PRECISION MEDICINE FOR CARDIOVASCULAR DISEASE PREVENTION: WHERE DO WE STAND IN 2019 WITH A FOCUS ON INFLAMMATION AND LIPIDS?

Abstract

In this manuscript, I will discuss where we stand in 2019, with a focus on inflammation and lipids, in regard to precision medicine for cardiovascular disease prevention. This manuscript will reflect my career journey working in the cardiovascular disease field.

INTRODUCTION

I joined the faculty at Baylor College of Medicine in 1998, and my first grant was a K08 award, which was submitted in June 1998, to study intercellular adhesion molecule–1 (ICAM–1). The initial review was highly critical and asked the question, “Why is a cardiology fellow working at a genetics laboratory studying ICAM-1, which has no proven role in cardiovascular disease?” At the time I submitted the grant, a Pub Med search would have shown six papers. In January 2019, there were 26,640 papers.

As indicated by the large number of publications, the field has exploded, with tremendous insights gained into the molecular mechanisms for leukocyte migration, including endothelial adhesion molecules of the immunoglobulin (Ig) superfamily, leukocyte integrins, chemokines, and cytokines and their roles in leukocyte migration from the bloodstream to the extravascular space (1).

My laboratory focused on the development of mice that were deficient in the CD11 integrins and their role in vascular disease (2-5). Initially, we concentrated on acute models and worked collaboratively with other investigators on models of atherosclerosis. In CD11b-deficient mice, there was no impact on atherosclerosis (6), but there was reduced intimal proliferation post–mechanical injury (7). We observed that CD11d-deficient mice had reduced lipid accumulation and reduced macrophages (8), whereas wild-type mice showed upregulation in CD11d in macrophages and in atherosclerosis.

Almost 20 years after joining the faculty at Baylor College of Medicine, I shifted my research focus to mouse models of atherosclerosis; together, my colleague Huaizhu Wu and I studied mice that had deficiency in CD11c. These mice had reduced atherosclerosis along with reduced lipid accumulation in the aorta (4).

We noted that in apolipoprotein (apo) E–deficient mice on a high-fat diet, circulating monocytes had increased lipid and were foamy in appearance (4). These foamy monocytes had increased expression of CD11c. This observation challenged the traditional concept that “foamy” macrophages were due solely to the accumulation of lipid in the arterial intimal space.

A substantial amount of work was done to show that monocytes deficient in CD11c had reduced adhesion when studied in vitro and that mice deficient in CD11c had reduced atherosclerosis as mentioned. Additional work by other groups has confirmed that indeed hypercholesterolemia in humans leads to increased foamy monocytes with increased monocyte expression of CD11c, and aggressive lipid-lowering therapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduced not only the level of low-density lipoprotein cholesterol (LDL-C) but also the number of foamy monocytes (9) as well as the rate of atherosclerotic cardiovascular disease events.

After spending many years focusing on bench research and animal models of inflammation and cardiovascular disease, I started working with clinical trials of novel therapies and became a member of the steering committee of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), which was led by Paul Ridker and Peter Libby. This was a randomized, placebo-controlled trial examining the efficacy of three doses of canakinumab on the reduction of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease in a secondary prevention population that also had an elevated level of high-sensitivity C-reactive protein (hs-CRP). This was the first trial to show that an anti-inflammatory therapy targeting interleukin-1β reduced the primary composite cardiovascular endpoint by 15%; hs-CRP was reduced by 39%, and LDL-C was not changed (10). As expected, the trial found a small but significant increase in fatal infections; however, there was also a significant reduction in fatal malignancies. A post hoc analysis showed a dose–response reduction in death from cancer, with a 51% reduction at the highest dose (11).

As a young faculty member, my basic research focused on inflammation, and my clinical interests were in lipids, atherosclerosis, and preventive cardiology. Because of my interest in cell adhesion molecules, I examined the levels of soluble cell adhesion molecules in patients with severe elevations of cholesterol and triglycerides and found that patients with severe elevation of triglycerides had increased levels of soluble vascular cell adhesion molecule–1 (VCAM-1) and ICAM-1 (12). I then examined the effects of high-dose omega-3 fatty acids in the treatment of patients with severe hypertriglyceridemia and found that there was a reduction both in triglycerides and in the levels of soluble ICAM-1 and soluble E-selectin (13). Very high triglycerides were an important clinical issue in regard to the development of pancreatitis, but the role of triglyceride-rich lipoproteins in the development of atherosclerosis was very controversial until the last decade. When multiple epidemiological studies that had long-term information on the association of lipids and lipoproteins with atherosclerotic cardiovascular disease events as well as extensive genetic information allowed Mendelian randomization studies, the evidence was overwhelming that genetic variants related to higher triglyceride levels were also associated with increased risk for atherosclerotic cardiovascular disease events (14). This has made a dramatic impact on the entire cardiovascular disease field and led to a much greater focus on triglyceride-rich lipoproteins and genes involved with triglyceride metabolism, in particular, genes that influence lipolysis of very-low-density lipoprotein (VLDL). Gain-of-function variants in the genes encoding lipoprotein lipase and apoA-V and loss-of-function variants in genes encoding apoC-III and angiopoietin-related protein 3 (ANGPTL3) are associated with lower levels of triglycerides and less atherosclerotic cardiovascular disease (15). Because of our interest in inflammatory monocyte phenotypes and lipids, we examined the monocyte changes with postprandial lipemia. Individuals who develop marked elevations of triglycerides in the postprandial state also develop foamy monocytes (16), which have increased expression of CD11c and very late activation antigen 4 (VLA4) and increased adhesion to VCAM-1 when studied with in vitro assays (17).

Multiple clinical trials have shown that lowering cholesterol in patients with increased LDL-C and increased risk for cardiovascular disease leads to a reduction in cardiovascular disease events (18,19), but no trials had focused on treating patients with high triglycerides and increased risk for cardiovascular disease. Based on the Japan EPA Lipid Intervention Study (JELIS) (20), which showed the benefits of eicosapentaenoic acid (EPA) in Japanese patients with hypercholesterolemia who were already treated with statins, a small company named Amarin Pharmaceuticals approached me about studying icosapent ethyl in patients with cardiovascular disease on statin therapy who had persistent elevations of triglycerides. In the ANCHOR study, Amarin researchers showed that 4 g/day led to a 22% reduction in triglycerides, with favorable reductions in non–high-density lipoprotein cholesterol (non-HDL-C), apoB, and inflammatory markers (21). Based on these results, Amarin launched a large randomized placebo-controlled outcomes trial. The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) was performed on 8179 patients either with established cardiovascular disease or with diabetes and other risk factors who were on statin therapy and had fasting triglycerides 135–499 mg/dL and LDL-C 41–100 mg/dL. Compared to the placebo, icosapent ethyl 4 g/day significantly reduced triglycerides by 19.7%, non-HDL-C by 13.1%, LDL-C by 6.6%, apoB by 9.7%, and hs-CRP by 39.9% at a one-year follow-up. In addition to these improvements in biomarkers, the primary endpoint—a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and unstable angina—was significantly reduced by 25% at a median follow-up of 4.9 years. Treatment effects were consistent across baseline triglyceride subgroups and in both primary and secondary prevention. The low rate of adverse effects included a small but significant increase in atrial fibrillation or flutter and an increase in serious bleeding that was not statistically significant (22).

CONCLUSIONS

In summary, as we now enter the era of precision medicine with respect to the treatment of atherosclerotic cardiovascular disease, it is extraordinary to reflect on how far we have come since I completed my cardiology fellowship just over 30 years ago. I have had the opportunity to be involved in both basic and clinical research with two entirely new approaches: the role of inflammation and anti-inflammatory therapies in atherosclerotic cardiovascular disease and atherosclerotic cardiovascular disease prevention and the role of triglyceride-rich lipoproteins and omega-3 fatty acids in atherosclerosis and the treatment of individuals who have elevated triglyceride levels. As I look back on my career and look forward to the future, I can see that research is not a destination, it is a journey. I have had extraordinary guides and companions throughout my career, beginning in medical school at Baylor College of Medicine; my residency at the University of Texas Southwestern Medical School; my cardiology fellowship and postdoctoral training in genetics at Baylor; and my numerous collaborators, postdocs, and students throughout the years. My most important guides and companions on this journey have been my wife Yasmine and my daughters Leyla, Christina, and Katina.

DISCUSSION

Due to technical problems with the Grand Hotel audiovisual equipment, the questions by Drs. Thorner, Oates, and Wolf associated with this paper and the responses by Dr. Ballantyne could not be transcribed.