Exposure to non-optimal levels of LDL cholesterol during young adulthood is a strong risk factor for coronary calcification later in life. LDL cholesterol levels 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 removing the potentially obscuring influences of medication use and clinically abnormal levels of other lipids, the graded association between non-optimal LDL cholesterol and coronary calcium remained, and we also observed an association with HDL cholesterol (in the opposite direction), but not with triglyceride. Our results suggest that atherosclerotic changes begin during young adulthood as a result of non-optimal lipids, 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 1950’s14, 15
. Descriptions of the effects of lipid levels during young adulthood, which require long-term follow-up and/or measurement of subclinical disease, are less complete. Several long-term follow-up studies have demonstrated associations between total serum cholesterol measured once during young adulthood with CHD events later in life4-6
, but lipid elevations later in life could explain these associations. Follow-up studies in middle-aged16
and elderly adults17
suggest that vascular damage from lipid abnormalities may persist for many years, but it is unclear if damage accumulates as early as young adulthood from borderline and modestly abnormal lipid levels typical of this age. A previous CARDIA analysis found that baseline lipids were stronger predictors of coronary calcium than current lipids, but no attempt was made to measure cumulative time-averaged exposure or to isolate exposure during a particular age range (e.g., young adulthood)18
. Other studies among children and young adults show associations between lipid levels and atherosclerosis, demonstrated by autopsy19-22
, carotid intima-media thickness23-28
and coronary calcium29
, but no prior study has provided adequate sample size, repeated measurements of the three major lipids, and follow-up long enough 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 four race-gender subgroups) and uses repeated measures of the three major lipids over a long enough period (two decades before measuring coronary calcium during middle age) to provide these answers.
Even the moderate lipid levels seen in the majority of young adults were associated with coronary calcium later in life, and the smoothly graded association with LDL cholesterol appeared to extend to very low levels. CARDIA participants maintaining optimal LDL cholesterol levels below 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 showing associations with CHD events down to a total cholesterol level of 135 mg/dl2
and randomized trials showing benefits from very aggressive lipid-lowering30
in both primary31
prevention studies. Moderate elevations in LDL cholesterol (and other lipids) are commonly ignored by both patients and physicians during young adulthood35
Our findings – that LDL cholesterol, HDL cholesterol, and triglycerides all predicted coronary calcium in unadjusted analyses, but that only LDL and HDL cholesterol did so in adjusted analysis of participants without clinically abnormal lipids or lipid treatment – mirror many previous epidemiologic studies of older populations that have found a similar pattern of associations for lipid predictors of coronary heart disease (CHD)36, 37
. The strong clinical trial evidence that LDL cholesterol-lowering agents reduce CHD incidence and mortality1
leaves little doubt about the causal basis of the association between LDL cholesterol and CHD. The evidence that low HDL cholesterol is causally related to CHD is less certain, though supported by epidemiologic and pathophysiologic evidence1
, and by the Veteran’s Affairs HDL cholesterol Intervention Trial (HIT)38
. The causal relationships supported by these lines of evidence suggest that some of the atherosclerotic changes occurring during young adulthood may be preventable with optimization of LDL and HDL levels.
Several limitations are worth noting. Despite standardized approaches to measuring lipids at seven examinations over 20 years, our findings are susceptible to measurement error and within-individual 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 (regression dilution bias39
). On the other hand, measurement error in covariates (including later life lipid exposure, self-reported factors like alcohol use, etc) or unmeasured factors could lead to residual confounding. We rely on a subclinical endpoint (coronary calcium) because our cohort is still too young to have suffered many myocardial infarctions or deaths from CHD; coronary calcium, however, is a strong, independent predictor of these CHD events40-42
, and the complete absence of coronary calcium is a strongly protective factor43, 44
Our findings may have implications for the prevention of CHD. Average
LDL cholesterol levels in young adults (114 mg/dl for 20-29 year-olds and 126 mg/dl in 30-39 year-olds35
) are well above what is considered optimal1
. Our results suggest that non-optimal lipids, particularly LDL cholesterol, are not just a cause of short-term CHD event rates during middle age, as is well known, but cause atherosclerotic changes even during young adulthood that persist into middle-age, and probably contribute to higher CHD event rates through subsequent years of life. These findings reinforce the importance of a heart-healthy diet, exercise, and maintenance of normal weight beginning at least as early as young adulthood.
Whether to screen and/or treat adults for sub-optimal lipids before middle age is less clear1, 45, 46
. The benefits of lipid-lowering do not appear to be any smaller at younger ages3
, but previous trials have not tested effectiveness in adults younger than 40 years of age, and safety concerns rightly magnify when contemplating treatment starting early in life. Our observational study cannot provide evidence for effectiveness or safety of initiating pharmacological lipid-lowering during young adulthood, but does suggest 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 matters even early in life when short-term CHD risk is extremely low, and that healthy behavior modifications should not be deferred until middle-age.