Atherosclerosis is a universally suffered condition of aging in which oxidized lipids are the seeds for ever-expanding fatty deposits in blood vessel walls. Blood vessels are progressively weakened and narrowed, and this ultimately leads to the catastrophic structural failure of a stroke or heart attack. Atherosclerosis is one of the largest single causes of death in our species.
Cholesterol is carried in the bloodstream, attached to low density lipoprotein (LDL) particles. Lacking any other viable approach to the condition, methods of reducing LDL cholesterol such as statin drugs are widely use to slow atherosclerosis. They reduce one of the inputs to the progression of the condition, the supply of cholesterol, but haven't been shown to produce any sizable reversal of established atherosclerotic lesions in humans. The animal evidence suggests that greater benefit may occur in the earlier stages of the disease, when it might be possible for lowered LDL cholesterol to allow repair mechanisms to catch up sufficiently to remove smaller, more recent lesions. In general, intervening early is a good idea: fixing smaller problems is easier than fixing larger ones. Researchers are now seeking to trial this concept in humans.
I think it remains the case, however, that any meaningful therapy for atherosclerosis must remove or at least significantly diminish the larger and more widespread lesions present in later stages of the condition. This sort of therapy will likely involve mechanisms capable of enhancing reverse cholesterol transport. This describes the way in which macrophages mine cholesterol from lesions and then hand it off to high density lipoprotein (HDL) particles that carry the cholesterol back to the liver. There are many places in which this process might be made more efficient: increased HDL particle count; improved cholesterol export in macrophages; greater macrophage resilience to cholesterol overload; and so forth.
Variants on most of these approaches have been shown to produce some degree of reversal of atherosclerosis in mice, as much as 50% reversal in some cases. Unfortunately, of these potential therapies, only increases in HDL particle numbers have been tried in humans. Those efforts didn't work well at all, which raises a number of interesting questions. There is some uncertainty as whether any of the other approaches presently in the pipeline will do any better in humans, as clearly the dynamics of the process must be substantially different between humans and animal models to produce such different results for the HDL particle trials.
Researchers have proposed a unique study in humans to reduce the early onset of atherosclerosis, the buildup of the artery-clogging plaque that can lead to heart attacks and strokes. The proposed trial, CURing Early ATHEROsclerosis, or CURE ATHERO, would set out to determine if atherosclerosis in high-risk adults ages 25 to 55 might be reversed by using medicines called statins and PCSK9 inhibitors over the course of three years. "The idea is to get the cholesterol very low for a short period of time, let all the early cholesterol buildup dissolve, and let the arteries heal. Then patients might need to be retreated every decade or two if the atherosclerosis begins to develop again."
The proposal is a "very compelling idea" that might show whether older adults can avoid heart attacks and strokes by making sure they have low LDL and apo B levels earlier in their lives. "It's a very important question that we really need to answer, because we have therapies now to lower apo B lipoproteins and LDL cholesterol. We know that people who have low LDL cholesterol for genetic reasons have a very low risk of having cardiovascular events, so if we can replicate one of these genetic states and get people's LDL cholesterol really low in early adulthood, perhaps these people won't have downstream complications like heart attack and stroke."
A new paradigm for preventing atherosclerotic cardiovascular disease (ASCVD) is needed. The most recent US data show the long-term decline in cardiovascular deaths has stopped, and has started to increase in the most at-risk populations.
Systemic approaches to improving lifestyle habits and better risk factor control are clearly needed. Given the difficulty of these endeavors to date, and the persistently high burden of ASCVD when risk factor modification is started later in adulthood, we propose a new paradigm for ASCVD prevention. We consider that it is now time to investigate whether intensively lowering plasma apolipoprotein (apo) B lipoprotein levels in younger and early midlife adults will regress earlier stages of atherosclerosis, thereby eliminating the risk of developing clinical ASCVD events later in life.
As a next step, we describe a proposed clinical trial to test early intervention to profoundly lower the concentration of low-density lipoprotein (assessed by its cholesterol component, LDL-C) and other apo B-containing lipoprotein in individuals aged 25 to 55 years who have image-documented preclinical atherosclerosis. Such a trial may provide the first direct evidence to support marked or even complete regression of early atherosclerosis in humans, and lay the ground work for definitive trials to support a new prevention paradigm of intensive regression therapy followed by intermittent retreatment for eradication of the clinical burden of ASCVD.