Skip main navigation

Preterm Birth and Hypertension Risk

The Oxidative Stress Paradigm
Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.113.01276Hypertension. 2014;63:12–18

Preterm Birth

The majority of epidemiological studies in developmental programming have explored the influence of low birth weight (irrespective of gestational age) on long-term chronic disease in individuals born during the first half of the 20th century.1,2 Low birth weight neonates may represent infants born at term with intrauterine growth restriction (IUGR) or born preterm with or without IUGR. As such, there is emerging interest in the effects of preterm birth alone (beyond birth weight and IUGR) on specific aspects of human development and long-term health.

Approximately 10% of all births worldwide are preterm (before 37 completed weeks of gestation).3 Besides being of low birth weight, preterm neonates are suddenly and prematurely exposed to the extrauterine environment at a time when organogenesis is incomplete. Exposure postnatally to factors such as high oxygen concentrations,4 medications5 (including glucocorticoids),6 and inadequate nutrition7 likely adversely influence postnatal growth and ongoing organ development. In addition to possible genetic and epigenetic factors that may contribute to hypertension risk (including hypertension-related complications of pregnancy), a multitude of aspects related to both intrauterine and extrauterine growth, as well as the postnatal environment, may all play an important role in the programming of hypertension in individuals born preterm. In this review, we will highlight, in particular, the potential effect of oxidative stress associated with preterm birth on neonatal development and future disease risk.

Evidence From Epidemiological Studies: Preterm Birth and an Increased Risk of Developing Hypertension

The survival of neonates born at low and very low gestational ages is recent in the history of medicine and has increased remarkably over the last few decades. The first generations of survivors of very preterm birth are currently just reaching adulthood and as such are providing emerging evidence of chronic health conditions, such as hypertension. The link between preterm birth and hypertension risk (independent of birth weight) has been clearly demonstrated in a number of epidemiological studies. A significant inverse correlation between systolic blood pressure and gestational age at birth has been consistently observed from childhood to adulthood in preterm-born individuals821; in particular, a recent meta-analysis demonstrated that systolic blood pressure in preterm-born children and young adults was an average of 2.5 mm Hg (95% confidence interval, 2.6–5.0 mm Hg) higher than those born at term.21 We have also recently shown in a population-based study in Quebec, Canada, that women born preterm, particularly if birth occurred <32 weeks gestation, had an increased risk (independent of birth weight) of pregnancy complications (including gestational diabetes mellitus, gestational hypertension, and preeclampsia), as well as chronic hypertension compared with women born at term.22 It is to be noted, however, that many studies have not taken into account the effect of other confounding factors, such as chronic lung disease, that have effect on exercise capacity and thus cardiovascular health.

Possible Contributors to Increased Hypertension Risk in Neonates Born Preterm

The increased risk of hypertension evidenced in neonates born preterm is likely to be multifactorial in origin, with preterm birth resulting in alterations to cardiac, renal, and vascular development/function, as well as neural pathways.

Vascular

Preterm birth may disrupt or even prematurely arrest proper development of the vascular tree, resulting in stiffer arteries, a restricted vascular bed, and relatively narrowed blood vessels, all predisposing to endothelial dysfunction and arterial hypertension.23,24 Preterm birth often results from an abnormal pregnancy, with conditions such as preterm premature rupture of membranes, uteroplacental insufficiency, and preeclampsia being major causes of medically induced preterm birth. Therefore, it is to be noted that impairments to vascular system development may initially occur before preterm birth via IUGR and exposure to an inflammatory and antiangiogenic environment.25,26

In humans, elastin synthesis in arterial walls peaks toward the end of gestation (near term) and then declines very rapidly after birth.27,28 Arterial distensibility and elasticity depend largely on the ratio of elastin to the more rigid collagen in arterial walls; therefore, a disruption to elastin synthesis at the end of gestation (such as in the event of preterm birth) may have long-term consequences. To date, studies have reported increased aortic stiffness in children as early as 7 to 14 years of age that were born moderately or very preterm.2931 In addition, adolescents and young adults born preterm were found to have smaller aortic, carotid, and brachial artery luminal diameters compared with controls born at term18,32,33; aortic growth was shown to be impaired from the early neonatal period after preterm birth.34 Furthermore, in a sheep model of moderate preterm birth, evidence of vascular injury to the ascending aorta was observed in animals examined at 11 weeks postnatal age.35 Carotid intima-media thickness, an early marker of atherosclerosis and nonatherosclerotic remodeling, has also been shown to be increased in relation to lumen diameter.31,33

The effect of preterm birth on microvascular development has also been highlighted by studies showing reduced retinal vascular caliber and density (independently of retinopathy of prematurity), as well as reduced cutaneous capillary density in children and young adults born very preterm.19,36 To date, studies assessing endothelial function have shown either no effect18,19,31 or diminished brachial artery flow-mediated dilatation37 in children and young adults born preterm; whether changes will be apparent later in adult life remain to be evaluated.

Cardiac

During maturation of the heart, fetal cardiomyocytes undergo both hyperplasia and hypertrophy; in humans, cardiomyocytes proliferate actively until 36-week gestation after which maturation, differentiation, and growth by hypertrophy take place.38 Although hypertension would not be caused by changes in cardiac structure and function after preterm birth per se, the heart of preterm-born neonates may be particularly susceptible to the effect of elevated blood pressure and associated risk factors for heart disease.

Preterm birth has been described to result in cardiac dysfunction that can be detected in infants at a very early age.39,40 In preterm infants, a progressive increase of left ventricular dimensions was reported in the first month of life,41 as well as discreet left ventricular systolic and diastolic dysfunction at the same age.40 Later in life, preterm-born children at 5 years of age exhibited increased interventricular septum thickness and smaller left ventricular cavity diameters compared with those born at term, which is indicative of premature cardiac hypertrophy.42 Altered cardiac shape, primarily characterized by increased left ventricular mass (with shorter left ventricles and smaller internal diameters), has also been observed in 20- to 39-year-old adults born preterm.43 These cardiac shape alterations were accompanied by impaired systolic and diastolic functions. A strong inverse correlation between gestational age and increased left ventricular mass was further observed in this study, suggesting causality.43 Findings relating preterm birth to altered heart development are supported by mechanistic studies in animal models. Bensley et al44 recently showed in a sheep model that moderate preterm birth resulted in cardiomyocyte hypertrophy and altered maturation (evidenced by an increased number of bi- and trinucleated cardiomyocytes and increased nuclear ploidy), as well as increased myocardial interstitial fibrosis by 11 weeks postnatal age.

Renal

Nephrogenesis (the formation of nephrons in the kidney) occurs largely in the second half of pregnancy.45,46 Although nephrogenesis continues postnatally after preterm birth,47 the process is likely disrupted.4749 Nephron number is an important indicator of renal functional capacity, with impaired renal development (reduced nephron endowment), as well as later nephron loss, strongly correlated with the development of high blood pressure.50

Whether preterm birth results in a reduced nephron endowment has to date only been investigated in animal models. In a mouse model of preterm birth (animals delivered at a relatively early stage of nephrogenesis), nephron number was significantly decreased.51 Additionally, these animals exhibited high blood pressure, low glomerular filtration rate, and albuminuria at 5 weeks of age. In comparison, Gubhaju et al52 showed that nephron number in preterm-born baboons (delivered at a timepoint equivalent to 27-week gestation in humans) was within normal range. However, nephron density was significantly reduced in the preterm kidneys, and a large proportion of newly formed glomeruli in the outer renal cortex was morphologically abnormal, with a shrunken glomerular capillary tuft.52 Importantly, these undervascularized (potentially atubular) glomeruli were also observed in human neonatal kidneys after preterm birth.47,49 In addition, the kidneys of human preterm neonates had a significantly reduced nephrogenic zone width, along with more generations of mature glomeruli compared with age-matched fetal controls; together, these findings suggest that renal maturation is accelerated postnatally and is possibility indicative of an early cessation to nephrogenesis.53 It is certainly conceivable that these alterations in the neonatal kidney (accelerated maturation and the potential early loss of abnormal glomeruli) would result in a diminished endowment of functional nephrons at the beginning of life.

Renin–Angiotensin System

Another critical regulator of systemic blood pressure is the renin–angiotensin system (RAS). The RAS is activated to increase glomerular filtration rate in the presence of oligonephronia and contributes to the increase in, and maintenance of, high blood pressure.54,55 In genetic hypertension, RAS activity is a key factor underlying vascular dysfunction, vasoconstriction, and vascular rigidity56; in the heart, myocardial hypertrophy, fibrosis, and inflammation also result from angiotensin II and its receptor type 1 activation.57 Importantly, alterations to the RAS have been evidenced in a number of animal models of hypertension programming.58 In preterm neonates, the urinary angiotensin-converting enzyme activity is increased compared with infants born at term, with a significant inverse association between angiotensin-converting enzyme activity and both gestational and postnatal age.59 However, very few studies have been conducted in this area, and further research is undoubtedly required to understand the potential role of the RAS in the programming of high blood pressure after preterm birth.

Sympathetic Nerve Activity

During the third trimester of gestation, the efferent sympathetic nervous system continues to mature.60 Sympathetic nerve activity contributes to blood pressure maintenance, to the elevation in blood pressure in situations of overactivation (or impaired counterregulatory mechanisms) in many forms of chronic hypertension, and after deleterious perinatal conditions (such as IUGR) in both humans and experimental models.6163 Sympathetic nerve activity can also be activated by chronic inflammation (including through inflammatory cytokines secreted by adipose tissue) and increased expression of the RAS.64 In infants born preterm, the sympathetic system is overactivated, and parasympathetic nervous system tone is deficient.65 Although there is a probable role for sympathetic activation in the programming of hypertension in preterm-born children and adults, it has not yet been fully established.

The Oxidative Stress Paradigm

Important factors that may underlie the early life origin of hypertension susceptibility are hyperoxia exposure and oxidative stress. Infants are exposed upon birth to relatively high concentrations of oxygen (O2) compared with intrauterine life. Indeed, under physiological conditions, blood oxygen saturation levels (SpO2) of the fetus average 45% to 55%.66 During the fetal to neonatal transition, blood oxygen content and O2 availability abruptly increase in the first few minutes after birth to adult values.67

Importantly, this exposure to higher circulating oxygen concentrations elicits a burst of free radicals, known as reactive oxygen species.68,69 The preterm infant is also exposed to a number of pro-oxidant molecules from parenteral nutrition, medications, plastic derivatives, and x-ray imaging, in addition to supplemental oxygen.7072 However, neonates born preterm have an immature antioxidant defense system: virtually all research has demonstrated lower levels of antioxidant enzymes and reduced induction capacity thereof,73,74 as well as significantly increased indices of oxidative stress in preterm newborns.7579 In the setting of organ development, significantly reduced cellular proliferation and increased apoptosis (via lipid peroxidation, protein aggregation, and DNA damage) because of the activity of reactive oxygen species may be particularly injurious.80

Besides an increase in reactive oxygen species, exposure to high oxygen concentrations after birth may also alter oxygen-sensing pathways in the preterm neonates. In the presence of oxygen, the transcription factor hypoxia-inducible factor 1 (HIF-1) is hydroxylated, which triggers its rapid proteosomal degradation. HIF-1 is known to regulate the expression of a multitude of genes involved in cellular proliferation, angiogenesis, and apoptosis.81 In HIF-1 knockout animal models, embryos are arrested mid development with significant cardiovascular defects.82 Therefore, it is possible that reduced HIF-1 expression after oxygen exposure may have adverse consequences for ongoing postnatal development in the preterm neonates. As such, it is undoubtedly important to determine the effect of early life exposure to hyperoxia and oxidative stress on organ and vascular development, which may contribute to vascular dysfunction and hypertension later in life.

Vascular Development and Rarefaction

Endothelial progenitor cells differentiate into endothelial cells during the process of vasculogenesis and also function to replace mature cells in the case of vascular injury.83 Preterm neonates have higher levels of endothelial progenitor cells than term infants, which is indicative of a greater capacity for vasculogenesis; however, the endothelial progenitor cells of preterm infants were found to have a heightened susceptibility to hyperoxia exposure, evidenced by reduced proliferation and increased cell death.84,85 In 1 animal study, neonatal mice exposed to 10 days of hyperoxia had lower endothelial progenitor cell numbers and decreased vessel density in the lung.86

In immature newborns, exposure to supplemental O2 halts microvessel growth, particularly in the lung and retina.4 This impaired microvascular development can be traced to significant reductions in vascular endothelial growth factor expression87; vascular endothelial growth factor expression is likely reduced because of lowered HIF-1 signaling of vascular endothelial growth factor transcription in the oxygen-rich extrauterine environment.81 In this regard, we have previously shown that neonatal hyperoxia exposure was associated with significantly reduced microvascular density (rarefaction) in the skeletal muscle of adult rats.88 In addition, animals exposed to hyperoxia as neonates exhibited increased vascular superoxide anion production and decreased NO production (linked to eNOS uncoupling), impaired endothelium-mediated vasodilation, and elevated blood pressure from ≈7 weeks of age.88,89 This finding of increased blood pressure subsequent to a hyperoxic insult during development is strongly indicative that high oxygen levels may play an important role in the programming of hypertension after preterm birth.

Renal and Cardiac Development

Findings from organ explant studies have indicated that low oxygen concentrations are required for correct renal90 and cardiac91 development. In addition, we have recently shown in a rat model that hyperoxic gas exposure (80% O2) in the early neonatal period (postnatal days 3–10, during the period of ongoing postnatal nephrogenesis in the rat) is associated with a 25% reduction in nephron number in adulthood.88 In contrast, however, exposure to 65% O2 from postnatal days 1 to 7 in a mouse model did not lead to any significant alterations in renal development or nephron number.92 A study on heart development found that in combination with maternal inflammation during gestation (commonly linked to preterm birth), postnatal hyperoxia exposure (85% O2 from postnatal days 1 to 14) was associated with both structural remodeling and dysfunction of the left ventricle.93 Certainly further studies are required to investigate completely the effect of hyperoxia exposure alone on renal and cardiac development.

Vascular Aging

In humans, as in animal models of developmental programming, individuals are not born with hypertension but undergo an age-dependant premature increase in blood pressure.88,94 Aging is a process characterized by the accumulation of oxidant-related damage,95 resulting in structural and functional changes to the vasculature, including increased vascular stiffness (increased collagen and decreased elastin), reduced compliance, endothelial dysfunction, decreased NO bioavailability, increased reactive oxygen species production, increased vasoconstrictive tone,96 and impaired vascular repair capacity.97 As discussed above, preterm birth is associated with a number of these vascular consequences; therefore, it is possible that they are mediated by accelerated cellular aging triggered by an oxidative insult in early development.

Like other mitotic cells, vascular cells may undergo replicative senescence driven by telomere shortening or stress-induced premature senescence98,99; senescent vascular cells have decreased proliferative and angiogenic capacity. Importantly, oxidative stress has been linked to accelerated telomere shortening, DNA damage, senescence of endothelial and vascular smooth muscle cells, and atherosclerosis.99101 Telomere length has been shown to be similar in low birth weight versus control infants assessed at birth102; however, another study demonstrated that telomere length was decreased in 5-year olds that were born with low birth weight,103 which together suggests accelerated attrition. To our knowledge, the effect of preterm birth on telomere shortening, however, has not been reported.

Inflammation

Preterm birth reflects intrauterine disturbances that are often inherently pro-oxidant and proinflammatory in nature104; conditions such as preeclampsia, maternal diabetes mellitus, and obesity, infection, and preterm premature rupture of membranes all lead to increased inflammation markers in both mother and newborn, including those born preterm.105

Inflammatory and oxidative pathways are intimately associated, with reciprocal and synergistic activation in response to intrauterine or neonatal stress.104 Both human and animal studies have provided evidence that an oxidative insult in the fetal/neonatal period can have long-term consequences on redox equilibrium and inflammation. In particular, children (4–13 years of age) born IUGR or to mothers with diabetes mellitus were shown to have demonstrable increases in markers of oxidative stress, lipid peroxidation, and inflammation.106108 In experimental studies, inflammatory challenges given periconception, midgestation and in the neonatal period led to increased visceral fat and metabolic syndrome in mice offspring in adulthood.4446 Furthermore, adult guinea pigs that were administered parenteral nutrition (a contributor to oxidative stress) as pups exhibited dyslipidemia, glucose intolerance, and energy deficiency.70 In adult rats exposed to hyperoxic stress as neonates, increased vascular superoxide production has been observed.88 We have also shown that antioxidant supplementation in dams fed a low-protein diet prevents low glutathione levels, hypertension, and vascular dysfunction in the offspring.109 These observations are particularly important considering that an oxidized redox state, oxidative stress, and low-grade inflammation all contribute to the pathogenesis of chronic disorders, such as hypertension, cardiovascular and kidney diseases, and type 2 diabetes mellitus110,111; in this way, it is possible that these processes may enhance significantly the risk of chronic disease in neonates born preterm.

Conclusions

Emerging epidemiological and experimental findings have increasingly demonstrated that preterm birth is a key risk factor for the development of hypertension. Through the evidence reviewed here, we propose that underlying this risk may be exposure to hyperoxia and oxidative stress in the early neonatal period; at birth, all preterm neonates are prematurely exposed to oxygen concentrations markedly higher than those in the intrauterine environment, and this may have important consequences for ongoing postnatal development. Preterm infants are particularly susceptible to the damaging effect of oxidative stress because of an immature antioxidant system at birth. In a rodent model, we have shown that neonatal hyperoxia exposure leads to vascular dysfunction, hypertension, microvascular rarefaction, and reduced nephron number. To date, however, very few studies have been conducted to investigate the effects of oxygen exposure alone on cardiovascular development and hypertension risk. In the future, further research designed to delineate clearly the mechanisms involved and also to determine clinically which infants are at the highest risk for the later development of hypertension is essential. The overall goal of this research should be focused toward the future introduction of strategies to the clinical care of preterm neonates to prevent any adverse long-term consequences, such as through the enhancement of vasculogenesis and cardiac/renal development postnatally. In the meantime, there is also a need for increased awareness among pediatricians and general practitioners on the heightened risk of adult-onset cardiovascular disease in neonates born preterm.

Footnotes

Correspondence to Anne Monique Nuyt, Department of Pediatrics, Sainte-Justine University Hospital and Research Center, Université de Montréal, 3175 Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1C5. E-mail

References

  • 1. Barker DJ. In utero programming of chronic disease.Clin Sci (Lond). 1998; 95:115–128.CrossrefMedlineGoogle Scholar
  • 2. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease.N Engl J Med. 2008; 359:61–73.CrossrefMedlineGoogle Scholar
  • 3. Beck S, Wojdyla D, Say L, Betran AP, Merialdi M, Requejo JH, Rubens C, Menon R, Van Look PF. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity.Bull World Health Organ. 2010; 88:31–38.CrossrefMedlineGoogle Scholar
  • 4. Saugstad OD. Update on oxygen radical disease in neonatology.Curr Opin Obstet Gynecol. 2001; 13:147–153.CrossrefMedlineGoogle Scholar
  • 5. Schreuder MF, Bueters RR, Huigen MC, Russel FG, Masereeuw R, van den Heuvel LP. Effect of drugs on renal development.Clin J Am Soc Nephrol. 2011; 6:212–217.CrossrefMedlineGoogle Scholar
  • 6. Halliday HL, Ehrenkranz RA, Doyle LW. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.Cochrane Database Syst Rev. 2010:CD001146.MedlineGoogle Scholar
  • 7. Martin CR, Brown YF, Ehrenkranz RA, O’Shea TM, Allred EN, Belfort MB, McCormick MC, Leviton A; Extremely Low Gestational Age Newborns Study Investigators. Nutritional practices and growth velocity in the first month of life in extremely premature infants.Pediatrics. 2009; 124:649–657.CrossrefMedlineGoogle Scholar
  • 8. Cooper R, Atherton K, Power C. Gestational age and risk factors for cardiovascular disease: evidence from the 1958 British birth cohort followed to mid-life.Int J Epidemiol. 2009; 38(1):235–44.CrossrefMedlineGoogle Scholar
  • 9. Siewert-Delle A, Ljungman S. The impact of birth weight and gestational age on blood pressure in adult life. A population-based study of 49-year-old men.AJH. 1998; 11:946–953.Google Scholar
  • 10. Kistner A, Celsi G, Vanpee M, Jacobson SH. Increased blood pressure but normal renal function in adult women born preterm.Pediatr Nephrol. 2000; 15:215–220.CrossrefMedlineGoogle Scholar
  • 11. Doyle LW, Faber B, Callanan C, Morley R. Blood pressure in late adolescence and very low birth weight.Pediatrics. 2003; 111:252–257.CrossrefMedlineGoogle Scholar
  • 12. Keijzer-Veen MG, Finken MJ, Nauta J, Dekker FW, Hille ET, Frölich M, Wit JM, van der Heijden AJ; Dutch POPS-19 Collaborative Study Group. Is blood pressure increased 19 years after intrauterine growth restriction and preterm birth? A prospective follow-up study in The Netherlands.Pediatrics. 2005; 116:725–731.CrossrefMedlineGoogle Scholar
  • 13. Keijzer-Veen MG, Kleinveld HA, Lequin MH, Dekker FW, Nauta J, de Rijke YB, van der Heijden BJ. Renal function and size at young adult age after intrauterine growth restriction and very premature birth.Am J Kidney Dis. 2007; 50:542–551.CrossrefMedlineGoogle Scholar
  • 14. Johansson S, Iliadou A, Bergvall N, Tuvemo T, Norman M, Cnattingius S. Risk of high blood pressure among young men increases with the degree of immaturity at birth.Circulation. 2005; 112:3430–3436.LinkGoogle Scholar
  • 15. Hack M, Schluchter M, Cartar L, Rahman M. Blood pressure among very low birth weight (<1.5 kg) young adults.Pediatr Res. 2005; 58:677–684.CrossrefMedlineGoogle Scholar
  • 16. Lawlor DA, Hübinette A, Tynelius P, Leon DA, Smith GD, Rasmussen F. Associations of gestational age and intrauterine growth with systolic blood pressure in a family-based study of 386,485 men in 331,089 families.Circulation. 2007; 115:562–568.LinkGoogle Scholar
  • 17. Stevenson CJ, West CR, Pharoah PO. Dermatoglyphic patterns, very low birth weight, and blood pressure in adolescence.Arch Dis Child Fetal Neonatal Ed. 2001; 84:F18–F22.CrossrefMedlineGoogle Scholar
  • 18. Bonamy AK, Bendito A, Martin H, Andolf E, Sedin G, Norman M. Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls.Pediatr Res. 2005; 58:845–849.CrossrefMedlineGoogle Scholar
  • 19. Bonamy AK, Martin H, Jörneskog G, Norman M. Lower skin capillary density, normal endothelial function and higher blood pressure in children born preterm.J Intern Med. 2007; 262:635–642.CrossrefMedlineGoogle Scholar
  • 20. Poplawska K, Dudek K, Koziarz M, Cieniawski D, Drożdż T, Smiałek S, Drożdż D, Kwinta P. Prematurity-related hypertension in children and adolescents.Int J Pediatr. 2012; 2012:537936.CrossrefMedlineGoogle Scholar
  • 21. de Jong F, Monuteaux MC, van Elburg RM, Gillman MW, Belfort MB. Systematic review and meta-analysis of preterm birth and later systolic blood pressure.Hypertension. 2012; 59:226–234.LinkGoogle Scholar
  • 22. Boivin A, Luo ZC, Audibert F, Mâsse B, Lefebvre F, Tessier R, Nuyt AM. Pregnancy complications among women born preterm.CMAJ. 2012; 184:1777–1784.CrossrefMedlineGoogle Scholar
  • 23. Norman M. Low birth weight and the developing vascular tree: a systematic review.Acta Paediatr. 2008; 97:1165–1172.CrossrefMedlineGoogle Scholar
  • 24. Ligi I, Grandvuillemin I, Andres V, Dignat-George F, Simeoni U. Low birth weight infants and the developmental programming of hypertension: a focus on vascular factors.Semin Perinatol. 2010; 34:188–192.CrossrefMedlineGoogle Scholar
  • 25. Intapad S, Alexander BT. Pregnancy complications and later development of hypertension.Curr Cardiovasc Risk Rep. 2013; 7:183–189.CrossrefMedlineGoogle Scholar
  • 26. Tsao PN, Wei SC, Su YN, Chou HC, Chen CY, Hsieh WS. Excess soluble fms-like tyrosine kinase 1 and low platelet counts in premature neonates of preeclamptic mothers.Pediatrics. 2005; 116:468–472.CrossrefMedlineGoogle Scholar
  • 27. Martyn CN, Greenwald SE. Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension.Lancet. 1997; 350:953–955.CrossrefMedlineGoogle Scholar
  • 28. Berry CL, Looker T, Germain J. Nucleic acid and scleroprotein content of the developing human aorta.J Pathol. 1972; 108:265–274.CrossrefMedlineGoogle Scholar
  • 29. McEniery CM, Bolton CE, Fawke J, Hennessy E, Stocks J, Wilkinson IB, Cockcroft JR, Marlow N. Cardiovascular consequences of extreme prematurity: the EPICure study.J Hypertens. 2011; 29:1367–1373.CrossrefMedlineGoogle Scholar
  • 30. Rossi P, Tauzin L, Marchand E, Boussuges A, Gaudart J, Frances Y. Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence.J Adolesc Health. 2011; 48:520–522.CrossrefMedlineGoogle Scholar
  • 31. Lazdam M, de la Horra A, Pitcher A, Mannie Z, Diesch J, Trevitt C, Kylintireas I, Contractor H, Singhal A, Lucas A, Neubauer S, Kharbanda R, Alp N, Kelly B, Leeson P. Elevated blood pressure in offspring born premature to hypertensive pregnancy: is endothelial dysfunction the underlying vascular mechanism?Hypertension. 2010; 56:159–165.LinkGoogle Scholar
  • 32. Edstedt Bonamy AK, Bengtsson J, Nagy Z, De Keyzer H, Norman M. Preterm birth and maternal smoking in pregnancy are strong risk factors for aortic narrowing in adolescence.Acta Paediatr. 2008; 97:1080–1085.CrossrefMedlineGoogle Scholar
  • 33. Hovi P, Turanlahti M, Strang-Karlsson S, Wehkalampi K, Järvenpää AL, Eriksson JG, Kajantie E, Andersson S. Intima-media thickness and flow-mediated dilatation in the Helsinki study of very low birth weight adults.Pediatrics. 2011; 127:e304–e311.CrossrefMedlineGoogle Scholar
  • 34. Schubert U, Müllera M, Edstedt Bonamy AK, Abdul-Khaliqa H, Norman M. Aortic growth arrest after preterm birth: a lasting structural change of the vascular tree.J Dev Orig Health Dis. 2011; 2:218–225.CrossrefMedlineGoogle Scholar
  • 35. Bensley JG, De Matteo R, Harding R, Black MJ. Preterm birth with antenatal corticosteroid administration has injurious and persistent effects on the structure and composition of the aorta and pulmonary artery.Pediatr Res. 2012; 71:150–155.CrossrefMedlineGoogle Scholar
  • 36. Kistner A, Jacobson L, Jacobson SH, Svensson E, Hellstrom A. Low gestational age associated with abnormal retinal vascularization and increased blood pressure in adult women.Pediatr Res. 2002; 51:675–680.CrossrefMedlineGoogle Scholar
  • 37. Bassareo PP, Fanos V, Puddu M, Demuru P, Cadeddu F, Balzarini M, Mercuro G. Reduced brachial flow-mediated vasodilation in young adult ex extremely low birth weight preterm: a condition predictive of increased cardiovascular risk?J Matern Fetal Neonatal Med. 2010; 23(suppl 3):121–124.CrossrefMedlineGoogle Scholar
  • 38. Oparil S, Bishop SP, Clubb FJ. Myocardial cell hypertrophy or hyperplasia.Hypertension. 1984; 6(6 Pt 2):III38–III43.LinkGoogle Scholar
  • 39. Appleton RS, Graham TP, Cotton RB, Moreau GA, Boucek RJ. Altered early left ventricular diastolic cardiac function in the premature infant.Am J Cardiol. 1987; 59:1391–1394.CrossrefMedlineGoogle Scholar
  • 40. Kozák-Bárány A, Jokinen E, Saraste M, Tuominen J, Välimäki I. Development of left ventricular systolic and diastolic function in preterm infants during the first month of life: a prospective follow-up study.J Pediatr. 2001; 139:539–545.CrossrefMedlineGoogle Scholar
  • 41. Zecca E, Romagnoli C, Vento G, De Carolis MP, De Rosa G, Tortorolo G. Left ventricle dimensions in preterm infants during the first month of life.Eur J Pediatr. 2001; 160:227–230.CrossrefMedlineGoogle Scholar
  • 42. Mikkola K, Leipälä J, Boldt T, Fellman V. Fetal growth restriction in preterm infants and cardiovascular function at five years of age.J Pediatr. 2007; 151:494–9, 499.e1.CrossrefMedlineGoogle Scholar
  • 43. Lewandowski AJ, Augustine D, Lamata P, Davis EF, Lazdam M, Francis J, McCormick K, Wilkinson AR, Singhal A, Lucas A, Smith NP, Neubauer S, Leeson P. Preterm heart in adult life: cardiovascular magnetic resonance reveals distinct differences in left ventricular mass, geometry, and function.Circulation. 2013; 127:197–206.LinkGoogle Scholar
  • 44. Bensley JG, Stacy VK, De Matteo R, Harding R, Black MJ. Cardiac remodelling as a result of pre-term birth: implications for future cardiovascular disease.Eur Heart J. 2010; 31:2058–2066.CrossrefMedlineGoogle Scholar
  • 45. Hinchliffe SA, Sargent PH, Howard CV, Chan YF, van Velzen D. Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle.Lab Invest. 1991; 64:777–784.MedlineGoogle Scholar
  • 46. Gasser B, Mauss Y, Ghnassia JP, Favre R, Kohler M, Yu O, Vonesch JL. A quantitative study of normal nephrogenesis in the human fetus: its implication in the natural history of kidney changes due to low obstructive uropathies.Fetal Diagn Ther. 1993; 8:371–384.CrossrefMedlineGoogle Scholar
  • 47. Sutherland MR, Gubhaju L, Moore L, Kent AL, Dahlstrom JE, Horne RS, Hoy WE, Bertram JF, Black MJ. Accelerated maturation and abnormal morphology in the preterm neonatal kidney.J Am Soc Nephrol. 2011; 22:1365–1374.CrossrefMedlineGoogle Scholar
  • 48. Gubhaju L, Sutherland MR, Black MJ. Preterm birth and the kidney: implications for long-term renal health.Reprod Sci. 2011; 18:322–333.CrossrefMedlineGoogle Scholar
  • 49. Rodríguez MM, Gómez AH, Abitbol CL, Chandar JJ, Duara S, Zilleruelo GE. Histomorphometric analysis of postnatal glomerulogenesis in extremely preterm infants.Pediatr Dev Pathol. 2004; 7:17–25.CrossrefMedlineGoogle Scholar
  • 50. Hoy WE, Bertram JF, Denton RD, Zimanyi M, Samuel T, Hughson MD. Nephron number, glomerular volume, renal disease and hypertension.Curr Opin Nephrol Hypertens. 2008; 17:258–265.CrossrefMedlineGoogle Scholar
  • 51. Stelloh C, Allen KP, Mattson DL, Lerch-Gaggl A, Reddy S, El-Meanawy A. Prematurity in mice leads to reduction in nephron number, hypertension, and proteinuria.Transl Res. 2012; 159:80–89.CrossrefMedlineGoogle Scholar
  • 52. Gubhaju L, Sutherland MR, Yoder BA, Zulli A, Bertram JF, Black MJ. Is nephrogenesis affected by preterm birth? Studies in a non-human primate model.Am J Physiol Renal Physiol. 2009; 297:F1668–F1677.CrossrefMedlineGoogle Scholar
  • 53. Sutherland MR, Gubhaju L, Black MJ. Stereological assessment of renal development in a baboon model of preterm birth.Am J Nephrol. 2011; 33(suppl 1):25–33.CrossrefMedlineGoogle Scholar
  • 54. Langley-Evans SC, Sherman RC, Welham SJ, Nwagwu MO, Gardner DS, Jackson AA. Intrauterine programming of hypertension: the role of the renin-angiotensin system.Biochem Soc Trans. 1999; 27:88–93.CrossrefMedlineGoogle Scholar
  • 55. Yzydorczyk C, Gobeil F, Cambonie G, Lahaie I, Lê NL, Samarani S, Ahmad A, Lavoie JC, Oligny LL, Pladys P, Hardy P, Nuyt AM. Exaggerated vasomotor response to ANG II in rats with fetal programming of hypertension associated with exposure to a low-protein diet during gestation.Am J Physiol Regul Integr Comp Physiol. 2006; 291:R1060–R1068.CrossrefMedlineGoogle Scholar
  • 56. Santos RA, Ferreira AJ. Angiotensin-(1-7) and the renin-angiotensin system.Curr Opin Nephrol Hypertens. 2007; 16:122–128.CrossrefMedlineGoogle Scholar
  • 57. Wright JW, Mizutani S, Harding JW. Pathways involved in the transition from hypertension to hypertrophy to heart failure. Treatment strategies.Heart Fail Rev. 2008; 13:367–375.CrossrefMedlineGoogle Scholar
  • 58. Moritz KM, Cuffe JS, Wilson LB, Dickinson H, Wlodek ME, Simmons DG, Denton KM. Review: Sex specific programming: a critical role for the renal renin-angiotensin system.Placenta. 2010; 31:S40–S46.CrossrefMedlineGoogle Scholar
  • 59. Lopes Del Ben G, Redublo Quinto BM, Casarini DE, Bueno Ferreira LC, Sousa Ayres S, de Abreu Carvalhaes JT. The urinary activity of angiotensin-converting enzyme in preterm, full-term newborns, and children.Pediatr Nephrol. 2006; 21:1138–1143.CrossrefMedlineGoogle Scholar
  • 60. Booth LC, Bennet L, Guild SJ, Barrett CJ, May CN, Gunn AJ, Malpas SC. Maturation-related changes in the pattern of renal sympathetic nerve activity from fetal life to adulthood.Exp Physiol. 2011; 96:85–93.CrossrefMedlineGoogle Scholar
  • 61. Henry SL, Barzel B, Wood-Bradley RJ, Burke SL, Head GA, Armitage JA. Developmental origins of obesity-related hypertension.Clin Exp Pharmacol Physiol. 2012; 39:799–806.CrossrefMedlineGoogle Scholar
  • 62. Intapad S, Tull FL, Brown AD, Dasinger JH, Ojeda NB, Fahling JM, Alexander BT. Renal denervation abolishes the age-dependent increase in blood pressure in female intrauterine growth-restricted rats at 12 months of age.Hypertension. 2013; 61:828–834.LinkGoogle Scholar
  • 63. Pladys P, Lahaie I, Cambonie G, Thibault G, Lê NL, Abran D, Nuyt AM. Role of brain and peripheral angiotensin II in hypertension and altered arterial baroreflex programmed during fetal life in rat.Pediatr Res. 2004; 55:1042–1049.CrossrefMedlineGoogle Scholar
  • 64. Marvar PJ, Lob H, Vinh A, Zarreen F, Harrison DG. The central nervous system and inflammation in hypertension.Curr Opin Pharmacol. 2011; 11:156–161.CrossrefMedlineGoogle Scholar
  • 65. Smith SL, Doig AK, Dudley WN. Impaired parasympathetic response to feeding in ventilated preterm babies.Arch Dis Child Fetal Neonatal Ed. 2005; 90:F505–F508.CrossrefMedlineGoogle Scholar
  • 66. Finer N, Saugstad O, Vento M, Barrington K, Davis P, Duara S, Leone T, Lui K, Martin R, Morley C, Rabi Y, Rich W. Use of oxygen for resuscitation of the extremely low birth weight infant.Pediatrics. 2010; 125:389–391.CrossrefMedlineGoogle Scholar
  • 67. Kamlin CO, O’Donnell CP, Davis PG, Morley CJ. Oxygen saturation in healthy infants immediately after birth.J Pediatr. 2006; 148:585–589.CrossrefMedlineGoogle Scholar
  • 68. Comporti M, Signorini C, Leoncini S, Buonocore G, Rossi V, Ciccoli L. Plasma F2-isoprostanes are elevated in newborns and inversely correlated to gestational age.Free Radic Biol Med. 2004; 37:724–732.CrossrefMedlineGoogle Scholar
  • 69. Vento M, Asensi M, Sastre J, Lloret A, García-Sala F, Miñana JB, Viña J. Hyperoxemia caused by resuscitation with pure oxygen may alter intracellular redox status by increasing oxidized glutathione in asphyxiated newly born infants.Semin Perinatol. 2002; 26:406–410.CrossrefMedlineGoogle Scholar
  • 70. Kleiber N, Chessex P, Rouleau T, Nuyt AM, Perreault M, Lavoie JC. Neonatal exposure to oxidants induces later in life a metabolic response associated to a phenotype of energy deficiency in an animal model of total parenteral nutrition.Pediatr Res. 2010; 68:188–192.CrossrefMedlineGoogle Scholar
  • 71. Lavoie JC, Bélanger S, Spalinger M, Chessex P. Admixture of a multivitamin preparation to parenteral nutrition: the major contributor to in vitro generation of peroxides.Pediatrics. 1997; 99:E6.CrossrefMedlineGoogle Scholar
  • 72. Lai TT, Bearer CF. Iatrogenic environmental hazards in the neonatal intensive care unit.Clin Perinatol. 2008; 35:163–81, ix.CrossrefMedlineGoogle Scholar
  • 73. Georgeson GD, Szony BJ, Streitman K, Varga IS, Kovács A, Kovács L, László A. Antioxidant enzyme activities are decreased in preterm infants and in neonates born via caesarean section.Eur J Obstet Gynecol Reprod Biol. 2002; 103:136–139.CrossrefMedlineGoogle Scholar
  • 74. Saik LA, Hsieh HL, Baricos WH, Shapira E. Enzymatic and immunologic quantitation of erythrocyte superoxide dismutase in adults and in neonates of different gestational ages.Pediatr Res. 1982; 16:933–937.CrossrefMedlineGoogle Scholar
  • 75. Vento M, Moro M, Escrig R, Arruza L, Villar G, Izquierdo I, Roberts LJ, Arduini A, Escobar JJ, Sastre J, Asensi MA. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease.Pediatrics. 2009; 124:e439–e449.mCrossrefMedlineGoogle Scholar
  • 76. Viña J, Vento M, García-Sala F, Puertes IR, Gascó E, Sastre J, Asensi M, Pallardó FV. L-cysteine and glutathione metabolism are impaired in premature infants due to cystathionase deficiency.Am J Clin Nutr. 1995; 61:1067–1069.CrossrefMedlineGoogle Scholar
  • 77. Asikainen TM, White CW. Pulmonary antioxidant defenses in the preterm newborn with respiratory distress and bronchopulmonary dysplasia in evolution: implications for antioxidant therapy.Antioxid Redox Signal. 2004; 6:155–167.CrossrefMedlineGoogle Scholar
  • 78. Thibeault DW. The precarious antioxidant defenses of the preterm infant.Am J Perinatol. 2000; 17:167–181.CrossrefMedlineGoogle Scholar
  • 79. O’Donovan DJ, Fernandes CJ. Free radicals and diseases in premature infants.Antioxid Redox Signal. 2004; 6:169–176.CrossrefMedlineGoogle Scholar
  • 80. Dennery PA. Effects of oxidative stress on embryonic development.Birth Defects Res C Embryo Today. 2007; 81:155–162.CrossrefMedlineGoogle Scholar
  • 81. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system.Nat Med. 2003; 9:677–684.CrossrefMedlineGoogle Scholar
  • 82. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.Genes Dev. 1998; 12:149–162.CrossrefMedlineGoogle Scholar
  • 83. Critser PJ, Yoder MC. Endothelial colony-forming cell role in neoangiogenesis and tissue repair.Curr Opin Organ Transplant. 2010; 15:68–72.CrossrefMedlineGoogle Scholar
  • 84. Baker CD, Ryan SL, Ingram DA, Seedorf GJ, Abman SH, Balasubramaniam V. Endothelial colony-forming cells from preterm infants are increased and more susceptible to hyperoxia.Am J Respir Crit Care Med. 2009; 180:454–461.CrossrefMedlineGoogle Scholar
  • 85. Fujinaga H, Baker CD, Ryan SL, Markham NE, Seedorf GJ, Balasubramaniam V, Abman SH. Hyperoxia disrupts vascular endothelial growth factor-nitric oxide signaling and decreases growth of endothelial colony-forming cells from preterm infants.Am J Physiol Lung Cell Mol Physiol. 2009; 297:L1160–L1169.CrossrefMedlineGoogle Scholar
  • 86. Balasubramaniam V, Mervis CF, Maxey AM, Markham NE, Abman SH. Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia.Am J Physiol Lung Cell Mol Physiol. 2007; 292:L1073–L1084.CrossrefMedlineGoogle Scholar
  • 87. Levesque BM, Kalish LA, Winston AB, Parad RB, Hernandez-Diaz S, Phillips M, Zolit A, Morey J, Gupta M, Mammoto A, Ingber DE, Van Marter LJ. Low urine vascular endothelial growth factor levels are associated with mechanical ventilation, bronchopulmonary dysplasia and retinopathy of prematurity.Neonatology. 2013; 104:56–64.CrossrefMedlineGoogle Scholar
  • 88. Yzydorczyk C, Comte B, Cambonie G, Lavoie JC, Germain N, Ting Shun Y, Wolff J, Deschepper C, Touyz RM, Lelièvre-Pegorier M, Nuyt AM. Neonatal oxygen exposure in rats leads to cardiovascular and renal alterations in adulthood.Hypertension. 2008; 52:889–895.LinkGoogle Scholar
  • 89. Yzydorczyk C, Comte B, Huyard F, Cloutier A, Germain N, Bertagnolli M, Nuyt AM. Developmental programming of eNOS uncoupling and enhanced vascular oxidative stress in adult rats after transient neonatal oxygen exposure.J Cardiovasc Pharmacol. 2013; 61:8–16.CrossrefMedlineGoogle Scholar
  • 90. Tufro-McReddie A, Norwood VF, Aylor KW, Botkin SJ, Carey RM, Gomez RA. Oxygen regulates vascular endothelial growth factor-mediated vasculogenesis and tubulogenesis.Dev Biol. 1997; 183:139–149.CrossrefMedlineGoogle Scholar
  • 91. Yue X, Tomanek RJ. Stimulation of coronary vasculogenesis/angiogenesis by hypoxia in cultured embryonic hearts.Dev Dyn. 1999; 216:28–36.CrossrefMedlineGoogle Scholar
  • 92. Sutherland MR, O’Reilly M, Kenna K, Ong K, Harding R, Sozo F, Black MJ. Neonatal hyperoxia: effects on nephrogenesis and long-term glomerular structure.Am J Physiol Renal Physiol. 2013; 304:F1308–F1316.CrossrefMedlineGoogle Scholar
  • 93. Velten M, Hutchinson KR, Gorr MW, Wold LE, Lucchesi PA, Rogers LK. Systemic maternal inflammation and neonatal hyperoxia induces remodeling and left ventricular dysfunction in mice.PLoS One. 2011; 6:e24544.CrossrefMedlineGoogle Scholar
  • 94. Law CM, de Swiet M, Osmond C, Fayers PM, Barker DJ, Cruddas AM, Fall CH. Initiation of hypertension in utero and its amplification throughout life.BMJ. 1993; 306:24–27.CrossrefMedlineGoogle Scholar
  • 95. Harman D. Aging: a theory based on free radical and radiation chemistry.J Gerontol. 1956; 11:298–300.CrossrefMedlineGoogle Scholar
  • 96. Nilsson PM, Boutouyrie P, Laurent S. Vascular aging: A tale of EVA and ADAM in cardiovascular risk assessment and prevention.Hypertension. 2009; 54:3–10.LinkGoogle Scholar
  • 97. Hoenig MR, Bianchi C, Rosenzweig A, Sellke FW. Decreased vascular repair and neovascularization with ageing: mechanisms and clinical relevance with an emphasis on hypoxia-inducible factor-1.Curr Mol Med. 2008; 8:754–767.CrossrefMedlineGoogle Scholar
  • 98. Aviv A. Chronology versus biology: telomeres, essential hypertension, and vascular aging.Hypertension. 2002; 40:229–232.LinkGoogle Scholar
  • 99. Kovacic JC, Moreno P, Hachinski V, Nabel EG, Fuster V. Cellular senescence, vascular disease, and aging: part 1 of a 2-part review.Circulation. 2011; 123:1650–1660.LinkGoogle Scholar
  • 100. Voghel G, Thorin-Trescases N, Farhat N, Nguyen A, Villeneuve L, Mamarbachi AM, Fortier A, Perrault LP, Carrier M, Thorin E. Cellular senescence in endothelial cells from atherosclerotic patients is accelerated by oxidative stress associated with cardiovascular risk factors.Mech Ageing Dev. 2007; 128:662–671.CrossrefMedlineGoogle Scholar
  • 101. Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P, Ritchie A, Goddard M, Bennett M. Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress.Circ Res. 2006; 99:156–164.LinkGoogle Scholar
  • 102. Akkad A, Hastings R, Konje JC, Bell SC, Thurston H, Williams B. Telomere length in small-for-gestational-age babies.BJOG. 2006; 113:318–323.CrossrefMedlineGoogle Scholar
  • 103. Raqib R, Alam DS, Sarker P, Ahmad SM, Ara G, Yunus M, Moore SE, Fuchs G. Low birth weight is associated with altered immune function in rural Bangladeshi children: a birth cohort study.Am J Clin Nutr. 2007; 85:845–852.CrossrefMedlineGoogle Scholar
  • 104. Burton GJ, Jauniaux E. Oxidative stress.Best Pract Res Clin Obstet Gynaecol. 2011; 25:287–299.CrossrefMedlineGoogle Scholar
  • 105. Aghai ZH, Camacho J, Saslow JG, Mody K, Eydelman R, Bhat V, Stahl G, Pyon K, Bhandari V. Impact of histological chorioamnionitis on tracheal aspirate cytokines in premature infants.Am J Perinatol. 2012; 29:567–572.MedlineGoogle Scholar
  • 106. Mohn A, Chiavaroli V, Cerruto M, Blasetti A, Giannini C, Bucciarelli T, Chiarelli F. Increased oxidative stress in prepubertal children born small for gestational age.J Clin Endocrinol Metab. 2007; 92:1372–1378.CrossrefMedlineGoogle Scholar
  • 107. Franco MC, Kawamoto EM, Gorjão R, Rastelli VM, Curi R, Scavone C, Sawaya AL, Fortes ZB, Sesso R. Biomarkers of oxidative stress and antioxidant status in children born small for gestational age: evidence of lipid peroxidation.Pediatr Res. 2007; 62:204–208.CrossrefMedlineGoogle Scholar
  • 108. Manderson JG, Mullan B, Patterson CC, Hadden DR, Traub AI, McCance DR. Cardiovascular and metabolic abnormalities in the offspring of diabetic pregnancy.Diabetologia. 2002; 45:991–996.CrossrefMedlineGoogle Scholar
  • 109. Cambonie G, Comte B, Yzydorczyk C, Ntimbane T, Germain N, Lê NL, Pladys P, Gauthier C, Lahaie I, Abran D, Lavoie JC, Nuyt AM. Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet.Am J Physiol Regul Integr Comp Physiol. 2007; 292:R1236–R1245.CrossrefMedlineGoogle Scholar
  • 110. Balistreri CR, Caruso C, Candore G. The role of adipose tissue and adipokines in obesity-related inflammatory diseases.Mediators Inflamm. 2010; 2010:802078.CrossrefMedlineGoogle Scholar
  • 111. Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease.Circ Res. 2005; 96:939–949.LinkGoogle Scholar

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.