t Coronary Artery Disease in Young Asian Indians: Thoughts onnesis, Prevention, and Therapy

_ I .131-135 (1995)

_W ..F.A.C.C., AND JAWAHAR MEHTA, M.D., PH.D. *

High Incidence of CAD in Asian Indian Men andWomen

_ Disease in Asian Indians (CADI) Study, Woodridge, lllinois, and *Di vision of Cardiology, University of Florida College.\J01Ul<~ville, Florida, USA

Asian Indians have the highest rates of coronaryCAD) of any ethnic group studied, despite the

_ half of this group are life-long vegetarians. CADge and generally follows a malignant course.

~ )lOCI(' ience of classic risk factors is low, high triglyc-igh-density lipoprotein cholesterol levels, highvels. hyperinsulinemia, and apple-type obesi-rantial prevalence in this population. Aggres-

of life style beginning before adolescencein,iew of the malignant nature of CAD in this

IIl!mrm~cologic intervention similar to that of see-of CAD seems justified as primary preven-

- Asian Indians.

nary artery disease, Asian Indians, lipop-

me world's population lives in India and a pop-that of Australia is added to this every year.Asian Indians live outside India, including one

L _-\.Of these, 27,000 are physicians andconsti-k lom_" <;I'cian population of the USA. Asian Indians

subcontinent of India, Pakistan, and Bangla-- the highest rates of coronary artery disease

ic group studied, despite the fact that nearly_ vegetarians. In this article we review the inci-

. hospitalization, and mortality from CAD"Indians and present some thoughts on prevention

- malignant premature CAD in this population.

Several studies have reported high rates of CAD in this pop-ulation. For example, men in New Delhi, North India werefound to have four times higher (2.5 vs. 9.7%) prevalence ofCAD than in Framingham, Mass.': 2 The hospitalization rate forCAD at Christian Medical College Vellore, South India, has in-creased from 4% of all cardiac admissions in 1960 to 33% in1989.3 The prevalence of CAD among male physicians whowere born in India and migrated to the United States is three tofour times higher than that of the general physician populationof the United States+ 5 The hospitalizationrate for CAD in theUnited States among Asian Indians who are not physicians isfour times higher than that of Caucasians, Japanese, and Fili-pinos, and five times higher than that of Chinese and otherAsians." In a prospective study of men in Trinidad, the inci-dence of CAD per 1,000 person years was found to be 16.4 inmen of Indian descent, 6.8 in men of African descent, 6.2 inthose of European descent, and 2.4 in men of mixed descent?The high rates of CAD mortality in the U'K, four to five timesgreater than in France, may be partly due to very high CADmortality rates in Asian Indians. Indeed, the standardized mor-tality ratio (SMR) for CAD among Asian Indian males in theU.K. is twice the national average between the ages of 30 and39 and more than three times the national average between theages of 20 and 29, despite universal access to similar advancedhealth care under the National Health Service,"

The CAD rates are high in Asian Indian women as well. Forexample, the prevalence of CAD in women in New Delhi isabout 10%.1The SMR for CAD among Asian Indian immigrantwomen in the Ll.K. is 1.5 times higher than of native Britishwomen and 2.6 times higher than of the immigrant Americanwomenf Asian Indian women in South Africa also have thehighest SMR for CAD of all ethnic groups: 4 times higher thanthat of U.S. women, 14 times higher than that of French wom-en, and 21 times higher than that of Japanese women. 9

The most striking feature of CAD in Asian Indians is its pre-dilection for accelerated atherosclerosis resulting in an unusu-ally high rate of premature morbidity and mortaliry+!' Athero-sclerosis in young Asian Indians is very severe, extensive,virulent, and rapidly progressive as illustrated by the follow-ingcase.

132

Angiographic Data from India

Clin. Cardiol. Vol. 18, March 1995

Case Report

A 39-year-old Asian Indian psychiatrist, a life-time non-smoker, with a family history of premature CAD was hospital-ized with an acute inferior myocardial infarction (MI). He was5' 7" tall and weighed 180 pounds. He had no hypertension ordiabetes. His total cholesterol was 208 mg/dl, high-density lipo-protein (HDL) 28 mg/dl, and triglyceride 152 mg/dl. His coro-nary angiogram showed total occlusion of the right coronaryartery with no significant disease in other vessels. Four weeksafter the uncomplicated MI, he was able to exercise 12 min ontreadmill (Bruce protocol) without ischemic changes on theelectrocardiogram. His advised medical management consist-ed of a low-fat diet, exercise, weight reduction, and cholesterol-lowering medication. Nine years later the patient developed se-vere exertional dyspnea and fatigue. A thallium perfusion scanshowed extensive defects in the anterior inferior, posterior, andlateral walls, and in the septum with minimal change betweenrest and exercise. A two-dimensional echocardiogram con-firmed extensive wall motion abnormalities with an ejectionfraction of25%. Left ventricular angiogram showed a mildlydilated cavity with posterior, basilar, anterolateral akinesia, andapical dyskinesia. The estimated ejection fraction was 25-30%.Left ventricular end-diastolic pressure was 36 mmHg. Coronaryangiogram showed severe diffuse disease with total occlusionof all three major coronary arteries. The patient underwentquadruple aortocoronary bypass surgery, but sought permanentdisability due to persistent symptoms. Lipoprotein (a) [Lp(a)]level was found to be lO2 mg/dl in the patient and 90 mg/dl inhis 18-year-old son.

Malignant Atherosclerosis in Young Asian Indians

Premature CAD is defmed as CAD occurring below the ageof 65 in women and 55 in men. CAD in the young is defined asCAD occurring in patients < 40 years of age!" and may repre-sent the most severe form of premature CAD. Of all cases ofCAD in the West, less than 5% occur in the young. 14The largestand most recent data from Texas involving 5,316 patientsshowed a prevalence of CAD in the young of only 2%.15 How-ever, CAD in the young is being recognized with increasing fre-quency and is as high as 12% in lndia.l"

In an angiographic study of patients with CAD under 40years of age in Malaysia, 56% were Asian Indians, althoughAsian Indians comprise only 10% of the population. After tak-ing into account the distribution of population of Malaysia,young Asian Indians had a 15-fold higher rate of CAD comparedwith Chinese and a lO-fold higherrate compared with Malays."Similarly, a review of patients hospitalized with a diagnosis ofMI in Quatar showed that 23 % were under 40 years of age, and71 % of these were Asian Indians, although these immigrantsform only a very small minority of the population. 12In studiesin the U .K., first:MI was noted to occur on an average of 5 yearsearlier, and its occurrence before age 40 was 10-fold higher inIndians than in Caucasians. 17Asian Indians had a substantiallyhigher frequency of triple-vessel CAD (54 vs. 21 %) and athero-

ma scores in coronary arteries (3.66 vs. 1.97). Infarct size as-sessed by peak creatine kinase or degree of ventricular dysfunc-tion was also significantly greater in Asian Indians. The first MIin this population was usually massive, resulting in a high rate ofdeath or disability. Many Asian Indians were found to be un-suitable for coronary artery bypass surgery because of the sever-ity of CAD, and 25% of these patients died soon afterward (vs.6% of Caucasians), indicating the severe nature of the disease. IS

Data from India seem to confirm the extensive and severeCAD among young Indians I9-23which seems to occur early inlife. In an angiographic study of 1,066 consecutive male pa-tients at Christian Medical College, Vellore, significant CADwas noted in 877 subjects. Of these, 55% were <50 years of age,34% were <45 years of age, and 12 % were <40 years of age. 16Although the mean age of patients with CAD was 48 years,triple-vessel disease was more common (55%) than double-ves-sel disease (24%) and single-vessel disease (21 %) combined.Multiple sites of obstruction in each vessel was a common find-ing. Recent reports from the All India Institute of MedicalSciences, New Delhi, 19.21have also confirmed the high preva-lence of triple-vessel CAD. The high prevalence of triple- ves-sel CAD among young Indians, approaching that of older pa-tients from the same institution (45 vs. 53%), is in sharp contrastto the 8-15% reported in the young in the West. 14.15Among theAsian Indian women with angiographically documented CAD.frequency of triple-vessel CAD was 35% in nonsmoking pre-menopausal women-? and 57% in postmenopausal women.P

The prognosis of CAD depends mainly on the extent ofatherosclerosis, the degree of left ventricular dysfunction, ane:the involvement of the proximal left anterior descending arter;(LAD).14, 15Pahlajani et at. from Bombay reported elevatedLVEDP in 28%, reduced left ventricular ejection fraction'51 %, and severely reduced « 25%) ejection fraction in lO* -their patients under 40 years of age.22 Among young Indians,36% had collaterals, suggestive of chronic and severe disease;28% had diffuse disease; and lO% had ectasia (aneuryCAD). The average number of vessels diseased per patient _2.7. In most series, the vessel most commonly diseased was . -LAD. Thus, atherosclerotic disease among young Asian Indizsoften resembles the pattern seen in their older counterparts-:

Increasing Excess Risk of CAD with Decreasing Age

The marked prematurity and extensive atherosclerosis ~to markedly higher mortality in young Asian Indians cowith other ethnic groups. For example, the overall S11R .CAD in Asian Indian men in the U.K. was only 36% hi.:-than that of Caucasians, but it was 313 % higher in the age ex-

of 20-29 years.f An even greater increase in SMR for C-with decreasing age was noted in Singapore. ComparedChinese, the SMR for CAD in Indian men was 300% higthe 60-69 age group. This increased to 390% in the 50--

E. A. Enas and J. Mehta: Coronary artery disease in Asian Indians 133

group, to 500% in the 40-49 age group, and to 1,250% in the30-39 age group. A similar pattern was seen in Indian women.l"

Conventional Risk Factors for CAD among AsianIndians

The conventional risk factors such as high serum cholesterol,hypertension, and cigarette smoking have not fully explainedthe high rate of premature and severe CAD in Asian Indians.Although smoking is common in young men with CAD, it isalmost nonexistent in Asian Indian women.19-22 Studies fromVellore have demonstrated that while cigarette smoking in-creases the rate of clinical events in CAD, it does not correlatewith the extent of coronary atherosclerosis.P The prevalence ofhypertension in young patients with CAD in India varies from12_32%19-23 and cannot explain the malignant nature of CAD.The frequency of clinical diabetes mellitus in young Indians isat 5_18%.19-23

The mean serum cholesterol level among Asian Indians issimilar to that of the general population in the U.S. and lowerthan in the U.K.4, 24Thus CAD is present in Asian Indians at lowtotal cholesterol and triglyceride levels. 16This is often inter-preted to imply that total cholesterol is a relatively unimportantrisk factor in the pathogenesis of CAD in this population. Instudies from Vellore, the mean total cholesterol was 205 mg/dlin patients with CAD and 186 mgldl in controls; the meantriglyceride level was 158 mgldl and 140 mg/dl, respectively.Among patients with CAD, 15% had total cholesterol < 150mg/dl and 45% had total cholesterol < 200 mg/dl.l" These datasuggest a correlation between atherogenic lipids and the pres-ence of CAD; however, "normal" serum cholesterol and triglyc-eride levels in the Caucasian population may be high for theAsian Indian population. Thus, the lower level of total choles-terol in Asian Indians compared with Caucasians may be mis-leading if we fail to recognize that the mean levels of totalcholesterol and triglycerides in Asian Indians with CAD are20-40 mg/dllower than in Caucasians with CAD.2, 16,24

The HDL cholesterol levels are low and triglyceride levelsare high in Asian Indian patients with CAD.24 Univariate anal-ysis has shown that the relative risk ofMI correlates directlywith triglyceride levels and inversely with HDL cholesterol lev-els in both Caucasians and Asian Indians. In multivariate anal-ysis, however, the ratio of total cholesterol to HDL (TCIHDLratio) emerges as the most powerful predictor ofMI in both pop-ulation groups, with triglyceride becoming an insignificant con-mbutor.>' The TCIHDL ratio was found to be superior in pre-dicting the risk of CAD in the Physicians Health Study, theFramingham Heart Study, and in explaining the interpopulationdifferences in CAD mortality in 19 industrialized countries.e- 27

High serum levels of apolipoprotein B and low serum levelstestosterone were recently found in young Asian Indian men

ith premature CAD.25, 28However the totality of the data sup-rts a more important role oflow HDL, high triglyceride, di-tes mellitus, hyperinsulinemia, and apple-type obesity, all

which are the hallmarks of the insulin resistance syndrome,hich has a substantially high prevalence in this population?

Lipoprotein (a) and Premature CAD

In comparison with Asian Indians, Mexican Americans havean even higher prevalence of diabetes and insulin resistance, buthave a lower CAD incidence and mortality. This paradox wasrecently explained by the lower level of Lp(a) in MexicanAmericans.P Lp(a) is a powerful independent risk factor forpremature atherosclerosis-v+' and multivessel CAD.33 It is asubfraction of low-density lipoprotein (LDL) but 10 times asatherogenic as LDL.37 Scanu has defmed Lp(a) as "a lipopro-tein particle having as a protein moiety, apolipoprotein B-100,disulfide-linked to apolipoprotein (a), the distinctive lipopro-tein of Lp(a) that is homologous to plasminogen.v'" It is a ge-netically determined dual pathogen related to both atheroscle-rosis and thrombosis. Serum levels ofLp (a) correlate directlywith the presence, extent, severity, and lesion score on coronaryangiogram, family history of premature CAD, restenosis aftercoronary angioplasty, and coronary artery bypass surgery, aswell as the infarct artery patency in survivors ofMI.31-43 Lp(a)is also the most powerful independent risk factor for the occur-rence and recurrence of MI and early death in men under 45years of age. 32

In a study of 1,150 subjects involving several countries andseven ethnic groups, mean Lp(a) levels among Asian Indiansin Singapore were two times higher than among all other eth-nic groups, with the exception of blacks. The mean Lp(a) levelwas three times higher (20 mg/dl vs. 7 mg/dl) in Asian Indiansthan in the Chinese in Singapore." This parallels the three-foldexcess of CAD reported among Indians compared with Chi-nese. to The Coronary Artery Disease in Asian Indians (CADI)Study also found the mean Lp(a) levels among Asian Indiansto be high.> In addition, the proportion of persons with Lp( a)above 30 mg/dl, the threshold at which increased risk of CADis believed to occur, is considerably higher among Asian Indians(25 %) compared with Caucasians (19%) and Mexican Ameri-cans (8%). The three-fold difference in Lp(a) levels betweenAsian Indians and Mexican Americans offers the best explana-tion for the markedly different rates of CAD in these two pop-ulations wi th high prevalence of insulin resistance.

Whereas Lp(a) is a powerful independent risk factor, its ef-fects are magnified in the presence of high LDL, or a high TCIHDL ratio.35, 42 The risk for premature CAD in women in-creases by more than 100-fold when the TCIHDL ratio is 6 andLp(a) is >55 mg/dl, compared with a TCIHDL ratio of 4 andLp(a) of < 15 mg/dl/? It may be hypothesized that in the pres-ence of abdominal obesity, insulin resistance, low HDL, andhigh triglycerides, the threshold for the detrimental effects ofLDL and Lp(a) is lowered and the adverse effects of LDL,Lp( a), and perhaps other conventional risk factors are magni-fied and contribute to the heightened susceptibility of CAD seenin Asian Indians.

Adverse Effects of High Lp(a) Begin in Infancy

Most studies on premature CAD have shown strong familyhistory signifying genetic factors. This may be important in ex-

i34 Chn. Cardiol. Vol. 18, March 1995

plaining the high prevalence of premature CAD in Asian In-dians despite the absence of excess of other conventional riskfactors. More than 90% ofLp(a) levels are determined geneti-cally+' and adult levels are reached by 8 months of age. 4SLp( a)levels in infants have been documented to be identical withthose of the affected parent." This suggests that the pathologicprocesses associated with high levels of Lp(a) start soon afterbirth, or about 15-20 years earlier than other risk factors, suchas hypertension and cigarette smoking, begin to contribute tothe pathogenesis of CAD. This also explains why the patho-logic effects ofLp(a) are most marked in the young. Its power-ful role in atherogenesis and thrombogenesis may underlie theextensive and severe nature of CAD and high mortality in youngAsian Indians.

reductase inhibitor, niacin can help optimize the lipid profile inmost individuals.

Conclusions

Asian Indians have the highest rate of CAD of any ethnicgroups studied thus far. Coronary atherosclerosis in this popu-lation occurs early and is very severe, extensive, and follows amalignant course with high mortality. Though conventional riskfactors, such as high cholesterol, hypertension, and cigarettesmoking, have failed to explain the excess risk of CAD fully,the importance of these risk factors cannot be ignored. Diabetes,insulin resistance, high triglyceride, low HDL cholesterol, andabdominal obesity are also important risk factors in the genesisof CAD in Asian Indians, but cannot account for the 5-1 O-foldhigher rate of CAD in individuals under 40 years of age. A ge-netic predisposition to CAD is suggested by the high levels ofLp(a). Measurements of Lp(a) may offer a unique opportunityto implement early high-risk prevention strategies in AsianIndians>' and should be included in all future studies in assess-ing the lipid-related risk of CAD in Asian Indians.

Since Lp(a) levels are not influenced by diet and environ-mental factors, pharmacologic means may have to be institut-ed in high-risk individuals earlier than in other populations.Guidelines developed for pharmacologic treatment of dyslipi-dernias in Caucasians may be too generous for this population.Aggressive modification of life style and careful evaluation ofall lipoproteins, including Lp(a), beginning before adolescence,seem justified in view of the malignant nature of atherosclero-sis in this population. Pharmacologic intervention similar to thatof secondary prevention of CAD, such as an LDL goal of 100mg/dl, seems justified as primary prevention in high-risk indi-viduals.

Preventive and Therapeutic hnpiications

Since Asian Indians develop CAD at a younger age and atlower levels of cholesterol and triglyceride than Caucasians, pre-ventive and therapeutic interventions should also begin earlyand at lower levels of cholesterol, triglyceride, and Lp(a). AllAsian Indians should strive to keep the TC/HDL ratio below 4.5,which often requires bringing the triglyceride level to < 150mg/dl, the cholesterol level to < 150 mg/dl, and LDL to < 100mg/dl. Avoidance of tobacco use and apple-type of obesity, aswell as careful selection of lipid-neutral or lipid-favorable anti-hypertensive medication to guard against aggravation of dys-lipidernias, cannot be overemphasized.

High Lp(a), high triglyceride, low HDL, and diabetes melli-tus, which are common among Asian Indians, may enhance theatherogenic effects ofLDL and contribute to heightened sus-ceptibility to CAD. Therefore, an LDL of 100 mg/dl, the levelrecommended for secondary prevention of CAD in the West46should be considered the desirable LDL level for primary pre-vention in Asian Indians, unless all other risk factors, includinghigh levels of Lp(a), are absent and HDL cholesterol is high (>60 mg/dl). It is important to note that the Indian vegetarians areno exception as they have the same high rate of CAD as non-vegetarians.' Since HDL cholesterol and Lp(a) are not amenableto dietary modification, increased physical activity may be moreimportant in this population. This will also help raise the HDLcholesterol, lower triglyceride levels, and modify insulin resis-tance. However, diet does influence the serum levels of LDLand triglyceride. If one fails to achieve the optimum lipid pro-file with life-style modification, then aggressive pharmacolog-ic treatment, often with multiple medications, may be neces-sary. This is particularly true in patients with premature CADand others undergoing coronary angioplasty, coronary bypasssurgery, or other revascularization procedures.

The adverse effects of Lp(a) can be reduced by loweringLDL cholesterol substantially= Safe and effective medicationsto lower LDL, such as cholestyrarnine and hydroxymethyl glu-taryl (HMG) coenzyme A reductase inhibitors are now avail-able." Though more difficult to take in large doses, moderatedoses of niacin can lower the levels ofLp(a) and triglyceride andraise HDL cholesterol. Together with an HMG coenzyme A

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