International Journal of Cardiovascular ResearchISSN: 2324-8602

All submissions of the EM system will be redirected to Online Manuscript Submission System. Authors are requested to submit articles directly to Online Manuscript Submission System of respective journal.

Review Article, Int J Cardiovasc Res Vol: 2 Issue: 5

Developmental Origins of Cardiovascular Disease. A Missing Link in the Puzzle

Maqsood M Elahi1 and Bashir M Matata2*
1Division of Cardiothoracic Surgery, Department of Surgery, Texas A and M Health Science Centre at Scott and White Memorial Hospital, Texas, USA
2Department of Clinical Research, The Liverpool Heart and Chest Hospital NHS Foundation Trust, Thomas Drive, Liverpool, L14 3PE, United Kingdom
Corresponding author : Matata BM
Liverpool Heart and Chest Hospital NHS Foundation Trust, Thomas Drive, Liverpool, L14 3PE, UK
Tel: +44-151-600-1380
E-mail: [email protected]
Received: July 03, 2013 Accepted: August 29, 2013 Published: September 06, 2013
Citation: Elahi MM, Matata BM (2013) Developmental Origins of Cardiovascular Disease. A Missing Link in the Puzzle. Int J Cardiovasc Res 2:5. doi:10.4172/2324-8602.1000140

 

Abstract

Developmental Origins of Cardiovascular Disease. A Missing Link in the Puzzle

Cardiovascular disease (CVD) is the leading cause of death worldwide and cause of early death in developing countries. The acceleration of early CVD epidemic is believed to be a consequence of interaction between the distribution of relative genotype frequencies and environmental exposures. In accordance with the developmental origin of health and disease (DOHaD)hypothesis adverse intrauterine influences such as poor maternal nutrition lead to impaired fetal growth. These adverse influences are postulated to also induce the fetus to develop adaptive metabolic and physiological responses.

Keywords: Cardiovascular disease, genetic variations, developmental origin of health and disease, DNA variations

Introduction

It is now widely recognized that cardiovascular disease (CVD) is still the leading global cause of morbidity and mortality in the world [1,2]. It is estimated that developing countries contribute a greater share (a relative excess of 70%) to the global burden of CVD than the developed countries [3,4]. This high, yet inadequately recognized contribution to the absolute burden of CVD in developing countries is illustrated by the fact that 78% of the 49.9 million global deaths from all causes occurred in regions other than the established market economies [3].
A greater cause for concern is the early age of CVD deaths in the developing countries with rates estimated at 46.7% as compared with 26.5% for developed countries for people below the age of 70 years [3,4]. In addition, there is concern that the contribution of the developing countries to the global burden of CVD in terms of disability adjusted years of life lost is 2.8 times higher than that of the developed countries [2-4]. A potential cause for alarm is the projected rise in both proportional and absolute CVD mortality rates in the developing countries over the coming years [4]. Reasons for this acceleration of the CVD epidemic is thought to be related to genetic, economic, political, demographic and nutritional factors.

Mechanisms of Genetics

It is becoming increasingly apparent that genetic pre determinants of susceptibility to CVD is dependent on a number of factors i.e. the segregating susceptibility genes, the number of alleles of each gene, and the interaction between the relative genotype frequencies and environmental exposures [5,6]. In each population, the relative frequencies of genetic variations in evolutionary time, new DNA variations arise in isolation and different populations will have different combinations of DNA variations [7,8]. Therefore different combinations of susceptibility genes will be involved in determining CVD risk in different individuals, however, only few genetic studies of common multifactorial diseases recognize the importance of this question [9,10].
So far up to nine known risk factors for CVD have been studied by the INTERHEART study [11]. These include smoking, diabetes, hypertension, obesity, diet, inactivity, no alcohol intake, ApoB: ApoA1 ratio and psychosocial factors accounted for 90-94% of populationattributable risk. The model suggested [11] that populations with all these risk factors are 337 times more likely to suffer cardiac disease than populations with none. However, the complex interplay between environment and genetics demonstrated in INTERHEART made it clear that similar approaches are unlikely to identify the poorly penetrant and multiple causative genes that account for non- Mendelian diseases, such as CVD [12,13]. Though, in rare occasions CVD can also be inherited in a Mendelian fashion (predominantly in conditions leading to elevated LDL), this only accounts for a small proportion [14], most of which are likely to be polygenic.
Recent technological advancement, coupled with greater understanding of the structure of the human genome derived from genome sequencing projects [15,16], now make unbiased wholegenome association studies (GWAS) possible [17]. However, studies are suggesting that SNP-based GWAS knowledge provides no additional benefit [18], despite the availability of genotyping via the internet. Therefore, incorporation of risk-conferring alleles and others into a CAD prediction algorithm is still not clear and thus remains to be substantiated in terms of its true importance under the current models and on clinical parameters [19].

Influence of Demographics

The role of classical CVD risk factors is clearly important despite the patterns of these risk factors varying significantly by ethnic groups. For example, the CVD epidemiology of African Americans does not represent well the morbidity and mortality experience seen in black Africans and black Caribbean’s, both in Britain and in their native African countries. Data for population surveillance of CVD and metabolic disorders are limited in many countries. The World Health Organization (WHO) has set up a range of projects aimed at improving the amount and quality of relevant data [20]. The Surveillance of Risk Factors (SuRFs) project, launched in 2003, presents chronic disease risk factor profiles from 170 WHO member states. These data include patterns of physical inactivity, low fruit/ vegetable intake, obesity, blood pressure, cholesterol, and diabetes [21,22].
Although, the biological determinants of CVD and metabolic disorders in low and middle income countries are likely to be similar to those in affluent countries, [11] the drivers of these determinants are likely to differ. For example, rural–urban migration may be an important factor in promoting the adoption of Western dietary habits and activity patterns, leading to an increased CVD risks. Socioeconomic patterns of disease risk, so well established in affluent countries, are more complex in some low and middle income countries [11,22]. New opportunities to use large demographic surveillance projects as tools to study CVD and metabolic disorders are emerging rapidly as part on the work of INDEPTH (International Network of field sites with continuous Demographic Evaluation of Populations and their Health in developing countries) [23]. Even with such studies of understanding of determinants for rising CVD/ metabolic disorder epidemic, explaining such differences as to how rural-urban migration increases risks of obesity, diabetes and CVD would not be possible.

Lifestyle Changes

If population levels of CVD risk factors rise due to adverse lifestyle changes, industrialization and urbanization, the rates of CVD mortality and morbidity could rise even higher than the rates predicted solely by demographic changes. It is suggested that both the degree and the duration of exposure to CVD risk factors would increase due to higher risk factor levels coupled with a longer life expectancy [24]. An increase in body weight (adjusted for height), blood pressure, and cholesterol levels in Chinese population samples aged 35 to 64 years, between the two phases of the Sino-MONICA study (1984 to 1986 and 1988 to 1989) and the substantially higher levels of CVD risk factors in urban population groups compared with rural population groups in India provide evidence of such trends [24,25].
The increasing use of tobacco in a number of developing countries has also translated into higher mortality rates of CVD, CHD and other tobacco-related diseases. As reviewed by Drewnowski and Popkin [26] the global availability of cheap vegetable oils and fats has resulted in greatly increased fat consumption among many countries.

How Complex the CVD Issue is?

CVD has a complex multifactorial aetiology leading to a reassessment of the ways in which three key factors- genome, development and environment- influence the adult phenotype, including the individual’s susceptibility to disease. Neither genetic makeup nor exposures to adverse environments predict with certainty the onset, progression, or severity of CVD. CVD research has revealed tens of high-risk environmental factors and hundreds of genes, each with many variations that influence disease risk. The phenotypic measures of health are constantly being shaped, changed, and transposed as a consequence of epigenetic networks of cellular and organismal dimensions that change over the lifetime of the individual. At the level of the cell, these networks influence DNA methylation and repair [27].
Studies have suggested that different ethnic groups that live in the same geographic areas and share similar environmental risks have different profiles of disease markers and prevalence, which may propose a genetic cause for differences in disease susceptibility [28,29]. Yet, with some notable exceptions few ancestry-specific alleles have been discovered that can explain particular pathologies. For example, high incidences of metabolic disease are found in those ethnic groups in which the average birthweight is low or the rates of gestational diabetes and maternal obesity are high [30].
Untangling the effects of genes from those of environmentally determined developmental processes is not straightforward. Compelling evidence supports both the developmental origins of health and disease (DOHaD) and the underlying epigenetic mechanisms, [31,32] many features of the latter remain insufficiently understood. These elements include the differences among epigenetic mechanisms across species and between patterns of epigenetic modifications on paternal and maternal genomes, the mechanisms that regulate the establishment, stability and flexibility of epigenetic changes, and the precise connection between an epigenetic change, altered gene expression and the resultant phenotype for CVD epidemic in countries.
DOHaD hypothesizes that the adverse intrauterine conditions arising from poor maternal nutrition can lead to impaired fetal growth. These adverse influences may induce the fetus to develop adaptive metabolic and physiological responses and could lead to disorders induced by environmental challenges as the child grows, resulting in an increased risk of glucose intolerance, hypertension, and dyslipidaemia in later life and adult CVD as a consequence [33-36]. Given that, the supportive evidence is based mostly on [28,37-40] it awaits further evaluation for a causal role. If it does emerge as an important risk factor for CVD, the populations in developing countries would be at an especially enhanced risk because of the greater numbers of poorly nourished infants who have been born in the past several decades now suffer a threat through an overnourished rich environment.
Lucas suggested that that there are embryonic and fetal adaptive responses to a suboptimal intrauterine environment which could result in permanent adverse consequences either via the induction, deletion, or impaired development of a permanent somatic structure or the physiological system [41]. All this highlights a possible relationship between intrauterine nutritional experiences and subsequent health outcomes.
Animal models of human diseases often view the effects of early life events as the developmental plasticity. This embodies the idea that developmental plasticity is the ability of a single genotype to produce more than one alternative form of structure, physiological state, or behaviour in response to environmental conditions [42-44]. Consistent with this, it is thought that CVD may be a consequence of fetal adaptations to under nutrition that are beneficial for shortterm survival, even though they are detrimental to health in post reproductive life [43]. Such maternal effects can result in the effects of a specific environmental factor persisting across several generations [42-45]. If the effects of the past conditions produce mismatches with current, changed conditions, however, then developmental plasticity may have a detrimental effect on survival and reproductive success [46]. Thus Bateson et al. [45] propose that for individuals whose early environment has predicted a high level of nutrition in adult life and who develop a large phenotype, the better the postnatal conditions the better will be their adult health. For individuals whose conditions in fetal life predicted poor adult nutrition and who develop a small phenotype, the expected outcomes may vary, although they are predicted to be worse off when there is a relative excess of nutrition in postnatal life.
In case of fetal origins of disease, this would require that environmental conditions present early in life are predictive of the conditions the individual will encounter in the future over a range of timescales (Figure 1). It is suggested that at one extreme, rapid and reversible homoeostatic mechanisms counter an immediate challenge. Then, stressors or exposures during critical developmental periods can affect growth, tissue differentiation, and physiological set-points, affecting responses to environmental challenges for life. New evidence suggests that epigenetic mechanisms could contribute to such challenges [42].
Figure 1: Modes of human adaptability.
The genomes of populations can change over many generations as a result of selection or drift, and there are many examples of responses to environmental change becoming integrated into the human genome [47,48]. Clinical medicine and public health research have focused largely on causation and intervention at the short-term end of this spectrum. In this context consideration of the outcomes of developmental plasticity acting over the intermediate timescale is now important. In humans, development plasticity can induce responses that have short-term benefits for the mother or the fetus but on longer term costs reduced fitness leading to disease process [49]. It is suggested that when environmental conditions change strikingly between conception and adulthood, as has happened in most current human populations, the potential for a substantial mismatch is especially great, and this difference contributes to increased disease risk.

Human Development and Environmental Impact

The above mentioned complex developmental adaptations play a critical role to permanently change structure, physiology, and metabolism and hence predispose to cardiovascular, metabolic, and endocrine disease in adult life [49,50]. For example, the human baby responds to under nutrition, placental dysfunction and other adverse influences by changing the trajectory of his or her development and slowing growth. Although the fetus was thought to be wellbuffered against fluctuations in its mother’s condition, a growing body of evidence suggests that the morphology and physiology of the human baby is affected by the state of the mother [51]. Therefore it is plausible that human development may get cues capable of inducing particular patterns of development. These patterns therefore, prepare the developing individual for the type of environment in which one is likely to survive. Individuals may be affected adversely if the environmental prediction provided by the mother and the conditions of early infancy prove to be incorrect [42,45-51]. Thus, people whose birth weights were towards the lower end of the normal range and who subsequently grows up in affluent environments are at increased risk of developing coronary heart disease, type-2 diabetes and hypertension [42,45-51]. A functional and evolutionary approach suggests that the pregnant women in poor nutritional condition may signal to her unborn baby that help it to cope with a shortage of food. When sufficiently high levels of nutrition are available after the development of a small phenotype has been initiated, marginal benefits of rapid growth may offset the costs [52], but they may also trigger the health problems arising in later life. This concept is illustrated in Figure 2. Although adaptive responses may explain some variation in human development, it would be implausible to argue that all responses to the environment should be explained in these terms. Under nutrition, stress or hypoxia may impair normal development. Babies with low birth weight have a reduced functional capacity and fewer cells. In our opinion, the latter may be part of a general reduction in cell numbers or a selective trade-off in the development of tissues that are less important to the baby, such as the kidney. Reduced numbers of nephrons at birth is a life-long deficit, as all nephrons are formed during a sensitive period of development in late gestation. The resulting increased functional demand on each individual nephron, for example by increased blood flow through each nephron, may lead to acceleration of the nephron’s death that accompanies normal ageing, with a consequent rise in blood pressure [53,54]. Similarly, it is postulated that the sharp increase in glucose intolerance leading to type-2 diabetes may have arisen from genetic differences between populations [55]. The possibility of a thrifty genotype well adapted to harsh conditions is not incompatible with the plastic induction of thrifty phenotypes from a pool of uniform genotypes. However, the hypothesis that differences in susceptibility to diabetes are explained by genetic differences would not readily account for the evidence from the Dutch famine of 1944-1945 that glucose intolerance is induced by maternal malnutrition during the final three months of pregnancy [56].
Figure 2: The hypothetical relationship between adult health and nutritional level during later development for two extreme human phenotypes that were initiated by cues received by the fetus [45].

Summary

Numerous epidemiological and animal studies discussed so far have shown an association between altered maternal nutrition and cardiovascular or metabolic disease in the offspring [57]. Namely, alterations in fetal nutrition (either under- or over-nutrition) may result during critical periods when offspring are most vulnerable to developmental adaptations that permanently change the structure, physiology and metabolism of the offspring, thereby predisposing individuals to metabolic and cardiovascular diseases in adult life.
Today the most common maternal dietary imbalance in populations is an excessive intake of dietary fat. There is growing body of evidence that significant health problems for women of reproductive age result from being overweight or obese due to overeating. Extensive studies have shown that maternal over nutrition retards placental and fetal growth, and increases fetal and neonatal mortality in animal models [58]. Results of epidemiological studies indicate that almost 65% of the adult population in the US is overweight [defined as a body mass index (BMI)>25 kg/m2], while 31% of the adult population is obese (defined as BMI>30 kg/m2). Many overweight and obese women unknowingly enter pregnancy and continue overeating during gestation. These women usually gain more weight during the first pregnancy and accumulate more fat during subsequent pregnancies [59]. Maternal obesity or overnutrition before or during pregnancy may result in fetal growth restriction and increased risk of neonatal metabolic syndrome and cardiovascular risk factors.
Previously, studies have demonstrated abnormalities in plasma lipids, vascular fatty acids, and evidence for reduced endotheliumdependent relaxation in adult offspring of rodent models fed on a lardrich diet during pregnancy, suckling or lactation. However, neither the designs of these studies carried out nor the fat intake mimic the typical high-fat Western diet and human situation. Moreover, to date no one has determined the role of early pharmacological intervention in mothers and its effects on offspring in terms of cardiovascular control using the animal model.

Conflict of Interest

The authors declare that no conflict of interest exists.

References




























































Track Your Manuscript

Scheduled supplementary issues

View More »

Media Partners