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Heart Disease in HIV: 64-slice multidetector row computed tomography coronary angiography predicts outcome,
are we evaluating risk for heart disease in HIV correctly?
 
 
  "using standard cardiovascular risk testing like the Framingham score were not reliable, that they underestimated CVD risk and that computed tomography (CT) more reliably detected risk"...."Framingham risk prediction algorithm is not a reliable clinical tool for identification of patient who qualify for primary prevention. Agreement between Framingham and clinical tools is less than ideal......Figure 2 below depicts that 8.3% of HIV+ individuals do not need primary prevention intervention for heart disease when using the Framingham Risk Score despite having a high risk score when evaluated by CT (computed tomography) for coronary artery calcium (CAC)......This study suggests that HIV asymptomatic young individuals may be reasonable candidates for electron bean CT as a potential means of modifying risk prediction and altering therapy."
 
Moving from risk factor assessment to atherosclerosis imaging to select the most appropriate patient for primary prevention: CVD algorithms underestimate risk in HIV+ - (11/30/09)
 
-----"A renewed attitude for prevention of cardiovascular disease suggests a changing paradigm in clinical assessment, moving from risk prediction to identification of people who qualify for CVD primary prevention."
 
"Our findings suggest a high prevalence and significant degree of coronary atherosclerosis among young HIV-infected men with a long duration of HIV disease, without any symptoms of cardiac disease or a prior diagnosis of cardiac disease and with a generally low Framingham risk score"
...Giovanni Guaraldi found that using standard cardiovascular risk testing like the Framingham score were not reliable, that they underestimated CVD risk and that computed tomography (CT) more reliably detected risk....CRP and IL-6 were not increased in our participants......there is a relationship between HIV infection and coronary artery atherosclerosis independent of traditional cardiovascular risk factors, as traditional risk factors were generally similar between the groups, yet significant differences in plaque prevalence and plaque burden were seen between the HIV and non-HIV groups......."Coronary calcium score alone may not provide a true measure of early atherosclerosis in young HIV patients as plaque calcification usually occurs at a later stage and may not detect more vulnerable plaque lesions, which tend to be noncalcified or mixed calcified and noncalcified. In addition, the atherosclerotic disease process in HIV may be different from conventional atherosclerosis [25]. No published studies to date have used coronary CTA to assess noncalcified plaques in HIV patients. Our data using CTA show that a significant proportion of patients with coronary atherosclerosis would have been missed if calcium score was used as the sole criterion for coronary atherosclerosis as 23.8% (95% confidence interval 13.5- 38.5%) of HIV patients had evidence of noncalcified plaque seen on CTA among those with calcium score of zero"
 
1. IAC: Coronary CT Sees Blockage in Half of HIV Group With No Heart Disease Symptoms - written by Mark Mascolini - (07/27/10"We investigated the degree of subclinical atherosclerosis and the relationship of traditional and nontraditional risk factors to early atherosclerotic disease using coronary computed tomography angiography.....without history or symptoms of CAD..... 64-slice multidetector row computed tomography coronary angiography was performed to determine prevalence of coronary atherosclerosis, coronary stenosis, and quantitative plaque burden.HIV-infected men demonstrated higher prevalence of coronary atherosclerosis than non-HIV-infected men (59 vs. 34%; P = 0.02), higher coronary plaque volume [55.9 (0-207.7); median (IQR) vs. 0 (0-80.5) [mu]l; P = 0.02], greater number of coronary segments with plaque [1 (0-3) vs. 0 (0-1) segments; P = 0.03], andhigher prevalence of Agatston calcium score more than 0 (46 vs. 25%, P = 0.04), despite similar Framingham 10-year risk for myocardial infarction, family history of CAD, and smoking status. Among HIV-infected patients, Framingham score, total cholesterol, low-density lipoprotein, CD4/CD8 ratio, and monocyte chemoattractant protein 1 were significantly associated with plaque burden (from Jules: triglycerides borderline significance). Duration of HIV infection was significantly associated with plaque volume (P = 0.002) and segments with plaque (P = 0.0009) and these relationships remained significant after adjustment for age, traditional risk factors, or duration of antiretroviral therapy. A total of 6.5% (95% confidence interval 2-15%) of our study population demonstrated angiographic evidence of obstructive CAD (>70% luminal narrowing) as compared with 0% in controls.
 
"all 3258 CARDIA study participants who received cardiac computed tomography to evaluate coronary calcium after age 35 years......Nearly one half (44%) of persons with time-averaged LDL cholesterol levels of 4.14 mmol/L (160 mg/dL) or greater during young adulthood had coronary calcium, compared with only 8% of those with levels of less than 1.81 mmol/L (70 mg/dL). Extensive coronary calcification (coronary calcium score >100) was absent in the latter group (prevalence, 0% [CI, 0% to 3%]). Similar trends were present for HDL cholesterol (inverse) and triglyceride levels (Figure 1). ......Our findings reveal that nonoptimal LDL cholesterol levels during young adulthood are associated with coronary calcification later in life. Levels of LDL cholesterol during young adulthood are correlated with lipid levels later in life, but accounting for later-life lipid exposure did not explain the association of young adult LDL cholesterol levels with calcification.......After we removed the potentially obscuring influences of medication use and clinically abnormal levels of other lipids, we also observed an inverse association with HDL cholesterol levels but no association with triglyceride levels. Our results suggest that atherosclerotic changes begin during young adulthood as a result of commonly observed nonoptimal lipid levels, that these changes persist into middle age, and that maintaining optimal levels of lipids (particularly LDL cholesterol) throughout young adulthood could provide substantial benefits in terms of lifetime CHD prevention.....young adults and their physicians should realize that what they eat and how much they exercise seem to matter even early in life, when short-term CHD risk is extremely low, and that healthy behaviors should not be deferred until middle age.
 
"In the subset of participants who did not have clinically abnormal lipid levels and never reported receiving a lipid-lowering medication, the association with LDL cholesterol level remained strong (Table 3). Coronary calcium was rare in those with optimal LDL cholesterol levels (prevalence, 4%), and even modest increases in LDL cholesterol level of 3.37 to 4.12 mmol/L (130 to 159 mg/dL) were associated with a higher prevalence of coronary calcium (17%). In this subset, lower HDL cholesterol levels before age 35 years were also associated with coronary calcium later in life, with higher odds of coronary calcium when participants were exposed to time-averaged HDL cholesterol levels of 1.04 to 1.27 mmol/L (40 to 49 mg/dL) compared with levels of 1.81 mmol/L (70 mg/dL) or greater (OR, 2.8 [CI, 1.1 to 6.8]), after we adjusted for LDL cholesterol level, triglyceride level, HDL cholesterol level after age 35 years, and other CHD risk factors. After multivariate adjustment, we found no association between triglyceride levels and coronary calcium.""
 

"can lipid levels early in life......contribute to atherosclerotic damage during later life.....study participants underwent cardiac computed tomography to evaluate for the presence of coronary calcium 10 or 15 years after enrollment......The prevalence of coronary calcium was only 4% in subjects with optimal LDL cholesterol levels, and even modest elevations in LDL to the range of 3.37 to 4.12 mmol/L led to an increase in prevalence of coronary calcium to 17%.....coronary calcium -- a surrogate measure of coronary artery disease....For young adults ages 18 to 30 years whose low-density lipoprotein (LDL) cholesterol levels were 4.14 mmol/L or greater, the adjusted odds ratio for having coronary calcium two decades later was 5.6"

 
High LDL in Youth Predicts Coronary Calcification Later
 
MedPage Today
Published: August 03, 2010
 
Young adults whose lipid levels are less than optimal are likely in midlife to develop coronary calcium -- a surrogate measure of coronary artery disease, a large prospective cohort study found.
 
For young adults ages 18 to 30 years whose low-density lipoprotein (LDL) cholesterol levels were 4.14 mmol/L or greater, the adjusted odds ratio for having coronary calcium two decades later was 5.6 (95% CI 2 to 16) compared with those whose levels were below 1.81 mmol/L, according to Mark J. Pletcher, MD, of the University of California San Francisco, and colleagues.
 
Moreover, even those whose levels were as low as 2.59 to 3.34 mmol/L had increased risk (adjusted OR 2.4, 95% CI 1.1 to 5.3), the investigators reported in the Aug. 3 issue of the Annals of Internal Medicine.
 
Action Points
 
* Explain to interested patients that lipid abnormalities in early adulthood, particularly elevated levels of LDL, or bad cholesterol, may result in the early development of atherosclerosis.
 
* Tell them that proper diet, maintaining a healthy weight, and exercise can all help keep lipids normal throughout life.
 
Because it has not yet been clearly determined whether lipid levels in early life can contribute to atherosclerotic damage during later life, Pletcher and colleagues analyzed data from the CARDIA (Coronary Artery Risk Development in Young Adults) study, a longitudinal cohort of 5,115 black and white men and women ages 18 to 30 years recruited from four U.S. cities in 1985.
 
Lipids were measured during follow-up examinations at years two, five, seven, 10, 15, and 20.
 
A total of 3,258 study participants underwent cardiac computed tomography to evaluate for the presence of coronary calcium 10 or 15 years after enrollment and were included in this analysis.
 
Participants were evenly divided with regard to race and sex, and the average age at the time of the coronary calcium scan was 45 years.
 
Coronary calcium was detected in 17% of participants, and 4% had scores exceeding 100, indicating extensive calcification.
 
In only 13% were lipid levels maintained at normal levels throughout young adulthood, and 75% of participants had abnormal levels.
 
Factors associated with lipid abnormalities included male sex, white race, family history of premature heart disease, high body mass index, diabetes, and hypertension.
 
The presence and extent of calcification were strongly associated with lipid abnormalities before age 35, with nearly one-half of subjects who had time-averaged LDL levels of 4.14 mmol/L or higher having evidence of coronary calcium, compared with only 8% of those whose levels were below 1.81 mmol/L.
 
None of those whose levels were below 1.81 mmol/L had calcium scores above 100.
 
The prevalence of coronary calcium was only 4% in subjects with optimal LDL cholesterol levels, and even modest elevations in LDL to the range of 3.37 to 4.12 mmol/L led to an increase in prevalence of coronary calcium to 17%.
 
Statistically significant associations were not seen for triglycerides or high-density lipoprotein cholesterol.
 
"Our results suggest that atherosclerotic changes begin during young adulthood as a result of commonly observed nonoptimal lipid levels, that these changes persist into middle age, and that maintaining optimal levels of lipids (particularly LDL cholesterol) throughout young adulthood could provide substantial benefits in terms of lifetime [coronary heart disease] prevention," they observed.
 
Limitations of the study included the possibility of within-person variations in lipid levels between examinations, and the use of a subclinical endpoint (coronary calcium score) because the cohort has not yet reached an age where clinical events such as myocardial infarction are likely.
 
In an editorial accompanying the study, Gerald S. Berenson, MD, and Sathanur R. Srinivasan, PhD, of Tulane University in New Orleans, observed that the findings suggest that the focus of primary and secondary prevention of coronary atherosclerosis should not focus only on lipids but should be expanded to include primordial prevention among high-risk children, "who have an excess prevalence of interrelated risk factors, an epidemic of obesity, increasing occurrence of diabetes, and heart disease that is out of control as adults."
 
"Pediatric epidemiologic studies have provided more than sufficient data to awaken interest in primordial prevention, which involves improving lifestyle and health behaviors beginning in childhood before abnormal risk factors develop," Berenson and Srinivasan asserted.
 
The CARDIA study is funded by the National Heart, Lung, and Blood Institute.
 
The authors and editorialists declared no conflicts of interest.
 
Primary source: Annals of Internal Medicine
Source reference:
Pletcher M, et al "Nonoptimal lipids commonly present in young adults and coronary calcium later in life: the CARDIA (Coronary Artery Risk Development in Young Adults) study" Ann Intern Med 2010; 153: 137-146.
 
Additional source: Annals of Internal Medicine
Source reference:
Berenson G, Srinivasan S "Cardiovascular risk in young persons: secondary or primordial prevention?" Ann Intern Med 2010; 153: 202-203.
 

Article
 
Nonoptimal Lipids Commonly Present in Young Adults and Coronary Calcium Later in Life: The CARDIA (Coronary Artery Risk Development in Young Adults) Study
 
Mark J. Pletcher, MD, MPH; Kirsten Bibbins-Domingo, PhD, MD; Kiang Liu, PhD; Steve Sidney, MD, MPH; Feng Lin, MS; Eric Vittinghoff, PhD; and Stephen B. Hulley, MD, MPH
 
Editors' Notes
 
Context

 
* Whether dyslipidemia contributes to atherosclerosis later in life in otherwise healthy young adults is controversial.
 
Contribution
 
*These researchers found associations between cumulative exposure to dyslipidemia between 18 and 30 years of age and presence of coronary artery calcium 15 to 20 years later.
 
Caution
 
*Coronary artery calcium is an imperfect surrogate measure of clinically significant coronary artery disease.
 
Implication
 
*Dyslipidemia during young adulthood is associated with coronary artery calcium 2 decades later.
 
-The Editors
 
------------------------
 
Abstract
 
Background: Dyslipidemia causes coronary heart disease in middle-aged and elderly adults, but the consequences of lipid exposure during young adulthood are unclear.
 
Objective: To assess whether nonoptimal lipid levels during young adulthood cause atherosclerotic changes that persist into middle age.
 
Design: Prospective cohort study.
 
Setting: 4 cities in the United States.
 
Participants: 3258 participants from the 5115 black and white men and women recruited at age 18 to 30 years in 1985 to 1986 for the CARDIA (Coronary Artery Risk Development in Young Adults) study.
 
Measurements: Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides, and coronary calcium. Time-averaged cumulative exposures to lipids between age 20 and 35 years were estimated by using repeated serum lipid measurements over 20 years in the CARDIA study; these measurements were then related to coronary calcium scores assessed later in life (45 years [SD, 4]).
 
Results: 2824 participants (87%) had nonoptimal levels of LDL cholesterol (≥2.59 mmol/L [≥100 mg/dL]), HDL cholesterol (<1.55 mmol/L [<60 mg/dL]), or triglycerides (≥1.70 mmol/L [≥150 mg/dL]) during young adulthood. Coronary calcium prevalence 2 decades later was 8% in participants who maintained optimal LDL levels (<1.81 mmol/L [<70 mg/dL]), and 44% in participants with LDL cholesterol levels of 4.14 mmol/L (160 mg/dL) or greater (P < 0.001). The association was similar across race and sex and strongly graded, with odds ratios for coronary calcium of 1.5 (95% CI, 0.7 to 3.3) for LDL cholesterol levels of 1.81 to 2.56 mmol/L (70 to 99 mg/dL), 2.4 (CI, 1.1 to 5.3) for levels of 2.59 to 3.34 mmol/L (100 to 129 mg/dL), 3.3 (CI, 1.3 to 7.8) for levels of 3.37 to 4.12 mmol/L (130 to 159 mg/dL), and 5.6 (CI, 2.0 to 16) for levels of 4.14 mmol/L (160 mg/dL) or greater, compared with levels less than 1.81 mmol/L (<70 mg/dL), after adjustment for lipid exposure after age 35 years and other coronary risk factors. Both LDL and HDL cholesterol levels were independently associated with coronary calcium after participants who were receiving lipid-lowering medications or had clinically abnormal lipid levels were excluded.
 
Limitation: Coronary calcium, although a strong predictor of future coronary heart disease, is not a clinical outcome.
 
Conclusion: Nonoptimal levels of LDL and HDL cholesterol during young adulthood are independently associated with coronary atherosclerosis 2 decades later.
 
Abnormal blood lipid levels are a major cause of coronary heart disease (CHD) in middle-aged and older adults (1). Observed associations with CHD risk are consistent across a wide range of cholesterol levels, in both men and women, and in persons as young as 40 years (2), and lowering the cholesterol level reduces CHD risk in these age groups (3).
 
However, it is unclear whether cholesterol levels are important earlier in life, when short-term CHD risk is low. Long-term follow-up studies (4-6) demonstrate associations between total cholesterol level measured once during young adulthood and CHD events later in life, but this association could be wholly attributable to later-life lipid abnormalities, which are strongly associated with lipid levels earlier in life (7). Whether early-life lipid levels can cause atherosclerotic damage during young adulthood that persists into middle age is unknown.
 
The CARDIA (Coronary Artery Risk Development in Young Adults) study provides a unique opportunity to evaluate the consequences of lipid abnormalities during young adulthood. Using the study's repeated measurements of fasting lipids, beginning at the onset of adulthood and continuing over 20 years of follow-up, we estimated cumulative exposure to lipid abnormalities between age 20 and 35 years and examined associations with coronary calcium levels measured after age 35 years, with adjustment for lipid levels later in life.
 
Discussion
 
Our findings reveal that nonoptimal LDL cholesterol levels during young adulthood are associated with coronary calcification later in life. Levels of LDL cholesterol during young adulthood are correlated with lipid levels later in life, but accounting for later-life lipid exposure did not explain the association of young adult LDL cholesterol levels with calcification. After we removed the potentially obscuring influences of medication use and clinically abnormal levels of other lipids, we also observed an inverse association with HDL cholesterol levels but no association with triglyceride levels. Our results suggest that atherosclerotic changes begin during young adulthood as a result of commonly observed nonoptimal lipid levels, that these changes persist into middle age, and that maintaining optimal levels of lipids (particularly LDL cholesterol) throughout young adulthood could provide substantial benefits in terms of lifetime CHD prevention.
 
Associations between cholesterol and CHD events in middle-aged and elderly adults have been described in many studies since the 1950s (14, 15). Descriptions of the effects of lipid levels during young adulthood, which require long-term follow-up and measurement of subclinical disease, are less complete. Several long-term follow-up studies (4-6) have demonstrated associations between total serum cholesterol level measured once during young adulthood and CHD events later in life, but lipid level elevations later in life could explain these associations. Follow-up studies in middle-aged (16) and elderly adults (17) suggest that vascular damage from lipid abnormalities may persist for many years, but it is unclear whether damage accumulates as early as young adulthood from the borderline or modestly abnormal lipid levels typical of this age. A previous CARDIA study analysis (18) found that baseline lipid levels were stronger predictors of coronary calcium than current lipid levels, but no attempt was made to measure cumulative time-averaged exposure or to isolate the influence of exposure during a particular age range (such as young adulthood). Other studies of children and young adults show associations between lipid levels and atherosclerosis, demonstrated by autopsy (19-22), carotid intima-media thickness (23-28), and coronary calcium (29). However, no previous study has had an adequate sample size, repeated measurements of the 3 major lipids, and long enough follow-up to isolate the association of lipid levels during young adulthood with atherosclerosis during middle age while controlling for confounding from other risk factors, including lipid levels later in life. Our analysis is large enough (overall and for the 4 race-sex subgroups) and uses repeated measures of the 3 major lipids over a long enough period (2 decades before measurement of coronary calcium during middle age) to remedy these limitations.
 
Even the moderate lipid levels seen in most young adults were associated with coronary calcium later in life, and the smoothly graded association with LDL cholesterol level seemed to extend to very low levels. Participants who maintained LDL cholesterol levels less than 1.81 mmol/L (<70 mg/dL) during young adulthood without lipid-lowering medications had a very low prevalence of coronary calcium in middle age, and none had evidence of extensive atherosclerosis. These findings are consistent with cohort studies in middle-aged and older adults (2) that showed associations with CHD events even with total cholesterol levels as low as 3.50 mmol/L (135 mg/dL) and randomized trials that showed benefits from very aggressive lipid-lowering therapy (30) in both primary (31) and secondary (32-34) prevention studies. Moderate elevations in levels of LDL cholesterol and other lipids are commonly ignored by both patients and physicians during young adulthood (35).
 
Our unadjusted analyses indicated associations between LDL cholesterol, HDL cholesterol, and triglyceride levels and coronary calcium, and our adjusted analyses indicated associations between LDL and HDL cholesterol (but not triglyceride) levels and coronary calcium. These findings mirror many previous epidemiologic studies of older populations (36, 37) that have found a similar pattern of associations for lipid predictors of CHD. The strong clinical trial evidence that LDL cholesterol-lowering agents reduce CHD incidence and mortality (1) leaves little doubt about the causal basis of the association between LDL cholesterol and CHD. The evidence that a low HDL cholesterol level is causally related to CHD is less certain, although it is supported by both epidemiologic and pathophysiologic evidence (1) and by the U.S. Department of Veterans Affairs' HIT (HDL cholesterol Intervention Trial) (38). The causal relationships supported by these lines of evidence suggest that some of the atherosclerotic changes that occur during young adulthood may be preventable with optimization of LDL and HDL cholesterol levels.
 
Our study has limitations. Despite standardized approaches to measuring lipid levels at 7 examinations over 20 years, our findings are susceptible to measurement error and within-person variation in lipid levels between examinations. Our mixed-modeling approach should minimize these problems, but random error in the primary lipid predictor could result in underestimation of true associations with coronary calcium levels (regression dilution bias [39]). Measurement error in covariates (including later-life lipid exposure and such self-reported factors as alcohol use) or unmeasured factors could lead to residual confounding. We relied on a subclinical end point (coronary calcium score) because our cohort is still too young to have had many myocardial infarctions or deaths from CHD; however, coronary calcium is a strong independent predictor of these CHD events (40-42), and the absence of coronary calcium is a strongly protective factor (43, 44).
 
Our findings may have implications for the prevention of CHD. Average LDL cholesterol levels in young adults (2.95 mmol/L [114 mg/dL] for those aged 20 to 29 years and 3.26 mmol/L [126 mg/dL] for those aged 30 to 39 years [35]) are higher than what is considered to be optimal (1). Our results suggest that nonoptimal lipid levels, particularly LDL cholesterol levels, are not just a cause of higher short-term CHD event rates during middle age, as is well known, but are also associated with atherosclerotic changes during young adulthood that persist into middle age and probably contribute to higher CHD event rates subsequently. These findings reinforce the importance of a heart-healthy diet, exercise, and maintenance of normal weight beginning in young adulthood.
 
Whether to screen or treat adults for suboptimal lipid levels before middle age is less clear (1, 45, 46). The benefits of lipid-lowering therapy do not seem to be any smaller at younger ages (3), but previous trials have not tested its effectiveness in adults younger than 40 years, and safety concerns are rightly magnified when starting treatment early in life is considered. Our observational study cannot provide evidence for the effectiveness or safety of initiating pharmacologic lipid-lowering therapy during young adulthood but suggests that this could be an area for further investigation. Meanwhile, young adults and their physicians should realize that what they eat and how much they exercise seem to matter even early in life, when short-term CHD risk is extremely low, and that healthy behaviors should not be deferred until middle age.
 
Results
 
Coronary calcium and CHD risk factor measurements were available for 3258 CARDIA study participants. About one half of the participants were black (47%), one half were female (56%), and the average age was 45 years (SD, 4) at the time of the coronary calcium scan. Coronary calcium was present in 17% of participants, and 4% had a coronary calcium score greater than 100.
 
The National Cholesterol Education Program guidelines define normal or optimal lipid levels as less than 2.59 mmol/L (<100 mg/dL) for LDL cholesterol, greater than 1.55 mmol/L (>60 mg/dL) for HDL cholesterol, and less than 1.70 mmol/L (<150 mg/dL) for triglycerides. Only 434 participants (13%) maintained normal or optimal average lipid levels throughout young adulthood; 381 (12%) had at least 1 lipid level that was in the abnormal range on average during young adulthood, and the remaining 2443 (75%) had nonoptimal lipid levels. Abnormal lipid levels were associated with male sex, white race, higher income, family history of premature CHD, low levels of self-reported activity and alcohol consumption, high body mass index and waist circumference, diabetes, and higher blood pressure. Lipid levels during young adulthood were also strongly related to lipid levels at the time of the coronary calcium scan (Table 1).
 
The presence and extent of coronary calcification were strongly associated with lipid exposure before age 35 years (Figure 1). Nearly one half (44%) of persons with time-averaged LDL cholesterol levels of 4.14 mmol/L (160 mg/dL) or greater during young adulthood had coronary calcium, compared with only 8% of those with levels of less than 1.81 mmol/L (70 mg/dL). Extensive coronary calcification (coronary calcium score >100) was absent in the latter group (prevalence, 0% [CI, 0% to 3%]). Similar trends were present for HDL cholesterol (inverse) and triglyceride levels (Figure 1). These trends were generally consistent across the 4 race-sex subgroups (Figure 2).
 
After we adjusted for lipid exposure after age 35 years and other CHD risk factors, LDL cholesterol levels during young adulthood remained strongly associated with coronary calcium later in life (Table 2). The odds of coronary calcium in persons with levels of 4.14 mmol/L (160 mg/dL) or greater were higher (adjusted odds ratio [OR], 5.6 [CI, 2.0 to 16]) than for those with levels of less than 1.81 mmol/L (<70 mg/dL); even participants with levels as low as 2.59 to 3.34 mmol/L (100 to 129 mg/dL) had increased odds (adjusted OR, 2.4 [CI, 1.1 to 5.3]). Triglyceride and HDL cholesterol levels had weaker associations that were not statistically significant in the adjusted analysis. We found no statistical evidence that the association of coronary calcium with LDL cholesterol level varied by age (20 to 35 years vs. >35 years; interaction P = 0.29) or within age subintervals during young adulthood (20 to 25 years, 25 to 30 years, and 30 to 35 years; interaction trend P = 0.17).
 
In the subset of participants who did not have clinically abnormal lipid levels and never reported receiving a lipid-lowering medication, the association with LDL cholesterol level remained strong (Table 3). Coronary calcium was rare in those with optimal LDL cholesterol levels (prevalence, 4%), and even modest increases in LDL cholesterol level of 3.37 to 4.12 mmol/L (130 to 159 mg/dL) were associated with a higher prevalence of coronary calcium (17%). In this subset, lower HDL cholesterol levels before age 35 years were also associated with coronary calcium later in life, with higher odds of coronary calcium when participants were exposed to time-averaged HDL cholesterol levels of 1.04 to 1.27 mmol/L (40 to 49 mg/dL) compared with levels of 1.81 mmol/L (70 mg/dL) or greater (OR, 2.8 [CI, 1.1 to 6.8]), after we adjusted for LDL cholesterol level, triglyceride level, HDL cholesterol level after age 35 years, and other CHD risk factors. After multivariate adjustment, we found no association between triglyceride levels and coronary calcium.
 
Methods
 
Study Design and Sample

 
The CARDIA study is an institutional review board-approved longitudinal cohort of 5115 black and white women and men, aged 18 to 30 years, who were recruited from 4 U.S. cities and were healthy at the time of enrollment in 1985 (8). Consenting participants underwent a baseline examination and follow-up examinations at years 2, 5, 7, 10, 15, and 20. For this report, we assessed all 3258 CARDIA study participants who received cardiac computed tomography to evaluate coronary calcium after age 35 years at either the year-15 or year-20 follow-up examination and had complete CHD risk factor data at the time of the scan, excluding the 375 participants with missing risk factor measurements. Excluded participants were slightly older (45.2 vs. 44.6 years) and did not differ in sex, race, income, education, or cumulative exposure to low-density lipoprotein (LDL) cholesterol but had slightly lower time-averaged high-density lipoprotein (HDL) cholesterol exposure (1.35 vs. 1.40 mmol/L [52 vs. 54 mg/dL]) and higher time-averaged triglyceride exposure (0.85 vs. 0.77 mmol/L [75 vs. 68 mg/dL]) between age 20 and 35 years. Including these participants in unadjusted analyses (and adjusted analyses, when possible) had no qualitative effect on results.
 
Lipid Measurements
 
Fasting blood samples were drawn at each CARDIA study examination, and measurements on plasma stored at -70 °C were carried out at the Northwest Lipid Research Laboratory (University of Washington, Seattle, Washington). Total cholesterol and triglyceride levels were measured enzymatically, HDL cholesterol was determined by precipitation with dextran sulfate-magnesium chloride, and LDL cholesterol was calculated by using the Friedewald equation. We have described these methods and our extensive quality control procedures elsewhere (9).
 
Estimating Lipid Trajectories and Cumulative Exposure
 
We used mixed models to estimate trajectories (age-dependent, within-person average values) for LDL cholesterol, HDL cholesterol, and triglyceride levels for each participant, from age 20 years until the time of coronary calcium measurement, by using the methods described for blood pressure in the CARDIA study (10). Triglyceride measurements were normally distributed after log transformation, so we used log-transformed values for all statistical purposes and then back-transformed them to triglyceride levels for presentation. Because we assumed that trajectories for each participant had a constant slope in each decade of life (age 20 to 29 years, 30 to 39 years, and 40 to 49 years), we allowed each participant a different random intercept and 3 random slopes, modeled as deviations from race- and sex-specific mean trajectories (Appendix).
 
For each participant, we then calculated the area under the curve for each lipid trajectory. These measurements estimate the cumulative exposure to each lipid and, when divided by the number of years of exposure, provide time-averaged lipid levels for the given period. Time-averaged exposures for each lipid from age 20 to 35 years were the primary predictors in this analysis. We used cumulative exposure after age 35 years and the lipid measurements made at the time of each participant's coronary calcium scan as covariates in the multivariate analysis to isolate the putative effects of lipid exposure during young adulthood. We also examined exposure before age 35 years with finer stratification by age (20 to 25 years, 25 to 30 years, and 30 to 35 years) to evaluate for interaction by recency of exposure.
 
We categorized participants by their average exposure to each lipid from age 20 to 35 years and also categorized them as having normal, borderline, or abnormal lipid exposure from age 20 to 35 years on the basis of cutoff values derived from National Cholesterol Education Program guidelines (1). Participants self-reported their use of cholesterol-lowering medications; the 302 participants (9%) who reported receiving a lipid-lowering medication at any examination were included in the primary analysis and then excluded in a secondary analysis.
 
Coronary Calcium
 
Consenting CARDIA study participants underwent cardiac computed tomography at year 15 and year 20 to measure coronary calcium. We obtained 2 sequential scans by using an electron-beam or multidetector, electrocardiographically gated cardiac computed tomography scanner with a standard phantom for calibration. Image analysts, who were blinded to participant characteristics and paired scan results, calculated a total coronary calcium score by using a modified Agatston method (11), with selected overreading by a physician expert in cardiovascular imaging. The accuracy, comparability, and reproducibility of these methods are described elsewhere (12, 13). We used the scan from year 20, if available (2792 patients), and otherwise used the scan from year 15 (466 patients).
 
Other Measurements
 
We ascertained sex, ethnicity, date of birth, serum cotinine levels, and family history of premature CHD (defined as a mother or father with myocardial infarction before age 60 years) at baseline. We used measurements of systolic and diastolic blood pressure and smoking habits from all CARDIA study examinations. For other covariates, including educational grade attained, income, fasting glucose level, diabetes history and medication use, body mass index and waist circumference, alcohol use, and physical activity (self-reported on a scale of 1 to 5), we used the measurements obtained at the time of the coronary calcium scan (9). We estimated total cumulative exposure to systolic and diastolic blood pressure by using the same method that we used for lipids, as described elsewhere (10).
 
Statistical Analysis
 
We described persons with normal, borderline, and abnormal lipid exposure during young adulthood and compared characteristics by using Spearman rank correlation for continuous variables and chi-square tests of trend for dichotomous variables. We then described coronary calcium presence and extent by level of exposure to each lipid and by race-sex subgroups, using chi-square tests of trend.
 
We used logistic regression to analyze adjusted associations between average lipid exposures and the presence or absence of coronary calcium. We fit models for each lipid predictor, with full adjustment for potential confounders, and used linear splines to flexibly model them, with knots where suggested by lowess plots (Appendix). For example, our fully adjusted models for LDL cholesterol included adjustments for current levels and cumulative exposure to HDL cholesterol and triglycerides from age 20 years onward; current systolic and diastolic blood pressure and cumulative exposure to both from age 20 years onward, measured in mm Hg-years as described elsewhere (10); current levels and cumulative exposure to LDL cholesterol after age 35 years; and the following characteristics, obtained at the time of the coronary calcium scan: age, sex, race, serum cotinine level, family history of premature CHD at baseline, socioeconomic status (income and education), body mass index, waist circumference, self-reported physical activity, alcohol use, diabetes, and pack-years of tobacco exposure. We also fit-adjusted models after excluding participants with clinically abnormal lipid levels (LDL cholesterol ≥4.14 mmol/L [≥160 mg/dL], HDL cholesterol <1.04 mmol/L [<40 mg/dL], or triglycerides ≥2.26 mmol/L [≥200 mg/dL]) or self-reported use of a lipid-lowering medication at any CARDIA study examination.
 
Role of the Funding Source
 
The CARDIA study is funded by the National Heart, Lung, and Blood Institute, which had input into the overall design and conduct of our study and was represented on the publications committee that approved this manuscript.
 
 
 
 
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