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Environmental Cardiology
Pollution and Heart Disease
By Aruni Bhatnagar The Royal Society of Chemistry
Copyright © 2011 Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-005-1
CHAPTER 1
Environmental Basis of Cardiovascular Disease
1.1 Introduction
The term cardiovascular disease (CVD) refers to a group of illnesses caused by the disorders of the heart, blood vessels and blood flow. The most common cause of cardiovascular diseases is atherosclerosis, which is the hardening of arteries due to the formation of an atheromatous plaque. Abrupt changes in blood flow in atherosclerotic vessels result in acute myocardial infarction and stroke, which are the major clinical manifestations of chronic changes in the vessel wall. In the heart, ischemic injury due to atherosclerotic disease often leads to arrhythmia, hypertrophy, cardiomyopathy and heart failure. Heart disease is accompanied by chronic metabolic and physiological changes that precede and contribute to its clinical manifestations. These include metabolic changes such as high cholesterol (hypercholesterolemia) and insulin resistance and physiological changes such as an increase in blood pressure (hypertension) and changes in cardiac contractility. Although the causes of diabetes are not well understood, diabetes primarily affects the heart and blood vessels and is, therefore, considered to be a major CVD risk factor. Therefore diabetes and obesity are included in this discussion of heart disease.
Significant CVD is also associated with rheumatic disease, which is due to myocardial damage caused by streptococcal bacteria and congenital malformation of the structures of the heart or blood vessels. Several other types of congenital CVD are also common. These defects could be overt, resulting from gross malformation of major blood vessels or myocardial tissue in the fetus, or they may be more subtle, leading to an increase in susceptibility to stress or exercise. Congenital defects or prolonged hypertension and infectious diseases could also result in the dilation and rupture of the aorta leading to aortic aneurysm and dissection. Additionally, cardiovascular disorder associated with deep vein thrombosis and pulmonary embolism could result from blood clots in the leg veins that can dislodge and move to the heart and the lungs.
As a group, CVD is the leading cause of death world-wide (Figure 1.1). According to the WHO in 2004, CVD accounted for nearly 30% of all deaths worldwide. It killed twice as many people as infectious and parasitic disease and 3 times as many people as all forms of cancer. Globally, most (43–45%) cardiovascular deaths are due to coronary heart disease (CHD) or ischemic heart disease (IHD), whereas stroke accounts for 33% of CVD. A similar distribution of CVD deaths has been reported for countries such as the US (Figure 1.2).
These statistics suggest that heart disease is the major cause of mortality world-wide. Although the prevalence of heart disease varies considerably (vide infra) it still remains a major cause of death in all human populations regardless of their geographic location or ethnicity. It shows no preference for gender or economic status. Both men and women appear to be equally susceptible. World-wide, more women (31.5%) than men (26.8%) die of heart disease. Even in low-income countries (per capita ≤$825) IHD is the number two leading cause of death (9.4%), second only to deaths caused by lower respiratory infections (11.2%), whereas in middle and high income countries ($10, 066 or more) IHD and cerebrovascular disease account for 25 to 28% of all deaths (WHO, 2005). What is more alarming is that the prevalence of heart disease in increasing. The WHO estimates that 80% of all current CVD deaths are in developing, low- and middle-income countries and it is estimated that by 2010, CVD will be the leading cause of death in developing, low-income countries as well. In developed countries, the emergent epidemics of diabetes and obesity are threatening to erode the pattern of recent gains in health. In the US, the increase in obesity alone has been forecasted to slow down the increase in life expectancy that has been steadily increasing since the early 20th century. Thus, CVD is the most frequent cause of death throughout the world, independent of economic status, gender, or ethnic differences.
The universally high burden of CVD and the extraordinarily high rates of CVD mortality across all communities, suggests that humans as a species are particularly prone to heart disease. It may be argued that CVD is an inevitable consequence of aging, that blood pressure and cholesterol levels inexorably increase with age and that if an individual survives middle age without succumbing to infectious disease, sporadic cancers, accidents or violence, their most likely fate is cardiovascular death. This view is consistent with data showing that the risk of dying from CVD increases with age. In the US, the percentage of population with CVD increases from 14.9 and 8.7% for men and women of 20–39 years of age to 78.8 and 84.7% for men and women more than 80 years of age. It has been suggested that because heart disease develops more often in old individuals, it is not subject to direct selective pressure, i.e. that natural selection during evolution is unable to weed out these diseases as they do not affect reproductive success. Natural selection, it is believed, tends to maintain the frequency of genes that increase reproductive success even if the genes have other effects that increase disease susceptibility in older age. However, as we shall see, these arguments do not take into account the important role of the environment, which affects not only the long-range evolutionary susceptibility to disease, but also the proximate causes that lead to the disease development in a specific individual. Moreover, changes in the environment can modify (slow down or accelerate) age-dependent changes in the heart and blood vessels. In addition, a changing environment could continuously alter the context within which the effects of a gene manifest. Thus, a gene could be beneficial in one environment but not the other. As a result, changes in the environment could impart maladaptive predilection to a previously well-adapted genetic variance; thereby significantly and robustly modifying disease susceptibility.
1.1.1 My Family and Other Animals
The high prevalence of CVD in human populations suggests shared genetic susceptibility. In comparison with other species, humans are genetically very similar. The low genetic diversity in humans has been linked to a rather small population of ancestors from which modern humans have descended. By some accounts, all modern humans are descendents of a small ancestral family of only 10, 000 individuals. As a result, humans are very similar to each other. Moreover, their gene pool has remained shallow because humans spread very quickly over vast expanses of land without acquiring sufficient genetic diversity. Because of their high cognitive abilities and greater capacity to adapt to different environments they migrated to different parts of the planet and segregated into small inbreeding populations, which did not have the time to diverge before significant interbreeding began again. It is therefore not surprising that all humans have similar disease susceptibility and that they succumb to very similar afflictions. But if we take a less parochial view and look outside the human family we might ask – what about other species? Are other animals susceptible to heart disease as well?
In the wild, captivity or domestication, mammals such as dogs, rabbits, rats and mice rarely develop spontaneous atherosclerosis of the type seen in humans. Even when cholesterol metabolism in mice is severely compromised by genetic engineering, they rarely suffer from myocardial infarctions or stroke. This difference may be due to the large evolutionary distance that separates humans from most other mammals and perhaps it is more instructive to look at the great apes, particularly gorillas and chimpanzees. Humans, gorillas, and chimpanzees have descended from a common ancestor that lived 7.3 million years ago. The chimpanzees are our closet living cousins from whom we diverged 5.4 million years ago. Nevertheless, the amino acid sequences of humans and chimpanzees show 99% homology. Hence, it may be expected that, because of their high genetic similarity, humans and chimpanzees would have similar disease susceptibility and might die of similar causes.
Fortunately, several investigators have studied chimpanzee and gorilla mortality both in the wild and in captivity. As expected, the life expectancy of a chimpanzee in the wild is shorter than in captivity. In the wild most chimpanzees live to be around 15 years of age, although occasionally 40- to 50-year-old chimpanzees have been sighted. In the wild they succumb mostly to infectious diseases, most chimpanzees die of respiratory infections while gorillas fall prey to various types of entrocolitis due to viral or fungal infections. In captivity, however, it has been found that cardiac disease is the primary cause of mortality in both gorillas and chimpanzees. Cardiac disease has been reported to be responsible for 41% of deaths of captive adult lowland gorillas and 67.8% of captive chimpanzees. However, the type of heart disease described in chimpanzees and gorillas is not the type commonly seen in humans. In one study most of the heart disease in chimpanzees was reported to be due to an unusual form of cardiomyopathy that was associated with congestive heart failure and the presence of multifocal to coalescing areas of fibrosis, necrosis, mineralization and inflammation and ventricular arrhythmias. Similar findings have been reported by others. This type of diffuse cardiac fibrosis leading to congestive heart failure has also been observed in western lowland gorillas. Such pathology is rarely seen in humans and it certainly does not contribute to garden-variety heart disease that kills most humans. In humans, a majority of heart disease is due to atherosclerosis that results in coronary artery disease and stroke. Together, these diseases account for 76% of all cardiovascular deaths world-wide. In contrast, only 2.3% of the captive chimpanzees have been reported to have atherosclerotic disease and although hypertension and hyperlipidemia have been diagnosed in both captive chimpanzees and gorillas, these conditions were found not to be associated with coronary heart disease or with atherosclerosis.
There may be several reasons why chimpanzees are genetically less susceptible to atherosclerotic disease. One of these may relate to the 1% difference in the human and chimpanzee genome. While this does not seem like much, it accounts for the starkly different cognitive, cultural and behavioral differences between humans and chimpanzees. However, this appears not be the case because most the genetic differences between human and chimpanzees are in cortical genes. By contrast, the genes in chimpanzee hearts and livers are nearly identical to humans. Thus, it seems unlikely that humans have recently acquired genes that have increased their susceptibility to metabolic diseases. An alternative explanation is that perhaps during evolution, humans have lost some of the genes that protect chimpanzees from atherosclerotic disease. Indeed, current theories of human evolution suggest that humans have evolved from chimpanzees by loss-of-function mutations (the "less-is-more" hypothesis). It is believed that in many respects, humans are "degenerate apes" who have lost, among other characteristics, much of their muscle strength, hair etc., or their ability to synthesize certain metabolites such as sialic acid. By shedding this excessive baggage, humans have been able to evolve at a more nimble and rapid pace than chimpanzees. Hence, it is conceivable that by losing some genes and acquiring a more retrograde phenotype, humans have become more susceptible to atherosclerotic disease. It is well known that several human diseases such as cystic fibrosis, phenylketouria, and familial breast cancer are due to loss-of-function mutations. Nevertheless, a comparison of human and chimpanzee genomes shows that humans have not lost any of the genes that regulate cardiovascular and hepatic function. On the contrary, several common genetic polymorphisms that are clearly linked to coronary disease and diabetes in humans (e.g., PPARG A12P, PON1 Q192R, and ABCA1 I883M) are ancestral alleles carried not only by chimpanzees but also by out-groups such as macaque. A most likely explanation is that humans and chimpanzees carry the same gene variant and that these ancestral alleles have become human-specific risk factors, not because of a loss of function, but because of a change in the environment. These alleles are natural and widely distributed in living apes. They have evolved and they have assumed the form that they do so that the apes could adapt to their environment. It is likely that they were equally beneficial to humans in their early, ape-like environment, but because the environment in which human live now has changed these genetic variations are no longer beneficial. Instead, they increase disease risk. Thus, a change in the environment has dramatically changed the survival advantage and the disease-risk associated with specific allelic variations.
1.1.2 Peacocks in Siberia
Why have the genes that were protective in the ancient environment become maladapted in the current environment? There are several answers to this question. One explanation is that an ancestral gene, which was adaptive in an ancient environment, is no longer beneficial in the modern environment because the environment has changed drastically. In other words, it has become maladaptive in the modern environment. Ancient and modern humans live in very different environments and the gene variants that were important for survival, growth and health under those conditions may not be protective in the modern environment (A to B; Figure 1.3). This model is consistent with the "thrifty-gene" hypothesis, which states that genes that favor energy conservation in the wild, food-scarce environment, impart genetic risk for obesity and diabetes in the modern, food-rich environment. Maladaptation between an ancestral allele and modern environment arises because natural selection cannot keep pace with rapid changes in the environment. This is particularly true for human environments, which could change completely within a few generations. However, if after the change, the environment reaches a steady state and if the gene has a survival advantage, the ancestral allele changes to a derived allele under positive selection. The derived allele, once again, confers protection and survival advantage, but only as long as the environment does not change. If the environment changes again, the derived allele may or not may not be beneficial. Because many aspects of human environment are continuously changing, there may be a constant mismatch between environment and gene adaptation. This mismatch could provide a selective pressure for genetic adaptation, but could also account for the temporary persistence of several disease-susceptibility genes in the current environment (the mismatch hypothesis).
Another explanation is that the genes that affect CVD susceptibility are retained just by chance (Neutrality hypothesis). Because heart disease develops after the reproductive years, it is believed that there are no selective pressures either for or against the genes that regulate CVD susceptibility. When mismatched with the environment these gene variants are not eliminated by a strong purifying selection because they do not impair reproductive fitness. As a result, harmful ancestral genes are retained and tolerated because there is no evolutionary pressure to change them. In addition, new gene variants could arise by genetic drift and these new variants are either beneficial or harmful, but regardless of their effects, these rare variants accumulate because they do not impair reproductive fitness and are therefore not eliminated by strong purifying selection (the rare-variant-common disease hypothesis).
A third explanation is that gene variants that drive human evolution by promoting early life survival impair human health in old age. It is believed that one reason that these variants appear and are retained is because they increase reproductive success. Therefore, there is strong positive selection that enriches a derived allele in a population. The derived allele confers a well-adaptive phenotype and promotes reproductive success; however, this victory comes at a high cost because the very gene variants that were advantageous in youth increase disease susceptibility in old age. Thus, early life acclimatization is optimized at the cost of late-life adaptation so that the derived allele is adaptive in youth but not in old age (since this is victory gained at too great a cost, we can call this the pyrrhic hypothesis). However, regardless of mechanisms, it is evident that the environment plays a leading role in driving the change and in providing context to the derived or retained alleles because it is only within the framework of the environment that a gene is either adapted or maladaptive.
(Continues...)
Excerpted from Environmental Cardiology by Aruni Bhatnagar. Copyright © 2011 Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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