Foundation Research Explores Relationship Between RA and Cardiovascular Disease

Dr. Pennathur

Subramaniam Pennathur MD, associate professor of medicine at University of Michigan School of Medicine in Ann Arbor, is a nephrologist by training. His research focuses primarily on the complications caused by metabolic diseases, particularly diabetes, but a conversation with a colleague and a grant from the Rheumatology Research Foundation set him on different course—studying why rheumatoid arthritis (RA) patients have an elevated risk of heart disease.

“I got interested in this subject, in part, because one of my colleagues here at the University of Michigan, Dr. Mariana Kaplan, is interested in autoimmune diseases, especially rheumatoid arthritis,” says Dr. Pennathur. “We had a discussion initially about the causes of cardiovascular disease, and she talked about how rheumatoid arthritis markedly increases the risk of cardiovascular disease, and it is not very well known what the factors are. For example, premenopausal women in general are protected from cardiovascular disease. Yet in RA, that protection seems to be lost. We were discussing how best to look at our common interest in cardiovascular disease, and actually apply my expertise in that area to a new area of research, which is rheumatoid arthritis.”

After Dr. Pennathur’s discussions with Dr. Kaplan, associate professor of medicine in the rheumatology division at the University of Michigan School of Medicine, the pair started looking at RA patients who were already enrolled in an NIH-funded study where Dr. Kaplan was the principal investigator, and started examining how high-density lipoprotein (HDL), which is associated with protection from cardiovascular disease, is different in RA patients.

“The premise of our proposal was to look at HDL cholesterol and how that is changed in patients with rheumatoid arthritis,” says Dr. Pennathur.

Drs. Pennathur and Kaplan quickly discovered that RA does affect HDL.

“Our first finding was that patients with RA, even without cardiovascular disease, had significantly damaged HDL. That damage occurs through oxidation via an enzyme called myeloperoxidase,” Pennathur explains. “The enzyme is present in white blood cells, so it is present in neutrophils and macrophages. Our hypothesis was that the joint inflammation and the general state of increased inflammation that characterizes RA makes the white blood cells secrete more myeloperoxidase that, in turn, damages HDL. Normally the neutrophil myeloperoxidase is utilized for killing bacteria.

When you have an infection of some sort, the myeloperoxidase actually generates oxidants, which actually kill the bacteria. In this circumstance, it’s damaging circulating HDL, which, in turn, loses its protective effect. Patients with rheumatoid arthritis, even without cardiovascular disease, have this problem.”

The research also showed that RA patients with heart disease have even higher degrees of oxidation than RA patients without heart disease. From there, Dr. Pennathur used a reverse cholesterol transport assay to measure how effective the damaged HDL in RA patients was in removing cholesterol.

“We were able to show that HDL, in patients with rheumatoid arthritis, has less ability to remove cholesterol in cell cultures,” says Dr. Pennathur.

Another finding of the study was that the composition of HDL molecules in RA patients was different than in those who did not have the disease.

“One of the things we found was that patients with RA tend to have a different protein composition compared to normal people,” says Dr. Pennathur. “Patients with heart disease and RA have even more pronounced changes in their HDL. In and of itself, it doesn’t prove a whole lot, but what we are trying to figure out is how the different protein composition of this HDL may account for the dysfunction that we see in this function.”

Dr. Pennathur says the Foundation-funded research has led to several papers, and that the next step is to replicate the study with a larger sample.

“Our next goal is to do this with a larger group of patients to see if these markers can predict the future occurrence of disease,” he says.

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