Clinical Laboratory Strategies: October 14, 2010

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Linking Cholesterol Levels in Young Adults with CVD Later in Life
Time-Averaged LDL-C Strongest Risk Predictor
By Genna Rollins

Considerable research has linked unfavorable cholesterol levels with atherosclerotic heart disease and mortality in adults. Evidence also indicates that non-optimal low density lipoprotein and total cholesterol levels in children and young adults is strongly associated with atherosclerosis during middle age. However, studies examining the latter had limitations that made it difficult to isolate how much coronary heart disease in middle age was due to nonoptimal lipid levels in young adulthood versus middle age. This issue of Strategies reports on a longitudinal study of lipid levels in young adults that addresses these limitations.

The link between abnormal serum cholesterol levels and coronary artery disease (CAD) has been documented extensively across a wide range of cholesterol levels, in men and women, and through a range of ages. Likewise, the benefit of lowering cholesterol levels has been demonstrated repeatedly across a spectrum of adult subgroups. Studies also have correlated total cholesterol levels measured in childhood with CAD later in life. However, due to limitations such as inadequate sample size, single rather than repeated lipid measurements, and insufficient length of follow-up, some studies that began when the subjects were young adults made it difficult to discern how much CAD in middle age was due to abnormal lipid levels early in life versus middle age. Now, researchers involved in the Coronary Artery Risk Development in Young Adults (CARDIA) study have published research that takes on this issue (Ann Intern Med 2010;153:137-46).

The CARDIA study is an ongoing, long-term cohort study examining the development and determinants of clinical and subclinical cardiovascular disease and its risk factors. In 1985 and 1986, CARDIA enrolled more than 5,000 individuals who were between ages 18 and 30 at that time. The participants had numerous baseline physiological parameters measured, and they returned for 2, 5, 7, 10, 15 and 20-year reassessments. In addition, they underwent cardiac computed tomography to detect subclinical atherosclerosis at the 15 and 20-year follow-ups, respectively. Serum measurements included total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C).

The goal of the study was to examine the link between dyslipidemia in young adulthood and atherosclerosis later in life, according to lead author, Mark Pletcher, MD, MPH. “We’ve known for a long time that abnormal cholesterol levels cause heart attacks, especially in middle-aged and older adults. What we haven’t really known is whether or not it matters what your cholesterol levels are early in life, when the short-term risk of having a heart attack is low. It wasn’t clear if your cholesterol level in young adulthood carries any risk that persists into middle age,” explained Pletcher, an associate professor of epidemiology and biostatistics at the University of California, San Francisco. “Before our study, you might have argued that it doesn’t matter what happens in young adulthood because you’re at low risk during that time, and that once you hit middle age, then you need to start thinking about cholesterol levels. But our study showed that cholesterol levels in young adulthood do matter in terms of your risk later in life.”

Pletcher and his colleagues used a linear mixed model method to estimate trajectories for LDL-C, HDL-C and triglycerides for three decades of life (20-29 years, 30-39 years, and 40-49 years). The trajectories, which included age-dependent and within-person average values, provided time-averaged exposures for each analyte for each period in question. Time-averaged exposures for each lipid type from age 20 to 35 years were the primary predictors used in the analysis. These measurements were then related to coronary calcium scores from cardiac computed tomography scans taken during the 15 and 20-year follow-up assessments.

The researchers found that 87% of participants had nonoptimal LDL-C, HDL-C, or triglyceride levels during young adulthood, with nonoptimal values defined as LDL-C ≥100 mg/dL, HDL-C <60 mg/dL, and triglycerides ≥150 mg/dL. Coronary calcium was present in just 8% of subjects with optimal LDL-C levels, defined as <70 mg/dL. This compared with 44% in those with LDL-C levels >160 mg/dL. This association, which was similar across race and gender, also was strongly graded. The odds ratio of coronary calcium rose significantly with rising time-averaged LDL-C and declining HDL-C levels after adjustment for other factors. For example, the adjusted odds ratio of coronary calcium ranged from a low of 2.2 for LDL-C levels 70-99 mg/dL to as much as 5.2 for LDL-C levels 130-159 mg/dL.

These findings suggest “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,” the authors wrote.

“I was surprised that we found early in life cholesterol such a strong predictor of atherosclerosis and that it was a substantially stronger predictor of atherosclerotic disease than current cholesterol,” said Pletcher. “But perhaps this is not too surprising if you think of atherosclerosis as being caused by cumulative damage from persistent exposure to non-optimal risk factors over many years. According to this cumulative damage hypothesis, your current status in terms of atherosclerotic plaques would be determined by many past years of cholesterol exposure.”

Researchers not involved in the CARDIA study agreed that the findings clearly demonstrate the adverse effects of nonoptimal LDL-C and HDL-C levels in young persons. However, at least one investigator argued that Pletcher and his colleagues discounted prior studies that have reached similar conclusions. “We know from other tracking studies of cholesterol levels or blood pressure on children, that they’re predictive of what we find in adulthood. They’re not perfect predictors, but they are predictors,” said Gerald Berenson, MD, clinical professor of medicine and pediatrics and research professor of epidemiology at Tulane University School of Medicine in New Orleans. Berenson, who wrote the editorial that accompanied Pletcher’s study, also is the principal investigator of the Bogalusa Heart Study, a 4-decade-long clinical study exploring the early natural history of heart disease (Ann intern Med 2010:153:202-203).

Pletcher emphasized that the CARDIA findings built on a considerable body of evidence. “This is one more piece in the puzzle of a very consistent general picture. It’s not that surprising, but it does allow us to say more forcefully that young adulthood lifestyle matters in terms of heart disease later in life,” he said.

Berenson believes the study outcomes should renew attention on the importance of prevention not only in young adults, but even in children. “It further points out that even at below-optimal levels you begin to find abnormalities. This applies not only to cholesterol but also to blood pressure, obesity, and other risk factors like the cluster cardiometabolic syndrome,” he said. “We live in such a toxic environment and the prevalence of heart disease is so great, we ought to focus on cardiovascular, diabetic and hypertension prevention in childhood.”

Pletcher stressed that the CARDIA findings did not extend to children. “It’s possible that cholesterol levels earlier in life also matter, but we don’t know that from our study,” he indicated. “Our study supports measuring cholesterol in early adulthood because it may be more of an incentive to change your lifestyle if you know your numbers. It also supports the idea of having a fasting lipid panel with LDL-cholesterol, because that would be the more important factor over total cholesterol and HDL.”

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