375 m) and/or hypercapnia (3% CO 2 ), at rest for 6 min. Pulmonary ventilation, pulse oxygen saturation and the arterial partial pressures of O 2 and CO 2 were similar in pre‐term and full‐term individuals under all conditions. Higher ventilation in hypoxia compared to normoxia was only observed at terrestrial altitude, despite an equivalent (normobaric) hypoxic stimulus administered at sea level (0.138 ). Assessment of oscillations in key variables revealed that combined hypoxic hypercapnia induced greater underlying fluctuations in ventilation in pre‐term individuals only. In general, higher pulse oxygen saturation fluctuations were observed with hypoxia, and lower fluctuations in end‐tidal CO 2 with hypercapnia, despite similar ventilatory oscillations observed between conditions. These findings suggest that healthy prematurely born adults display similar overall ventilation to their term‐born counterparts under various environmental stressors, but that combined ventilatory stimuli could induce an irregular underlying ventilatory pattern. Moreover, barometric pressure may be an important factor when assessing ventilatory responsiveness to moderate hypoxic stimuli. image
Key points
Evidence exists for unique pulmonary and respiratory function under hypoxic conditions in adult survivors of pre‐term birth. Whether pre‐term birth per se causes these differences requires a comparison of conventionally healthy prematurely born adults with an appropriately matched sample of term‐born individuals.
According to the present data, there is no difference between healthy pre‐term and well‐matched term‐born individuals in the magnitude of pulmonary ventilation or arterial blood gases during independent and combined hypobaria, hypoxia and hypercapnia.
Terrestrial altitude (hypobaria) was necessary to induce differences in ventilation between normoxia and a hypoxic stimulus equivalent to ∼3375 m of altitude. Furthermore, peak power in pulse oxygen saturation was similar between hypobaric normoxia and normobaric hypoxia.
The observed similarities between groups suggest that ventilatory regulation under various environmental stimuli is not impaired by pre‐term birth per se . Instead, an integrated combination of neonatal treatment strategies and cardiorespiratory fitness/disease status might underlie previously observed chemosensitivity impairments.
... Indeed, many studies have reported the persistence, and further deterioration of, arterial dysfunction throughout infancy (Schubert et al., 2011;Tauzin et al., 2014), childhood (H. Martin et al., 2000), adolescence (Bonamy et al., 2005;Johansson et al., 2005) and adulthood (Hovi et al., 2011;Tauzin et al., 2014). ...
Preterm‐born individuals are a uniquely vulnerable population. Preterm exposure to the extrauterine environment and the (mal)adaptations that occur during the transitional period can result in alterations to their macro‐ and micro‐physiological state. The physiological adaptations that increase survival in the short term may place those born preterm on a trajectory of lifelong dysfunction and later‐life decompensation. Cardiovascular compensation in children and adolescents, which masks this trajectory of dysfunction, is overcome under stress, such that the functional cardiovascular capacity is reduced and recovery impaired following physiological stress. This has implications for their response to thermal stress. As the Anthropocene introduces greater changes in our environment, thermal extremes will impact vulnerable populations as yet unidentified in the climate change context. Here, we present the hypothesis that individuals born preterm are a vulnerable population at an increased risk of cardiovascular morbidity and mortality during thermal extremes.
... Hypertension is prevalent among children and adults born prematurely and its severity is directly related to the degree of prematurity (Markopoulou et al., 2019). The mechanism remains unclear; arrested angiogenesis has been postulated (Bertagnolli et al., 2016), and varying degrees of large artery hypoplasia and increased arterial stiffness have been reported (Bonamy, 2005;Sehgal, 2018). The significance of these findings is difficult to interpret in the context of atypical somatic growth and hypertension . ...
Computational modeling has well‐established utility in the study of cardiovascular hemodynamics, with applications in medical research and, increasingly, in clinical settings to improve the diagnosis and treatment of cardiovascular diseases. Most cardiovascular models developed to date have been of the adult circulatory system; however, the perinatal period is unique as cardiovascular physiology undergoes drastic changes from the fetal circulation, during the birth transition, and into neonatal life. There may also be further complications in this period: for example, preterm birth (defined as birth before completed weeks of gestation) carries risks of short‐term cardiovascular instability and is associated with increased lifetime cardiovascular risk. Here, we review computational models of the cardiovascular system in early life, their applications to date and potential improvements and enhancements of these models. We propose a roadmap for developing an open‐source cardiovascular model that spans the fetal, perinatal, and postnatal periods.
This article is categorized under: Cardiovascular Diseases > Computational Models
Cardiovascular Diseases > Biomedical Engineering
Congenital Diseases > Computational Models
... Prematurity also causes functional limitations, such as decreased lung function [29] or cardiorespiratory capacity [30]. Increased blood pressure, signs of increased peripheral vascular resistance, and cardiac remodeling can be observed in early childhood in preterm-born children [31][32][33][34]. Moreover, preterm-born children have reduced insulin sensitivity and a higher risk for markers of metabolic syndrome when there is excessive childhood weight gain [35,36]. ...
Introduction:
Suspected preterm labor (SPL), defined as the presence of regular and painful uterine contractions and cervical shortening, represents a prenatal insult with potential long-term consequences. However, despite recent evidence demonstrating suboptimal neurodevelopment at 2 years in this population, it remains underestimated as a significant risk factor for neurodevelopmental disorders or other chronic diseases. The aim of this study is to assess the impact of suspected preterm labor during pregnancy on cardiometabolic profile and neurodevelopment during childhood (6-8 years).
Methods and analysis:
Prospective cohort study including children whose mothers suffered suspected preterm labour during pregnancy and paired controls. Neurodevelopmental, cardiovascular, and metabolic assessments will be performed at 6-8 years of age. A trained psychologist will carry out the neurodevelopment assessment including intelligence, visual perception, and behavioral assessment. Body composition and physical fitness assessment will be performed by one trained pediatrician and nurse. Finally, cardiovascular evaluation, including echocardiography and blood pressure, will be performed by two pediatric cardiologists. Data regarding perinatal and postnatal characteristics, diet, lifestyle, and weekly screen time of the child will be obtained from medical history and direct interviews with families. Primary outcome measures will include body mass index and adiposity, percentage of fat mass and total and regional lean mass, bone mineral content and density, cardiorespiratory resistance, isometric muscle strength, dynamic lower body strength, systolic and diastolic blood pressure, left ventricle (LV) systolic and diastolic function, general intelligence index, visuospatial working memory span, oculomotor control test, index of emotional, and behavioral problems.
... Adults born preterm have an increased risk for developing CKD, detectable as early as childhood [10][11][12]14 . These children are also at increased risk of high blood pressure and hypertension during childhood [14][15][16][17][18][19][20] . Although growing evidence suggests a signi cant connection between preterm birth and CKD, it is challenging to study the direct effect of preterm birth on long-term kidney outcomes. ...
Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants.
... Furthermore, the oxidative stress and chronic inflammation of the tissues due to preterm birth and epigenetic mechanisms may be responsible for the increased risk of developing cardiovascular disease in later life [56]. The studies' findings about the association of pulse wave velocity (PWV), as a marker of arterial stiffness, and preterm birth, are rather conflicting (Table 2) [57][58][59][60][61][62][63][64][65][66][67][68][69]. In a survey by Boardman et al., including a population sample of 102 ex-preterm adults and 102 controls, arterial stiffness was assessed by three different methods (carotid-femoral PWV, branchial-femoral PWV and cardiovascular magnetic resonance PWV) and did differ in association with a preterm perinatal history [64]. ...
Over recent decades, there has been a global increase in preterm birth rate, which constitutes about 11% of total births worldwide. The present review aims to summarize the current knowledge on the long-term consequences of prematurity on renal and cardiovascular development and function. Recent literature supports that prematurity, intrauterine growth restriction or low birth weight (LBW) may have an adverse impact on the development of multiple organ systems, predisposing to chronic diseases in childhood and adulthood, such as arterial hypertension and chronic kidney disease. According to human autopsy and epidemiological studies, children born preterm have a lower nephron number, decreased kidney size and, in some cases, affected renal function. The origin of hypertension in children and adults born preterm seems to be multifactorial as a result of alterations in renal, cardiac and vascular development and function. The majority of the studies report increased systolic and diastolic blood pressure (BP) in individuals born preterm compared to full term. The early prevention and detection of chronic non-communicable diseases, which start from childhood and track until adulthood in children with a history of prematurity or LBW, are important.
... | (2021) 11:21667 | https://doi.org/10.1038/s41598-021-00489-y www.nature.com/scientificreports/ of high blood pressure and hypertension during childhood [14][15][16][17][18][19][20] . Although growing evidence suggests a significant connection between preterm birth and CKD, it is challenging to study the direct effect of preterm birth on long-term kidney outcomes. ...
Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants.
... For example, the association between preterm birth and increased blood pressure is observed from as early as 2.5 years of age [30]. An inverse relationship between gestational age at birth and levels of blood pressure has been evident in population-based studies in childhood [31,32], and in adolescence and adulthood [33][34][35]. The increase in blood pressure in those born preterm likely renders vulnerability to the development of cardiovascular disease, given that hypertension is a major risk factor for cardiovascular disease and is often associated with left ventricular hypertrophy [36][37][38][39]. ...
Preterm birth coincides with a key developmental window of cardiac growth and maturation, and thus has the potential to influence long-term cardiac function. Individuals born preterm have structural cardiac remodelling and altered cardiac growth and function by early adulthood. The evidence linking preterm birth and cardiovascular disease in later life is mounting. Advances in the perinatal care of preterm infants, such as glucocorticoid therapy, have improved survival rates, but at what cost? This review highlights the short-term and long-term impact of preterm birth on the structure and function of the heart and focuses on the impact of antenatal and postnatal glucocorticoid treatment on the immature preterm heart.
... The chance of survival for infants born in Sweden between 22 and 26 weeks gestational age (GA) increased from 70% to 77% between 2004-2007 and 2014-2017 [1]. Consequently, there are more survivors of preterm birth growing up, resulting in more people at risk of developing long-term consequences in later life [2][3][4][5][6][7][8][9]. It is well-known that inactivity in childhood is associated with health risks in adulthood [10,11] while physical activity (PA) is beneficial and can prevent major chronic diseases such as cardiovascular diseases and diabetes [12][13][14]. ...
Physical activity (PA) can prevent cardiovascular diseases. Because of increased risks of impairments affecting motor activity, PA in children born preterm may differ from that in children born at term. In this prospective cohort study, we compared objectively measured PA in 71 children born extremely preterm (<27 weeks gestational age), to their 87 peers born at term, at 6.5 years of age. PA measured with accelerometer on the non-dominant wrist for 7 consecutive days was compared between index and control children and analyzed for associations to prenatal growth, major neonatal brain injury, bronchopulmonary dysplasia and neonatal septicemia, using ANOVA. Boys born extremely preterm spent on average 22 min less time per day in moderate to vigorous physical activity (MVPA) than control boys (95% CI: -8, -37). There was no difference in girls. Amongst children born extremely preterm, major neonatal brain injury was associated with 56 min less time in MVPA per day (95%CI: -88, -26). Subgroups of children born extremely preterm exhibit lower levels of physical activity which may be a contributory factor in the development of cardiovascular diseases as adults.
... The mechanisms by which BP levels are affected by preterm birth are not fully understood. Different theories include underdevelopment of the kidneys with lower number of nephrons, disturbed growth of the vascular tree leading to increased peripheral vascular resistance, and increased activity along the sympathetic-adrenal axis (172)(173)(174). A recently published study suggested that decreased growth in the postnatal period induces higher cortisol and dehydroepiandrosterone levels at six years of age, which in turn were associated with higher systolic blood pressure (SBP) at this age (175). ...
Background
Survival among very low birth weight (VLBW) and extremely preterm (EPT) infants has increased markedly during the last decades. Neonatal hyperglycemia is common in these infants and is known to be associated with adverse outcomes. However, much about neonatal hyperglycemia is still unknown: which mechanisms are responsible for it, its long-term risk profile, how to treat it and even how to define it. This thesis focuses on neonatal hyperglycemia in preterm-born infants - its prevalence, possible causes (including postnatal nutrition and its possible programming effect of later outcomes), consequences and treatment.
Methods
Two cohorts were studied in this thesis. The EXtremely PREterm infants in Sweden Study (EXPRESS) – a national population-based cohort - included all infants born before completed 27 gestational weeks during the years 2004-2007 in Sweden. Nutritional data as well as glucose measurements (n=9850) and insulin treatment data for the first 28 days of life were obtained for 580 infants. In a sub-cohort of 171 children, blood pressure measurements were obtained at a follow-up visit at 6.5 years of age. Neurodevelopment was assessed at 6.5 years of age in 436 children. Intellectual ability was assessed using Wechsler Intelligence Scale for Children IV (WISC-IV; n=355). Gross and fine motor function were assessed using Movement Assessment Battery for Children 2 (MABC-2; n=345).
The very Low birth weight Infants - Glucose and Hormonal profiles over Time (LIGHT) study was a prospective cohort study that included 50 VLBW infants born in Umeå, Sweden, between 2016-2019. Infants were placed on continuous glucose monitoring (CGM) for a 48-hour period when a postmenstrual age (PMA) of 36 gestational weeks was reached (n=35).
Results
Daily prevalence of hyperglycemia > 10 mmol/L in EPT infants was high during the first two weeks of life (up to 30%), followed by a slow decrease thereafter. Protracted hyperglycemia > 8 mmol/L was detected in more than half of VLBW infants at PMA 36 weeks.
In EPT infants, glucose concentrations during the first 28 days of life were increased by 1.6% on the day following an increase of 1 g/kg/day in parenteral carbohydrate intake. Male sex, amnionitis and prior hypoglycemia and hyperglycemia episodes were risk factors for hyperglycemia at PMA 36 weeks in VLBW infants.
In EPT infants, neonatal hyperglycemia > 10 mmol/L was associated with increased 28-day mortality. Neonatal hyperglycemia, its severity and duration were associated with increased diastolic blood pressure (DBP) and lower MABC-2 scores at 6.5 years of age. Insulin treatment was associated with improved 28- and 70-day survival but not with BP or neurodevelopmental outcomes at 6.5 years of age.
Higher protein intake during the first eight weeks of life was associated with higher DBP at 6.5 years of age. An increase of the carbohydrate intake by 1 g/kg/day during this period was associated with an increase of 0.18 SDS in systolic (SBP) and 0.14 SDS in DBP at 6.5 years. Growth during the same period was not associated with BP at 6.5 years.
Conclusions
Neonatal hyperglycemia during the first four weeks of life was more common in EPT infants than has previously been described. Remaining glucose disturbances were common at PMA 36 weeks in VLBW infants. Parenteral glucose intakes within the range given seems to have had low contribution to glucose concentration variability. Neonatal hyperglycemia was associated with increased 28-day mortality as well as with increased blood pressure and reduced motor skills at 6.5 years of age. Carbohydrate intake in the immediate postnatal period was indepentently associated with increased blood pressure at 6.5 years of age. The results add to the knowledge regarding important risk factors and health effects of neonatal hyperglycemia. Different treatment options for neonatal hyperglycemia should be evaluated in animal models and in randomized controlled clinical trials in premature infants.
... Comparing preterm born adolescent females (~16 years of age) with controls, BP was significantly higher in the former, whereas carotid stiffness and PWV were comparable with controls. 63 In contrast, brachioradial artery stiffness and BP was significantly higher amongst preterm FGR born children but not those born preterm or term appropriate for gestation. 64 ...
... One notable study found that single-nucleotide polymorphisms by perceived discrimination interactions combine to influence higher BP for AAs (85). Moreover, evidence shows that low birth weight is related to increased vascular resistance at birth, continuing into later life (86,87). Notably, the rate of low birth weight among AA mothers is twice that of EA, independent of SES (88). ...
Objectives:
Decades of research suggest there may be important ethnic differences in the hemodynamic mechanisms that co-determine arterial blood pressure (BP), the primary diagnostic index of hypertension. In general, studies have observed that, compared to European Americans (EA), African Americans (AA) exhibit higher total peripheral resistance (TPR), an important summative index of peripheral vascular constriction. In contrast, EAs have been reliably shown to exhibit greater cardiac output (CO), which is directly linked to left ventricle and overall cardiac blood flow. We have previously proposed that elevated basal TPR, in particular, represents one component of the Cardiovascular Conundrum, characterized, paradoxically, by elevated resting heart rate variability (HRV) among AAs, relative to EAs. The present meta-analysis and systematic review of the literature sought to extend this previous work by establishing the magnitude of the empirically-implied ethnic differences in resting TPR and CO.
Methods:
A search of the literature yielded 140 abstracts on differences in TPR between AAs & EAs; 40 were included. Sample sizes, means and standard deviations for baseline TPR with samples that included EAs and AAs were collected and Hedges' g was computed.
Results:
Findings indicated that AAs had higher baseline TPR than EAs (Hedges' g = .307, SE = 0.043, CI = 0.224, 0.391, p < 0.001). Additionally, EAs had higher resting cardiac output (CO) than AAs (Hedges' g = -0.214, SE = 0.056, CI = -0.324, -0.104, p < 0.001).
Conclusions:
We discuss the present findings in the context of the role of elevated TPR in the deleterious effects of high blood pressure specifically for AAs.
... Many researchers tried to find confounding variables to explain the varied results for the association of BW and BP. [24][25][26][27][28][29][30] 5/15 https://e-kcj.org https://doi.org/10.4070/kcj.2018.0448 ...
It has been known for a long time that elevated blood pressure (BP) in the young may persist and progress into adult hypertension (HTN). Multiple studies have revealed the predicted BP trajectory lines starting from childhood and related them to later cardiovascular (CV) risks in adulthood. As a small baby grows into a tall adult, BP will also naturally increase. Among early-life predictors of adult HTN, birth history, such as prematurity, and low birth weight have been popular subjects in research on pediatric HTN, because body size at birth has been reported to be inversely related to the risk of adulthood HTN. The hypothesis of HTN in prematurely born adolescents has been postulated as a physiological predisposition to postnatal excessive weight gain. Current body weight is a well-known independent predictor of HTN in children, and some studies showed that children demonstrating upward crossing of their weight percentiles while growing into adolescents have significantly increased risk for elevated BP later in life. Recently, reports focused on the adverse effect of excessive catch-up growth in this population are gradually drawing attention. Accordingly, children born prematurely or with intrauterine growth restriction who show rapid changes in their weight percentile should be under surveillance with BP monitoring. Prevention of childhood obesity, along with special care for premature infants or infants small for their gestational age, by providing healthy nutritional guidelines should be cardinal strategies for the prevention of adult HTN and CV risks later in life.
... In preterm animals born at GD62, as in preterm humans born prior to 29 weeks' completed gestation, there is a period of high microvascular flow after birth, associated with central cardiovascular compromise, morbidity and mortality (Stark et al. 2008;Dyson et al. 2012Dyson et al. , 2014 providing a model for studying cardiovascular transition at birth in preterm newborns, and the contribution of early microvascular compromise to adult cardiovascular disease in the ex-preterm adult. Human studies now consistently demonstrate higher blood pressure in ex-preterms than in controls (Hack et al. 2005), especially in females (Bonamy et al. 2005). Furthermore, this is associated with lower skin capillary density (Bonamy et al. 2007) and retinal microvascular changes (Kistner et al. 2002), which highlights the need for an appropriate animal model to interrogate the vascular mechanisms contributing to increased cardiovascular disease risk in the ex-preterm. ...
Over 30 years ago Sir David Barker first proposed the theory that events in early life could explain an individuals’ risk of non‐communicable disease in later life; the Developmental Origins of Health and Disease (DOHaD) theory. During the 1990s the validity of the DOHaD theory was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, their strengths and limitations as an experimental model of DOHaD and their potential to enhance clinical therapeutic innovation to improve human health. This article is protected by copyright. All rights reserved
... 11,12 Offspring born to women who have experienced pregnancy complications also display adverse cardiovascular findings. Those born preterm have increased blood pressure in adolescence [13][14][15][16][17][18] and adult life, 19-26 with a 10.5 % prevalence of clinical hypertension and 45.9 % prevalence of prehypertension in 19-year-old preterm born adults. 16 They are also relatively more likely to require antihypertensive medication in young adulthood. ...
Pregnancy complications, such as hypertensive disorders or preterm delivery, identify families predisposed to cardiovascular problems at other times in life. Whether the pregnancy complication induces cardiac disease or whether the pregnancy stress unmasks an underlying predisposition remains unclear. However, improved survival following severe pregnancy complications for both the mother and, in particular, the offspring – who is often born preterm – has resulted in a growing cohort of individuals who carry this increased cardiovascular risk. Research to understand the underlying pathological mechanisms that link these conditions might ultimately lead to novel therapeutic or prevention strategies for both cardiovascular and pregnancy disease.
... 3,4 However, the increasing numbers of preterm infants now surviving into later life may experience a complex set of longterm negative impacts, 3 including neurodevelopmental impairments and sensory deficits, [5][6][7] lower weight and shorter height 8,9 increased risk of obesity, hypertension, type-II diabetes and cardiovascular disease, 10 and higher blood pressure. [11][12][13][14] Many of these studies have examined subjects in childhood, with few extending to follow up in adulthood. ...
... 3,4 However, the increasing numbers of preterm infants now surviving into later life may experience a complex set of longterm negative impacts, 3 including neurodevelopmental impairments and sensory deficits, [5][6][7] lower weight and shorter height 8,9 increased risk of obesity, hypertension, type-II diabetes and cardiovascular disease, 10 and higher blood pressure. [11][12][13][14] Many of these studies have examined subjects in childhood, with few extending to follow up in adulthood. ...
Background:
To evaluate the long-term impact of preterm birth on respiratory function in female patients born preterm, we undertook spirometric examinations twice, as they reached the age of puberty, then follow-up examinations of part of the same cohort in adulthood. We sought evidence that preterm birth is correlated with poorer spirometric results into adulthood.
Methods:
A total of 70 girls (aged 12.2 ± 1.5 years in 1997) who had been born preterm (at 34.7 ± 1.86 weeks, none having experienced bronchopulmonary dysplasia) took part in spriometric examinations in 1997 and again in 1998. Of those, after a gap of 17 years, a group of 12 were successfully recontacted and participated in the 2015 examination as adults (then aged 27.6 ± 2.6 years, born at 34.5 ± 1.92 weeks). We compared spirometric results across the adolescent and adult examinations, and compared the adult results with an adult reference group.
Results:
The percentage values of FEV1(forced expiratory volume in 1 s), FVC (forced vital capacity) and MVV (maximal voluntary ventilation) showed significant improvement between the two examinations in the early adolescent period. In adulthood, FEV1%pred (percentage predicted forced expiratory volume in 1 s) showed no statistically significant difference. The mean values of both FVC and FVC%pred (percentage predicted forced vital capacity) for the preterm-born group were lower than for the reference group, but this was not statistically significant. The preterm-born group showed lower values of such parameters as forced expiratory flow at 25-75% of FVC, MEF25(maximal expiratory flow at 25% of forced vital capacity) and FEV1/FVC as compared with the reference group, but again without statistical significance.
Conclusions:
(1) A somewhat below-norm level of respiratory parameters among preterm-born girls entering pubescence may attest to continued negative impact on their respiratory system. (2) A significant improvement in their spirometric results 1 year later may indicate that pubescence helps compensate for the earlier negative effect of preterm birth. (3) No significant differences were seen in lung function in preterm-born adults as compared with a reference group of adults, although the preterm-born group did exhibit lower values of all parameters studied and more frequent obstructive disorders.
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.g., diet, smoking). Whereas preterm cardiovascular disease risk is driven by structural changes incurred at birth. Much of the proliferative growth in the developing heart and major vessels ceases at birth, leading to permanently reduced dimensions compared to their term-born cohort. These structural changes take a back seat to functional and clinical complications within the neonatal period, but become increasingly pronounced from adolescence, at which point functional decompensation can be observed. While the cause may differ from ‘traditional’ populations, the eventual disease outcomes do not, leading them to be an overlooked population. This means that aetiology, and thus, treatment options may be very different due to the underlying mechanisms. Here, we propose that the structural cause of preterm-associated cardiovascular disease is apparent and observable early in life. Understanding the differences in cardiovascular disease aetiology may therefore aid in the early treatment of preterm-associated cardiovascular disease risk.
To systematically review the potential causes and possible effects of preterm birth [<37 weeks gestational duration]. We searched PubMed, google scholar, clinicaltrials.gov and science direct for English language articles published from 2004 to march 2021. All kinds of study schemes were considered acceptable, comprising case –control, cohort studies, experimental and cross- sectional studies. Significant evidences indicate that social stress, elevated cadmium exposure, genomic variations, vitamin D deficiency, pre-conception hepatitis B infection, declined vaginal microbial community, intrauterine infection, reduction in cervical consistency index, strong exposure of creatinine corrected thallium, systemic autoimmune diseases, ozone, primary traffic air pollutants, road traffic noise, potential exposure of arsenic, HIV exposure, maternal thyroid dysfunction, maternal plasma protein level and COVID-19 exposure in pregnant females are the major risk factors for PTBs. Results of earlier investigations indicated prominent risk of insulin resistance, hypertension, neurological defects, heart failure, Chronic kidney disease, Lung function impairment, lower birth weight, thalamocortical system defects, cancer, altered cardiac phenotype and cardio metabolic diseases in survivors of preterm births. This review will help clinicians to isolate the fundamental etiology and to proactively identify, cope and improve outcomes of at-risk pregnancies.
Background and aims
Certain exposures and risk factors during the first 1,000 days of life are known to influence future cardiovascular disease (CVD) risk. Pulse wave velocity (PWV) is a measure of arterial stiffness and a recognised surrogate marker of CVD. We performed a systematic review and meta-analyses to investigate whether early life exposures were associated with increased PWV compared with controls in youth.
Methods
Databases AMED, MEDLINE, EMBASE, CINAHL and Scopus were searched from inception until February 2022. Eligibility criteria: observational controlled studies in youth aged <20 years with risk factors/exposure during the first 1,000 days and PWV measurement. This review is registered with PROSPERO (CRD42019137559). Outcome data were pooled using random-effects meta-analysis. Meta-regression was used to investigate potential confounders.
Results
We identified 24 eligible studies. Age of participants ranged from 1-day to 19-years at time of PWV assessment. Exposures included pre-term birth, small for gestational age (SGA), maternal diabetes and assisted reproductive technologies, none of which were significantly associated with PWV in meta-analysis. Sub-group analysis by age demonstrated increased PWV in childhood and adolescence in those exposed to maternal diabetes or born SGA. In meta-regression of pre-term studies, higher prevalence of SGA was associated with increased PWV compared with controls (p = 0.034, R² = 1).
Conclusions
We found limited evidence that youth exposed to maternal diabetes or born SGA have increased PWV, consistent with increased future CVD risk. These changes in PWV appear to manifest in later childhood and adolescence. Further research is required to better understand the observed relationships.
Background and aims
Reduced maternal placental growth factor (PlGF) and higher soluble fms-like tyrosine kinase (sFlt-1) concentrations in pregnancy may have persistent effects on offspring vasculature. We hypothesized that suboptimal maternal angiogenic factors in pregnancy may adversely affect fetal vascular development, leading to an increased risk of adverse atheriosclerotic adaptations and higher blood pressure in offspring.
Methods
In a population-based prospective cohort among 4565 women and their offspring, we examined the associations of maternal serum PlGF and sFlt-1 concentrations in the first half of pregnancy with offspring vascular development. We measured childhood blood pressure and obtained childhood carotid intima media thickness and carotid distensibility through ultrasonography at 9 years.
Results
After adjustment for maternal sociodemographic and lifestyle characteristics, no associations were present of maternal first and second trimester angiogenic factors with childhood blood pressure, carotid IMT or distensibility in the total population. In preterm born children only, higher maternal second trimester PlGF concentrations, but not sFlt-1 concentrations, were associated with a lower childhood diastolic blood pressure (difference: -0.16 SDS (95% CI -0.30, −0.03) per SDS increase in maternal second trimester PlGF concentration). No associations among children born small-for-gestational age were present.
Conclusions
In a low-risk population, maternal angiogenic factors in the first half of pregnancy are not associated with childhood blood pressure, carotid IMT or carotid distensibility after considering maternal socio-demographic and lifestyle factors. Only in children born preterm, lower maternal second trimester PlGF concentrations are associated with higher childhood diastolic blood pressure, but not with other vascular outcomes.
Arterial hypertension (AH) remains one of the most common diseases and a leading risk factor for cardiovascular diseases (CVD) in the 21st century. It determines the importance of a search for new factors provoking an increase in blood pressure. This review focuses on studies of preclinical predictors of hypertension. Orthostatic circulatory disorders with clinical signs of cardiovascular deconditioning are risk factors for the development of hypertension and CVD, accompanied by a more rapid increase in vascular stiff ness. Such abnormalities, even minor ones without clinical manifestations, increase the risk of hypertension development in the young population. The review deals with orthostatic changes in hemodynamics and features of neurohormonal change. It has been shown that adaptive processes counteracting an increase in hydrostatic pressure contribute to a significant transient increase in vascular stiff ness. The evolution of orthostatic hemodynamic disorders from preclinical to clinical forms accelerates the process of vascular wall remodeling, leading to a spontaneous increase in its rigidity — one of the significant risk factors for hypertension and CVD. To identify preclinical predictors, a new protocol of passive orthostatic test (POT) was developed. It was standardized not by the tilt angle, but by the height of the hydrostatic column. Further research is needed to evaluate the prognostic capabilities of predictors, to reveal the pathogenetic connection of orthostatic disorders with the development of hypertension, and to remodeling the vascular wall, which causes an increase in its rigidity. It is also required to search for ways to correct preclinical orthostatic disorders in healthy young population for early prevention of hypertension.
Purpose
Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR).
Methods
We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932–1933) and the WWII (1941–1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942–1945.
Results
During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05).
Conclusion
In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications.
Human fetal regulatory systems are highly sensitive to maternal stress, toxins, nutritional deprivation, maternal infection, and inflammation. The developmental origins of health and disease (DOHaD) hypothesis posits that fetal adaptation to stressful intrauterine conditions may alter organ development and function, increasing the risk for disease later in life. Adverse intrauterine conditions are reflected in shortened gestation, smaller body size at birth, and, in some cases, fetal growth restriction as well. Extremely preterm birth is a complex, multi-faceted risk factor that may warrant significant management across the lifespan. As adults, survivors continue to face significant physiological and psychological stresses that affect their health, education, mobility, work, and social functioning. In the present chapter, we compare long-term functional outcomes in adult survivors of extremely low birth weight (ELBW; ≤1000 g) and adults born at normal birth weight (NBW; ≥2500 g) in the McMaster ELBW Cohort, the oldest known prospectively followed cohort of ELBW survivors, born from 1977 to 1982. While some consequences of these early stresses are not subject to mitigation, strategies exist to manage their long-term effects. We examine naturalistic and structural models of acquired resilience that may reduce the impact of stressors associated with extremely preterm birth.
Relación de la prematuridad con la fuerza y la composición corporal en niños y niñas de 7 a 11 años de edad
Poor fetal and neonatal nutrition interacts with the environment to produce subtle changes in the development, structure, and function of organs. Over the lifetime, these subtle changes alter an individual’s response to stressors and increase disease susceptibility. One mechanism by which early-life nutrition causes long-term effects is via epigenetic programming. The inherent complexities in epigenetic programming and subsequent modulation of gene expression in response to early life events are beginning to be understood. However, work remains to be done in identifying susceptible genes with phenotypic contributions, as well as in understanding how epigenetic modifications contribute to changes in gene expression during development.
Emerging evidence demonstrates a link between preterm birth (PTB) and later life cardiovascular disease (CVD). We conducted a systematic review and meta-analysis to compare conventional CVD risk factors between those born preterm and at term. PubMed, CINAHL, SCOPUS, and EMBASE databases were searched. The review protocol is registered in PROSPERO (CRD42018095005). CVD risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index, lipid profile, blood glucose, and fasting insulin among those born preterm (<37 weeks' gestation) were compared with those born at term (≥37 weeks' gestation). Subgroup analyses based on gender, age, gestational at birth (<32 weeks' gestation and <28 weeks' gestation), and PTB associated with small for gestational age or average for gestational age were also performed. Fifty-six studies provided data on 308,987 individuals. Being born preterm was associated with 3.26 mmHg (95% confidence interval [CI] 2.08 to 4.44) higher mean SBP and 1.32 mmHg (95% CI: 0.61 to 2.04) higher mean DBP compared to being born at term. Subgroup analyses demonstrated that SBP was higher among (a) preterm compared to term groups from early adolescence until adulthood; (b) females born preterm but not among males born preterm compared to term controls; and (c) those born at <32 weeks or <28 weeks compared to term. Our meta-analyses demonstrate higher SBP and DBP among those born preterm compared to term. The difference in SBP is evident from early adolescence until adulthood.
Current evidence indicates that maternal diets before and during pregnancy could influence rates of preterm birth, low birth weight (LBW), and small for gestational age (SGA) births. However, findings have been inconsistent. This review summarised evidence concerning the effects of maternal diets before and during pregnancy on preterm birth, LBW, and SGA. Systematic electronic database searches were carried out using PubMed, EMBASE, Scopus, and Cochrane library using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The review included forty eligible articles, comprising mostly of prospective cohort studies, with five randomized controlled trials (RCT). The dietary patterns during pregnancy associated with a lower risk of preterm birth were commonly characterized by high consumption of vegetables, fruits, whole grains, fish, and dairy products. Those associated with a lower risk of SGA also had similar characteristics, including high consumption of vegetables, fruits, legumes, seafood/fish, and milk products. Results from a limited number of studies suggested there was a beneficial effect on the risk of preterm birth of pre-pregnancy diet quality characterized by a high intake of fruits and proteins and less intake of added sugars, saturated fats, and fast foods. The evidence was mixed for the relationship between maternal dietary patterns during pregnancy and LBW. These findings indicate that better maternal diet quality during pregnancy, characterized by a high intake of vegetables, fruits, whole grains, dairy, and protein diets, may have a synergistic effect on reducing the risk of preterm birth and SGA.
Objectives:
We aimed to investigate possible associations between birth weight and adult life carotid-femoral pulse wave velocity (cfPWV) and augmentation pressure index (AIx).
Design and method:
This study included 1598 participants, that is, 340 elderly individuals from the Malmö Birth Data Cohort (MBDC) and 1258 young-middle aged individuals from the Malmö Offspring Study (MOS) with full data on birth weight and gestational age. Participants underwent cfPWV and AIx measurements with Sphygmocor (AtCor, Australia). Analysis of data was performed with multiple linear regression models including adjustments for age, sex, gestational age and risk factors. Furthermore, comparisons were made between participants born prematurely or at term or born small-for-gestational age (SGA) or appropriate-for-gestational age (AGA).
Results:
Birth weight was positively associated with cfPWV after full adjustment (β = 0.057; P < 0.001), a finding that remained significant in the younger age group 18-27 years (β = 0.138, P = 0.008). Furthermore, birth weight was inversely associated with AIx (β = -0.058, P = 0.001). Participants born SGA had significantly higher AIx (P = 0.007) and MAP (P = 0.037) compared with AGA born. Preterm-born participants showed significantly higher SBP compared with term-born (P = 0.034). Finally, birth weight was inversely associated with MAP (β = -0.058, P = 0.017) and SBP (β = -0.047, P = 0.031), respectively.
Conclusion:
Birth weight is positively associated with cfPWV, shown strongest in the youngest individuals, a finding that could possibly be explained by increasing trends for maternal overweight/obesity in recent decades. Furthermore, birth weight is inversely associated with AIx, a risk marker of cardiovascular disease. This calls for screening of risk factors in subjects with adverse conditions at birth.
The human embryo is totally dependent on the mother. Anything that affects the mother might have a direct impact on the growing embryo. While intoxication due to maternal drug abuse in industrialized countries is rare, chronic or intermittent hypoxia due to various causes remains one of the highest risks during pregnancy for the unborn child. This chapter will focus on the different mechanisms for intrauterine hypoxia and their impact on the fetal cardiovascular system. © Springer International Publishing AG, part of Springer Nature 2018. All rights reserved.
Ce projet traite de la programmation développementale de l'hypertension artérielle (HTA) à travers des influences néonatales précoces pouvant moduler le développement vasculaire. Les bébés prématurés présentent des défenses antioxydantes diminuées comparés aux nouveau-nés à terme et sont exposés à la naissance à des concentrations élevées en oxygène (O2) engendrant la production d'espèces réactives de l'O2 (ERO). Les conséquences vasculaires à long terme de dommages liés aux ERO en période néonatale et les mécanismes impliqués sont très partiellement compris. Les précédents résultats du laboratoire ont montré qu'un stress hyperoxique néonatal conduit chez le rat adulte à de l'HTA, une dysfonction endothéliale et une rigidité artérielle, éléments de vieillissement vasculaire. Nous émettons l'hypothèse qu'un stress hyperoxique néonatale conduit à long terme à l'altération de la structure vasculaire et à un vieillissement vasculaire précoce. Nous avons démontré une diminution de la prolifération cellulaire, une capacité angiogénique altérée, des dommages à l'ADN et une augmentation de l'expression de protéines de sénescences (des indices de sénescence cellulaire) au-delà de la période néonatale suite à une exposition brève à l'O2 au niveau vasculaire dans un modèle animal (ratons Sprague-Dawley exposés à 80 % d'O2 du 3ème au 10ème jour de vie comparés à des ratons restés à l'air ambiant) et cellulaire (cellules musculaires lisses d'aortes thoraciques d'embryon de rat exposées à 40% O2 pendant 24h ou 48h, puis remises en normoxie pendant 96h). De plus, des altérations des composants de la structure vasculaire indiquant un remodelage vasculaire aortique ont été mises en évidence. Ces changements précèdent tous l'HTA et la dysfonction vasculaire observées dans le modèle animal à l'âge adulte et pourraient y contribuer. L'étude de jeunes adultes nés < 29 semaines comparés à des jeunes adultes nés à terme indique une augmentation de marqueurs de rigidité artérielle (indices d'un vieillissement vasculaire précoce) chez la population prématurée. L'ensemble des résultats démontre un vieillissement vasculaire précoce après une exposition néonatale transitoire à un stress hyperoxique permettant une meilleure compréhension des mécanismes physiopathologiques impliqués dans la survenue des troubles vasculaires retrouvés chez l'adulte et contribue à la mise en place de moyens de prévention chez des patients prématurés
Atherosclerotic cardiovascular disease is a leading cause of death and disability worldwide, and the atherosclerotic process begins in childhood. Prevention or containment of risk factors that accelerate atherosclerosis can delay the development of atherosclerotic cardiovascular disease. Although current recommendations are to periodically screen for commonly prevailing risk factors for atherosclerosis in children, a single test that could quantify the cumulative effect of all risk factors on the vasculature, thus assessing arterial health, would be helpful in further stratifying risk. Measurement of pulse wave velocity and assessment of augmentation index – measures of arterial stiffness – are easy-to-use, non-invasive methods of examining arterial health. Various studies have assessed pulse wave velocity and augmentation index in children with commonly occurring conditions including obesity, hypertension, insulin resistance, diabetes mellitus, dyslipidaemia, physical inactivity, chronic kidney disease, CHD and acquired heart diseases, and in children who were born premature or small for gestational age. This article summarises pulse wave velocity and augmentation index assessments and the effects of commonly prevailing chronic conditions on arterial health in children. In addition, currently available reference values for pulse wave velocity and augmentation index in healthy children are included. Further research to establish widely applicable normative values and the effect of lifestyle and pharmacological interventions on arterial health in children is needed.
New findings:
What is the central question of this study? Late preterm infants are often assumed to escape long-term morbidities known to impact earlier preterm offspring. Is this true for the cardiovascular system? What is the main finding and its importance? We show that late preterm birth is a risk factor for cardiovascular dysfunction in early adulthood and is influenced by sex. Early signs of cardiovascular dysfunction might predispose to heart disease in adulthood. Very preterm infants have an increased risk of cardiovascular disease; however, the effects of a late preterm birth on future cardiovascular function are not known. We hypothesized that after a late preterm birth, the well-described impairments in heart rate variability and baroreflex sensitivity would persist into adulthood. To test this hypothesis, sheep born preterm (0.9 gestation; nine male and seven female) or term (11 male and six female) underwent surgery at 14 months of age for insertion of femoral arterial and venous catheters and a femoral flow probe. After recovery, heart rate variability was assessed, followed by a baroreflex challenge (using the vasoactive agents phenylephrine and sodium nitroprusside) in conscious adult lambs. Our data demonstrate decreased low-frequency normalised units (LFnu) and low-frequency/high-frequency ratio in female but not male ex-preterm sheep at rest. When challenged, mature male ex-preterm sheep have an increased blood pressure response but dampened heart rate baroreflex response. We show that even a late preterm birth leads to cardiovascular dysfunction in adulthood. These early signs of cardiovascular dysfunction might underpin the later hypertension and increased risk of heart disease observed in adults born preterm. These findings are particularly important because late preterm infants are often assumed to escape the long-term morbidities known to impact on very preterm and extremely preterm offspring.
Low birth weight (LBW) and preterm birth (PB) are associated with newborn mortality and diseases in adulthood. We explored factors related to LBW and PB by conducting a population-based case-control study from January 2011 to December 2013 in Wuhan, China. A total of 337 LBW newborn babies, 472 PB babies, and 708 babies with normal birth weights and born from term pregnancies were included in this study. Information of newborns and their parents was collected by trained investigators using questionnaires and referring to medical records. Univariate and logistic regression analyses with the stepwise selection method were used to determine the associations of related factors with LBW and PB. Results showed that maternal hypertension (OR=6.78, 95% CI: 2.27–20.29, P=0.001), maternal high-risk pregnancy (OR=1.53, 95% CI: 1.06–2.21, P=0.022), and maternal fruit intake ≥300 g per day during the first trimester (OR=1.70, 95% CI: 1.17–2.45, P=0.005) were associated with LBW. BMI ≥24 kg/m² of mother prior to delivery (OR=0.48, 95% CI: 0.32–0.74, P=0.001) and gestation ≥37 weeks (OR=0.01, 95% CI: 0.00–0.02, P<0.034) were protective factors for LBW. Maternal hypertension (OR=3.36, 95% CI: 1.26–8.98, P=0.016), maternal high-risk pregnancy (OR=4.38, 95% CI: 3.26–5.88, P<0.001), maternal meal intake of only twice per day (OR=1.88, 95% CI: 1.10–3.20, P=0.021), and mother liking food with lots of aginomoto and salt (OR=1.60, 95% CI: 1.02–2.51, P=0.040) were risk factors for PB. BMI ≥24 kg/m² of mother prior to delivery (OR=0.66, 95% CI: 0.47–0.93, P=0.018), distance of house from road ≥36 meters (OR=0.72, 95% CI: 0.53–0.97, P=0.028), and living in rural area (OR= 0.60, 95% CI: 0.37–0.99, P=0.047) were protective factors for PB. Our study demonstrated some risk factors and protective factors for LBW and PB, and provided valuable information for the prevention of the conditions among newborns. © 2017, Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg.
Background:
There is a paucity of data on blood pressures (BP), urinary albumin, and mineral excretion in early childhood in contemporary cohorts of extremely low gestational age (GA) neonates. Our aim was to compare BPs and the urinary excretion of albumin, calcium, and phosphate in preterm and term-born cohorts in early childhood.
Methods:
This was a prospective observational study conducted at a single center, involving children <5 years age, born preterm (GA <30 weeks) or at term (≥37 weeks' GA). Urinary albumin (mg/L), calcium and phosphate levels indexed to creatinine (mg/dL), and BP were measured.
Results:
The median (IQR) follow-up age of our cohort (n = 106) was 30 (16-48) months. Preterm-born children (n = 55) had a significantly lower mean GA and birth weight and higher mean systolic, diastolic, and mean BPs, compared with term (n = 51) controls. A significantly higher proportion of preterm-born children weighed <10th centile and had systolic BP >95th centile at follow-up. Albumin and calcium excretion did not differ between the groups; median urine-phosphate creatinine ratios were higher in the preterm group. On logistic regression, lower GA and younger age at follow-up were significantly associated with an increased risk of systolic and diastolic BP above the 95th centile; male gender was associated with decreased risk of diastolic hypertension.
Conclusions:
Even in early childhood, children born preterm had significantly elevated BP, compared with their term-born counterparts. Closer monitoring of BPs in this population may be warranted.
Extremely preterm babies are exposed to various sources of injury during critical stages of development. The extremely preterm infant faces premature transition to ex utero physiology and undergoes adaptive mechanisms that may be deleterious in the long term because of permanent alterations in organ structure and function. Perinatal events can also directly cause structural injury. These disturbances induce morphologic and functional changes in their organ systems that might heighten their risks for later adult chronic diseases. This review examines the pathophysiology of programming of long-term health and diseases after preterm birth and associated perinatal risk factors.
KEYWORDS:
Cardiovascular diseases; Developmental origin of adult health and diseases; Hypertension; Inflammation; Metabolic syndrome; Oxygen; Parenteral nutrition; Preterm birth
In adults, cardiovascular risk factors reinforce each other in their effect on cardiovascular events. However, information is scant on the relation of multiple risk factors to the extent of asymptomatic atherosclerosis in young people.
We performed autopsies on 204 young persons 2 to 39 years of age, who had died from various causes, principally trauma. Data on antemortem risk factors were available for 93 of these persons, who were the focus of this study. We correlated risk factors with the extent of atherosclerosis in the aorta and coronary arteries.
The extent of fatty streaks and fibrous plaques in the aorta and coronary arteries increased with age. The association between fatty streaks and fibrous plaques was much stronger in the coronary arteries (r=0.60, P<0.001) than in the aorta (r=0.23, P=0.03). Among the cardiovascular risk factors, body-mass index, systolic and diastolic blood pressure, and serum concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, as a group, were strongly associated with the extent of lesions in the aorta and coronary arteries (canonical correlation [a measure of the association between groups of variables]: r=0.70; P<0.001). In addition, cigarette smoking increased the percentage of the intimal surface involved with fibrous plaques in the aorta (1.22 percent in smokers vs. 0.12 percent in nonsmokers, P=0.02) and fatty streaks in the coronary vessels (8.27 percent vs. 2.89 percent, P=0.04). The effect of multiple risk factors on the extent of atherosclerosis was quite evident. Subjects with 0, 1, 2, and 3 or 4 risk factors had, respectively, 19.1 percent, 30.3 percent, 37.9 percent, and 35.0 percent of the intimal surface covered with fatty streaks in the aorta (P for trend=0.01). The comparable figures for the coronary arteries were 1.3 percent, 2.5 percent, 7.9 percent, and 11.0 percent, respectively, for fatty streaks (P for trend=0.01) and 0.6 percent, 0.7 percent, 2.4 percent, and 7.2 percent for collagenous fibrous plaques (P for trend=0.003).
These findings indicate that as the number of cardiovascular risk factors increases, so does the severity of asymptomatic coronary and aortic atherosclerosis in young people.
It has been reported that 17beta-estradiol (E2) may enhance the proliferation of bovine retinal vascular endothelial cells (BRECs) by increasing the expression of VEGFR-2 and VEGF. The hypothesis in the current study was that estrogen may contribute to fetal vascular development and the cessation of exposure to estrogen of premature infants on birth may have an inhibitory effect on retinopathy of prematurity (ROP). Because ROP is thought to develop under relative hypoxia after exposure to high-dose oxygen, this study was conducted to investigate how estrogen modulates hypoxia-induced VEGF in BRECs and mouse ROP.
Gene expression of VEGF and hypoxia-inducible factor (HIF)-1alpha were studied in BRECs, with or without E2, under normoxia and hypoxia (1% O2). A binding assay was performed to determine whether estrogen interferes with HIF-1-mediated induction of VEGF. In a mouse ROP model, effects of E2 were evaluated by avascular area, subsequent extraretinal neovascularization, and retinal expression of the VEGF gene, by administering E2 during hyperoxia (75% O2) and/or after exposure to room air.
Hypoxia-induced VEGF mRNA in BRECs was reduced dose dependently by 1 to 100 nM E2. E2 reduced hypoxia-induced binding of HIF-1 to the VEGF promoter site and reduced the HIF-1alpha mRNA level. In mouse ROP, injection of E2 during hyperoxia increased retinal VEGF mRNA and reduced the retinal avascular area at the end of hyperoxia. E2 treatment during the normoxia that followed reduced VEGF mRNA and extraretinal neovascularization. Treatment with E2 throughout both periods significantly improved retinopathy.
Estrogen may function as a significant modulator of the level of VEGF mRNA under different oxygen conditions and could serve as a prophylactic agent for ROP.
It has been hypothesised that oestrogen exposure in utero influences the risk for breast cancer in adult life. Although several studies report associations between breast cancer and maternal factors associated with birthweight of the offspring – a marker for antenatal oestriol exposure – little is known about the relations between maternal oestrogen levels and these factors per se. We therefore analysed the association between oestriol levels in 188 women in the 17th, 25th, 33rd and 37th weeks of pregnancy, and maternal age, prepregnancy weight, height and pregnancy weight gain.
Both maternal prepregnancy body mass index and maternal height were, after controlling for infant birthweight, independently and inversely associated with oestriol levels (P = 0.0021 and P = 0.0006 respectively). We found no association between maternal age or pregnancy weight gain and pregnancy oestriol levels. These findings suggest that the previously reported associations between maternal age and maternal pregnancy weight gain and the offspring’s risk of breast cancer are due to factors other than antenatal exposure to oestriol.
DNA methylation is a major epigenetic modification of the genome that has the potential to silence gene expression. Recently, the role of epigenetic alteration as a distinct and crucial mechanism to regulate genes governing cell proliferation in atherosclerosis has emerged. Aberrant methylation is related to aging, and, because it affects a large number of CpG islands, age-related methylation may be an important contributor to increased atherosclerosis among older individuals by upregulating atherosclerosis-susceptible genes and downregulating atherosclerosis-protective genes. Further dissection of epigenetic alterations in atherosclerosis and aging will lead to the identification of novel epigenetic modifiers and improved diagnosis and treatment for atherosclerosis-related diseases.
The present studies examine the effect of gonadal hormones on the development of hypertension in Dahl salt-sensitive rats fed a high salt diet. In the first study, administration of estradiol benzoate did not prevent hypertension in either adult ovariectomized females or intact males. In a second study, neonatal castration of males slowed the onset of salt-induced hypertension, and females that were treated neonatally with testosterone developed somewhat higher pressures that did untreated females. These data extend to Dahl S rats the findings observed originally in spontaneously hypertensive rats that blood pressure is modulated by gonadal hormones. These results are consistent with the conclusion that gonadal hormones may exert organizational effects on cardiovascular control regions of the brain during early postnatal development in rats.
We noninvasively measured changes in average aortic stiffness in 79 cynomolgus monkeys being fed cholesterol progression, regression, and control diets by measuring pulse wave velocity (PWV) in 260 experiments during a 30-month period. Every 6 months, a group of monkeys was studied with invasive aortic PWV techniques and with ultrasonically determined pressure-strain elastic modulus (Ep) of the carotid artery, and then the group was killed so that morphometric evaluation of atherosclerosis severity could be made. After 6 months of a cholesterol progression diet, PWV decreased slightly from 6.2 +/- 0.1 to 5.7 +/- 0.1 m/sec, followed by an approximate linear increase to 8.8 +/- 1.2 m/sec after 30 months on the diet. The corresponding ratio of intimal (plaque) area to medial area (IA/MA) measured on perfusion-fixed cross-sections of the abdominal and thoracic aortas increased from 0.16 +/- 0.07 at 6 months to 1.23 +/- 0.22 at 30 months. Monkeys in the regression groups were fed the cholesterol progression diet for 18 months, followed by a chow diet for 6 or 12 months. In the first 6 months of the cholesterol regression diet, PWV continued to increase from 7.0 +/- 0.2 to 8.1 +/- 0.4 m/sec, and IA/MA was 1.24 +/- 0.18. However, after 12 months of the cholesterol regression diet, PWV decreased to 6.8 +/- 0.4 m/sec, and IA/MA was 0.90 +/- 0.18. The variability of the data demonstrates that PWV is not a simple function of atherosclerosis severity, and the best simple correlation was r = 0.69 (r2 = 0.48) between PWV and intimal area. However, multiple regression analysis of aortic PWV, systolic (SP) and diastolic (DP) blood pressures, and total plasma cholesterol concentration (TPC), all of which can be measured with minimally invasive techniques, improved the prediction of the IA/MA ratio through the following equation: IA/MA = 0.127 PWV-0.039 DP+0.023SP+0.0003TPC-0.292 (r = 0.81, r2 = 0.66). These data suggest that arterial stiffness in combination with minimally invasive parameters can be used to predict the severity of diffuse asymptomatic atherosclerosis in monkeys. However, more widespread application of these data to humans is uncertain because of biological variability and differences between animal models and human subjects.
We have examined aortic growth and aortic hemodynamics in lambs in the perinatal period. Morphometry of histological cross sections indicated that abdominal aortic circumference decreased by 31% between 131 days of gestation and 2-3 wk postpartum. In contrast, the internal circumference of the thoracic aorta increased by 34% over the same time interval; thus size reduction of the abdominal aorta was not part of a generalized arterial response to ex utero life. We also determined medial cross-sectional area as an index of medial tissue mass. In the perinatal period (120 days gestation to 21 days postpartum), this index increased by 144% for the thoracic aorta but only by 69% in the abdominal aorta. Differences in rate of medial tissue accumulation were much greater postpartum than in utero. The relationship between abdominal aortic growth and hemodynamic changes was examined by instrumenting fetal lambs with blood pressure catheters, abdominal aortic blood velocity transducers, and sonomicrometer diameter crystals mounted on the abdominal aorta. Parturition, and the consequent loss of the placental circulation, caused a 73% reduction in abdominal aortic blood velocity. Abdominal aortic external diameter in the period between 4 and 14 days postpartum was reduced significantly compared with in utero values. These data are consistent with the hypothesis that blood flow changes at birth significantly influence arterial growth postpartum.
The goal of the study was the determination of the relative roles of the placenta and the fetus in causing low serum estriol (E3) levels in women bearing fetuses with intrauterine growth retardation (IUGR). Umbilical venous levels of E3 and dehydroepiandrosterone sulfate (DHAS) were measured in 31 samples from fetuses with IUGR, 21 of whom were vaginally delivered and 10 who were delivered by cesarean section. In addition, estrone (E1) and estradiol (E2) were measured in 11 of the samples. The results were compared with 11 samples from cesarean section delivered control term infants and 54 samples from vaginally delivered control infants. The vaginally delivered IUGR group had a significantly lower mean umbilical venous DHAS level than did their control group (2128 +/- 158 ng/ml SEM versus 2645 +/- 130, p less than 0.05). Both the vaginally delivered and cesarean section delivered IUGR infants had umbilical venous E3 levels significantly lower than in their control groups (70 +/- 10 ng/ml SEM versus 144 +/- 10, p less than 0.001, and 46 +/- 11 ng/ml SEM versus 136 +/- 23, p less than .01, respectively). Umbilical venous E1 and E2 levels were not different from the control values. E1, E2, E3, and DHAS were measured in eight maternal venous samples obtained from mothers bearing fetuses with IUGR. In comparison with 11 control mothers, only E3 was significantly different (10.7 +/- 3.0 ng/ml SEM in mothers with IUGR fetuses versus 25.0 +/- 4.9 in control mothers p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Estradiol-producing ovarian cysts were found in four very preterm females at a postconceptional age that slightly preceded the expected time of delivery. The serum concentration of estradiol was very high. In the first infant one cystic ovary was removed surgically. When cysts appeared in the other ovary, the girl was treated with medroxyprogesterone acetate. The serum concentration of estradiol then fell and the cysts disappeared. Medroxyprogesterone acetate treatment was given also to the second girl, who had a high and rising serum concentration of estradiol. In infants 3 and 4 the cysts disappeared and the serum estradiol normalized spontaneously. Measurements of serum concentrations of luteinizing hormone and follicle-stimulating hormone before and after an iv injection of luteinizing hormone releasing hormone showed that preterm girls with early estradiol-producing ovarian cysts have a postpubertal type of response to luteinizing hormone-releasing hormone. When the test is repeated some months later they have a prepubertal type of response, which is normal for their age.
This article reviews historical studies and recent advances regarding the direct effects of estrogen on the blood vessel wall. It is organized into two sections that summarize effects of estrogen on vasomotor tone and on vascular cell growth and atherogenesis, based on two recognized actions of estrogen on the vasculature: a rapid vasodilatory effect, and an atheroprotective effect involving inhibition of smooth-muscle cell proliferation. These effects are likely mediated by different mechanisms. The rapid vasodilatory effects of estrogen are probably nongenomic, whereas the antiproliferative effects of estrogen are likely due to estrogen receptor-dependent alterations in gene expression. Overlap between these two mechanisms also exists, in that genes regulating the production of two important vasodilators synthesized by the vessel wall (prostacyclin and nitric oxide) can be up-regulated by estrogen. Potential molecular mechanisms by which estrogen exerts its effects are discussed, and future directions in this rapidly evolving area of research are considered.
Vascular disease is differentiated throughout the vascular regions, with central arteries more prone to dilation and with peripheral arteries more prone to occlusive disease. In this study we investigated the diameter and compliance in the common carotid artery and abdominal aorta in healthy males at varying ages to assess potential differences in the aging process.
An ultrasound phase-locked echo-tracking system was used to determine differences in diameter and pulsatile diameter changes of the common carotid artery and abdominal aorta in 56 healthy Caucasian males ages 10 to 74 years. Pressure strain elastic modulus (Ep) and stiffness (beta) were calculated from diameter, pulsatile diameter change, and blood pressure obtained by the auscultatory method. Compliance was defined as the inverse of Ep and stiffness.
The diameter of both common carotid artery and abdominal aorta increases not only when a person is a child, but also when they are between 25 and 70 years old. The dilation in adults seems to be more accentuated in the abdominal aorta (27%) than in the common carotid artery (17%). Ep and stiffness (beta) are higher in the common carotid artery when a person is 10 years of age (p < 0.01 and 0.05). However, during aging, Ep and stiffness (beta) increase to a higher extent in the aorta than in the common carotid artery, with a significantly higher Ep and stiffness (beta) in the aorta when a person is 45 years and older (45 years: p < 0.05 and p = NS; 60 years: p < 0.001 and p < 0.001; 70 years: p < 0.01 and p < 0.01).
This investigation demonstrates regional differences in diameter change and compliance in the common carotid artery and abdominal aorta and implies that the abdominal aorta is more prone to degenerative changes than the common carotid artery. This may be one etiologic factor for the regional differences in vascular disease.
Available standard intrauterine growth curves based on birthweights underestimate foetal growth in preterm period. New growth curves are presented based on data from four Scandinavian centres for 759 ultrasonically estimated foetal weights in 86 uncomplicated pregnancies. Mean weight of boys exceeded that of girls by 2-3%. A uniform SD value of 12% of the mean weight was adopted for the standard curves as the true SD varied non-systematically between 9.1 and 12.4%. Applied to an unselected population of 8663 singleton births, before 210 days of gestation, 32% of birthweights were classified as small-for-gestational age (SGA; i.e. below mean - 2 SD); the corresponding figures were 11.1% for gestational ages between 210 and 258 days, and 2.6% for ages of 259 days or longer. The new growth curves reveal better the true distribution of SGA foetuses and neonates, and are suggested for use in perinatological practice.
Early life factors, particularly size at birth, may influence later risk of cardiovascular disease, but a mechanism for this influence has not been established. We have examined the relation between birth weight and endothelial function (a key event in atherosclerosis) in a population-based study of children, taking into account classic cardiovascular risk factors in childhood.
We studied 333 British children aged 9 to 11 years in whom information on birth weight, maternal factors, and risk factors (including blood pressure, lipid fractions, preload and postload glucose levels, smoking exposure, and socioeconomic status) was available. A noninvasive ultrasound technique was used to assess the ability of the brachial artery to dilate in response to increased blood flow (induced by forearm cuff occlusion and release), an endothelium-dependent response. Birth weight showed a significant, graded, positive association with flow-mediated dilation (0.027 mm/kg; 95% CI, 0.003 to 0.051 mm/kg; P=.02). Childhood cardiovascular risk factors (blood pressure, total and LDL cholesterol, and salivary cotinine level) showed no relation with flow-mediated dilation, but HDL cholesterol level was inversely related (-0.067 mm/mmol; 95% CI, -0.021 to -0.113 mm/mmol; P=.005). The relation between birth weight and flow-mediated dilation was not affected by adjustment for childhood body build, parity, cardiovascular risk factors, social class, or ethnicity.
Low birth weight is associated with impaired endothelial function in childhood, a key early event in atherogenesis. Growth in utero may be associated with long-term changes in vascular function that are manifest by the first decade of life and that may influence the long-term risk of cardiovascular disease.
The impact of birth weight and gestational age on blood pressure in adult life was studied in a population of 49-year-old men born in 1926–27 who took part in a screening investigation of blood pressure performed in 1975–76 in Göteborg, Sweden. Birth records were traced in 430 subjects and compared with screening records. The adult systolic blood pressure (SBP) was not correlated with birth weight but was inversely correlated with gestational age in the whole study group (r = −0.10, P = .04; n = 430). The correlation between adult blood pressure and gestational age was stronger in preterm subjects, ie, those with a gestational age less than 38 weeks (for SBP, r = −0.46, P = .001 and for diastolic blood pressure [DBP], r = −0.44, P = .01; n = 44), and these correlations were independent of birth weight. There was, however, no correlation between adult blood pressure and gestational age in subjects born at term (between 38 and 41 complete weeks of gestation) or postterm (more than 42 weeks of gestation).
The inverse correlation between adult SBP and gestational age was stronger in low-birth-weight subjects (≤ 2500 g; r = −0.86, P < .001; n = 14). After adjustment for birth weight, in this group an increase by 1 week of gestation was associated with a decrease in adult SBP of 7.2 mm Hg (95% CI, 10.1–4.2). In the whole study group, a positive correlation was found between adult blood pressure and adult body mass index (BMI) (r = 0.30, P < .001 for SBP and r = 0.33, P < .001 for DBP). In preterm subjects, however, no such correlation was found, but in subjects born at term or postterm, adult blood pressure was significantly correlated with BMI (for SBP at term, r = 0.34, P < .001 and postterm, r = 0.47, P < .001 and for DBP at term, r = 0.36, P < .001 and postterm, r = 0.30, P < .05).
This study indicates that adult blood pressure appears to be related to different variables in different ranges of gestation. In preterm subjects, gestational age appears to have a great impact on adult blood pressure. In subjects born at term or later, however, adult blood pressure was not associated with factors related to birth, but only to the adult BMI.
We recently showed that rarefaction of skin capillaries in the dorsum of the fingers of patients with essential hypertension is due to the structural (anatomic) absence of capillaries rather than functional nonperfusion. It is not known whether this rarefaction is primary (ie, antedates the onset of hypertension) or secondary (ie, as a consequence of sustained and prolonged elevation of blood pressure [BP]). The aim of the present investigation was to study skin capillary density in a group of patients with mild borderline hypertension to assess whether rarefaction antedates the onset of sustained elevation of BP. The study group included 18 patients with mild borderline hypertension (mean supine BP, 136/83 mm Hg), 32 normotensive controls (mean BP, 126/77 mm Hg), and 45 patients with established essential hypertension (mean BP, 156/98 mm Hg). The skin of the dorsum of the fingers was examined by intravital capillary videomicroscopy before and after venous congestion at 60 mm Hg for 2 minutes. Patients with borderline essential hypertension had the lowest resting capillary density when compared with normotensive controls and patients with established hypertension. Maximal capillary density with venous congestion in the borderline group remained the lowest. The study confirmed that patients with borderline essential hypertension have skin capillary densities that are equally low as or even lower than patients with established hypertension. Both groups had significantly lower capillary densities than normal controls. One explanation for the results is that capillary rarefaction may be due to an early structural abnormality in essential hypertension.
Blood cholesterol levels are a key determinant of coronary heart disease risk in adults, but the importance of lipid levels in the general population during childhood is less clear. We related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9 to 11 years.
A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. This measure was related to their pulse pressure to assess arterial distensibility. All the children had previously had a comprehensive assessment of cardiovascular risk including a full lipid profile, cotinine-assessed smoke exposure, serum glucose, and questionnaire data on socioeconomic and dietary factors. Mean total cholesterol in the population was 4.72 [SD 0.75] mmol/L. There was a significant, inverse relation between cholesterol and distension of the artery across this range (linear regression coefficient -11.8 microm. mmol(-1). L(-1), P=0.003). Similar relationships were demonstrated with LDL and apolipoprotein B (-12.9 microm. mmol(-1). L(-1), P=0. 005 and -36.9 microm/mmol/L, P=0.01). HDL and triglyceride levels showed no consistent association with distensibility.
LDL cholesterol levels had an impact on arterial distensibility in the first decade of life. Furthermore, the functional differences in the arterial wall were demonstrated within the lipid range found in normal children, a finding that raises the possibility that cholesterol levels in the general population during childhood may already be relevant to the development of vascular disease.
Low birth weight is associated with an increased risk of adult hypertension. To elucidate whether this association reflects altered vascular physiology already at birth, we studied acetylcholine-induced vasodilation. Forty newborn infants and their mothers were studied 3 d after delivery. Vasodilation in skin was induced by local application of acetylcholine and local heating to 44 degrees C. Perfusion changes were measured with the laser Doppler technique. In response to acetylcholine, the mean skin perfusion increased by 240% in low birth weight infants compared with 650% in normal birth weight controls (p < 0.001). In contrast, mothers of low birth weight infants showed a mean increase in perfusion of 1100% after acetylcholine administration compared with 680% in mothers of control infants (p < 0.05). The perfusion increase at 44 degrees C local skin temperature did not differ between the two groups of infants or between their mothers. Blood pressure was normal in all subjects. We conclude that low birth weight infants show signs of endothelial dysfunction at birth. Such findings may help us understand the link between low birth weight and adult hypertension.
Background:
The goal of this study was to evaluate whether endothelial dysfunction associated with acute estrogen deprivation is caused by an alteration in the L-arginine-nitric oxide (NO) pathway and oxidative stress. Methods and Results-In 26 healthy women (age, 45.7+/-5.4 years) and 18 fertile women with leiomyoma (age, 44.5+/-5.1 years), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intrabrachial acetylcholine (0. 15, 0.45, 1.5, 4.5, or 15 microgram. 100 mL(-1). min(-1)) or sodium nitroprusside (1, 2, or 4 microgram. 100 mL(-1). min(-1)), an endothelium-dependent or -independent vasodilator, respectively. The NO pathway was evaluated by repeating acetylcholine during L-arginine (200 microgram. 100 mL(-1). min(-1); 13 control subjects and 9 patients) or N(G)-monomethyl-L-arginine (L-NMMA; 100 microgram. 100 mL(-1). min(-1); 13 control subjects and 9 patients); production of cyclooxygenase-derived vasoconstrictors was assessed by repeating acetylcholine during indomethacin (50 microgram. 100 mL(-1). min(-1); 13 control subjects and 9 patients) or vitamin C (8 mg. 100 mL(-1). min(-1); 13 control subjects and 9 patients). Patients repeated the study within 1 month after ovariectomy and again after 3 months of estrogen replacement therapy (ERT; 17 beta-estradiol TTS, 50 microgram/d). Basally, vasodilation to acetylcholine was potentiated and inhibited by L-arginine and L-NMMA, respectively (P<0.05), but was unaffected by indomethacin or vitamin C. After ovariectomy, the modulating effect of L-arginine and L-NMMA disappeared, whereas indomethacin and vitamin C potentiated the response to acetylcholine (P<0.05). ERT restored L-arginine and L-NMMA effects on vasodilation to acetylcholine but prevented the potentiation caused by indomethacin or vitamin C. Response to sodium nitroprusside was unaffected by either ovariectomy or ERT.
Conclusions:
Endothelial dysfunction secondary to acute endogenous estrogen deprivation is caused by reduced NO availability. Cyclooxygenase-dependent production of oxidative stress could be responsible for this alteration.
Among babies born at term, low birthweight predicts cardiovascular risk factors and disease in adulthood. This study shows that babies born prematurely, whether or not they have intrauterine growth retardation, are predisposed to similar risks as adults.
To conduct a systematic review in order to (i) summarize the relationship between birthweight and blood pressure, following numerous publications in the last 3 years, (ii) assess whether other measures of size at birth are related to blood pressure, and (iii) study the role of postnatal catch-up growth in predicting blood pressure.
All papers published between March 1996 and March 2000 that examined the relationship between birth weight and systolic blood pressure were identified and combined with the papers examined in a previous review.
More than 444,000 male and female subjects aged 0-84 years of all ages and races.
Eighty studies described the relationship of blood pressure with birth weight The majority of the studies in children, adolescents and adults reported that blood pressure fell with increasing birth weight, the size of the effect being approximately 2 mmHg/kg. Head circumference was the only other birth measurement to be most consistently associated with blood pressure, the magnitude of the association being a decrease in blood pressure by approximately 0.5 mmHg/cm. Skeletal and non-skeletal postnatal catch-up growth were positively associated with blood pressure, with the highest blood pressures occurring in individuals of low birth weight but high rates of growth subsequently.
Both birth weight and head circumference at birth are inversely related to systolic blood pressure. The relationship is present in adolescence but attenuated compared to both the pre- and post-adolescence periods. Accelerated postnatal growth is also associated with raised blood pressure.
The objective of this study was to identify specific components of fetal growth that may underlie the observed association between birth weight and later blood pressure. A record linkage was made between the Swedish Medical Birth Registry, the Military Conscription Register, and censuses. For 165,136 men born in Sweden between 1973 and 1976 and conscripted from 1990 to 1996, systolic blood pressure was measured at age 18 years. Systolic pressure was independently inversely associated with birth weight for gestational age and with gestational age itself but not with birth length for gestational age. The difference in systolic pressure between the top and the bottom quintiles of birth weight for gestational age was -1.61 mmHg (95% confidence interval: -1.82 to -1.40) after adjustment for birth length for gestational age, height, and weight. The change in systolic pressure was -0.25 mmHg (-0.29 to -0.22) for a 1-week increase in gestational age. How far the inverse association of systolic pressure with length of gestation represents an independent effect of maturation is unclear. These findings help to refine the fetal origins hypothesis and provide further criteria against which potential biological mechanisms that link circumstances in utero to later blood pressure can be assessed.
Low birthweight (LBW) has been associated with an increased incidence of adult cardiovascular disease. Endothelial dysfunction and loss of arterial elasticity are early markers of hypertension and atherosclerosis. We studied the prevalence of these markers in 44 healthy, prepubertal (age 9+/-1.3 years) children, 22 with LBW for age.
Endothelial function in skin was tested with the local application of acetylcholine (inducing endothelium-dependent vasodilation) and nitroglycerin (endothelium-independent vasodilation), and local perfusion changes were measured with the laser Doppler method. The elastic properties of the abdominal aorta and common carotid artery were measured with an ultrasonic vessel-wall tracking system. Endothelium-dependent vasodilation was lower in children with LBW (88+/-33 perfusion units [PU]) than in normal-birthweight controls (133+/-34 PU, P<0.001). There was no difference in aortic or carotid elasticity between the 2 groups, but a negative correlation was found between birthweight and stiffness of the carotid artery wall (r=-0.45, P<0.01). Endothelium-independent vasodilation and blood pressure were similar in the 2 groups.
Schoolchildren with a history of LBW show impaired endothelial function and a trend toward increased carotid stiffness. These findings may be early expressions of vascular compromise, contributing to susceptibility to disease in adult life.
It has been suggested that children born small for gestational age may develop hypertension and renal dysfunction in adulthood due to impaired fetal kidney development. Very little information on this issue is available on children born preterm. The objective of this study was to investigate the relationship between birth weight, blood pressure, and kidney function in adult subjects who were born preterm or born small for gestational age (SGA).
Subjects (n = 50), all women born between 1966 and 1974, were evaluated at a mean age of 26 +/- 1.9 years. They were allocated to three groups: (1) born before gestational week 32 (n = 15), (2) born full term with birth weight < 2600 g (n = 18) (SGA), and (3) controls, born full term with appropriate birth weight (n = 17). Casual blood pressure, ambulatory 24-h blood pressure (ABPM), glomerular filtration rate (GFR), renal plasma flow (ERPF) and urinary albumin excretion were determined.
Preterms had significantly higher casual systolic and mean arterial blood pressure levels compared to controls (123 +/- 13 vs 110 +/- 7 mmHg, P < 0.01, and 87 +/- 9 vs 79 +/- 6 mmHg, P < 0.005, respectively). ABPM was not significantly different between the groups. When the number of systolic recordings > 130 mmHg/subject during ABPM was calculated, the preterms had significantly more recordings above this value (P < 0.05) as well as a significantly increased area under the curve > 130 mmHg and > 140 mmHg systolic (P < 0.05) compared to the controls. SGA subjects were not significantly different from controls. There were no significant differences in GFR, ERPF or urinary albumin excretion between the three groups.
Women born preterm seem to have a disturbance in blood pressure regulation in adulthood, a finding that is not observed for those born small for gestational age. Kidney function in early adulthood seems to be normal in subjects born preterm or small for gestational age.
Despite data relating body size in early life to later cardiovascular outcomes, the hypothesis that nutrition affects such outcomes has not been established. Breastfeeding has been associated with lower blood pressure in later life, but previous studies have not controlled for possible confounding factors by using a randomised design with prospective follow-up. We undertook such a study to test the hypothesis that early diet programmes blood pressure in later life in children randomly assigned different diets at birth.
Blood pressure was measured at age 13-16 years in 216 (23%) of a cohort of 926 children who were born prematurely and had participated at birth in two parallel randomised trials in five neonatal units in the UK. Dietary interventions were: donated banked breastmilk versus preterm formula and standard term formula versus preterm formula.
Children followed up at age 13-16 years were similar to those not followed up in terms of social class and anthropometry at birth. Mean arterial blood pressure at age 13-16 years was lower in the 66 children assigned banked breastmilk (alone or in addition to mother's milk) than in the 64 assigned preterm formula (mean 81.9 [SD 7.8] vs 86.1 [6.5] mm Hg; 95% CI for difference -6.6 to -1.6; p=0.001). In non-randomised analyses, the proportion of enteral intake as human milk in the neonatal period was inversely related to later mean arterial pressure (beta=-0.3 mm Hg per 10% increase [95% CI -0.5 to -0.1]; p=0.006). No differences were found in the term formula (n=44) versus preterm formula (n=42) comparison.
Breastmilk consumption was associated with lower later blood pressure in children born prematurely. Our data provide experimental evidence of programming of a cardiovascular risk factor by early diet and further support the long-term beneficial effects of breastmilk.
To analyse if size at birth is associated with blood pressure and body mass index (BMI) at conscription in males, and if linear catch-up growth in height modifies these associations.
A population-based cohort study of 276 033 single-born males aged 17-24. Information from the Swedish Birth Register was individually linked to the Swedish Conscript Register. Systolic blood pressure was standardized for final height.
Compared to males not being small for gestational age at birth, males being light for gestational age [<-2 standard deviation scores (SDS)] were at increased risk of high systolic blood pressure [odds ratio (OR) 1.33; 95% confidence intervals (CI) 1.20-1.46], and a short adult stature was associated with a further increased risk [OR 1.65 (CI 1.13-2.40)]. Being born short for gestational age (<-2 SDS) was associated with a slightly increased risk of high systolic blood pressure [OR 1.16 (CI 1.04-1.29)], and linear catch-up growth in height did not increase this risk. Males born short for gestational age, who also were short at conscription, had an increased risk of a high BMI [OR 1.65 (CI 1.25-2.19)].
Males born light for gestational age have an increased risk of high systolic blood pressure, especially if they end up with short adult stature. Being born short for gestational age is associated with a slightly increased risk of high systolic blood pressure, and catch-up growth is not associated with a further risk. Lack of catch-up growth is, among males born short for gestational age, associated with an increased risk of overweight.
Low birthweight may predispose to the development of atherosclerosis later in life. We have tested the hypothesis that low birthweight as a result of preterm birth is associated with reduced flow-mediated endothelial-dependent vasodilation (FMD), which is an early stage in the development of atherosclerosis. Mean FMD in adolescents born preterm who had a low birthweight did not differ from that for controls born at term (0.225 mm vs 0.220 mm, SD 0.1 for both means, p=0.78). Our findings indicate that low birthweight attributable to prematurity does not increase the risk of vascular disease later in life.
Pressure wave reflection in the upper limb causes amplification of the arterial pulse so that radial systolic and pulse pressures are greater than in the ascending aorta. Wave transmission properties in the upper limbs (in contrast to the descending aorta and lower limbs) change little with age, disease, and drug therapy in adult humans. Such consistency has led to use of a generalized transfer function to synthesize the ascending aortic pressure pulse from the radial pulse. Validity of this approach was tested for estimation of aortic systolic, diastolic, pulse, and mean pressures from the radial pressure waveform. Ascending aortic and radial pressure waveforms were recorded simultaneously at cardiac surgery, before initiation of cardiopulmonary bypass, with matched, fluid-filled manometer systems in 62 patients under control conditions and during nitroglycerin infusion. Aortic pressure pulse waves, generated from the radial pulse, showed agreement with the measured aortic pulse waves with respect to systolic, diastolic, pulse, and mean pressures, with mean differences <1 mm Hg. Control differences in Bland-Altman plots for mean+/-SD in mm Hg were systolic, 0.0+/-4.4; diastolic, 0.6+/-1.7; pulse, -0.7+/-4.2; and mean pressure, -0.5+/-2.0. For nitroglycerin infusion, differences respectively were systolic, -0.2+/-4.3; diastolic, 0.6+/-1.7; pulse, -0.8+/-4.1; and mean pressure, -0.4+/-1.8. Differences were within specified limits of the Association for the Advancement of Medical Instrumentation SP10 criteria. In contrast, differences between recorded radial and aortic systolic and pulse pressures were well outside the criteria (respectively, 15.7+/-8.4 and 16.3+/-8.5 for control and 14.5+/-7.3 and 15.1+/-7.3 mm Hg for nitroglycerin). Use of a generalized transfer function to synthesize radial artery pressure waveforms can provide substantially equivalent values of aortic systolic, pulse, mean, and diastolic pressures.
The objective was to investigate any possible relationship between functional and structural vascular changes in women with low gestational age and/or low birth weight by analyzing the retinal vascular pattern in women with thoroughly documented blood pressure. Retinal vessel morphology was evaluated by digital image analysis of ocular fundus photographs in 47 subjects, aged 23-30 y. The women were allocated into three groups: 1) those born preterm and appropriate for gestational age (AGA), with a median gestational age at birth of 30 wk and a median birth weight of 1250 g (n = 14); 2) those born small for gestational age (SGA) but full term (median 40 wk), with a median birth weight of 2130 g (n = 17), and 3) those born full term, AGA, and with a median birth weight of 3640 g (n = 16). Women born preterm had significantly higher length index for arterioles compared with the other two groups (median 1.11 and 1.08, respectively, p = 0.005). In addition, the preterm-born women had significantly fewer number of vascular branching points compared with the controls (median 27 and 30, respectively, p = 0.03). The abnormal retinal vascularization observed in ex-preterm women together with an increased casual blood pressure observed in these subjects suggests that being born preterm does have effects on the vascular system that persist into adult life. In addition, it demonstrates that preterm birth seems to affect the vascular system both functionally and structurally, which, in adulthood, could result in a lower threshold for the development of vascular disease.
DNA methylation is a major epigenetic modification of the genome that has the potential to silence gene expression. Recently, the role of epigenetic alteration as a distinct and crucial mechanism to regulate genes governing cell proliferation in atherosclerosis has emerged. Aberrant methylation is related to aging, and, because it affects a large number of CpG islands, age-related methylation may be an important contributor to increased atherosclerosis among older individuals by upregulating atherosclerosis-susceptible genes and downregulating atherosclerosis-protective genes. Further dissection of epigenetic alterations in atherosclerosis and aging will lead to the identification of novel epigenetic modifiers and improved diagnosis and treatment for atherosclerosis-related diseases.
We aimed to validate a new method for measuring arterial pulsewave transit time and pulsewave velocity (a measure of arterial elasticity), based on the principle of photoplethysmography (PPG), and to compare transcutaneous values with those obtained by intra-arterial measurements. Three validation experiments are described. (a) PPG pulse wave delay times (defined as the time interval between the ECG R wave and the foot of the arterial pulse wave measured at the wrist or ankle) were compared to values obtained simultaneously from an established methodology (Doppler ultrasound). (b) Aortic pulsewave delay times in 17 subjects obtained non-invasively by the PPG method were compared with those obtained from the intra-arterial pressure wave. (c)
Repeatability measurements of PWV on the same subjects were carried out over two timescales (minutes and hours) in the arm, the leg and the trunk. The Doppler and PPG delay times correlated well, as did intra-arterial and transcutaneous values. Repeatability at short timescales was good (coefficients of variation (CV) <6% for all measurement sites) and, at the longer timescale, was satisfactory (CVs in the aorta, the arm and leg were 6.3, 13.1 and 16.0, respectively). The PWV values agreed well with others in the literature.We conclude that the PPG technique provides a complement to existing methods for the non-invasive measurement of arterial compliance. Its simplicity and ease of use make it suitable for large-scale epidemiological studies.
Alterations in microvascular function have been hypothesized as a possible mechanism explaining the negative association of weight at birth with blood pressure and insulin resistance in adult life. However, these variables are closely associated, so that it has been difficult to establish whether microvascular dysfunction is a cause or a consequence of increased blood pressure or insulin resistance.
Cohort study.
VU University Medical Center, Amsterdam, The Netherlands.
Twenty-one prepubertal healthy children showing a wide range in birth weight.
Birth weight data were obtained from hospital records. Blood pressure was measured with an ambulatory 24-h blood pressure monitor, and insulin sensitivity was assessed with the hyperinsulinaemic euglycaemic clamp technique. Microvascular function (i.e. capillary recruitment during post-occlusive reactive hyperaemia and endothelium (in)dependent vasodilatation of the skin) was evaluated by videomicroscopy and iontophoresis of acetylcholine and sodium nitroprusside.
Birth weight was positively and significantly associated with capillary recruitment [slope, 22%/kg birth weight; 95% confidence interval (CI), 0.1-43; 0.05]. Birth weight was not associated with insulin sensitivity and systolic blood pressure (slope, -0.11 mg/kg per min per pmol/l; 95% CI, -2.4 to 2.2; = 0.9; and slope, 1.4 mmHg; 95% CI, -5.0 to 7.7/kg birth weight; = 0.7, respectively). The association between low birth weight and impaired capillary recruitment was not affected by adjustment for blood pressure and insulin sensitivity. Birth weight was not associated with endothelium-(in)dependent vasodilatation.
These results suggest that the association between birth weight and capillary recruitment is independent of blood pressure and insulin sensitivity. These findings are consistent with the hypothesis that an impaired capillary recruitment plays a mechanistic role in the association of birth weight with blood pressure and insulin resistance in adult life.
To determine whether blood pressure (BP) differed between very low birth weight (VLBW; birth weight <or=1500 g) subjects and normal birth weight (NBW; birth weight >2499 g) subjects in late adolescence, and to determine whether growth restriction in utero was related to BP in VLBW survivors at this age.
This was a cohort study of 210 preterm survivors with birth weights <1501 g born from January 1, 1977, to March 31, 1982, and 60 randomly selected NBW subjects from the Royal Women's Hospital, Melbourne. BP was measured at 18+ years of age in 156 (74%) VLBW subjects and 38 (63%) NBW subjects with both a standard mercury sphygmomanometer and an ambulatory BP monitor.
VLBW subjects had higher sphygmomanometer systolic and diastolic BPs than NBW subjects (mm Hg; mean difference [95% confidence interval]; systolic, 8.6 [3.4, 13.9]; diastolic, 4.3 [1.0, 7.6]). VLBW subjects also had significantly higher mean systolic ambulatory BPs (mm Hg; mean difference [95% confidence interval]) for the 24-hour period (4.7 [1.4, 8.0]), and for both the awake (5.0 [1.6, 8.5]) and asleep (3.6 [0.04, 7.1]) periods. There were no significant differences between the birth weight groups for any ambulatory diastolic BPs. Within the VLBW subjects, there was no significant relationship between birth weight standard deviation score and any measure of BP.
BP was significantly higher in late adolescence in VLBW survivors than in NBW subjects. Growth restriction in utero was not significantly related to BP in VLBW survivors.
Investigation of arterial stiffness, especially of the large arteries, has gathered pace in recent years with the development of readily available noninvasive assessment techniques. These include the measurement of pulse wave velocity, the use of ultrasound to relate the change in diameter or area of an artery to distending pressure, and analysis of arterial waveforms obtained by applanation tonometry. Here, we describe each of these techniques and their limitations and discuss how the measured parameters relate to established cardiovascular risk factors and clinical outcome. We also consider which techniques might be most appropriate for wider clinical application. Finally, the effects of current and future cardiovascular drugs on arterial stiffness are also discussed, as is the relationship between arterial elasticity and endothelial function.
Low birth weight predisposes to later coronary disease. To further elucidate the mechanisms behind this association and their timing, vascular endothelial function-a key factor in early pathophysiology of atherosclerosis-was studied in 54 infants born either before the third trimester or at term.
All subjects were studied at 3 months of postnatal age. A laser-Doppler technique was used to measure skin perfusion before and after transdermal iontophoresis of acetylcholine (ACh; an endothelium-dependent vasodilator). In infants born at term (n=19; birth weight range: 2230 to 4205 g), maximum perfusion after ACh was 109+/-8 perfusion units (PU, mean+/-SEM) in normal-birth weight controls compared with 56+/-13 PU among those who had been small for gestational age at birth (P<0.01). In infants born preterm (n=35; birth weight range, 722 to 1868 g), ACh induced similar perfusion responses among subjects appropriate for gestational age (113+/-16 PU) and in those small for gestational age at birth (109+/-19 PU).
Impairment in human endothelial function associated with low birth weight occurs or emerges late in pregnancy. Very preterm birth attenuates this association. Different gene-environment interactions in the third trimester may contribute to this finding.
The association between low birth weight and high blood pressure is well established, but underlying mechanisms remain undefined. Vascular rarefaction, which may elevate peripheral vascular resistance, has been observed in capillaries of young men at risk for hypertension and men who had low birth weight. We looked for evidence that capillary rarefaction explains the association of low birth weight with high blood pressure in two cohorts. Participants in study 1 included 107 healthy boys aged 6 to 16 years recruited at random from a single school. Study 2 included 61 members of a cohort recruited at birth and studied at age 24 years. Measurements included indices of current size, blood pressure by automated sphygmomanometer, and dermal capillary density by video capillaroscopy of dorsal index finger skin after 10 minutes of venous occlusion. Lower birth weight predicted higher systolic blood pressure in both studies: in study 1, 3.57 mm Hg/kg birth weight (after adjustment for current height, 95% confidence interval 0.38 to 6.75, P<0.05); in study 2, 122+/-12 mm Hg in low birth weight (<2 kg) versus 115+/-9 in controls (P<0.05). Dermal capillary density was not associated in either group with birth weight or systolic blood pressure. We have found no evidence in these 2 cohorts that reduced capillary density explains the associations between lower birth weight and higher blood pressure.
Fetal growth is determined by the interaction between the environment and the fetal genome. The fetal environment, in turn, is determined by the maternal environment and by maternal and placental physiology. There is evidence that the interaction between the fetal environment and genome can determine the risk of postnatal disease, as well as the individual's capacity to cope with the postnatal environment. Furthermore, the role of various forms of maternal constraint of fetal growth in determining the persistence of these responses is reviewed. A limited number of biologic processes can contribute to the mechanistic basis of these phenomena. In addition to immediate homeostatic responses, the developing organism may make predictive adaptive responses of no immediate advantage but with long-term consequences. An evolutionary perspective is provided, as well as a review of possible biologic processes. The "developmental origins of disease" paradigm is a reflection of the persistence of such mechanisms in humans who now live in very different environments from those within which they evolved. The developmental origins paradigm and its underlying mechanistic and evolutionary basis have major implications for addressing the increasing burden of metabolic and cardiovascular disease.
To compare different non-invasive methods for determination of human endothelial function in peripheral circulation.
Observational, cross-sectional study in 39 healthy subjects (21 females, age 17-56 years).
Vascular research laboratory at university hospital.
Laser Doppler (LD) flowmetry was used to compare skin microvascular perfusion changes during postocclusive reactive hyperaemia with those induced by iontophoretic administration of acetylcholine (ACh), an endothelial-dependent vasodilator. LD measurements were compared with ultrasonographic measurements of postocclusive flow-mediated dilatation (FMD) in the brachial artery (n = 21).
Local ACh induced a larger and more sustained skin perfusion increase than reactive hyperaemia after 4 min of regional arterial occlusion (P<0.001). A significant correlation was found between the magnitude of ACh-induced vasodilatation and peak reactive hyperaemia, both in absolute (r = 0.62, P<0.001) and relative terms (r = 0.58, P<0.001). A correlation was also found between brachial artery FMD and the magnitude of ACh-induced skin perfusion increase (r = 0.43, P<0.05) but not between FMD and reactive hyperaemia.
Endothelial function, an early marker of cardiovascular risk, can be non-invasively assessed and graded by LD and FMD-measurements and despite inherent differences, both methods do correlate.
The cardiovascular risk of individuals who are born small as a result of prematurity remains controversial. Given the previous findings of stiffer peripheral conduit arteries in growth restricted donor twins in twin-twin transfusion syndrome regardless of gestational age, we hypothesised that among children born preterm, only those with intrauterine growth retardation are predisposed to an increase in cardiovascular risks.
To compare brachioradial arterial stiffness and systemic blood pressure (BP) among children born preterm and small for gestational age (group 1, n = 15), those born preterm but having birth weight appropriate for gestational age (group 2, n = 36), and those born at term with birth weight appropriate for gestational age (group 3, n = 35).
Systemic BP was measured by an automated device (Dinamap), while stiffness of the brachioradial arterial segment was assessed by measuring pulse wave velocity (PWV). The birth weight was adjusted for gestational age and expressed as a z score for analysis.
The 86 children were studied at a mean (SD) age of 8.2 (1.7) years. Subjects from group 1, who were born at 32.3 (2.0) weeks' gestation had a significantly lower z score of birth weight (-2.29 (0.63), p<0.001), compared with those from groups 2 and 3. They had a significantly higher mean blood pressure (p<0.001) and their diastolic blood pressure also tended to be higher (p = 0.07). Likewise, their brachioradial PWV, and hence arterial stiffness, was the highest of the three groups (p<0.001). While subjects from group 2 were similarly born preterm, their PWV was not significantly different from that of group 3 subjects (p = 1.00) and likewise their z score of birth weight did not differ (-0.01 (0.71) v -0.04 (1.1), p = 1.00). Brachioradial PWV correlated significantly with systolic (r = 0.31, p = 0.004), diastolic (r = 0.38, p<0.001), and mean (0.47, p<0.001) BP, and with z score of birth weight (r = -0.43, p<0.001). Multiple linear regression identified mean BP and z score of birth weight as significant determinants of PWV.
The findings of the present study support the hypothesis that among children born preterm, only those with intrauterine growth retardation are disadvantaged as a result of increase in systemic arterial stiffness and mean blood pressure.