South Asians are at higher risk of developing cardiovascular disease than other races: or so is the belief. By examining the role of genetic mal-adaptations, in context of altered environmental interactions, one can be begin to gauge the importance of glycemic abnormalities and insulin resistance, whether be it in metabolic syndrome or T2DM, in the lipid metabolism deregulations that result in subsequent atherogenic development. Moreover, conventional cardiovascular disease risk factors, which are believed by some, to be more prevalent in south Asians than other races, are found to be not significantly more important in the Indian sub-continent; however, it is the combination of worse control by Asians as well as the lowered thresholds above which such factors cause Asians equivalent damage, that results in this somewhat unfounded image. Nevertheless, it is the amalgamation of such risk factors as well as the genetic susceptibility to increased central obesity in Asians that have led to theories regarding inflammation coming to light: the dogma being that the higher stress that Asians' bodies are subjected to triggers off an inflammatory response from which stem both insulin resistance and atherosclerotic plaque formation.
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It has long been thought that south Asians, or people from the Indian sub-continent have an increased risk of developing cardiovascular disease, by comparison to people from other ethnicities. This essay aims to examine the main cardiovascular risk factors in context of their increased prevalence or severity in this race, giving possible theories as to why this is true. Unfortunately, despite the extensive research conducted in this area, we are in many ways limited to possible theories rather than concrete evidence as to why people from this race seem to suffer from cardiovascular disease more prematurely and the exact mechanisms by which this happens.
With type 2 diabetes (T2DM) being of pandemic status (Gholap N et. al, 2010), not only amongst indigenous South Asians but also amongst diasporas inhabiting other countries in the world, where cardiovascular disease (CVD) is less prevalent, the theory that cardiovascular complications follow on from insulin resistance and diabetic hyperglycemia strikes as one of the most significant events that contribute to the development of CVD. However, this is not the only risk factor but is obviously of paramount importance due to the huge problem that T2DM presents in the Indian sub continent. Other risk factors that predispose an individual to having cardiovascular disease include, abnormal levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, as well elevated levels of triglycerides (TGL). Dyslipidemia, as this imbalance in lipoprotein levels is otherwise known, in addition to a collection of other symptoms, such as a high waist: hip ratio, hyperinsulinemia, dysglycemia and hypertension are known as metabolic syndrome. The risk of developing T2DM from metabolic syndrome appears to be much higher in south Asians than in other races (Srinivasan B, et. al, 2007), leading to more cardiovascular morbidity for individuals within this race. The benefits of reducing insulin resistance to control glucose and lipid levels as well as maintaining a healthy living regime are therefore very evident.
Moreover, conventional risk factors such as genetics, smoking and lifestyle also play a key role. Whereas these are the conventional risk factors associated with any person developing cardiovascular disease and not a south Asian specifically, various studies such as that by Forouhi N et. al, in addition to the infamous INTERHEART study aim to draw inferences to the excess risk of south Asians in developing cardiovascular disease. The former, whilst showing a higher level of mortality between Asians points to lack of data from which to attribute this to metabolic syndrome or insulin resistance.
Relatively more recent theories (Pickup J, 2006), point to a possible underlying link between T2DM and the development of atheromas, suggesting that inflammation may trigger events that cause both insulin resistance and the development of CVD i.e. both pathologies may stem from the same cause, with the former also independently leading to exacerbation of cardiovascular co-morbidity.
It is therefore evident that a variety of links may be drawn between risk factors, in the quest to unravel the reasons behind this increased risk of CVD in south Asians.
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Ample studies illustrate just how serious an issue cardiovascular disease is within the South Asian population. Not only is the coronary heart disease (CHD) mortality rate highest amongst Asians, but is also notably premature, leading to a substantial number of young deaths from CHD (Mather H et. al, 1998). Particularly troubled are individuals from Pakistan and Bangladesh, with the former showing a fivefold increase in CVD rates in a relatively brief period of five years, and the latter showing the highest exposure to CVD risk factors than any other race (Harding S et. al, 2008). It is worthy of note that between the years of 1999 and 2004 there was a large rise in the number of Bangladeshi emigrants to the UK, highlighting that perhaps such exposure is more significant in the country of origin rather than in the UK. It is virtually impossible to have witnessed such a dramatic rise in risk factor exposure in such a narrow time frame.
The most significant in this case would have to be socio-economic status, which in many ways will have dictated the lifestyles such people would have sported in their countries of origin: the more affluent, will have probably been much less active in their native counties and will have resorted to a higher fat diet than the average person, which when combined with the various genetic predispositions Asians already have in place, and which will be examined later on in depth, will have been lethal in the development of CVD.
To demonstrate the extent of the issue further, various studies show that South Asians have a 50% increased risk of dying from CHD than other races (Golap N et. al, 2010). One particular study, obtained information from the 2001 census about patients, noting their age, sex and country of birth. Mortality rates and the underlying causes of death were underpinned, and standardised mortality ratios were used in order to adjust the distribution differences in age within the different populations included, reproducing somewhat reliable figures for England and Wales. Again the study shows increased mortality particularly within individuals born to the Bangladeshis, Indians and Pakistanis, the cause of death being most frequently ischaemic heart disease (Wild S et. al, 2007). It is interesting to note, that rates are even higher within Scottish and Irish born individuals, raising questions over the methodology of the study. Perhaps country of birth may not have been the best way to reflect a person's ethnicity; it may be that perhaps there were more second generation Asians living in Scotland or Ireland, at the time of the study and so giving an inaccurate picture of mortality rates accredited to these European countries. A possible improvement would be to group subjects in terms of ethnicity, which may be accounted for by observing the country of birth of individuals' parents, ensuring consistency between the subject's genetics and their proposed country of origin. rates highest amongst scottish n Irish/ perhaps ethnicity accounted for by country of birth of individuals rents would have ensured genetics consistent with proposed origin.
INSULIN RESISTANCE AND TYPE 2 DIABETES
In terms of causation, it is clear that T2DM is one of the major risk factors that leads to premature CVD events in South Asians; the mechanisms by which it speeds up CVD end points are less so clear, but there are a number of theories. An observational study looking at all cause mortality six months post suffering a myocardial infarction in 149 Asian patients and 313 white patients, shows that the former group displays higher mortality rates, with an almost 38% excess of people suffering from diabetes than in other race (Wilkinson P et. al, 1996). Ideally sample sizes should be similar, as a significantly fewer number of subjects could be indicative of a partial view of the Asian population but since the figures are adjusted for certain parameters, the paper is deemed overall a reliable source. Similarly, Joshi P et. al demonstrate that T2DM appears to be one of three major risk factors for south Asians developing CVD, with others being a high waist to hip ratio and dyslipidemia (Joshi P et al, 2007), which can also be directly linked to T2DM and insulin resistance.
So why then is this type of diabetes more prevalent in South Asians than other races? There are a number of theories why people from the Indian sub continent are more prone than other races. The most commonly advocated is the thrifty genotype idea, whereby it is believed that over the years Asians have developed genetic mutations as way of adaptation to enable their bodies to tolerate periods of starvation. The nomadic lifestyle sported by the Pima Indians hundreds of years back, was dictated by cycles of hunting and farming with long periods of famine in between. This adaptation is believed to have maximised the energy conserving capabilities of Asians, favouring their survival during times of hardship (Neel J, 1962). This would make good for an Indian farmer's ability to survive; however, for the average individual nowadays, that most probably overeats and does little in the way of exercise, the results are disastrous and culminate in central obesity.
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This theory is not the only one, however; the thrifty phenotype also offers a similar explanation: intrauterine under nourishment coupled with overfeeding and lack of physical activity later on in life, which defy the body's earlier programming to store excess amounts of fat, again lead to excess fat deposition centrally (Hales C and Barker D, 1992). This is especially true for the less affluent emigrants, who live in developed countries, who probably resort to cheaper, less healthy food and would have less knowledge at maintaining a healthy lifestyle. By contrast richer, more educated people adopting an urban lifestyle in India or other Asian countries probably demonstrate classic overeating and minimal physical activity due to the high availability of resources and capital property. It is difficult to gauge the exact effect of socio-economic status on this, nevertheless, due to a lack of cross data that shows both the effects of class and country of origin on CVD death rates (Wild S, 2007) and judging by other less recent papers which seem to show no correlation between such factors (Marmot M et. al, 1984).
Personally, the thrifty phenotype theory is flawed in the sense that other races e.g. Middle Easterners, who share similar circumstances, despite displaying high CVD mortality rates, do not seem to match their south Asian counterparts in such instances. The only explanation would be, is that the south Asians have developed those thrifty genes over hundreds of generations and that other races are currently in the process of evolving similar traits which will manifest in the future.
Following on from this theory, it is also of vital importance to note that the position of fat storage differs in south Asians than in Europeans. Sniderman A et. al, hypothesise that south Asians have a smaller capacity to store fat in the primary storage compartment (subcutaneously in the lower limb) than other people. This may be due to either insufficient numbers of adipocytes in this compartment or their inability to take up fat efficiently (Sniderman A et. al, 2007). The result is central obesity, with fat being deposited in more metabolically active compartments either subcutaneously in the upper body, or as visceral fat. Not only does this have serious consequences on insulin resistance, but also means that for a comparable body weight, Indians have a greater risk of atherogenesis development, and are so classified differently on the BMI scale, with values above 23.5 kg/m2 providing a cut off point for being overweight.
Expansion of adipocytes in metabolically active regions is believed to attract macrophages and T cell lymphocytes, encouraging cytokine release and inflammatory processes. Aside from the inflammatory theory, which will be examined shortly, this leads to lack of insulin sensitivity locally in the adipose tissue itself. The subsequent release of adipose tissue fatty acids leads to more cytokines, such as TNF α being released (Toyoda T et. al, 2008) altering insulin sensitivity systemically, by interfering directly with downstream insulin receptor pathways (Hotamisligil G et. al, 1994). The insulin resistance means high levels of circulating insulin, but little in the way of glycemic control as well as deregulation of fat metabolism. Expulsion of more free fatty acids from adipose tissue is typical, not only setting up a vicious feed forward loop involving insulin resistance and free fatty acid release, but also providing a perfect breeding ground for increased synthesis of VLDL by the liver (Gutierrez D et. al, 2009). Free fatty acids released from visceral fat compartments are directly taken up by the liver via the hepatic portal vein (Sam S et. al, 2008), and act as a substrate in the synthesis of triglyceride rich VLDL. Increased production of VLDL leads to an increase in the number of denser particles of LDL. The enzyme lipoprotein lipase catalyses the removal of triglycerides from VLDL (Diwan J, 2008), and with the action of cholesterol ester transfer protein (CETP) enzyme, LDL particles gain a substantial amount of cholesterol esters which can be readily deposited in arterial endothelial cells, thereafter triggering the process of atherosclerosis. Interestingly, the process of macrophage infiltration into truncal fat compartments is not only linked with a decrease in HDL cholesterol levels (Huber J et. al, 2008) but also in the size of the HDL particles available, hindering the beneficial actions of HDL, in removing cholesterol during the reverse cholesterol mechanism (Sam S et. al, 2008). The reduction of HDL cholesterol manifests in reduced total cholesterol levels, suggesting that perhaps a ratio of total cholesterol to HDL cholesterol would be more beneficial in predicting CVD risk in south Asians.
In summary, south Asians are predisposed to being centrally obese, which increases insulin resistance and therefore increases their likelihood of developing T2DM, exacerbating the above disturbances. In many patients, T2DM is preceded by metabolic syndrome.
The imbalance in lipid levels, when combined with central obesity, hyperinsulinemia, and impaired glucose tolerance, culminates in metabolic syndrome. It is no surprise, considering the advocated theories which predispose Asians to excess fat storage, that syndrome X, as it is otherwise known, is more common in the Indian sub-continent, raising the risks of T2DM and CVD development. Whilst this is true on the whole, many will only ever have impaired glucose tolerance (IGT) and not go onto develop full on T2DM; however, IGT is more prevalent within south Asian populations than others and again contributes to higher levels of CVD mortality (Aarabi M and Jackson P, 2004).
To highlight the importance of hyperinsulinemia and central obesity, people from an Afro-Caribbean origin have been observed. Despite T2DM levels nearly emulating those of south Asians, deaths from CVD are significantly lower, in diabetic patients. By contrast to the latter, such peoples do not have pronounced hyperinsulinemia and central obesity leading to comparable mortality rates with white Europeans. This suggests that perhaps the aetiology of T2DM contrasts greatly, in this race, than from those described above (the coupling of thrifty genes, with environmental factors).
With diet and other ritual practises varying significantly within the very diverse Indian subcontinent, which houses people from hundreds of religious sects and cultural backgrounds, some of the only common factors with which to explain increased CVD mortality within this race is again central obesity and high levels of insulin resistance (McKeigue P et. al, 1991).
That is not to undermine the value of other factors in explaining the increased risk to CVD: diet, for example appears to be a key reason why many south Asians have abnormal lipid levels. By contrast to an average European meal, an Asian meal contains at least a 20% excess of carbohydrates (Misra A and Vikram NK, 2004): considering that a reduction of carbohydrates in severely obese T2DM patients was shown to be more beneficial to weight loss and regulating fat levels than a reduction in total dietary fats (Samaha et. al, 2003), then it can be inferred that this high proportion of daily caloric intake from high glycemic foods may be a contributing factor to this dyslipidemia and subsequent CVD. The levels of carbohydrate intake may be even higher in vegetarian Asians, who get about 60-67% of their daily caloric intake from carbs (Shobana R et. al, 1998).
CONVENTIONAL RISK FACTORS
Aside from insulin resistance and other related mechanisms, conventional risk factors no doubt have a key role in the CVD status of south Asians. A large randomised case- control study (Joshi P et. al, 2007) examining the prevalence of risk factors in south Asian controls and CVD cases, in contrast to cases and controls from 15 medical centres around the world, found there to be an excess of harmful risk factors in the former as well as a deficit in protective mechanisms.
Despite the high number of vegetarianism in the subcontinent, excessive cooking of the vegetables results in 90% depletion of the vitamins believed to benefit CVD health e.g. folate (Mathews JH and Woods JK, 1984). Moreover, physical inactivity was found to be common and when combined with the low intake of fruit and vegetables resulted in lower levels of HDL. Other benefits of these protective measures, found to be much less prevalent in the Indian sub-continent, include an increase in insulin sensitivity and a lowering of blood pressure with improvements of endothelial function (Hambrecht R et. al, 2000).
In conjunction with harmful risk factors, the lack of protective 'factors' overall subjects people from this race to greater CVD morbidity. On the contrary to the above findings, a paper reviewing cross sectional data has shown that there is a grave miss-perception of south Asians' blood pressure status. For example Indians, particularly Sikhs, have a higher than normal blood pressure, whereas Bengalis in general have a much lower blood pressure (Agyemang C, 2002); however, it is the variation in study methods and techniques and a lack of awareness that south Asians are less likely to meet blood pressure guidelines (145 mmHG/ 95 mmHG), that causes the overall picture of blood pressure in the Indian subcontinent to appear unseemly high. Similarly, smoking was again not found to be any more prevalent in south Asians than other races (Golap N et. al, 2010), raising questions as to why CVD morbidities hit those from the Indian subcontinent harder than people from other races.
One way of finding a common platform on which to link all such theories is a relatively innovative one, suggesting that all such stresses whether chemical, physiological or psychological which cause injury to the body, lead to an inflammatory response, the purpose of which being to restore body functions. Innate immune cells such as macrophages, which recognise bodily trauma, subsequently release pro-inflammatory cytokines, particularly interleukin-6 (IL-6), which induce acute phase response effects by the liver. The liver produces proteins and causes effects, which contribute to both T2DM and CVD development, hence suggesting that inflammation may be an underlying contributory factor to both such conditions.
Serum Amyloid A protein secreted by the liver, not only binds more HDLs, but is believed to also inhibit glucose sensing properties of beta cells in the pancreas, hindering insulin release and exacerbating metabolic syndrome symptoms. IL-6 and TNF α can also directly affect insulin sensitivity systemically also leading to insulin resistance. Similarly, other proteins such as C reactive protein (CRP), lead to LDL take up by macrophages, a novel method of atherosclerotic development via foam cell formation and accumulation in arterial endothelial cells. Also relevant is the release of plasminogen activator inhibitor-1 and fibrinogen, which aid blood clotting, also an atherogenic component (Pickup J, 2006). Interestingly, CRP levels appear to be higher in south Asians than other races (Dodani S, 2010), and despite not yet being statistically proven to have a direct effect on CVD, the fact that laboratory inhibition of similar proteins such as sialic acid benefits cardiovascular health, then it can be strongly asserted that CRP is at the minimum a novel indicator of CVD. The diagram below is an eloquent way of illustrating such links. It is of vital importance to recognise that Asians are more susceptible to this process occurring, due to the increased burden of the conventional risk factors in combination with the genetic programming explored earlier :
To conclude, with ample evidence demonstrating the increased risk that south Asians have to developing CVD, there is more cause for speculation as to why this may be, in contrast to other races, considering that not all findings have been consistent.
Golap et. al's paper challenges contradictory findings stating that whereas there is subgroup heterogeneity in the Indian sub-continent with regards to hypertension, hypertension itself as well as other conventional risk factors for CVD, such as smoking and lipid levels do not vary too significantly between south Asians and other races. In fact, LDL levels were surprisingly found to be lower at baseline in both cases and controls, by the INTERHEART study, suggesting that perhaps LDL may be causing greater damage in south Asians at lower levels. Similarly, with south Asians shown to be less compliant at managing their hypertension and high cholesterol levels (Golap et. al, 2010), which do not appear significantly more prevalent in Asia than in other regions, one must begin to wonder whether such parameters are of any relevance for this race at all: like BMI, where south Asians have their own cut off point, it may be perhaps that new, lowered values are required for such peoples with regards to conventional risk factors, which hit the south Asians harder e.g. lower than 5mmol/l total cholesterol.
Not only that, but being in the medical field, one can appreciate that south Asians have different BMI brackets than the rest of the population; however, I doubt that this is at all common knowledge for the rest of the population, calling for more public awareness with regards to specific ethnic entities such as this.
Furthermore, with more widespread knowledge of the inflammatory theory expected in the coming years, we might witness a shift in the way T2DM is treated using anti-inflammatory drugs. With the big onus of CVD mortality attributed to insulin resistance particularly in south Asia, this may well prove to be a notable breakthrough.
Additionally, perhaps a shift in attitude within individuals themselves is needed. With many cultural barriers dictating the lifestyle adopted by south Asians, some tact may be required by doctors to mediate this change in lifestyle: helping abandon ideas regarding health status being dictated by fate (Webster R, et. al, 2003), might be of paramount importance in increasing preventative measures e.g. fruit and vegetable intake as well as physical activity levels. Other barriers, such as the lowered levels of vitamin D, newly shown to be a factor which can influence CVD status (Judd S and Tangpricha V, 2009), due to lack of exposure to the sun by most Asian women, satisfying cultural and religious values, may be more difficult to overcome but can be dealt with in the form of supplements and again by raising awareness.