Medical, Socialogical and environmental issues in cardiovascular disease epidemiology, prevention and rehabilitation.
Prashant P Joshi
MD (Medicine), MSc (Clinical Epidemiology, Australia),
Department of Medicine, Government Medical College, Nagpur
The epidemic of cardiovascular diseases (coronary artery disease and stroke) in India is advancing rapidly1. India is experiencing an epidemiological health transition characterized by rapid decline in nutritional and parasitic diseases (pre-transitional diseases) with an alarming rise in cardiovascular diseases, mainly coronary heart disease, and stroke (post-transitional diseases)1,2. There has been a dramatic rise in the prevalence of Coronary artery disease from 3.5% in 1960s to 11% in late 1990s in urban India, and it is projected to rise substantially in future3.

Overview of population surveys conducted over two decades in India reported a 9-fold increase of coronary heart disease (CHD) in urban centers3. This increase in urban areas is associated with increase in prevalence of lipid and glucose abnormalities as well as hypertension and obesity. It has been estimated by the World Bank that there will be doubling of deaths due to cardiovascular disease (CVD) in India from 1985 to 20154. The cardiovascular diseases account for one-third of all deaths world wide, two thirds of which occur in the developing countries. For any disease to be clinically manifest, confluence of genetic susceptibility and adverse environmental influences is important There is no reason to believe that there have been genetic mutations in Indians to account for this rising burden of CVD, but what has definitely altered is our environment and life style.

The factors responsible for this rising burden of cardiovascular diseases include:
1. Demographic shifts consisting of progressive aging of the population more people reach an age when cardiovascular diseases become clinically manifest. Life expectancy in India increased from 41.2 years in 1951-1961 to 61.4 years in 1991-1996, and with expanding population, the absolute number of CVD cases are increasing.
2. Life style transition with adoption of unhealthy life style comprising of sedentary habits, lack of physical activity associated with increased mechanization, excessive consumption of inexpensive tobacco),
3. Nutrition transition with consumption atherogenic and thrombogenic diet rich in cholesterol and salt but low in fresh fruits and vegetables.
4. Socio-economic transition associated with urbanization, industrialization and affluence.
Coronary heart disease in Indians has been shown to be premature, occurs at an early age and is more aggressive, extensive and malignant. 52.2% of deaths due to CVD occur below the age of 70 years in India as compared with only 22.8% in the developed world.5

Asian Indians are ethnically more prone to develop CVD. Studies in migrant South Asians living in United Kingdom, South Africa, Singapore, and North America show higher prevalence and 1.5 to 4 folds higher mortality from CHD than native population6,7,8. SHARE study8, involved nearly a thousand subjects from three ethnic groups (South Asians, Europeans, Chinese), and showed that Indians carry 4.5 higher odds of developing CHD, as compared to Europeans after adjusting for conventional and novel risk factors. The study also revealed that for similar level of atherosclerosis (determined by intima-media thickness by carotid ultrasound) Indians had higher prevalence of clinical CVD, indicating that pro-thrombotic factors (lipoprotein(a), plasminogen activator inhibitor-1, fibrinogen, less tissue plasminogen activator, which were higher in Indians are important in Indians.

The risk factors for CVD could be classified as- conventional or traditional risk factors, which have been shown to be causally associated with CVD, and the emerging or novel risk factors which have been shown to be associated with CVD but their causal role in development of CVD is still debated. Such risk factors, which have not been conclusively proven to have a cause and effect relationship with CVD, are best described as 'risk markers'. Some risk factors like obesity, which leads to high blood pressure, diabetes, lipid abnormalities are better described as a 'predisposing risk factor'. To asses whether a risk factor has an causal relationship. Bradford Hill's criteria should be fulfilled. These include consistency of evidence from different studies from different populations, strength of association, dose-response relationship, temporal relationship between risk factor and CVD, biological plausibility, reversible association demonstrated by randomized trials experimental evidence, specificity, and analogy.
Though conventional risk factors like hypertension, smoking, dyslipidemia, diabetes, obesity are important, they cannot fully explain the this excess risk in Indians. Conventional risk factors explain only half of variance in CHD. 30-50% of CAD lack conventional risk factors. Despite similar levels of conventional risk factors like smoking, hypertension and elevated cholesterol in migrant Indians, as compared to native Europeans, they have higher CHD7,8. Hence, emerging, putative, prothrombotic risk factors are postulated. Population studies have shown that almost 15% urban and overseas Indians have diabetes as compared with a 4% prevalence of diabetes in North Americans and Europeans. Indians also have increased risk of developing insulin resistance syndrome (metabolic syndrome) characterized by insulin resistance, hyperinsulinemia, non-insulin dependent diabetes (NIDDM), impaired glucose tolerance, central obesity, hypertension, dyslipidemia (high trigylcerides, low HDL) and CHD.

McKeigue9 comparing SA and native Europeans found higher prevalence of CAD, NIDDM, insulin resistance, central obesity and syndrome-X in South Asians. DM is a CHD equivalent. Risk of AMI in a diabetic is 4 fold as compared to nondiabetic and is similar to a person with previous myocardial infarction. A study from South India showed that prevalence of CAD rose with increasing blood sugar levels. The prevalence of CAD increased from 9.1% in subjects with normal glucose tolerance, to 14.99% in impaired glucose tolerance and 21.4% in diabetics.10

Indians have also been shown peculiar type of obesity characterized by higher waist-hip ratios and higher body fat % (as measured by DEXA scan) at given level of body-mass index (BMI) suggesting that BMI may not truly reflect obesity in Indians. Non obese (BMI<25kg/m2) Asian Indians with normal waist circumference have high cardiovascular risk13. The conventional cutoff point of body mass index of 25 might not define overweight and obesity optimally in Asian Indians because of their higher percentage of body fat and less lean mass as compared to whites14. Hence a lower cut-off level of BMI of 23 may be more appropriate for Indians.

Indians also have been shown to have a distinctive lipid profile, characterized by low HDL cholesterol, hypertriglyceridemia, high total cholesterol by HDL ratio, and high triglyceride by HDL ratio.15. CAD in Indians is probably more HDL, rather than LDL, driven.

Smoking lowers HDL, raises fibrinogen, and causes platelet aggregation and coronary spasm. Tobacco is used in various forms in India. In addition to cigarette smoking, beedi smoking and the use of chewed tobacco are quite prevalent, especially in rural populations. Beedi smoking has also been shown to be an important risk factor for CHD16 though for smokeless tobacco, there is less evidence. Despite their smaller size, beedis deliver higher carbon monoxide, tar and nicotine. Beedi smokers inhale deeply and more frequently, in order to keep the beedi alight.

Low birth weight has been associated with higher rates of CAD, diabetes and hypertension in later life when exposed to unhealthy life style (Barker hypothesis)17. Adverse intrauterine influences such as poor maternal nutrition lead to impaired fetal growth, resulting in low birth weight, short birth length, small head circumference. This causes irreversible in-utero programming so that the fetus becomes adapted to malnutrition. When exposed to over-nutrition in later life, this individual is more susceptible to develop NIDDM, hypertension, and lipid abnormalities. Causal relationship of this association has not been proved though there is some evidence from India. Yagnik et al18 reported that children with low birth weight had insulin resistance at 4 years age. The hypothesis needs to be further tested in Indians. However, if proven to be true would spell disaster, as low birth weight is common in Indians.
The novel risk factors, which are probably responsible for the excess risk of CHD in Indians, include prothrombotic factors like high lipoprotein(a), homocysteine, plasminogen activator inhibitor-1, fibrinogen and low tissue plasminogen activator.

Lipoprotein(a) has been identified as a major genetic risk factor in Indians. Lp(a) levels are about 2 times higher in Indians as compared with whites, and are probably responsible for the excess risk seen in Indians19-22. Mohan23 showed Lp(a) to be an independent risk factor in diabetics. It is atherogenic (5 times more atherogenic than LDL) and thrombogenic (increases activity of PAI-1) and causes plaque destabilization. It has been identified as an independent risk factor for CVD. It is not modified by age, gender, diet, exercise or other environmental factors. It acts synergistically with other risk factors and helps to identify high-risk individuals in whom aggressive risk factor reduction is indicated. Atherogenecity of Lp(a) is decreased by lowering LDL and other risk factors. However, the mechanism by which Lp(a) is associated with coronary heart disease is not entirely clear and there is lack of consensus on laboratory measurement of Lp(a). The normal levels are < 30mg%, but a more appropriate cut off point would be <20mg%

Mild to moderately raised levels of homocysteine (Hcy, >15 mols/l) are associated with increase in risk of CAD; raised levels have been found in Indians. Homocysteine is derived from dietary methionine and metabolized by vitamin dependent enzymes. Homocysteine is toxic to endothelium, and promotes atherosclerosis and, thrombosis. Several case-control studies have shown that elevated Hcy is an independent risk factor for CVD. Chambers24 showed plasma homocysteine to be independent risk factor for coronary artery diseases in Indian Asian men after controlling for conventional risk factors, including diabetes and insulin resistance syndrome. Homocysteine levels have been shown to be higher in immigrant Asian Indians compared with North Americans and Europeans8,25. However, causal relationship with CVD is still debated.

The relationship may be particularly important in developing countries where nutritional deficiency of folate, vitamin B12, and B6 is not uncommon. In prospective studies, homocysteine concentrations of 9, 15, and 20 micromols/l predicted total mortality ratios of 1.9, 2.8, and 4.5 respectively26. Deficiency of folate and vitamin B12 cause rise in homocysteine levels. Higher levels of homocysteine could be explained on basis of lower folate and vitamin B12 levels in Indians. Reduced intake of vitamin B12 has been reported in Asian Indian women and prolonged cooking of vegetables, which is a common practice in many Asian Indian households, may destroy about 90% of folate content27,28. Knowledge of the fact that modification of dietary patterns can have substantial effects on fasting levels of total serum homocysteine opens new doors to evaluate this hypothesis in Indians. Elevations of homocysteine levels are caused by genetic defects of enzymes involved in its metabolism (MTHFR , cystathione beta synthetase deficiency, and others in Europeans) or by nutritional deficiencies (in Indians). SHARE study8 also showed that SA had higher homocysteine, but there was no independent association with CVD.

Homocysteine levels can be reduced by low-cost, low-risk vitamin therapy (FA 0.5-5mg + B12 400µg / day, low dose FA) . However, benefits of lowering Hcy are not confirmed. Most data on homocysteine and CVD have come from developed countries, where the diet is obviously different from Indians. Several small case control studies from south India have failed to demonstrate any association of Hcy with CHD 29-32. The various reasons for these negative studies include: High levels of Hcy in both cases and controls, High variance in hcy levels, small sample sizes, lack of laboratory standardization. Normal levels are <15 µmol/L, however, a more appropriate cutoff could be <10 µmol/L.

Antioxidant vitamin (Vitamin E, C, A) deficiency leads to unchecked production of free radicals, which has been implicated in atherosclerosis and CAD. Oxidative modification of LDL a process called lipid peroxidation is an important step in the pathogenesis of atherosclerosis, which can be modified by use of antioxidants. Though observational studies have demonstrated the protective effect of intake of fresh fruits and vegetables, generally, randomised controlled trials have not demonstrated any beneficial effects of antioxidant vitamin supplementation. CHAOS (Cambridge Heart Antioxidant Study) has shown some benefit, but recent large randomized controlled trials like HOPE study, and Heart Protection study have not shown any protective effect of antioxidant vitamins. However, there are very few studies from India, where antioxidant vitamin deficiency may be common; hence this hypothesis remains untested in India.

Possible role of several infectious agents (Chlamydiae pneumoniae, Herpes simplex, Helicobacter pylori, cytomegalovirus, etc.) have been implicated in pathogenesis of atherosclerosis and CAD33,34. Gingival sepsis has been identified as a risk factor for CAD. The hypothesis remains to be tested in Indians.

C-Reactive protein (CRP), a sensitive indicator of inflammation, is an independent risk factor for CAD, and has been shown to be higher in Asian Indians than in European whites, which is accounted for by greater central obesity and insulin resistance in Asian Indians. Adiposity is also a major determinant of CRP. Though some studies have demonstrated the importance of haematologic factors like increased levels of fibrinogen, plasminogen activator inhibitor and increased platelet activity in Asian Indians35,36, the inflammation hypothesis remains to be tested.
However, the conventional risk factors are definitely important and there are number of reasons to believe that their importance of has been underestimated2. These include:
1. Regression dilution bias: Most associations are based on single measurement of risk factor (rather than multiple measurements), which results in large variance.
2. Lag effect: Risk factors take several years to manifest for e.g. smoking in British doctors and lung cancer showed a more stronger relationship at 40 year follow-up than at 20 years.
3. Dichotomous categorization of risk factors, and
4. Inability to quantify exposure in unexposed: (passive smokers are many times classified as non-smokers).
It should also be recognized that the relationship of risk factors and CVD is continuous and extends well below the conventional cut-off point, which are man-made. The dividing line between and normotension and hypertension is artifactual. For example, the Framingham data has clearly shown that substantial amount of CVD attributable to high blood pressure occurs in the range of blood pressure, which according to the current definition is normotension. Similarly, risk of CVD increases linearly as the levels of blood pressure, blood sugar and lipids increases with no threshold level. Mohan et. al. showed that the prevalence of CHD increased with increasing blood sugar levels.11. Majority of coronary and stroke events arise in a population from the middle of the distribution (of a risk factor) than from its high end.

Co-existence of risk factors leads to interactive risk, which is multiplicative. Risk factors often cluster together in individuals In most populations, the majority of CVD events arise from individuals with modest elevations of many risk factors than in individuals with marked elevation of a single risk factor. The absolute risk of a major CVD event (CHD/Stroke) is dependent on the overall risk profile contributed by co-existent risk factors operating in a continuum. To summarize, in addition to genetic susceptibility, the conventional, novel and some unknown risk factors are probably important in Indians. These include:
1. higher prevalence of diabetes,
2. higher prevalence of insulin resistance syndrome,
3. higher %body fat,
4. higher levels of triglycerides with low HDL,
5. high total cholesterol to HDL ratio,
6. high lipoprotein(a) levels,
7. mild to moderate raised homocysteine levels,
8. antioxidant deficiency,
9. high plasminogen activator inhibitor-1 levels
10. high fibrinogen levels,
11. lower tissue plasminogen activator l
12. low birth weight, and
13. infection and inflammation.


Larger epidemiological studies are warranted in Indians to study the causal and temporal relationships of novel risk factors. At present there is scanty and conflicting data from India. Lack of data from India highlights the gaps in our knowledge that needs to be bridged in order to understand the increased risk of CAD in Indians.
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