Editor's Corner: Looking to the Past, Shaping Lipidology's Future

We have come a very long way along the road of understanding the pathophysiology of cardiovascular vascular disease. Historical theories regarding atherogenesis proposed in the 19th century are now being validated.

Rudolf Virchow in 1856 created a new paradigm of cellular pathology. Virchow’s Triad although pertaining particularly to venous thromboembolism has become dogma in the study of atherosclerosis: altered vascular integrity, aberrant blood flow and abnormal coagulability—and through his work inflammation was identified as the central cause of atherosclerotic cardiovascular disease.

Nikolai Anichkov (variably Anistchkow) in the early 20th century, another pathologist, was the first to describe ‘cholesterinesterphagozyten’ –now known as foam cells. He established the linkage between cholesterol and atherosclerosis which is now widely viewed as one of the 10 greatest discoveries in science. As Anitchkov said “there is no atherosclerosis without cholesterol.”

He and his contemporary colleagues identified atherosclerosis as a result of injury to the vessel wall, and recognized metabolic changes in the human system may augment the effects of cholesterol on this process.

However, during the early to mid 20thcentury, attention was diverted from the understanding of cardiovascular disease to that of infectious disease. People died from infection in the pre-antibiotic era much sooner than they had the opportunity to develop cardiovascular disease, and many of the early theories were disputed as irrelevant.

That is, until Franklin Delano Roosevelt died of a massive stroke in 1945. As a result of that, half a million dollars (substantial during that time) was allocated to the United States Public Health Service, to research cardiovascular disease.

In 1953, the US government supported autopsy studies during the Korean War of soldiers who had died, and identified fatty streaks and early atherosclerotic plaque in the arteries of 22-year-old Army recruits.

Ancel Keys (whose name is attached to “K-rations” during World War II), a physiologist from the University of Minnesota, launched the Seven Countries study in 1958, which clearly correlated dietary impact of high fat diets with atherosclerotic cardiovascular disease.

Another milestone was the granting of the Nobel Prize to Brown and Goldstein in 1985 for their research on the LDL-receptor and the physiology of cholesterol synthesis.

We have now come full circle, to understand that indeed, atherosclerosis is the result of the impact of lipoproteins combined with systemic vascular inflammation and affirming the conclusion of our illustrious predecessors in science.

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“The lessons of history advise us against drawing conclusions for patient care which are not driven by facts and data.”

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We are also now confronted with the issue of whether pharmacologically reducing LDL-C to previously unheard of low levels. At this point, we do not know whether there is an optimal LDL-C level and we have not identified if there is recognized harm from ‘super-low LDL-C’ but more data is needed. In addition, the impact from hypoglycemic therapies (eg SGLT2 inhibitors, GP1 analogs), anti-inflammatory therapies, high dose omega 3 supplementation, and pharmacotherapy to reduce Lp(a) lead to expanded pharmacopeia in ASCVD risk reduction. In the face of low LDL-C levels induced by the PCSK9i we must evaluate the medication burden and know when it is safe and reasonable to discontinue other nonstatin therapies.

The lessons of history advise us against drawing conclusions for patient care which are not driven by facts and data. Let us remain aware of that caveat, and go forward with cautious optimism.

The current edition of the LipidSpinaddresses the evolution of new nonstatin therapies, the breadth of disease associated with lipid metabolism and steps forward in our continued search for understanding disease as it relates to lipoproteins.