From the LipidSpin Editor: Sparking the Conversation on Inflammatory Disease Management

The “response to retention” model of atherosclerosis holds up as the present and best narrative explanation for the initiation and propagation of atherosclerotic cardiovascular disease (ASCVD).(1) As you know, this model posits that the passage of apolipoprotein B (apoB)-containing lipoproteins (LP) triggers the initiation of the atheroma. Low density lipoproteins (LDL) and triglyceride rich lipoprotein remnants (TRLr) are retained by proteoglycans in the subendothelial space where they undergo modification (mostly oxidation). The oxidation of LDL is an inflammatory trigger for resident monocytes phagocytosis and conversion to the “foam cell.” It is thus, the formation of the foam cell that represents the necessary common pathway of atherosclerosis. The lipids carried by lipoproteins are thus the fuel for the fire (foam cell release of cytokines, subsequent recruitment of and targeting of monocytes, T-lymphocytes, neutrophils and the remodeling of the normal arterial morphology by expression of proteases, smooth muscle cell and fibroblast recruitment) that can burn down the entire house (myocardial infarction, cerebrovascular event).

It seems almost quaint to read a centuries-old argument that it is lipid, not inflammation and vice versa that causes atherosclerosis. The public disagreement between Virchow and Rokitansky (2) is right up there with “you got chocolate in my peanut butter ... no, you got peanut butter on my chocolate” or “tastes great ... less filling.” However, their disagreement spawned 100 years of science to bring us this far, and we are indebted to their passion in pursuit of the truth. We have come so far in that 100 years, so it is surprising that right after I introduce myself as a Clinical Lipidologist, I often hear some version of the following question: “Doc, does cholesterol matter? It’s all about inflammation, right?” I am sure I am not the only one who has had this experience. Invariably, this is followed by “Did you ever read the Cholesterol Myth?” and “Are eggs ok to eat?”

The last 40-plus years have seen large scale clinical trials confirm the role of LDL-cholesterol (LDL-c) reduction, value of statin drugs, role of non-high density lipoprotein-cholesterol (nonHDL-c) and apoB-lowering, confirming the critical role of statins and other therapies (ezetimibe, PCSK9 monoclonal antibodies and now high dose eicosapentaenoic acid), and reiteration of the value of comprehensive risk reduction in the care of our patients.

This issue of LipidSpin is dedicated to recent advances in the clinical antiinflammatory approach to ASCVD care. How important are inflammatory markers and the recognition of inflammatory diseases in risk stratification? Can we affect ASCVD risk by targeting inflammation? What aspects of inflammation are better targets than others?

Some of these questions are addressed by ongoing excellent science. Others just spawn new questions. The articles in this LipidSpin have shed light on this subject, Discuss this article at www.lipid.org/lipidspin Sparking the Conversation on Inflammatory Disease Management 6 LipidSpin • Volume 17, Issue 1 • January 2019 but I still have many other questions, including: Is it possible to customize diets that target inflammation and lipidlowering? How does the microbiome contribute to the inflammasome? If a drug lowers LDL-c effectively, but does not reduce inflammatory markers, how do we explain its benefit and vice versa? Should we go back to thinking about the pleiotropic effects of medicines (statins, eicoapentaenoic acid)? How good is the evidence that we should be treating individuals with inflammatory diseases as an indication of need for intensification of therapy? Should we expect antiinflammatory pharmacotherapy to be another tool in our belt in the future?

I hope you enjoy this issue of LipidSpin as our first foray into inflammatory disease management. I expect this conversation to continue for many years to come, possibly another 100 years.

“To keep a lamp burning, we have to keep putting oil in it.” Mother Theresa

Disclosure statement: Dr. Soffer has served as Consultant for Amgen Inc, Akcea Therapeutics, Medicure, Regeneron, and has been a disease management Speaker on disease states (FCS and FH respectively) for Amgen Inc and Sanofi.