Oxidative stress may account for the “lipid paradox,” a higher incidence of heart disease burden found in nonobese rheumatoid arthritis (RA) patients with lower levels of low-density lipoprotein (LDL). George Karpouzas, MD, an investigator at the Lundquist Institute of Biomedical Innovation, St, Torrance, Calif., discussed this exploratory finding at the virtual annual meeting of the American College of Rheumatology.
Dr. George Karpouzas
A complex dynamic exists between traditional risk factors and cardiovascular (CV) events in RA patients, said Dr. Karpouzas, professor of medicine at the University of California, Los Angeles, and chief of the division of rheumatology, Harbor-UCLA Medical Center. “Lower lipid levels, specifically total cholesterol and to a lesser extent LDL, may be associated with higher risk,” he said. One recent study found that coronary artery calcium (CAC) scores were four times higher in RA patients with lower LDL concentrations (> 70 mg/dL) than those in control groups. “This was especially true in patients who were nonobese, non-Hispanic Whites and never smokers,” said Dr. Karpouzas. Other studies have reported this association between low LDL and increased CVD risk.
These paradoxes led to several questions: Does obesity modify the effect of LDL on cardiovascular disease (CVD) risk in RA and does it moderate the effect of LDL on coronary plaque burden and progression? Do LDL particle composition and oxidation variations underlie the paradoxical association of low LDL with higher coronary atherosclerosis burden in RA? To find answers, Dr. Karpouzas’ team in the Prospective Evaluation of Latent Coronary Atherosclerosis in Rheumatoid Arthritis (PROTECT-RA) trial studied a cohort of 150 established RA patients without symptoms or diagnosis of CV disease.
Dr. Karpouzas presented two oral abstracts that summarized this research during the ACR 2020 session, “RA, diagnosis, manifestations and outcomes: heart of the matter,” which was held virtually.
Higher plaque burden seen in nonobese patients
In one part of the study, patients underwent baseline cardiac coronary CT angiography (CTA) over 1 year (2010-2011). Investigators evaluated CAC scores, segment involvement scores (SIS), segment stenosis scores (SSS), and extensive and obstructive disease. Low LDL was defined as < 70 mg/dL, obesity as a waist to height ratio of > 0.58 squared.
Investigators in follow-up work (2017-2018) evaluated for plaque progression, prospectively recording all cardiovascular disease events such as cardiac death, myocardial infarction, unstable angina, stroke, and heart failure hospitalization. Multivariable models assessed the effects of LDL lower than 70 mg/dL, obesity, and their interaction, accounting for factors such as age, sex, statin use, diabetes and hypertension.
Four LDL obesity cohorts
Nonobese RA patients with low LDL exhibited the highest plaque burden. “Despite no differences in RA inflammation, patients in this group were more likely to exhibit high levels of LDL oxidation,” Dr. Karpouzas said in an interview. “Nonobese patients with low LDL more likely exhibited new coronary plaque formation as well as increased stenotic severity of prevalent plaque after adjustments for relevant covariates,” he added.
The study’s observational nature exposed it to biases and unmeasured confounding, Dr. Karpouzas emphasized. Because it took place in a single center, the results might not be generalizable to ethnically and racially diverse cohorts. Patients with calcifications, extensive or obstructive coronary plaque at baseline scan received more aggressive treatments, which could have slowed CVD event risk and plaque progression. Investigators cautioned that the results should be seen as “exploratory,” given that CVD event analysis wasn’t applied to the original study design.
The oxidation-LDL connection
Another arm of the study examined the oxidation association question. Investigators did a similar analysis of the same patients but also evaluated for cholesterol content, Lp(a) mass, OxLDL levels, IgG and IgM anti-OxLDL and apoB100 immune complexes and proinflammatory cytokines.
RA patients with LDL lower than 70 mg/dL had higher SSS and CAC scores and were more likely to have extensive or obstructive plaque. Statin-naive patients with lower LDL exhibited greater LDL oxidation than higher LDL groups. In addition, those with lower LDL had higher anti-OxLDL and apoB100 than patients with higher LDL.
“Oxidation makes the cholesterol more ‘sticky,’ allowing it to penetrate into the walls of the endothelium, and changes macrophages to foam cells. This malignant process is very powerful and can potentially increase atheroma burden,” study coauthor Matthew Budoff, MD, professor of medicine at UCLA and endowed chair of preventive cardiology at the Lundquist Institute, said in an interview.
Investigators also found an independent association between Lp(a) content and LDL oxidation. This association seemed strong in patients with lower LDL compared to higher LDL groups. In addition, “greater oxidation and immune recognition of oxLDL further associated with higher IL-6 elaboration which may in turn augment atherosclerosis burden in the low LDL group,” said Dr. Karpouzas.
The analysis did not explore alternate mechanisms such as increased cholesterol loading capacity, lower efflux capacity or increased hepatocyte uptake through LDL-R upregulation, a key limitation. Dr. Karpouzas also acknowledged that higher cumulative inflammatory burden incurred before evaluating low LDL patients at baseline may have led to greater coronary plaque burden.
Overall, the study shows that low LDL is not protective in this population, said Dr. Budoff. “Low LDL patients who have atherosclerosis should be treated with statins and other therapies to lower their CV risk.”
Larger studies to confirm associations
Attendees of the ACR 2020 session called for additional studies to confirm that LDL oxidation leads to increased coronary atherosclerotic burden in RA patients.
The study provides “mechanistic insight into this important problem for patients with RA,” noted Jeffrey A. Sparks, MD, MMSc, assistant professor of medicine at Harvard Medical School and associate physician at Brigham and Women’s Hospital, Boston.
Some of the patients studied were on lipid-lowering drugs such as statins, though the statistical analysis adjusted for use of these medications, noted Dr. Sparks. “It is possible that excess systemic inflammation alone is responsible for changes in LDL oxidation that may ultimately lead to cardiovascular disease,” he offered.
Future mechanistic and interventional studies related specifically to LDL oxidation “should establish the importance of this pathway in the development of cardiovascular disease in patients with RA,” said Dr. Sparks.
Large studies of patients with different BMI and LDL values followed prospectively for CV events would be ideal, said Joel M. Kremer, MD, president of the Corrona Research Foundation and founder of Corrona, a biopharma data solutions firm. Investigators would need to follow patients for several years. And, such a venture might face some obstacles. “The practical impediments and cost would be substantial. Also, as LDL oxidation may be related to disease activity, there would be ethical and pragmatic issues associated with controlling disease activity in these patients. This would obscure these outcomes of interest,” said Dr. Kremer.
Dr. Karpouzas receives grant and research support from the American Heart Association and Pfizer-Aspire. Dr. Budoff receives grant support from General Electric.
SOURCE: Karpouzas G et al. ACR 2020. Abstract 0485 and Abstract 0486.