Turning Back Subclinical Atherosclerosis Possible in Some Middle-Age People

Subclinical atherosclerosis progressed in about one-third of healthy, middle-aged individuals followed for 6 years in the Progression of Early Subclinical Atherosclerosis (PESA) study, but intriguingly, it regressed in a small proportion, researchers report.

Overall, 8.0% of participants who had some evidence of atherosclerosis at baseline had no plaque at follow-up, showing that “regression is possible in early stages of the disease,” lead author Guiomar Mendieta, MD, PhD (Hospital Clínic of Barcelona, Spain), and colleagues write in a study published online ahead of the November 28, 2023, issue of the Journal of the American College of Cardiology.

Of note, levels of LDL cholesterol and systolic blood pressure (BP) were more tightly linked to progression among the youngest members of the cohort (ages 40 to 43) than among the oldest (ages 48 and higher), “suggesting that the prevention of atherosclerosis and its progression could be enhanced by tighter risk factor control at younger ages, with a likely long-term impact on reducing the risk of clinical events,” the authors say.

That’s “not necessarily something that we already didn’t know, but I think this gives us a little bit more ammunition to say we really need to get on those risk factors early, early, early,” said Charles German, MD (University of Chicago, IL), who wrote an accompanying editorial with Michael Shapiro, DO (Wake Forest University School of Medicine, Winston-Salem, NC).

That means exercising, eating a heart-healthy diet, not smoking, maintaining a healthy weight, and keeping BP under control, he told TCTMD. “These tenets that we all know we really have to start at the earliest stages in life,” he added, noting that once atherosclerosis progresses to a certain point and the plaques calcify, regression is unlikely.

Tracking Atherosclerosis

PESA is a longitudinal cohort study that enrolled healthy volunteers ages 40 to 55 who had no history of CVD. Subclinical atherosclerosis was measured at baseline and then at 3 and 6 years, with noncontrast cardiac CT used to assess coronary artery calcification (CAC) and 3D vascular ultrasound used to evaluate disease in the peripheral arteries.

The current analysis included 3,471 participants (mean age 45.8 years; 36% women) who had information available at both baseline and 6 years and focused on global plaque volume from scans of the bilateral carotid and femoral arteries. “CAC testing explores only the coronary territory and may miss earlier atherosclerosis (before calcification has occurred), especially in young persons at low-to-intermediate 10-year atherosclerotic CVD risk,” the investigators explain.

After 6 years, progression of subclinical atherosclerosis (at least a 100% increase in global plaque volume) occurred in 32.7% of participants, including 17.5% who didn’t have any plaque at baseline and 15.2% with some preexisting plaque. This drove an overall increase in the proportion who had plaque over time, from 44.1% at baseline to 51.4% at 3 years and 58.0% at 6 years.

Regression was possible among individuals with subclinical atherosclerosis at baseline, however, and it was most strongly predicted by being a nonsmoker, female sex, and having lower fibrinogen levels. Younger age and lower LDL cholesterol levels also were associated with regression.

The factors most strongly related to progression, on the other hand, were older age and higher LDL cholesterol levels, followed by male sex, active smoking, and higher systolic BP. Age significantly modified the associations between LDL cholesterol and systolic BP levels, however, with stronger relationships among the youngest individuals in the study.

“These results underscore the importance of optimal cardiovascular risk factor control during young adulthood in the prevention of subclinical atherosclerosis progression, and indeed they go further, suggesting that starting interventions earlier in life can delay the onset and perhaps reduce the incidence of atherosclerotic CVD,” Mendieta et al write.

A Change in Mindset

In their editorial, German and Shapiro present an idea about what earlier intervention might look like. It includes detection of subclinical plaque at age 20 and immediate initiation of lipid-lowering therapies, which will be continued until repeat imaging several decades later shows that the plaque has regressed and disappeared. At that point, lipid-lowering therapies can be stopped. All of this would be on a background of healthy lifestyle choices like exercising and eating a heart-healthy diet.

German stressed that this is just a conceptual model. “The argument is that we wait too long to treat cholesterol,” he said. Many patients start taking statins once they already have coronary artery calcifications, “but maybe that’s too late” because those types of plaques are less likely to regress, he added.

The idea is to treat plaque as soon as it’s found, German said, noting that subclinical atherosclerosis is known to develop as early as the teenage years. “Really this would be a radical change in the way that we think about treatment of atherosclerosis,” he added, acknowledging that the idea initiating lipid-lowering therapies more broadly at such a young age is “very controversial.”

More realistically, the takeaway from these findings is that “we need to be much more aggressive at earlier stages,” German said. “That may not be with pharmacotherapy. Maybe that just means we need to be really aggressive about lifestyle modification, and I think that is much more plausible from a population perspective.”

A key piece that’s missing in this discussion is proof that inducing plaque regression will lead to lower rates of hard clinical events like MI and stroke, German pointed out. It makes logical and biological sense that progression would lead to more events and regression would lead to fewer, but it hasn’t been shown in a randomized trial.

A study like that is likely not feasible, although longitudinal cohorts like PESA can provide some clues, German said.

“Our results are capable of changing the mindset and attitudes of both medical and patient communities on atherosclerosis,” Mendieta and colleagues say. “Until now, the prevailing notion has been that atherosclerosis is a progressive disease and that efforts should be placed on avoiding its transition to the clinical stages and consequent atherosclerotic CVD events.”

Thus, they continue, “delivering the concept of atherosclerosis remission as a realistic and attainable goal if tackled early is a key message likely to affect not only healthcare providers, but also policymakers and the general population.”