The changing landscape of atherosclerosis

“Short commentary on Review entitled: "The changing landscape of atherosclerosis" 

By Peter Libby

When Nature asked me to provide an Insight Review on Inflammation in Atherosclerosis in 2002 (Nature 2002;420:868-874), the field had already matured to a point that we had strong experimental evidence and some human biomarker data that suggested the operation of inflammatory pathways in atherosclerosis. Yet, there was then considerable skepticism regarding this concept in many quarters. We possessed convincing evidence that low density lipoprotein (LDL) was causal in atherosclerosis. We had great enthusiasm for the statin class of drugs which targeted LDL and reduced events. We had reason to suspect that pleiotropic effects of statins could lower inflammation, but a direct anti-inflammatory therapy that did not alter lipids was far from a reality. We were generally excited by the notion that raising high density lipoproteins (HDL) would confer cardiovascular benefit, based on strong observational epidemiology and extensive in vitro data. Most discounted a causal contribution of triglyceride-rich lipoproteins to atherosclerosis outcomes, as adjustment for HDL, the putative protective factor, attenuated the relationship between triglycerides and cardiovascular events. The dénouement of that chapter, recounted in the current review, taught us humility, and reminds us of the pitfalls of observational studies. We were in the throes of working out the cellular and molecular mechanisms of the formation of the thin-capped fibroatheroma, the so called “vulnerable plaque” responsible for plaque rupture, thrombosis, and many myocardial infarctions. We had no anti-diabetic medications that could reduce cardiovascular events, a source of considerable frustration to clinicians. The idea of a “precision” allocation of therapies that targeted inflammation was purely theoretical.

How things have changed in the almost two ensuing decades! When invited to contribute another review about atherosclerosis, I choose to focus The Changing Landscape of Atherosclerosis (Nature 592, 524–533; 2021; https://doi.org/10.1038/s41586-021-03392-8.)  My mentor, Dr. Eugene Braunwald, taught me when I was a student to keep my eyes on a moving target.  This advice has informed many of my choices in research. It contributed to my reluctance to accept received notions without critical examination, and to my striving to pursue new ideas even if they were unpopular. My Northern California upbringing and involvement in the civil rights and free speech movements as a student in Berkeley in the 1960s also contributed to my contrarian streak, I must confess. Another aspect colors my approach to research and thinking about the disease: I stay close to patients and strive to remain abreast of the clinical as well as the scientific literature.  I have always practiced both inpatient and ambulatory cardiovascular medicine and recently started a new “CHIP clinic” where I see patients with clonal hematopoiesis to counsel them regarding cardiovascular risk.  Having clinical activity close to my laboratory interests enriches in both directions, fosters new ideas, and spurs me to keep trying to solve clinically important questions. It reminds me that people are not just big mice without fur.

Of course, with strict word limitations, one cannot be encyclopedic, and I could not reference many who have contributed so decisively to the field.  I took a deliberately provocative stance, for purposes of argument, and apologize if I have not presented a sufficiently nuanced view.  Perhaps anti-oxidant therapies would show clinical benefit if started earlier? Maybe a functional subclass of HDL will prove able to confer atheroprotection?

The advances of the last two decades provide some grounds for satisfaction, but the things we got wrong, and the unfinished stories should keep us humble and motivated to dig ever deeper.  How many of the arguments I present today will seem antique 20 years hence?