Pilot study of coronary atherosclerotic risk and plaque burden in HIVpatients: ‘a call for cardiovascular prevention’

Monica Acevedo a, Dennis L. Sprecher a,*, Leonard Calabrese b, Gregory L. Pearce a,Denise L. Coyner a, Sandra S. Halliburton c, Richard D. White c, Elizabeth Sykora b,

George T. Kondos d, Julie A. Hoff d

a Section of Preventive Cardiology and Rehabilitation, Department of Cardiology, The Cleveland Clinic Foundation, Desk C 51, 9500 Euclid Avenue,

Mail Code C51, Cleveland, OH 44195, USAb Department of Rheumatic and Immunologic Disease, The Cleveland Clinic Foundation, Cleveland, OH, USA

c Section of Cardiovascular Imaging, Department of Radiology, The Cleveland Clinic Foundation, Cleveland, OH, USAd Section of Cardiology, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL, USA

Received 3 August 2001; received in revised form 5 December 2001; accepted 7 January 2002

Abstract

Background: Highly active antiretroviral therapy (HAART) has dramatically improved the life expectancy of patients with

human immunodeficiency virus (HIV) prompting increasing concerns related to chronic management. Suggestions of greater

cardiovascular risk, partially related to recently proposed HAART-induced dyslipidemia and glucose intolerance, amplify these

concerns. At this time, further corroboration of the emerging evidence for increased coronary risk, as well as complimentary

estimates of coronary artery atherosclerotic burden, would be valuable to practicing physicians. Methods: Seventeen HIV patients

on HAART (all from the same HIV clinic population) without coronary artery disease (CAD) were referred to Preventive

Cardiology for treatment of dyslipidemia (‘referred group’). Upon entry, they underwent computed tomography (CT) of the

coronary arteries. Subsequently, the referred group was matched (1:4) for age, gender and traditional risk to non-HIV non-CAD

subjects (matched group, n�68) from the University of Illinois CT database. A serial review of 90 subjects from the original HIV

population was sampled to determine general cardiovascular risk. Results: Thirteen (76%) of the 17 referred patients revealed the

presence of coronary calcium compared with 63% in the matched HIV seronegative controls (P�0.18). Log-transformed median

calcium score was 2.9392.3 in the referred group versus 1.9792.5 in the matched group (P�0.09). Fifty one percent of the overall

population smoked cigarettes, 11% were diabetic (30% diagnosed pre-HAART and 70% post-HAART) and 30% were hypertensive

(33% diagnosed pre-HAART and 67% post-HAART). Conclusions: In a particularly dyslipidemic subgroup of HIV subjects

without known CAD we found evidence for atherosclerosis in three-quarters based on coronary calcium. Further, in this population

of HIV patients on HAART, we found an enhanced prevalence of traditional cardiovascular risk. This pilot study encourages the

development of preventive strategies in this population. # 2002 Published by Elsevier Science Ireland Ltd.

Keywords: HIV; Coronary disease; Risk factors; Calcium; Tomography

1. Introduction

Through the use of highly active antiretroviral

therapy (HAART), the acute short-term mortality

concerns related to human immunodeficiency virus

(HIV) infection have been partially replaced by poten-

tially more long-term chronic disease issues [1�/4]. For

example, there is a growing concern that HIV patients

are at an increased risk of developing premature

coronary artery disease (CAD) [5�/7]. The attendant

dyslipidemia, smoking and reported chronic inflamma-

tory state [8,9] fuel these concerns. Currently, there are

few data to approximate the level of cardiovascular risk

or the prevalence of atherosclerotic lesions in HIV

patients [10].Herein, we performed computed tomography (CT) of

the coronary arteries to measure coronary calcium

* Corresponding author. Tel.: �1-216-444-9426; fax: �1-216-444-

8856.

E-mail address: sprechd@ccf.org (D.L. Sprecher).

Atherosclerosis 163 (2002) 349�/354

www.elsevier.com/locate/atherosclerosis

0021-9150/02/$ - see front matter # 2002 Published by Elsevier Science Ireland Ltd.

PII: S 0 0 2 1 - 9 1 5 0 ( 0 2 ) 0 0 0 1 6 - 3

scores in a small referred dyslipidemic cohort, as well as

characterized traditional cardiovascular risk in an HIV

clinic population.

2. Methods

2.1. Patients

The ‘referred group’ consisted of all HIV patients

referred to the Preventive Cardiology Unit based on

total plasma triglycerides (TG)�200 mg/dl (2.25 mmol/

l) and /or LDL cholesterol (LDL-C)�160 mg/dl (4.14mmol/l), HAART for at least 6 months and absence of

known CAD (n�19). Two patients refused to be

included in the study. None of the 17 remaining patients

had opportunistic infections. We subsequently requested

all the charts from the HIV patients actively seen in the

same referring clinic since January 2000 (n�98) and

selected the patients without CAD and on HAART for

at least 6 months (‘non-referred group’, n�73).Further, we utilized 35 426 entries from the University

of Illinois Electron Beam Tomography database [11] to

match each of our 17 referred patients to 4 database

HIV seronegative individuals for age, gender, BMI,

current smoking, as well as histories of hypertension,

diabetes or familial premature cardiovascular disease

(‘matched group’).

All the patients gave informed consent. The ClevelandClinic Foundation Investigational Review Board ap-

proved the study.

2.2. Study protocol

We recorded the traditional cardiovascular risk fac-

tors including age, gender, body mass index (BMI),

hypertension, diabetes, smoking, family history ofCAD, duration of HAART and presence of fat redis-

tribution (facial/extremity wasting and/or visceral fat

accumulation/buffalo hump assessed by HIV physician)

in the overall HIV cohort including both referred and

non-referred patients (n�90). Blood samples were

drawn after a 12-h fasting period in all the patients

(referred and non-referred groups) that did not have a

complete lipid profile available at least 6 months afterthe beginning of HAART. These included: total choles-

terol (TC), HDL cholesterol (HDL-C), LDL-C and TG

(Hitachi Analyzer, Boehringer Mannheim). LDL-C was

quantified by direct assays (immunoprecipitation) when

TG levels were �400 mg/dl (�4.5 mmol/l). In the

referred group, we also determined serum high-sensitiv-

ity C-reactive protein (hs-CRP; Dade-Behring Instru-

ments, Newark, Delaware). The normal value for hs-CRP ranges from 0.0 to B1 mg/l. CRP levels were

compared with the Harvard Health Physicians’ Study

population [12]. CD4 count and plasma HIV RNA

levels were also measured (Amplicor HIV-1 Monitor

Test).

Coronary artery imaging was performed on a state-of-

the-art multi-detector CT scanner (Somatom VolumeZoom, Siemens Medical System, Erlangen, Germany) in

the referred group. Multi-detector CT scanning of the

heart for various applications has been described [13,14].

Each image set was analyzed (coauthor RDW) off-line

(NetraMD, ScImage, Inc., Los Altos, CA). Agatston

method [15] was used to quantify coronary calcium. For

matched cases (HIV seronegative), coronary artery

calcium was determined using an Imatron electronbeam tomography scanner and calcium was quantified

also using the Agatston method [15]. We targeted the

prevalence of coronary artery calcium in the referred

group compared with matched patients. While not

utilizing equivalent scanning technologies for these two

populations, general similarity in sensitivities, as sug-

gested in two studies [16,17], or even possible enhanced

sensitivity of electron beam tomography, permits areasonable, if not conservative comparison.

2.3. Statistics

Traditional risk parameters are reported as median

and interquartile range (IQR) for continuous measures

and frequencies for categorical measures. Framingham

risk scores [18] were used to calculate the 10-year

cardiovascular risk for both the referred and non-referred populations. Differences between the referred

and non-referred groups were evaluated with Wilcoxon

rank sum tests for continuous measures and chi-square

tests for categorical measures. Calcium scores were

transformed using the natural logarithm of 1�calcium

score because calcium scores do not exhibit a Gaussian

distribution (1 was added to the calcium score because

the normal value is 0). Paired permutation tests (with10 000 permutations) were used to evaluate the prob-

ability that the observed differences in calcium scores

between the referred group and the matched group were

due to chance. A similar approach using simply the

presence or absence of calcium was also employed with

10 000 permutations.

3. Results

Fifty percent of the referred group smoked cigarettes

and 50% had hypertension (three patients pre-HAART

and five post-HAART). At the median age of 46 years,

the Framingham risk score was nearly 10% in 10 years

(Table 1). Thirteen of the 17 referred patients (76%) had

detectable coronary calcium on CT, while 43 of 68 (63%)revealed the same in the matched HIV seronegative

cohort (P�0.18). The mean transformed calcium score

tended to be higher in the referred group (2.9392.26)

M. Acevedo et al. / Atherosclerosis 163 (2002) 349�/354350

than in the matched group (1.9792.45; P�0.09; Table

2). Therefore, the average difference in coronary calcium

scores between these patients and the matched controls

was 0.96. When the paired permutation test was applied,

a difference score as great as 0.96 was recorded 933

times yielding a P value of 0.09.

Characteristics of the 90 HIV subjects on HAART are

presented in Table 1. The population was young

(median, 42 years) demonstrating a high prevalence of

cigarette use (51%), hypertension (n�27 (30%) of

whom 18 were diagnosed post-HAART) and diabetes

(n�10 (11%) of whom seven were diagnosed post-

HAART). LDL-C values were normal, HDL-C values

were low and TG values were high (Table 1). In the non-

referred group there was a 51% prevalence of hyperli-

pidemia (defined as TG�200 mg/dl (�2.25 mmol/l)

and/ or LDL�160 mg/dl (�4.15 mmol/l)). The re-

ferred group tended to be older (median, 46 years) and

have higher TG and TC levels. LDL-C and HDL-C

were comparable to the non-referred HIV group. The

BMI was lower in the referred group. Comparable

prevalence of smoking, hypertension, diabetes, duration

of HAART and percentage of protease inhibitor (PI)

use were observed in the referred and non-referred

groups. Fat redistribution was more prevalent in the

referred group. None of the patients in the referred

group was taking anabolic steroids or lipid lowering

medications. Among the others, 11 were on anabolic

steroids and one was taking atorvastatin. Mean Fra-

mingham risk score for 10-year CAD-risk was higher in

the referred group (Table 1).

In the overall HIV population (n�90), high TG

levels �200 mg/dl (�2.25 mmol/l) tended to be

associated with a higher incidence of diabetes

(P�0.09) and hypertension (P�0.05). In the referred

population, median hs-CRP was 2.50 mg/l (IQR�1.3�/

5.7) exceeding the third quartile (1.15 mg/l) of Harvard

Health Physicians’ Study (16) in 13 (76%) patients.

Table 1

Clinical characteristics for the overall HIV cohort and referred group

Total (n�90) Non-referred (n�73) Referred group (n�17) P value*

Age (years) 42 (37�/49) 41 (37�/48) 46 (40�/51) 0.11

HAART (months)** 36 (24�/45) 36 (23�/45) 37 (24�/34) 0.93

Fat redistribution (%) 37 32 59 0.04

CD4 count (cell per U) 442 (232�/326) 423 (224�/601) 590 (412�/946) 0.03

HIV RNA (copies per ml) 824 (0�/5646) 1064 (0�/6082) 450 (76�/4938) 0.97

Protease inhibitors (%) 78 79 76 0.75

Hypertension (%) 30 26 47 0.09

Cigarette use (%) 51 51 53 0.87

Diabetes (%) 11 10 18 0.39

Family history CAD (%) 28 31 18 0.38

TC (mg/dl) 219 (177�/254) 208 (169�/238) 261 (220�/330) 0.002

(mmol/l) 5.64 (4.56�/6.55) 5.36 (4.36�/6.13) 6.73 (5.67�/8.51)

LDL (mg/dl) 112 (85�/142) 109 (88�/136) 112 (72�/162) 0.74

(mmol/l) 2.87 (2.19�/3.66) 2.81 (2.27�/3.51) 2.89 (1.86�/4.18)

HDL (mg/dl) 39 (35�/50) 39 (34�/52) 39 (35�/42) 0.26

(mmol/l) 1.01 (0.90�/1.29) 1.01 (0.88�/1.34) 1.01 (0.90�/1.08)

TG (mg/dl) 231 (133�/355) 206 (121�/309) 490 (320�/768) B0.001

(mmol/l) 2.60 (1.50�/4.00) 2.32 (1.36�/3.48) 5.52 (3.60�/8.65)

Body mass index 25 (22�/28) 26 (23�/28) 22 (21�/25) 0.02

Framingham risk score 7.5196.26 6.9695.65 9.6598.15 0.11

Continuous measures are presented as median and IQRs and categorical measures as percentages. *, P value compared with non-referred group;

HAART, highly active antiretroviral therapy; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase

inhibitor; PI, Protease inhibitor. **, HAART combinations (Referred group): 2 NRTI�2 PI (four patients); 2 NRTI�1 PI (seven patients); 2

NRTI�1 NNRTI (three patients); 2 NRTI�1 NNRTI�2 PI (two patients); 3 NRTI�1 PI (one patient). **, HAART combinations (non-referred

group): 2 NRTI�1 PI (46 patients); 2 NRTI�1 NNRTI (12 patients); 2 NRTI�2 PI (four patients); 1 NRTI�1 NNRTI�1 PI (four patients); 3

NRTI�1 NNRTI (five patients); 1 NRTI�2 PI (two patients).

Table 2

Characterization of calcium load for referred patients and matched

controls

Referred group Matched group

N 17 68a

Median 14.4 1.0

IQR 1.0�/131.5 0.0�/44.9

ln(1�calcium score) 2.9392.3 1.9792.5

Calcium score �0.0 13 (76%) 43 (63%)

a Four to one match for age, gender, BMI, current smoking, history

of diabetes, history of hypertension and family history of premature

coronary artery disease.

M. Acevedo et al. / Atherosclerosis 163 (2002) 349�/354 351

4. Discussion

In a small dyslipidemic subgroup of HIV patients

treated with HAART who were not known to haveCAD, we found evidence for atherosclerosis in at least

75% of the subjects based on coronary arterial calcium.

These pilot data and the known vascular consequences

of dyslipidemia, hypertension and cigarette use, com-

monly observed in such a cohort, strongly encourage the

implementation of preventive treatment approaches.

The advent of HAART has offered the prospects of

long-term control of HIV infection and the potential forextended life expectancy. Unexpected metabolic com-

plications, such as body fat redistribution, dyslipidemia

and insulin resistance, at least partially related to

HAART, are now often being observed in those regimes

containing these combinations of drugs [1�/4,10]. The

enhanced prevalence of diabetes and hypertension in our

cohort, i.e. 11 and 30% (compared with 3.9% and 21%,

respectively in the NHANES III population for the 40�/

49-age range [19,20]) is consistent with this metabolic

phenotype. Indeed, the presence of a ‘metabolic syn-

drome’ is supported by the observed clustering of high

TG values with clinical expressions of diabetes and

hypertension [21], parallel to the recent findings of

Hadigan et al. [22]. Additionally, in our overall HIV

study group, 37% had some evidence of body fat

redistribution. These factors, along with excessive cigar-ette use (51% compared with the current US norm of

25% [23]), suggest considerable cardiovascular risk. It is

also worthy of consideration to note that the median

CD4 count in the referred group was well controlled at

590 cells per U, which when combined with a low

median HIV RNA, gives a low risk for HIV-related

clinical events in the next 5�/10 years. This, further,

emphasizes the long-term importance of the enhancedcardiovascular risk found in this population.

Seventeen HIV subjects were referred to Preventive

Cardiology for the management of dyslipidemia and

thus, studied more extensively. We found it impressive

that 76% of this referred HIV cohort revealed detectable

coronary calcium, implicating the presence of athero-

sclerosis. There was a trend towards a higher prevalence

of detected coronary calcium than in subjects matchedfor known cardiovascular risk (76 vs. 63%, P�0.18) or

compared with three historical populations [24�/26] (47,

50 and 55%, respectively). Calcium is not present in

normal coronary arteries. Therefore, the visualization of

coronary calcium on CT scanning strongly implicates

the presence of atherosclerotic plaque. This is true even

though calcification of the coronary arteries remains a

controversial arena for diagnostic evaluation of asymp-tomatic patients [27]. Beyond enhanced traditional risk

and coronary calcium, there was also a higher preva-

lence of hsCRP elevation (an accepted risk marker for

CAD [12]) in our patients when compared with the

Physicians’ Health Study [12]. Two small reports [8,12]

have suggested that symptom-free AIDS-patients have

higher plasma concentrations of CRP compared with

controls. The use of hsCRP has been recently proposedto be used in primary prevention subjects to improve

cardiovascular risk assessment [28] beyond traditional

risk. However, the specific relevance of CRP as a risk

factor for cardiovascular disease in HIV patients is still

unknown. Finally, the notion that recently imposed risk

(e.g. elevated TG or LDL with HAART, or the HIV

infection itself) may result in less atherogenesis than that

expected based on a lifetime of traditional risk is notsupported by these data. While the differences in

calcium scores between our high-risk HIV referred

population and the high-risk matched group HIV

patients are marginal, the trend is suggestive of even

more atherosclerotic burden in the HIV patients. Until

we have the results of ongoing studies in the HIV

population treated with HAART, the possibility of an

enhancement in cardiovascular risk in association withrecently imposed risk in these patients cannot be

ignored.

The high cardiovascular risk profile in the patients

attending our clinic, as well as in our referral base would

advocate for a screening of traditional cardiovascular

risk factors in all HIV patients before starting HAART.

Also, they would encourage cigarette cessation and low

fat diets as prudent proposals, while statins (specificallypravastatin [29] and atorvastatin [5]) and fibrates [5,29],

along with other standard preventive strategies, e.g.

aspirin, blood pressure control and diabetic therapy, as

particularly worthy of consideration.

Various factors, however, should be taken in account

when managing these patients, especially when treating

hyperlipidemia. Few data are available on potential

drug interactions with HAART [29], which may berelevant to therapeutic considerations. Many antiretro-

viral agents, particularly PIs, are metabolized in the liver

through the cytochrome P-450 3A4 [29,30] and are

known to inhibit its enzymes. Ritonavir, as a prime

example, is a potent inhibitor of this cytochrome. Most

statin agents (with the exception of pravastatin and the

upcoming rosuvastatin) are metabolized through the

cytochrome pathway as well. Thus, plasma statin levelsmay increase during HAART (including PIs) and,

therefore, could translate into a higher risk for myo-

pathy and rhabdomyolysis [31]. Pravastatin has been

reported as particularly safe among these agents when

used in combination with HAART in that its metabo-

lism is outside the p450 system and that it does not

appear to negatively affect antiviral efficacy (G. Moyle

et al. abstract presented at the XIII International AIDSConference, 9�/14 July 2000, Durban, South Africa).

Fibrates improve lipoprotein lipase activity (which may

be inhibited with PI therapy), reduce dense LDL, and

are the preferred drugs when TG levels are the main

M. Acevedo et al. / Atherosclerosis 163 (2002) 349�/354352

concern [29]. Significant interactions between HAART

treatment and fibrates have not been reported, however,

little is known about efficacy and safety with these

agents in HIV patients [30]. Combination of statins and

fibrates should be avoided, again because of enhanced

probability of rhabdomyolysis. Resins are not suggested

as they may increase TG levels and interfere with the

absorption of HIV-related oral therapies [29,30]. Niacin

may further exacerbate the glucose issues associated

with treated HIV patients. Finally, many patients

receiving HAART are already taking several medica-

tions (i.e. different prophylactic antibiotics for oppor-

tunistic infections) and some of them have also hepatitis

B or C, increasing even more the risk for drug

interactions [29,30].

Given the positive impact of the new HIV medications

on life expectancy, we believe that the noted presence of

multiple CV risk factors and atherosclerotic plaque

should promote preventive strategies and research for

long-term cardiovascular wellness in the HIV popula-

tion.

References

[1] Wanke CA. Epidemiological and clinical aspects of the metabolic

complications of HIV infection the fat redistribution syndrome

[editorial]. AIDS 1999;13(11):1287�/93.

[2] Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of

HIV-1-protease inhibitor-associated peripheral lipodystrophy,

hyperlipidaemia, and insulin resistance. Lancet

1998;351(9119):1881�/3.

[3] Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm

DJ, Cooper DA. Diagnosis, prediction, and natural course of

HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidae-

mia, and diabetes mellitus: a cohort study. Lancet

1999;353(9170):2093�/9.

[4] Periard D, Telenti A, Sudre P, Cheseaux JJ, Halfon P, Reymond

MJ, et al. Atherogenic dyslipidemia in HIV-infected individuals

treated with protease inhibitors. The swiss HIV cohort study.

Circulation 1999;100(7):700�/5.

[5] Henry K, Melroe H, Huebsch J, Hermundson J, Levine C,

Swensen L, et al. Severe premature coronary artery disease with

protease inhibitors [letter; see comments]. Lancet

1998;351(9112):1328.

[6] Behrens G, Schmidt H, Meyer D, Stoll M, Schmidt RE. Vascular

complications associated with use of HIV protease inhibitors

[letter; comment]. Lancet 1998;351(9120):1958.

[7] Flynn TE, Bricker LA. Myocardial infarction in HIV-infected

men receiving protease inhibitors [letter]. Annals of Internal

Medicine 1999;131(7):548.

[8] Jahoor F, Gazzard B, Phillips G, Sharpstone D, Delrosario M,

Frazer ME, et al. The acute-phase protein response to human

immunodeficiency virus infection in human subjects. American

Journal of Physiology 1999;276((6 Pt 1)):E1092�/8.

[9] Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P,

Feingold KR. Lipids, lipoproteins, triglyceride clearance, and

cytokines in human immunodeficiency virus infection and the

acquired immunodeficiency syndrome. Journal of Clinical En-

docrinology and Metabolism 1992;74(5):1045�/52.

[10] Maggi P, Serio G, Epifani G, Fiorentino G, Saracino A, Fico C,

et al. Premature lesions of the carotid vessels in HIV-1 infected

patients treated with protease inhibitors. AIDS 2000;14:123�/8.

[11] Hoff J, Chomka E, Krainik A, Daviglus M, Rich S, Kondos G.

Age and gender distributions of coronary artery calcium detected

by electron beam computed tomography: a study in 35 426 adults,

American Journal of Cardiology 2001;87(12):1335�/39.

[12] Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens

CH. Inflammation, aspirin, and the risk of cardiovascular disease

in apparently healthy men. New England Journal of Medicine

1997;336(14):973�/9.

[13] Ohnesorge B, Flohr T, Becker C, Kopp AF, Schoepf UJ, Baum

U, et al. Cardiac imaging by means of electrocardiographically

gated multisection spiral CT: initial experience. Radiology

2000;217(2):564�/71.

[14] Achenbach S, Ulzheimer S, Baum U, Kachelriess M, Ropers D,

Giesler T, et al. Noninvasive coronary angiography by retro-

spectively ECG-gated multislice spiral CT. Circulation

2000;102(23):2823�/8.

[15] Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte

M, Jr, Detrano R. Quantification of coronary artery calcium

using ultrafast computed tomography. Journal of the American

College of Cardiology 1990;15(4):827�/32.

[16] Becker CR, Jakobs TF, Aydemir S, Becker A, Knez A, Schoepf

UJ, et al. Helical and single-slice conventional CT versus electron

beam CT for the quantification of coronary artery calcification.

American Journal of Roentgenology 2000;174(2):543�/7.

[17] Carr JJ, Crouse JR, Goff DC, Jr, D’Agostino RB, Jr, Peterson

NP, Burke GL. Evaluation of subsecond gated helical CT for

quantification of coronary artery calcium and comparison with

electron beam CT. American Journal of Roentgenology

2000;174(4):915�/21.

[18] Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz

H, Kannel WB. Prediction of coronary heart disease using risk

factor categories [see comments]. Circulation 1998;97(18):1837�/

47.

[19] Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE,

Little RR, et al. Prevalence of diabetes, impaired fasting glucose,

and impaired glucose tolerance in US adults. The Third National

Health and Nutrition Examination Survey, 1988�/1994 [see

comments]. Diabetes Care 1998;21(4):518�/24.

[20] Burt VL, Culter JA, Higgins M, Horan MJ, Labarthe D, Whelton

P, et al. Trends in the prevalence, awareness, treatment, and

control of hypertension in the adult US population. Data from

the health examination surveys 1960�/1991. Hypertension

1960;26(1):60�/9.

[21] Reaven GM. Banting lecture 1998. Role of insulin resistance in

human disease. Diabetes 1988;37(12):1595�/15607.

[22] Hadigan C, Meigs J, Corcoran C, Rietschel P, Piecuch S, Basgoz

N, et al. Metabolic abnormalities and cardiovascular disease risk

factors in adults with human immunodeficiency virus infection

and lipodystrophy. Clinical of Infectious Diseases 2001;32:130�/9.

[23] From the Centers for Disease Control and Prevention. State-

specific prevalence of cigarette smoking among adults, and

children’s and adolescents’ exposure to environmental tobacco

smoke*/US, 1996. Journal of American Medical Association

1997;278(23):2056�/57.

[24] Janowitz WR, Agatston AS, Kaplan G, Viamonte M, Jr.

Differences in prevalence and extent of coronary artery calcium

detected by ultrafast computed tomography in asymptomatic men

and women. American Journal of Cardiology 1993;72(3):247�/54.

[25] Wong ND, Kouwabunpat D, Vo AN, Detrano RC, Eisenberg H,

Goel M, et al. Coronary calcium and atherosclerosis by ultrafast

computed tomography in asymptomatic men and women: relation

to age and risk factors. American Heart Journal 1994;127(2):422�/

30.

M. Acevedo et al. / Atherosclerosis 163 (2002) 349�/354 353

[26] Hecht H, Superko H, Smith L, McColgan B. Relation of

coronary artery calcium identified by electron beam computed

tomography to serum lipoprotein levels and implications for

treatment. American Journal of Cardiology 2001;87:406�/12.

[27] O’Rourke RA, Brundage BH, Froelicher VF, Greenland P,

Grundy SM, Hachamovitch R, et al. American College of

Cardiology/American Heart Association Expert Consensus docu-

ment on electron-beam computed tomography for the diagnosis

and prognosis of coronary artery disease. Circulation

2000;102(1):126�/40.

[28] Ridker PM. High-sensitivity c-reactive protein. Potential adjunct

for global risk assessment in the primary prevention of cardio-

vascular disease. Circulation 2001;103:1813�/8.

[29] Dube M, Sprecher D, Henry K, Aberg J, Fj T, Hodis H, et al.

Preliminary guidelines for the evaluation and management of

dyslipidemia in adults infected with human immunodeficiency

viru and receiving antiretroviral therapy: recommedentations of

the adult AIDS Clinical Trial Group Cardiovascular Disease

Focus Group. Clinical of Infectious Diseases 2000;31:1216�/24.

[30] Geletko SM, ZuWallack AR. Treatment of hyperlipidemia in

HIV-infected patients. American Journal of Health-System Phar-

macy 2001;58(7):607�/14.

[31] Mantel-Teeuwisse AK, Kloosterman JM, Maitland-van der Zee

AH, Klungel OH, Porsius AJ, de Boer A. Drug-Induced lipid

changes: a review of the unintended effects of some commonly

used drugs on serum lipid levels. Drug Safety 2001;24(6):443�/56.

M. Acevedo et al. / Atherosclerosis 163 (2002) 349�/354354