Eur J Cardiothorac Surg 2005;27:1036-1042
© 2005 Elsevier Science NL
Fetal origins of coronary heart disease—implications for cardiothoracic surgery?
Omar A. Khana,b,*,
Ryan Chaua,b,
Caroline Bertramb,
Mark A. Hansonb,
Sunil K. Ohria
a Department of Cardiothoracic Surgery, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
b Centre for Developmental Origins of Health and Disease, University of Southampton, Southampton, UK
Received 23 November 2004;
received in revised form 16 January 2005;
accepted 17 January 2005.
* Corresponding author. Address: Department of Cardiothoracic Surgery, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK. Tel.: +44 2380 798 421; fax: +44 2380 786 933. (E-mail: omarkhan{at}iname.com).
 |
Abstract
|
|---|
Over the last 15 years, there has been growing evidence that poor nutrition during gestation plays an important role in the development of coronary heart disease. This hypothesis, commonly known as the ‘fetal origins of adult disease’ has now gained widespread acceptance in the scientific community. In this review, we discuss the evidence for this theory and analyse the patho-physiological mechanisms underlying the relationship between altered fetal growth and coronary heart disease. Finally, the potential relevance of the theory to cardiac surgical practice will be evaluated.
Key Words: Coronary heart disease • Fetal • Undernutrition
|
1. Introduction
|
|---|
Coronary heart disease has traditionally been regarded as an age-related degenerative disease influenced by genetic predisposition coupled with behavioural factors such as smoking and lack of physical exercise. Over the last 15 years there has, however, been increasing evidence that exposure to an adverse environment in utero may also play an important role in the development of ischaemic heart disease. This concept of a ‘fetal origin of disease’, first proposed by Barker [1] has been extended to a number of chronic adult diseases including hypertension, Type II diabetes mellitus, chronic obstructive pulmonary disease and hypercholesterolemia [2]. Despite the growing acceptance of this hypothesis, there is a limited awareness within the surgical community of the potential significance of this concept. In this review, we analyse and critically appraise the epidemiological evidence of a relationship between the fetal environment and coronary heart disease. In addition, we discuss the possible mechanisms underlying this association using information gained from animal and human studies. Finally, we attempt to illustrate the potential implications of this concept for cardiac surgical practice.
|
2. Destructive model of coronary heart disease
|
|---|
Over the last 40 years, the search for the causes of coronary heart disease (CHD) has been guided by a so-called ‘destructive’ model [3]. At the heart of this model is the concept that development of coronary artery atherosclerosis is essentially an age-related phenomenon; and factors such as tobacco consumption, obesity and psychosocial factors accelerate what is essentially a degenerative process. Although these factors are undoubtedly very important risk factors for the development of CHD [4,5], this model suffers from a number of limitations. For a start, previous studies have shown that the classic risk factors for ischaemic heart disease, namely cigarette smoking, hypercholesterolemia, hypertension and diabetes account for only 50% of its incidence [6]. Indeed, Raslova et al. [7] showed that there were no significant lifestyle differences between a group of myocardial infarct survivors and a matched cohort with no family history of heart disease. Although more recent data [4,5] appears to suggest that the figure of 50% is in fact an underestimate of the importance of classical risk factors, what is clear is that the conventional risk factors for ischaemic heart disease cannot in themselves fully explain the incidence of this disease. Moreover, an implicit part of this model is the concept that modification of these risk factors should be associated with a reduced risk of cardiac events. The impact of modifying adult lifestyle, whilst significant, have, however, been relatively small when formally tested in randomised trials [8,9].
One explanation for the shortcomings of this model is the idea that individuals are heterogeneous in their responses to environmental influences. Smoking, for example, is harmful to some individuals but less harmful to others. It has therefore been argued that this heterogeneity results from genetic factors, which predispose certain individuals to cardiovascular disease. Although a number of candidate genes have been identified as promoting atherosclerosis (for a review see Novelli et al. [10]), this explanation alone does not fully account for the geographical pattern of coronary heart disease seen. In particular, genetic considerations cannot explain the finding that in the Western world, the poorest individuals in the poorest places tend to have the highest rates of cardiovascular disease. This finding, first noted by Forsdahl [11] has been confirmed in a number of studies [12,13]. Moreover, the risk of cardiovascular disease appears to be related to place of birth, and remains with an individual irrespective of migration in later life [11,12].
|
3. Fetal origins of coronary heart disease
|
|---|
The observation that deaths from ischaemic heart disease appeared linked to birthplace led to the suggestion that pre-natal and early post-natal factors may be risk factors for ischaemic heart disease. This hypothesis was first formally tested by Barker et al. [14] who examined the mortality records of 5654 men born during 1911–1930 in Hertfordshire, England. This study showed that men with the lowest weights at birth subsequently had the highest death rates from ischaemic heart disease. This association between coronary heart disease and small size at birth has now been replicated in a number of studies in Europe [15,16], North America [17] and India [18]. Moreover, this finding appears robust even when confounding risk factors such as social and behavioural variables are accounted for [16].
As a consequence of these findings, Barker [19,20] proposed the concept of a ‘fetal origin of coronary heart disease’. In essence this model proposes that in response to under-nourishment, the fetus undergoes a number of physiological and metabolic adaptations. These adaptations persist post-natally and predispose the individual to coronary heart disease in later life. Since the original formulation of this hypothesis, further work has led to a number of refinements in this theory. There is now growing awareness that the long-term effects of intrauterine undernutrition depend upon its timing during gestation. Retrospective analyses of babies born during the Dutch famine of 1945 have shown an association between CHD and early (as opposed to late) nutritional challenges during gestation [21]. Similarly, there is increasing evidence of the importance of not only the pre-natal environment, but also the early post-natal environment as a determinant of cardiac disease. Eriksson et al. [22] have recently shown an association between CHD and rapid childhood weight gain, and this finding has now been replicated in other studies [23]. This has led some to speculate that following a period of undernutrition in utero, children may undergo compensatory or catch-up growth, and it is this accelerated weight gain in childhood which leads to the increased risk of developing CHD [23]. Finally there is increasing appreciation of the concept that maternal nutrition must be extended beyond the mother's diet in pregnancy to include both her body composition and metabolism both during and prior to pregnancy. For example, Napoli et al. [24] have shown that maternal hypercholesterolaemia during pregnancy induces changes in the fetal aorta that determine the long-term susceptibility of children to subsequent atherosclerosis. This finding highlights the fact that although birth weight may be useful marker of maternal global undernutrition, it is a poor indicator of subtle nutritional abnormalities.
|
4. Fetal origins of adult diseases
|
|---|
Since the original formulation of the fetal origins hypothesis in terms of coronary heart disease, a large number of studies have attempted to correlate fetal growth with other chronic diseases of adulthood. Although detailed examination of this data is beyond the scope of this review, the diseases studied include hypertension, stroke, non-insulin-dependent diabetes, hypercholesterolemia, chronic obstructive airways disease, cancer.
4.1. Hypertension
The effect of birth weight on blood pressure is perhaps the most studied association between fetal growth and later physiological characteristics. In a systematic review of the literature incorporating over 66,000 subjects, Law and Shiell [25] showed that at all ages, with the possible exception of the pubertal period, there is a tendency for blood pressure to increase as birth weight reduces. Interestingly, more recent work on this subject [26] has shown that, as with CHD, rapid ‘compensatory’ growth in childhood is associated with an increased risk of hypertension. Similarly, Shiell et al. [27] have shown that ‘unbalanced’ maternal nutrition during gestation (namely a high-animal protein, low-carbohydrate diet) leads to offspring with higher diastolic pressures in adulthood.
4.2. Stroke
A number of studies have shown that low-birth weight is associated with raised rates of fatal and non-fatal stroke in adult life [16,17,28]. More recent work by Eriksson et al. [29] have shown that haemorrhagic stroke was particularly associated with men who had a low-birth weight in relation to their head circumference. They postulated that in response to malnutrition, the fetus redistributes the cardiac output to favour the brain at the expense of the trunk, and that this redistribution causes structural adaptations in the carotid arteries, which predisposes the individual to stroke in later life.
4.3. Non-insulin-dependent diabetes
Hales et al. [30] were the first to show that birth weight and ponderal index (birth weight/birth length3) were inversely related to the incidence of non-insulin-dependent diabetes in adults in Hertfordshire, England. Since then this finding has been replicated in both Europe [31] and the United States [32]. Although the mechanisms underlying this association have yet to be elucidated, there is some evidence to suggest that insulin resistance, as opposed to impaired beta cell function, may be the primary defect responsible for the development of impaired glucose tolerance [31,33].
4.4. Hypercholesterolemia
Barker et al. [34] was the first to describe an association between reduced abdominal circumference at birth and raised serum low density lipoprotein. This link was further investigated by Mogren et al. [35] who found that low-birth weight females had significantly higher triglycerides, whilst low-birth weight males had significantly higher total cholesterol. Interestingly, it has also been shown that high plasma concentrations of the haemostatic factors fibrinogen and factor VII also correlate with small abdominal circumference at birth [36]. One interpretation of these findings is that the reduced abdominal circumference at birth reflects impaired liver growth, and this in turn leads to abnormal liver metabolism in later life [37].
4.5. Chronic obstructive airways disease
The association between impaired fetal growth and adult lung function was first suggested by Barker et al. [38] who showed an association between the mean forced expiratory flow in 1s (FEV1) and birth weight in a cohort of 5000 men aged 59–70 years born in Hertfordshire in the early 1900s. Although this finding has been broadly supported by a number of other studies [39,40], it should be noted that the association between birth weight and adult lung disease is more tenuous. Although Lopuhaa et al. [41] observed an increased prevalence of obstructive airways disease in people exposed to famine in mid- and early gestation, this association between symptomatology and birth weight has not been replicated in other studies [38–40].
4.6. Cancer
It has been suggested that impaired fetal growth may affect the risk of developing a range of hormonally related cancers including cancer of the breast [42], testis [43] and prostate [44]. Although a number of mechanisms have been proposed to explain these associations [45], it should be noted that, to date, there is little consistency in the literature on this topic and hence the importance of impaired fetal growth in carcinogenesis is far from proven.
On reviewing some of the apparently contradictory epidemiological data, there is a natural tendency to question the strength of evidence for the fetal origins hypothesis. This issue was recently tackled by Huxley et al. [46] who undertook a review of the epidemiological evidence linking blood pressure and birth weight, and concluded that the association between birth weight and hypertension was far less significant than previously thought. While this has been interpreted by some as casting doubt on the whole fetal origins hypothesis, a number of provisos must be made. For a start, although the association between birth weight and surrogate markers of disease such as blood pressure may be debated, when birth weight is correlated against actual disease, and in particular CHD incidence, the associations are unequivocal [47]. In addition, by focusing on birth weight, it has been argued that that far from casting doubt on the fetal origins hypothesis, Huxley et al. [46] have simply highlighted the fact that birth weight is a relatively crude proxy for fetal growth [47]. Indeed what this whole debate highlights is the need to develop more sophisticated markers of maternal and fetal nutritional status during pregnancy.
|
5. Mechanisms underlying the development of CHD
|
|---|
Despite the controversy surrounding some aspects of the fetal origins hypothesis, with regards to CHD, there does appear to be robust epidemiological evidence linking this particular disease with impaired fetal growth. What is unclear is the patho-physiological mechanisms underlying this association. Part of the difficulty in elucidating these mechanisms lies in the problem of arranging appropriate human studies. For a start, there are many logistical difficulties in conducting a prospective study when the lag time between birth and the development of disease may be up to 80 years. Moreover, there are obvious practical and ethical problems in assessing and manipulating the diets of pregnant mothers. In addition, due to confounding factors such as smoking and lifestyle, it is remarkably difficult to demonstrate causality between fetal nutritional status and the aggressiveness of atherosclerosis later in life. Finally, with particular reference to CHD, there are as yet no cheap, reliable, non-invasive methods of assessing coronary artery atherosclerosis. In view of these difficulties, a number of groups have attempted to use animal models in order to elucidate the mechanisms linking fetal nutrition with increased incidence of adult diseases. From these, and some human studies, it is possible to speculate how impaired fetal growth may contribute to an increased risk of developing CHD. Potential mechanisms include coronary artery dysfunction, accelerated atherogenesis and reduction in cardiomyocyte number.
5.1. Coronary artery dysfunction
A number of human studies have shown that that vascular dysfunction occurs in individuals who are born small. Arterial endothelial dysfunction has been demonstrated in term infants [48], children [49], and young adults [50] with low-birth weight. The relationship between fetal nutrition and vascular reactivity has been further investigated in a number of animal models. Ozaki et al. [51] have demonstrated that in rats, global undernutrition during gestation causes enhanced thromboxane-induced contraction in the femoral arteries of the male offspring. Similarly, Brawley et al. [52] have shown that dietary protein restriction in pregnancy leads to impaired endothelium-dependent and -independent relaxation in male offspring. Using a sheep model, Nishina et al. [53] have shown that protein and global nutrient restriction in early gestation produce fetuses with impaired endothelium-dependent and -independent femoral artery dilation, and that this dysfunction is most pronounced in the protein-restricted group. What these studies illustrate is that undernutrition in utero is consistently associated with altered vascular reactivity across a number of vascular beds. Clearly, if this vascular dysfunction were to occur in coronary arteries, this could provide a plausible mechanism for explaining the increased incidence of CHD in low-birth weight babies. Unfortunately, there has not been to date any animal or human studies of the function of isolated coronary arteries with regard to perinatal undernutrition. There has, however, been some animal work on the in vivo function of coronary arteries in a similar context. Davis et al. [54] have shown that in response to prolonged hypoxemia in utero, fetal sheep show an increase in coronary artery conductance that persists into adulthood. They postulated that this remodelling of the coronary vascular tree might have a long-term negative effect on the endothelial function or vascular reactivity of the coronary vasculature. Whether or not such vascular dysfunction actually does occur remains to be proven.
5.2. Accelerated atherogenesis
Recent epidemiological studies have shown a direct relationship between impaired intrauterine growth and atherogenesis in later life. Martyn et al. [55] have shown that people who weighed less than 6.5lb at birth had an increased incidence of carotid artery stenosis as assessed by duplex ultrasonography. Moreover, this association remained present even after accounting for confounding variables such as serum cholesterol and smoking history. Similarly, Palinski and Napoli [56] have shown that maternal hypercholestrolaemia during gestation leads to an increase in the number of fatty steaks in seen in fetal aortas. Furthermore children of hypercholestrolaemic mothers appear to show faster progression of atherosclerosis, and this finding cannot be explained by conventional post-natal risk factors for atherosclerosis or genetic factors [24]. From these findings, it is tempting to postulate that impaired fetal growth directly promotes coronary artery atherogenesis, and that it is this mechanism which mediates the increased incidence of cardiovascular mortality seen in low-birth weight individuals. Although, this theory is superficially highly attractive, a number of provisos must be made. Firstly, the actual evidence linking accelerated atherogenesis and impaired fetal growth is far from robust and has not been confirmed in some studies [57]. Moreover, given the differing geometries and haemodynamics of the aortic, carotid and coronary circulation, it is questionable whether we can legitimately extrapolate data across different vascular beds. Finally, even if a relationship between impaired fetal growth and accelerated coronary atherosclerosis were shown to exist, it should be noted that the presence of atherosclerosis per se is not necessarily an indicator of clinically significant CHD.
5.3. Reduction in cardiomyocyte number
It is well established that cardiomyocytes undergo terminal differentiation in fetal or early post natal life; and following this process are essentially unable to proliferate in response to injury [58]. Work by Thornburg's group [59,60] has shown that in sheep, this process of terminal differentiation can be influenced by intrauterine factors. As a consequence of this, they hypothesised that growth restriction during fetal life may lead to a reduction in the total number of cardiomyocytes at birth, leading to a reduced myocardial reserve and hence an increase susceptibility to cardiac failure. Whilst this theory is highly plausible, it remains to be seen whether human cardiomyocytes show similar plasticity during fetal development.
Finally, it has been suggested that the relationship between impaired fetal growth and CHD is non-causal, and is merely secondary to other factors [59]. After all, as discussed earlier, impaired fetal growth is strongly associated with hypertension, diabetes and hypercholesterolemia, three well-established risk factors for the development of CHD [4]. This hypothesis has been tested by Koupilova et al. [61] who found the increased incidence of CHD to be independent of other risk factors such as hypertension. This finding illustrates the fact that the patho-physiological mechanisms underlying the relationship between impaired fetal growth and CHD are likely to be mutilfactorial and heterogenous for different individuals, making elucidation of these mechanisms highly complex.
|
6. Implications for cardiac surgery
|
|---|
The preceding discussion raises the obvious question of whether impaired fetal growth influences outcome following cardiac surgery. Unfortunately, for the reasons outlined earlier, there has been no work on this topic. However, based on the results obtained from animal and human studies, it is possible to speculate on the possible effects that undernutrition in utero may have on short and long-term outcomes following cardiac surgery.
6.1. Peri-operative outcome
Factors affecting mortality and morbidity following cardiac surgery, and in particular coronary artery bypass surgery (CABG), represent one of the most heavily investigated topics in surgery [62]. Unfortunately, there has to date been no study directly analysing the effect of impaired fetal growth on outcome following CABG. However, the results of other studies strongly suggest that birth weight may be a potential determinant of peri-operative outcome. Firstly, there is an outlined earlier unequivocal evidence linking Type II diabetes and hypertension with birth weight, conditions which are themselves associated with increased post-operative morbidity and mortality [62–64]. Moreover, it is possible that impaired fetal growth may directly contribute to poor peri-operative outcome. In particular, the sheep experiments of Thornburg et al. [59] appear to show an association between reduced cardiomyocyte numbers and impaired fetal growth. If this pattern also occurs in humans, this would imply that low-birth weight patients have a poorer myocardial reserve and hence have a greater risk of cardiac failure and death following cardiac surgery.
6.2. Arterial graft spasm
Over the last 10 years, there has been an increasing trend for utilising arterial conduits in preference to saphenous vein grafts in CABG. The rationale for this approach stems from the superior long-term patency of these conduits [65]. However, arterial grafts, and in particular radial artery grafts [66] are prone to spasm in the early post-operative period, and this spasm can in turn lead to post-operative myocardial infarction and death [67]. The precise factors mediating such arterial spasm are unclear, but it is likely that the process is dependent on both exaggerated vasoconstrictor responses and impaired endothelium-dependent relaxation [67]. It is therefore tempting to speculate that impaired fetal growth may predispose an individual to arterial graft spasm. After all, as discussed earlier, impaired fetal growth has been shown to lead to impaired peripheral arterial function in a number of animal models [51–53]. So what direct evidence is there linking arterial graft dysfunction and altered fetal growth? We have recently utilised a sheep model to show that undernutrition in early gestation leads to increased basal tone and vasoconstrictor sensitivity of the adult internal thoracic artery [68]. In addition, Goodfellow et al. [50] have shown that human adults of low-birth weight show impaired endothelium-dependent dilation of the brachial artery. Although confirmatory work must be undertaken, these two studies suggest that impaired fetal growth may an important contributor to arterial graft dysfunction following CABG.
6.3. Long-term outcome
Although CABG can provide excellent long-term clinical outcomes, approximately 10% of patients suffer with recurrent cardiac symptoms following surgery [69]. Although the factors affecting long-term outcome following CABG have been extensively investigated [69–72], there is, once again, no data on the importance of birth weight. Nonetheless, it is possible to speculate on the likely effects of impaired fetal growth on the risk of developing further cardiac events following CABG. As discussed earlier, there is a strong association between impaired fetal growth and diabetes, a condition which itself has been shown to adversely affect long-term survival following CABG [69]. Perhaps even more significant is the link between hyperlipidamia and low-birth weight. After all, hypercholesterolemia has been shown to mediate saphenous vein intimal hyperplasia and occlusion [70], mammary artery stenosis [71] and distal coronary artery atherosclerosis [72]. The association between hypercholesterolemia and impaired fetal growth may also have implications for the long-term outcome of valve surgery. For example, Nollert et al. [73] have shown that elevated cholesterol levels were associated with an increased risk of degeneration of aortic bio-prosthetic valves. These findings suggest that patients with impaired fetal growth who undergo CABG or tissue valve replacement are likely to have an increased incidence of hyperlipidaemia, and hence are at an increased risk of requiring redo surgery.
There is a danger on reviewing this evidence of adopting a fatalistic attitude—namely that low-birth weight individuals are simply pre-ordained to have a poorer outcome irrespective of any therapeutic interventions. While there may be an element of truth in this assertion, by identifying such potentially high-risk patients prior to surgery, it may be possible to tailor their medical and surgical therapy by, for example instituting an aggressive lipid-lowering regime.
|
7. Conclusions
|
|---|
The traditional view of heart disease as mediated by behavioural and genetic factors is inadequate in explaining the epidemiological patterns of this disease. Work over the last 15 years has now provided unequivocal evidence that, in addition to the classic risk factors such as smoking and obesity, impaired fetal growth is also associated with the development of coronary heart disease. Although the importance of this ‘fetal origins of adult disease’ hypothesis is now established, it is only recently that the patho-physiological mechanisms underlying this theory are being thoroughly investigated. While the relevance of this hypothesis to cardiac surgery has yet to be evaluated, there is strong circumstantial evidence to suggest that both early and late outcome following surgery are likely to be determined, at least in part, by impaired fetal growth. Such an association, if proven, may have important clinical implications for surgical practice.
|
Acknowledgments
|
|---|
The authors gratefully acknowledge the British Heart Foundation and HOPE for their research support.
|
References
|
|---|
- Barker DJP. Fetal origins of coronary heart disease. Br Med J 1995;311:171-174.[Free Full Text]
- Waterland RA, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr 1999;69(2):179-197.[Abstract/Free Full Text]
- Robinson SM, Barker DJP. Coronary heart disease: a disorder of growth. Proc Nutr Soc 2002;61(4):537-542.[CrossRef][Medline]
- Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control study. Lancet 2004;364(9438):937-952.[CrossRef][Medline]
- Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA, Blackett KN, Sitthi-amorn C, Sato H, Yusuf S, INTERHEART investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case–control study. Lancet 2004;364(9438):953-962.[CrossRef][Medline]
- Crouse JR. Progress in coronary artery disease risk-factor research: what remains to be done?. Clin Chem 1984;30:1125-1127.[Free Full Text]
- Raslova K, Smolkova B, Vohnout B, Frohlich JJ. Risk factors for atherosclerosis in survivors of myocardial infarction and their spouses: comparison to controls without personal and family history of atherosclerosis. Metabolism 2001;50(1):24-29.[CrossRef][Medline]
- Ebrahim S, Smith GD. Systematic review of randomised controlled trials of multiple risk factor interventions for preventing coronary heart disease. Br Med J 1997;314:1666-1674.[Abstract/Free Full Text]
- Hooper L, Summerbell CD, Higgins JPT, Thompson RL, Capps NE, Davey Smith G, Riemersma RA, Ebrahim S. Dietary fat intake and prevention of cardiovascular disease: systematic review. Br Med J 2001;322:757-763.[Abstract/Free Full Text]
- Novelli G, Borgiani P, Giardina E, Mango R, Contino G, Romeo F, Mehta JL. Role of genetics in prevention of coronary atherosclerosis. Curr Opin Cardiol 2003;18(5):368-371.[CrossRef][Medline]
- Forsdahl A. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease?. Br J Prev Soc Med 1977;31(2):91-95.[Medline]
- Barker DJP. Mothers, babies and disease in later life. 1st ed.. London: Br Med J Publishing Group; 1994.
- Acheson D. Independent inquiry into inequalities in health. London: H.M. Stationery Office; 1998.
- Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989;2(8663):577-580.[Medline]
- Frankel S, Elwood P, Sweetnam P, Yarnell J, Smith GD. Birthweight, body-mass index in middle age, and incident coronary heart disease. Lancet 1996;348:1478-1480.[CrossRef][Medline]
- Leon DA, Lithell HO, Vagero D, Koupilova I, Mohsen R, Berglund L, Lithell UB, McKeigue PM. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915–29. Br Med J 1998;317(7153):241-245.[Abstract/Free Full Text]
- Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA, Willett WC, Hennekens CH. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. Br Med J 1997;315:396-400.[Abstract/Free Full Text]
- Stein CE, Fall CHD, Kumaran K, Osmond C, Cox V, Barker DJP. Fetal growth and coronary heart disease in South India. Lancet 1996;348:1269-1273.[CrossRef][Medline]
- Barker DJ. The Wellcome Foundation Lecture. The fetal origins of adult disease. Proc R Soc Lond B Biol Sci 1995;262(1363):37-43.[Medline]
- Barker DJP. Fetal origins of coronary heart disease. Br Med J 1995;311:171-174.
- Roseboom TJ, van der Meulen JH, Ravelli AC, Osmond C, Barker DJ, Bleker OP. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Twin Res 2001;4(5):293-298.[CrossRef][Medline]
- Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJP. Early growth and coronary heart disease in later life: longitudinal study. Br Med J 2001;322:949-953.[Abstract/Free Full Text]
- Forsen T, Osmond C, Eriksson JG, Barker DJ. Growth of girls who later develop coronary heart disease. Heart 2004;90(1):20-24.[Abstract/Free Full Text]
- Napoli C, Glass CK, Witztum JL, Deutsch R, D'Armiento FP, Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 1999;354(9186):1234-1241.[CrossRef][Medline]
- Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens 1996;14(8):935-941.[Medline]
- Law CM, Shiell AW, Newsome CA, Syddall HE, Shinebourne EA, Fayers PM, Martyn CN, de Swiet M. Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age. Circulation 2002;105(9):1088-1092.[Abstract/Free Full Text]
- Shiell AW, Campbell-Brown M, Haselden S, Robinson S, Godfrey KM, Barker DJ. High-meat, low-carbohydrate diet in pregnancy: relation to adult blood pressure in the offspring. Hypertension 2001;38(6):1282-1288.[Abstract/Free Full Text]
- Martyn CN, Barker DJP, Osmond C. Mothers' pelvic size, fetal growth, and death from stroke and coronary heart disease in men in the UK. Lancet 1996;348:1264-1268.[CrossRef][Medline]
- Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ. Early growth, adult income, and risk of stroke. Stroke 2000;31(4):869-874.[Abstract/Free Full Text]
- Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. Br Med J 1991;303(6809):1019-1022.
- Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50–60 years. Br Med J 1996;312(7028):406-410.[Abstract/Free Full Text]
- Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation 1996;94(12):3246-3250.[Abstract/Free Full Text]
- Jaquet D, Chevenne D, Czernichow P, Levy-Marchal C. No evidence for a major beta-cell dysfunction in young adults born with intra-uterine growth retardation. Pediatr Diab 2000;1(4):181-185.[CrossRef]
- Barker DJ, Martyn CN, Osmond C, Hales CN, Fall CH. Growth in utero and serum cholesterol concentrations in adult life. Br Med J 1993;307(6918):1524-1527.
- Mogren I, Hogberg U, Stegmayr B, Lindahl B, Stenlund H. Fetal exposure, heredity and risk indicators for cardiovascular disease in a Swedish welfare cohort. Int J Epidemiol 2001;30(4):853-862.[Abstract/Free Full Text]
- Barker DJ, Meade TW, Fall CH, Lee A, Osmond C, Phipps K, Stirling Y. Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life. Br Med J 1992;304(6820):148-152.
- Barker DJ, Martyn CN, Osmond C, Wield GA. Abnormal liver growth in utero and death from coronary heart disease. Br Med J 1995;310(6981):703-704.[Free Full Text]
- Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO. Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. Br Med J 1991;303:671-675.
- Edwards CA, Osman LM, Godden DJ, Campbell DM, Douglas JG. Relationship between birth weight and adult lung function: controlling for maternal factors. Thorax 2003;58:1061-1065.[Abstract/Free Full Text]
- Stein CE, Kumaran K, Fall CH, Shaheen SO, Osmond C, Barker DJ. Relation of fetal growth to adult lung function in south India. Thorax 1997;52:895-899.[Abstract]
- Lopuhaa CE, Roseboom TJ, Osmond C, Barker DJ, Ravelli AC, Bleker OP, van der Zee JS, van der Meulen JH. Atopy, lung function, and obstructive airways disease after prenatal exposure to famine. Thorax 2000;55:555-561.[Abstract/Free Full Text]
- Michels KB, Trichopoulos D, Robins JM, Rosner BA, Manson JE, Hunter DJ, Colditz GA, Hankinson SE, Speizer FE, Willett WC. Birthweight as a risk factor for breast cancer. Lancet 1996;348(9041):1542-1546.[CrossRef][Medline]
- Richiardi L, Askling J, Granath F, Akre O. Body size at birth and adulthood and the risk for germ-cell testicular cancer. Cancer Epidemiol Biomarkers Prev 2003;12(7):669-673.[Abstract/Free Full Text]
- Ekbom A, Hsieh CC, Lipworth L, Wolk A, Ponten J, Adami HO, Trichopoulos D. Perinatal characteristics in relation to incidence of and mortality from prostate cancer. Br Med J 1996;313(7053):337-341.[Abstract/Free Full Text]
- Trichopoulos D, Lipworth L. Is cancer causation simpler than we thought, but more intractable?. Epidemiology 1995;6(4):347-349.[Medline]
- Huxley R, Neil A, Collins R. Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure?. Lancet 2002;360:659-665.[CrossRef][Medline]
- Gluckman PD, Hanson MA. The developmental origins of disease paradigm—a mechanistic and evolutionary perspective. Pediatr Res 2004;56(3):311-317.[Medline]
- Martin H, Gazelius B, Norman M. Impaired acetylcholine-induced vascular relaxation in low birth weight infants: implications for adult hypertension?. Pediatr Res 2000;47(4 Pt 1):457-462.[Medline]
- Leeson CP, Whincup PH, Cook DG, Donald AE, Papacosta O, Lucas A, Deanfield JE. Flow-mediated dilation in 9- to 11-year-old children: the influence of intrauterine and childhood factors. Circulation 1997;96(7):2233-2238.[Abstract/Free Full Text]
- Goodfellow J, Bellamy MF, Gorman ST, Brownlee M, Ramsey MW, Lewis MJ, Davies DP, Henderson AH. Endothelial function is impaired in fit young adults of low birth weight. Cardiovasc Res 1998;40(3):600-606.[Abstract/Free Full Text]
- Ozaki T, Nishina H, Hanson MA, Poston L. Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. J Physiol 2001;530(Pt 1):141-152.[Abstract/Free Full Text]
- Brawley L, Itoh S, Torrens C, Barker A, Bertram C, Poston L, Hanson M. Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring. Pediatr Res 2003;54(1):83-90.[CrossRef][Medline]
- Nishina H, Green LR, McGarrigle HHG, Noakes DE, Poston L, Hanson M. Effect of nutritional restriction in early pregnancy on isolated femoral artery function n mid-gestation fetal sheep. J Physiol 2003;553(Pt 2):637-647.[Abstract/Free Full Text]
- Davis L, Roullet JB, Thornburg KL, Shokry M, Hohimer AR, Giraud GD. Augmentation of coronary conductance in adult sheep made anaemic during fetal life. J Physiol 2003;547(Pt 1):53-59.[Abstract/Free Full Text]
- Martyn CN, Gale CR, Jespersen S, Sherriff SB. Impaired fetal growth and atherosclerosis of carotid and peripheral arteries. Lancet 1998;352(9123):173-178.[CrossRef][Medline]
- Palinski W, Napoli C. Pathophysiological events during pregnancy influence the development of atherosclerosis in humans. Trends Cardiovasc Med 1999(7):205-214.
- Gale CR, Ashurst HE, Hall NF, MacCallum PK, Martyn CN. Size at birth and carotid atherosclerosis in later life. Atherosclerosis 2002;163(1):141-147.[CrossRef][Medline]
- Etzion S, Kedes LH, Kloner RA, Leor J. Myocardial regeneration: present and future trends. Am J Cardiovasc Drugs 2001;1(4):233-244.[CrossRef][Medline]
- Thornburg KL, Giraud GD, Sundgren N, Jonker S, Davis L. Fetal roots of cardiac diseases. Pediatr Res 2003;53(Suppl. 6):3A.[CrossRef]
- Sundgren NC, Giraud GD, Schultz JM, Lasarev MR, Stork PJ, Thornburg KL. Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytes. Am J Physiol Regul Integr Comp Physiol 2003;285(6):R1481-R1489.[Abstract/Free Full Text]
- Koupilova I, Leon DA, McKeigue PM, Lithell HO. Is the effect of low birth weight on cardiovascular mortality mediated through high blood pressure?. J Hypertens 1999;17(1):19-25.[Medline]
- Roques F, Nashef SA, Michel P, Gauducheau E, de Vincentiis C, Baudet E, Cortina J, David M, Faichney A, Gabrielle F, Gams E, Harjula A, Jones MT, Pintor PP, Salamon R, Thulin L. Risk factors and outcome in European cardiac surgery: analysis of the EuroSCORE multinational database of 19030 patients. Eur J Cardiothorac Surg 1999;15(6):816-822.[Abstract/Free Full Text]
- Calafiore AM, Di Mauro M, Di Giammarco G, Contini M, Vitolla G, Iaco AL, Canosa C, D'Alessandro S. Effect of diabetes on early and late survival after isolated first coronary bypass surgery in multivessel disease. J Thorac Cardiovasc Surg 2003;125:144-154.[Abstract/Free Full Text]
- Wouters SC, Noyez L, Verheugt FW, Brouwer RM. Preoperative prediction of early mortality and morbidity in coronary bypass surgery. Cardiovasc Surg 2002;10(5):500-505.[CrossRef][Medline]
- Tatoulis J, Buxton BF, Fuller JA. Patencies of 2127 arterial to coronary conduits over 15 years. Ann Thorac Surg 2004;77(1):93-101.[Abstract/Free Full Text]
- Chardigny C, Jebara VA, Acar C, Descombes JJ, Verbeuren TJ, Carpentier A, Fabiani JN. Vasoreactivity of the radial artery. Comparison with the internal mammary and gastroepiploic arteries with implications for coronary artery surgery. Circulation 1993;88(5 Pt 2):II115-II127.
- Sarabu MR, McClung JA, Fass A, Reed GE. Early postoperative spasm in left internal mammary artery bypass grafts. Ann Thorac Surg 1987;44(2):199-200.[Abstract]
- Khan OA, Torrens C, Ohri SK, Noakes DE, Poston L, Hanson MA, Green LR. Effect of moderate early gestation undernutrition with or without undernutrition in early postnatal life on internal mammary artery function in sheep. Br J Obstet and Gynaecol 2005; in press..
- Stevens LM, Carrier M, Perrault L, Hebert Y, Cartier R, Bouchard D, Fortier A, El-Hamamsy I, Pellerin M. Single versus bilateral internal thoracic artery grafts with concomitant saphenous vein grafts for multivessel coronary artery bypass grafting: effects on mortality and event-free survival. J Thorac Cardiovasc Surg 2004;127(5):1408-1415.[Abstract/Free Full Text]
- Angelini GD, Lloyd C, Bush R, Johnson J, Newby AC. An external, oversized, porous polyester stent reduces vein graft neointima formation, cholesterol concentration, and vascular cell adhesion molecule 1 expression in cholesterol-fed pigs. J Thorac Cardiovasc Surg 2002;124(5):950-956.[Abstract/Free Full Text]
- Voors AA, Oosterga M, Buikema H, May JF, Grandjean JG, van Buiten A, van Gilst WH. Dyslipidemia and endothelium-dependent relaxation in internal mammary arteries used for coronary bypass surgery. Cardiovasc Res 1997;34(3):568-574.[Abstract/Free Full Text]
- Piperi C, Kalofoutis C, Papaevaggeliou D, Papapanagiotou A, Lekakis J, Kalofoutis A. The significance of serum HDL phospholipid levels in angiographically defined coronary artery disease. Clin Biochem 2004;37(5):377-381.[CrossRef][Medline]
- Nollert G, Miksch J, Kreuzer E, Reichart B. Risk factors for atherosclerosis and the degeneration of pericardial valves after aortic valve replacement. J Thorac Cardiovasc Surg 2003;126(4):965-968.[Abstract/Free Full Text]
Top
Abstract
1. Introduction
