As has been noted, CAD is very common among the Indians and many studies have been undertalcen to find out the reasons behind this predilection. While genetic factors have been evoked, the role of other risk factors - both conventional and novel - is being studied and defined.2.4.1 Genetic Factors It has been suggested that certain genetic defect(s) could be partly responsible for increased risk of CAD in Asian Indians. No specific genetic defect has yet been identified butan excess prevalence or activation of the so-called 'thrifty' or pig-out gene [B3 subunit of hetcromeric G protein (GNB3)l may be responsible for the development of obesity and metabolic syndrome when coupled with absence of regula excrcise (gcne-environmenl interaction) - ultinlately leading to Cwdio-vasciilar diseases. Ethnicity is a strong surrogate for this gene-environment interaction and may undcrlie the propensity to develop obesity and CVD due to natural selection of the 'thrifty' gene. Genetic prcdisposition nlay also be related to the Lipoprotein a (Lp-a), an atherogenic lipid fraction whose level is genetically delermined and is found to be higher in Indians.
Conventional factors
Smoking, Hypertension, diabetes mellitus, obesity, hypercholesterolemia, and reduced physical activity are considered as conventional risk factors h CAD. In a prospective case-control study nlnong patients with a first acute myocardial infarction (AMI) conducted in Bangalole, the adjusted odds ratios for smoking(either cigarcttcs or becdis), Hypertension and fasting blood glucose (FBG) level >I40 mgldl as 1.is1c factors for AM1 were 3.7, 3.0 and 2.8, respectively. Pais et al., from the same group confirmed these findings reiterating the inlportance of smoking as a risk factor in the Indian context and also showed an increasing risk of AM1 with increasing FBG cven in the euglycernic range, irrespective of the presence oi' insulin resistance. Although this study did not show any differences in lipid levcls between cases and controls, the high-density lipoprotein (HDL) lcvels were low and triglycel-ide (TG) lcvels were high in the population studied.the Chcnnai Usban Populalion Study 5 (CUPS-5), serllm levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, TG and the total cholestcrol to 1-IDL cholestcrol ~ x t i o were linked to the presence of CAD in thc Indians. The study also docunle~lted the prcdisposition of people with diabetes and impaired glucosc tolerance (IGT) to devclop CAD, and also showed significant association of systolic and diastolic blood pressurc and body mass index (BMI) with the presence oi' CAD.
In a study by in North India, high prevalence ol' smoking, elevated scium total cholesterol levels, low I-IDL Icvcls, E-Iypertcnsion and diabetes was doculnented in both the urban and rural populations. Furthel; the total cholesterol to I-IDL cholesterol ratio was found to be abnormal even in those subjects whose plasma cholcstcrol was in the normal rangc.The role of leisure-time and work-rclated physical activity in determining risk of CAD in native Indian patients has not been stlldicd in a sttuctured way. However in a study of an urban conlmunity in Rajasthun, it was found that more than 70 per cent of the subjects were having a scdcntary likstyle. The adjustcd odds ratios for a sedentary lifestyle as a risk factor for CAD were 1.7 in males and 4.5 in females.
In a study on the prevalence of Cnrdio-vascular risk fi~ctors in lndinn patients undergoing coronary artery bypass surgery, have shown high prevalence of most of the conventional Cardio-vascular risk factors especially diabetes, Hypertension,dyslipidaemia, smoking and obesity in the study population. About 96 per cent of the patients had at least one of the five major Cardio-vascular risk factors.Dyslipidemia, family history of premature CAD and smoking were commoncr in younger patients less than 45 ycars of age. 111 contrast, diabetes and Ilypcrtension were more prcvalerlt in the cilder individuals. Sevcral other studies have also documented the association of conventional risk factors with CAD in the Indian population.
In summary, although conventional risk factors might not be sufficient to explain the increased prevalence of CAD among Indians, they are very i~nportant in the context of disease preveiltion and control because they can be easily identified and measured and because adequate steps including drugs are available to eliminate or control them.
Non-conventional Factors
Insulin resistance
Insulin resistance refers to a generalized metabolic disorder in which various tissues are resistant to normal levels of plasma insulin. Metabolic abnormalities include defective glucose uptake by skeletal muscle, increased release of free fatty acids by adipose tissue, overproduction of glucose by the liver, and hy persecretion of insulin by pancreatic B-cells. On the basis of studies comparing South Asian immigrants in Britain and the native European population, McICeigue and co-workers have suggested that a pattern of insulin resistance and associated metabolic abnormalities might be the reason for the high rates of CAD and type two diabetes among South Asian people. In a subsequent study by the same group,it was found that major Q waves with or without a history of CAD were more common in South Asian patients with glucose intolerance and hy perinsulinemia than in those with normal glucose and insulin levels (6 per cent v. 1.9 per cent).The population attributable risk fraction (this is the proportion by which prevalence of disease would be expected to fall in the population if the risk factor was removed, assuming the association to be causal) in South Asian men aged
between 40 and 54 years was 73 per cent.
Abdominal obesity is an important component of the insulin resistance syndrome.Again, it was found that the average waist-hip ratio (WHR) was higher in South Asian men than in the Europeans studied. A W H R ' > O . ~ had~ an adjusted odds ratio of 3.1 for AM1 in the case-contsol study by Pais et al. Although Mohan and others did not find any difference in the WHR between the subjects with and without CAD in their community-based study, there was a significant association of obesity as measured by BMI and another estiinate of abdominal obesity, the waist-height ratio. The prevalence of an 'apple' shaped body linbitus (high WHR) was as high as 71 per cent in an urban population sample from Delhi. Urban Indians in this study were just as centrally obese as the South Asians in the Southall study. Although the average WHR of the rural populatioil sampled was less than that of the urban population, they were inore centrally obese than the Europeans in the Southall study.
Several studies have documeilted the clustering of other metabolic abnormalities associated with the insulin resistance syndrome. In immigrant South Asians in the UK, the average fasting and post-load seruin insulin, blood pressure and plasma TG levels were higher than the levels in the native European population. The HDL cholesterol was also significantly lower. High seruin TG levels and low HDL levels have also been seen in studies of native Indians with CAD. Although there is substantial evidence for an association between the metabolic syndrome and CAD in Indians, the mechanism by which atherosclerosis is caused by this syndron~e has been extensively debated. The most plausible explanation is that the risk of CAD is increased by the associated alteration in the lipid profile leading to atherogenic dyslipidaemia, Hypertension, a thrombotic tendency evidenced by elevated levels of plaslninogen activator inhibitor-1 (PAI-1) and by the presence of IGT or diabetes.
The question whether this South Asian predilection for insulin resistance is a genetic or acquired trait requires elucidation. In their coinparison of Punjabi immigrants in London and their siblings in rural Punjab, Bhatnagar et a1 had showed that the former had a greater BMI, higher systolic blood pressure, raised serum total cholesterol, apolipoprotein (Apo) B, FBG, and lower HDL cholesterol than the latter. However, the insulin sensitivity of the native Punjabi population was also impaired, suggesting a genetically determined propensity for insulin resistance. In another study, Shaukat et a1 analyzed the risk factor profiles of young siblings of UK-based Asians. When compared to their European counterparts, t l ~ e young Asians (mean age 22 years) were more sedentary, centrally obese, insulin resistant and had higher lipoprotein (a) [Lp(a)] levels. They also showed evidence of a prothrombotic tendency with elevated levels of PAI-1 and reduced tissue plasminogen activator (tPA) activity. The divergence from the European populalion diminished but did not disappear after adjustment for level of physical activity. Significantly, both the studies showed higher concentrations of Lp(a) in Asians iirespective of their place of residence. These facts point to an interplay between genetic predisposition and lifestyle changes in determining the increased risk of CAD.
Conventional factors
Smoking, Hypertension, diabetes mellitus, obesity, hypercholesterolemia, and reduced physical activity are considered as conventional risk factors h CAD. In a prospective case-control study nlnong patients with a first acute myocardial infarction (AMI) conducted in Bangalole, the adjusted odds ratios for smoking(either cigarcttcs or becdis), Hypertension and fasting blood glucose (FBG) level >I40 mgldl as 1.is1c factors for AM1 were 3.7, 3.0 and 2.8, respectively. Pais et al., from the same group confirmed these findings reiterating the inlportance of smoking as a risk factor in the Indian context and also showed an increasing risk of AM1 with increasing FBG cven in the euglycernic range, irrespective of the presence oi' insulin resistance. Although this study did not show any differences in lipid levcls between cases and controls, the high-density lipoprotein (HDL) lcvels were low and triglycel-ide (TG) lcvels were high in the population studied.the Chcnnai Usban Populalion Study 5 (CUPS-5), serllm levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, TG and the total cholestcrol to 1-IDL cholestcrol ~ x t i o were linked to the presence of CAD in thc Indians. The study also docunle~lted the prcdisposition of people with diabetes and impaired glucosc tolerance (IGT) to devclop CAD, and also showed significant association of systolic and diastolic blood pressurc and body mass index (BMI) with the presence oi' CAD.
In a study by in North India, high prevalence ol' smoking, elevated scium total cholesterol levels, low I-IDL Icvcls, E-Iypertcnsion and diabetes was doculnented in both the urban and rural populations. Furthel; the total cholesterol to I-IDL cholesterol ratio was found to be abnormal even in those subjects whose plasma cholcstcrol was in the normal rangc.The role of leisure-time and work-rclated physical activity in determining risk of CAD in native Indian patients has not been stlldicd in a sttuctured way. However in a study of an urban conlmunity in Rajasthun, it was found that more than 70 per cent of the subjects were having a scdcntary likstyle. The adjustcd odds ratios for a sedentary lifestyle as a risk factor for CAD were 1.7 in males and 4.5 in females.
In a study on the prevalence of Cnrdio-vascular risk fi~ctors in lndinn patients undergoing coronary artery bypass surgery, have shown high prevalence of most of the conventional Cardio-vascular risk factors especially diabetes, Hypertension,dyslipidaemia, smoking and obesity in the study population. About 96 per cent of the patients had at least one of the five major Cardio-vascular risk factors.Dyslipidemia, family history of premature CAD and smoking were commoncr in younger patients less than 45 ycars of age. 111 contrast, diabetes and Ilypcrtension were more prcvalerlt in the cilder individuals. Sevcral other studies have also documented the association of conventional risk factors with CAD in the Indian population.
In summary, although conventional risk factors might not be sufficient to explain the increased prevalence of CAD among Indians, they are very i~nportant in the context of disease preveiltion and control because they can be easily identified and measured and because adequate steps including drugs are available to eliminate or control them.
Non-conventional Factors
Insulin resistance
Insulin resistance refers to a generalized metabolic disorder in which various tissues are resistant to normal levels of plasma insulin. Metabolic abnormalities include defective glucose uptake by skeletal muscle, increased release of free fatty acids by adipose tissue, overproduction of glucose by the liver, and hy persecretion of insulin by pancreatic B-cells. On the basis of studies comparing South Asian immigrants in Britain and the native European population, McICeigue and co-workers have suggested that a pattern of insulin resistance and associated metabolic abnormalities might be the reason for the high rates of CAD and type two diabetes among South Asian people. In a subsequent study by the same group,it was found that major Q waves with or without a history of CAD were more common in South Asian patients with glucose intolerance and hy perinsulinemia than in those with normal glucose and insulin levels (6 per cent v. 1.9 per cent).The population attributable risk fraction (this is the proportion by which prevalence of disease would be expected to fall in the population if the risk factor was removed, assuming the association to be causal) in South Asian men aged
between 40 and 54 years was 73 per cent.
Abdominal obesity is an important component of the insulin resistance syndrome.Again, it was found that the average waist-hip ratio (WHR) was higher in South Asian men than in the Europeans studied. A W H R ' > O . ~ had~ an adjusted odds ratio of 3.1 for AM1 in the case-contsol study by Pais et al. Although Mohan and others did not find any difference in the WHR between the subjects with and without CAD in their community-based study, there was a significant association of obesity as measured by BMI and another estiinate of abdominal obesity, the waist-height ratio. The prevalence of an 'apple' shaped body linbitus (high WHR) was as high as 71 per cent in an urban population sample from Delhi. Urban Indians in this study were just as centrally obese as the South Asians in the Southall study. Although the average WHR of the rural populatioil sampled was less than that of the urban population, they were inore centrally obese than the Europeans in the Southall study.
Several studies have documeilted the clustering of other metabolic abnormalities associated with the insulin resistance syndrome. In immigrant South Asians in the UK, the average fasting and post-load seruin insulin, blood pressure and plasma TG levels were higher than the levels in the native European population. The HDL cholesterol was also significantly lower. High seruin TG levels and low HDL levels have also been seen in studies of native Indians with CAD. Although there is substantial evidence for an association between the metabolic syndrome and CAD in Indians, the mechanism by which atherosclerosis is caused by this syndron~e has been extensively debated. The most plausible explanation is that the risk of CAD is increased by the associated alteration in the lipid profile leading to atherogenic dyslipidaemia, Hypertension, a thrombotic tendency evidenced by elevated levels of plaslninogen activator inhibitor-1 (PAI-1) and by the presence of IGT or diabetes.
The question whether this South Asian predilection for insulin resistance is a genetic or acquired trait requires elucidation. In their coinparison of Punjabi immigrants in London and their siblings in rural Punjab, Bhatnagar et a1 had showed that the former had a greater BMI, higher systolic blood pressure, raised serum total cholesterol, apolipoprotein (Apo) B, FBG, and lower HDL cholesterol than the latter. However, the insulin sensitivity of the native Punjabi population was also impaired, suggesting a genetically determined propensity for insulin resistance. In another study, Shaukat et a1 analyzed the risk factor profiles of young siblings of UK-based Asians. When compared to their European counterparts, t l ~ e young Asians (mean age 22 years) were more sedentary, centrally obese, insulin resistant and had higher lipoprotein (a) [Lp(a)] levels. They also showed evidence of a prothrombotic tendency with elevated levels of PAI-1 and reduced tissue plasminogen activator (tPA) activity. The divergence from the European populalion diminished but did not disappear after adjustment for level of physical activity. Significantly, both the studies showed higher concentrations of Lp(a) in Asians iirespective of their place of residence. These facts point to an interplay between genetic predisposition and lifestyle changes in determining the increased risk of CAD.
The Role of Lipoprotein (a)
As discussed in the previous section, serum concentrations of Lp(a) are elevated in South Asians irrespective of their migrant status. Several studies have documeilted this elevation in Lp(a) levels in people of Indian origin whcn compared to other ethnic groups. Higher levels of Lp(a) have been associated with CAD especially if th&e is concoinitant elevatioi~ of LDL levels.Levels of Lp(a) are largely genetically determined and genetic factors account for over 70 per cent of the variatioi~ in the Lp(a) levels jn the populalion. This suggests the basis for a genetic predisposition to CAD among populations with elevated Lp(a) levels and concomitantly raised LDL levels. Proposed mechanisms of atherogenesis by Lp(a) include preferential uptake of Lp(a) into macrophages in atherosclerotic plaaues via binding to fibrin and plasminogen receptors. Because of the structural similarity between Lp(a) and plasminogen, it has also been suggested that the foimer interferes with plasrninogetl activities
Plasma Homocysteine Levels
Several studies have investigated the contribution of holnocysteine to CVD ~ i s k both among inlrnigrant Indians and those living in India. It was observed in two parallel case-control studies to evaluate fasting and post-methionine load holnocysteine as risk factors for CAD , one in Europeans and the other in Indians,.They found that elevated plasnla homocysteine levels wcre independently associated with CAD in both UK-based Indians and Europeans. In their study, the odds ratio for CAD for a 5 ymol1L increment in plasma homocysteine was 1.3 in Europeans and, 1.2 in Indians. However, the Indians in this study were not evaluated for the other known associations of CAD characteristic of' Indian ethnicity, namely abnormal WHR, raised Lp(a) and hy perinsulinemia. In the SHARE study which involved newly a thousand participants crom three ethnic groups (South Asians, Europeans and'chinese), the presence of clinical Cardio-vascular disease and carotid intima-media thickness lneasured by B-mode ultrasound were correlated with conventional and noncoi~ventio~lal risk factors.
Even though the South Asians had significantly higher levels of plasma homocysteine than their European and Chinese countei-parts, this did not trallslate into an independent association of homocysteine with CAD. Two.other'comparative studies from southern India also failed to show any difl'erence in plasma homocysteine lcvcls between patients with and without CAD. The case-control study by Shastry and colleagues, again confir~ns that Indians have higher plasma homocysteine levels, but fails to show any differences in the levels between patients with CAD and those without. The bulk of the evidence therefore suggests that the elevated plasma homocysteine' level found in patients of Indian origin is not independently associated with CAD.
Though co~lventional risk factors are not high in Indians, they remain at least as important in determining the risk of CAD in Indian patients as thcy are in olher populations. In addition to these traditional risk factors, it is clear that there ase other known and unknown factors which increase the predilection of Indians to develop premature and severe CAD. The most important set of conditions, which have been unequivocally associated with and are, more prevalent among Indians with CAD, are those constituting the syndrome of insulin resistance. Elevated levels of Lp(a) are seen in Indians irrespective of whether they reside in India or are immigrants to
another country, suggesting a genetic predisposition. In the light of current knowledge, adverse interaction between a genetic predispositior~ and unhealthy lifestyle changes best explains the increased vulnerability of Indians to CAD.
In summary, several factors likely to have contributed to the acceleration of CAD epidemic in India in recent times. These are:
i)Demographic transition to an older population, as a result of increasing life
expectancy.
ii)Confluence of both conventioiial risk factors and non-conventional risk factors in Indians. Conventional factors like Hypertension, diabetes,hypercholesterolaemia, smoking elc., owe their origin to growing urbanization and western 'acculturation' amongst Indians. Non-conventional risk factors like hy perinsulinaeinia, insulin resistance, lipoprotein A etc., are determined by genes or other 'programming' factors and their high prevalence amongst Indians probably explain the malignant, precocious nature of CAD that typically affects Indians.
iii) Recently indicated relationship between low birth-weight which is widely prevalent amongst Indian newborns and enhanced susceptibility to CAD in adult life ('Barker hypothesis').These multiplicative effects of conveiltional and emerging risk factors appeal'to provide a plausible explanation for the excess burden of CAD among Indians, many of whoin are lean, non-smoking, vegetarian, .yoga guru and even marathon athletes.The excess risk of CAD in Indians appears to. be greater at younger ages. When
people move fro111 a rural to an urbLm environment, they become sedentary and/or may adopt western lifestyles. Decreased physical activity and increased consu~nption of calories and saturated fat result in abdominal obesity, insulin resistance and ntherogeiiic dyslipidaeinia. These acquired metabolic abiior~~ialities appear t.0 have a synergistic effect on the development of CAD in genetically
p edisposed individunls.
Significant prevalence of conventional risk factors
As discussed in the previous section, serum concentrations of Lp(a) are elevated in South Asians irrespective of their migrant status. Several studies have documeilted this elevation in Lp(a) levels in people of Indian origin whcn compared to other ethnic groups. Higher levels of Lp(a) have been associated with CAD especially if th&e is concoinitant elevatioi~ of LDL levels.Levels of Lp(a) are largely genetically determined and genetic factors account for over 70 per cent of the variatioi~ in the Lp(a) levels jn the populalion. This suggests the basis for a genetic predisposition to CAD among populations with elevated Lp(a) levels and concomitantly raised LDL levels. Proposed mechanisms of atherogenesis by Lp(a) include preferential uptake of Lp(a) into macrophages in atherosclerotic plaaues via binding to fibrin and plasminogen receptors. Because of the structural similarity between Lp(a) and plasminogen, it has also been suggested that the foimer interferes with plasrninogetl activities
Plasma Homocysteine Levels
Several studies have investigated the contribution of holnocysteine to CVD ~ i s k both among inlrnigrant Indians and those living in India. It was observed in two parallel case-control studies to evaluate fasting and post-methionine load holnocysteine as risk factors for CAD , one in Europeans and the other in Indians,.They found that elevated plasnla homocysteine levels wcre independently associated with CAD in both UK-based Indians and Europeans. In their study, the odds ratio for CAD for a 5 ymol1L increment in plasma homocysteine was 1.3 in Europeans and, 1.2 in Indians. However, the Indians in this study were not evaluated for the other known associations of CAD characteristic of' Indian ethnicity, namely abnormal WHR, raised Lp(a) and hy perinsulinemia. In the SHARE study which involved newly a thousand participants crom three ethnic groups (South Asians, Europeans and'chinese), the presence of clinical Cardio-vascular disease and carotid intima-media thickness lneasured by B-mode ultrasound were correlated with conventional and noncoi~ventio~lal risk factors.
Even though the South Asians had significantly higher levels of plasma homocysteine than their European and Chinese countei-parts, this did not trallslate into an independent association of homocysteine with CAD. Two.other'comparative studies from southern India also failed to show any difl'erence in plasma homocysteine lcvcls between patients with and without CAD. The case-control study by Shastry and colleagues, again confir~ns that Indians have higher plasma homocysteine levels, but fails to show any differences in the levels between patients with CAD and those without. The bulk of the evidence therefore suggests that the elevated plasma homocysteine' level found in patients of Indian origin is not independently associated with CAD.
Though co~lventional risk factors are not high in Indians, they remain at least as important in determining the risk of CAD in Indian patients as thcy are in olher populations. In addition to these traditional risk factors, it is clear that there ase other known and unknown factors which increase the predilection of Indians to develop premature and severe CAD. The most important set of conditions, which have been unequivocally associated with and are, more prevalent among Indians with CAD, are those constituting the syndrome of insulin resistance. Elevated levels of Lp(a) are seen in Indians irrespective of whether they reside in India or are immigrants to
another country, suggesting a genetic predisposition. In the light of current knowledge, adverse interaction between a genetic predispositior~ and unhealthy lifestyle changes best explains the increased vulnerability of Indians to CAD.
In summary, several factors likely to have contributed to the acceleration of CAD epidemic in India in recent times. These are:
i)Demographic transition to an older population, as a result of increasing life
expectancy.
ii)Confluence of both conventioiial risk factors and non-conventional risk factors in Indians. Conventional factors like Hypertension, diabetes,hypercholesterolaemia, smoking elc., owe their origin to growing urbanization and western 'acculturation' amongst Indians. Non-conventional risk factors like hy perinsulinaeinia, insulin resistance, lipoprotein A etc., are determined by genes or other 'programming' factors and their high prevalence amongst Indians probably explain the malignant, precocious nature of CAD that typically affects Indians.
iii) Recently indicated relationship between low birth-weight which is widely prevalent amongst Indian newborns and enhanced susceptibility to CAD in adult life ('Barker hypothesis').These multiplicative effects of conveiltional and emerging risk factors appeal'to provide a plausible explanation for the excess burden of CAD among Indians, many of whoin are lean, non-smoking, vegetarian, .yoga guru and even marathon athletes.The excess risk of CAD in Indians appears to. be greater at younger ages. When
people move fro111 a rural to an urbLm environment, they become sedentary and/or may adopt western lifestyles. Decreased physical activity and increased consu~nption of calories and saturated fat result in abdominal obesity, insulin resistance and ntherogeiiic dyslipidaeinia. These acquired metabolic abiior~~ialities appear t.0 have a synergistic effect on the development of CAD in genetically
p edisposed individunls.
Significant prevalence of conventional risk factors
- Hypertension, cigarette smoking, high cholesterol
- Cholesterol levels - similar to Whites but higher than other Asians
- Higher rates of CAD at any level of conventional factors
- Two-fold higher after adjusting for conventional risk factors
- Underscore the need for lower cut-off points for intervenlion
- Underscore the need for lower cut-off points for intervenlion
- Higher prevalence of glucose intolerance
-Insulin resistance syndrome, diabetes, central obesity, metabolic
syndrome
syndrome
- Higher prevalence of emerging risk factors
- High levels of lipoprotein(a), homocysteine, Apo 0, triglyceride,fibrinogen, PAI-1
- Low levels of HDL and HDL 2b
- Small dense LDL, small HDL, large VLDL
- Low levels of HDL and HDL 2b
- Small dense LDL, small HDL, large VLDL
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