Higher low-density lipoprotein cholesterol (LDL-C) levels—even those considered well within normal range—were independently associated with subclinical atherosclerosis in a study of middle-aged adults without standard cardiovascular risk factors, researchers reported in the Journal of the American College of Cardiology.

“These findings support more effective LDL-C lowering for primordial prevention, even in individuals conventionally considered at optimal risk,” wrote lead author Leticia Fernandez-Friera, MD, PhD, and colleagues.

The researchers evaluated 1,779 individuals free of risk factors such as smoking, high blood pressure, high fasting glucose, total cholesterol above 240 milligrams per deciliter, LDL-C of 160 mg/dL or greater and high-density lipoprotein cholesterol below 40 mg/dL. Participants were 45 years old on average and split evenly between men and women.

Even in this population assumed to be at low risk, Fernandez-Friera et al. found 49.7 percent of participants showed evidence of subclinical atherosclerosis. Atherosclerosis was assessed by the presence of plaque during a vascular ultrasound or the presence of coronary artery calcium from a noncontrast cardiac CT.

Age, sex and LDL-C levels were associated with arterial plaque, with LDL-C being “the strongest modifiable factor associated with atherosclerosis.”

“As LDL-C levels increased, there was a linear and significant increase in the prevalence of atherosclerosis, ranging from 11 percent in the 60 to 70 mg/dl category to 64 percent in the 150 to 160 mg/dl subgroup (p < 0.001). This progressive increase was noted in both men and women,” Fernandez-Friera and co-authors wrote.

The researchers said the small number of participants with LDL-C below 70 mg/dL makes it difficult to determine whether there is a threshold below which atherosclerosis doesn’t occur, but the linear relationship shown at higher LDL-C levels suggests that threshold may exist.

“Although association does not equate with causation, in the context of extensive prior data, we believe that these unique data from a large human cohort eliminate some of the potential confounders mentioned previously and provide indirect but solid evidence for the central role of LDL-C in early human atherogenesis,” they wrote. “These results also support the notion that cholesterol alone, in the absence of other known conventional CVRFs, may be enough to drive the development of atherosclerosis in humans.”

In a related editorial, Vijay Nambi, MD, PhD, and Deepak L. Bhatt, MD, MPH, said the study exposes the issue of using hard cutoffs for markers of cardiovascular health. Grouping blood pressure and cholesterol levels into categories of “normal” or “high” doesn’t reflect the whole spectrum for risk within those categories.

“‘Lower’ may indeed be better for cholesterol, blood pressure, glucose, and now inflammation as well,” Nambi and Bhatt wrote. “However, how low to go and how to get there for all these different axes of risk without provoking side effects may be the key challenge in personalizing therapies.”