Rheumatoid Arthritis - Cardiovascular Disease
There was considerable interest during the meetings on the prevalence and nature of cardiovascular disease in RA. This stems from reports that patients with more severe RA have shortened lifespans (compared to patients without RA) and that this is due, in large part, to premature heart disease. The exact nature of the heart disease remains to be determined but a number of investigators presented data suggesting that there is accelerated atherosclerosis leading to acute coronary syndromes (i.e., myocardial infarctions) as the major pathology. Whether heart disease in RA is due to, or associated with, conventionally recognized risk factors for heart disease such as high cholesterol, diabetes, central obesity, etc. was the subject of some abstracts but remains controversial.
A symposium on Inflammation and Atherosclerotic Cardiovascular Disease was presented on Monday, October 30th. Paul Ridker, M.D. from Brigham and Womens Hospital in Boston reviewed the concept that coronary artery disease is a low-grade inflammatory process, and that mild elevation of CRP has been proven in a number of studies to be a powerful predictor for myocardial infarction and stroke, independently of conventionally accepted risk factors (such as elevated cholesterol). Whether CRP elevation is a surrogate marker for cytokine elevations or is itself involved in the pathogenesis and rupture of atherosclerotic plaques remains unclear. In a study of 12 risk (or putative risk) factors for ASCVD, elevated CRP plus elevated ratio of total cholesterol to HDL yielded the highest relative risk (5.8-fold) for acute myocardial events. Aspirin 325 mg qod was shown to reduce incidence of first ever MIs by 44% in the Physicians Health Study (New England J Medicine 1997). The most profound reduction occurred in subjects with the highest quartile of CRP, providing support that anti-inflammatory strategies may be preventive for ASCVD. A drug with dual properties - that is, cholesterol lowering and anti-inflammatory - may be ideal for the treatment and/or prevention of ASCVD. Dr. Ridker presented data suggesting that several cholesterol lowering agents (lovastatin and pravastatin) do indeed have both properties.
Mary Roman, M.D. from Cornell University in New York discussed techniques for detecting pre-clinical ASCVD. She reviewed the recent thinking that most MIs occur in vessels that are only mildly to moderately stenotic, and that acute rupture of a plaque within the vessel, resulting in acute thrombosis and occlusion, causes the MI. Plaques that are vulnerable (at increased risk of rupture) are characterized by: a thin fibrous cap, large lipid core, little calcium, and a macrophage-rich infiltrate. In contrast, stable plaques (low risk of rupture) are characterized by thick fibrous cap, small lipid core, heavy calcification, and sparse inflammatory infiltrate. She then discussed the usefulness of currently available tests for predicting likelihood of acute coronary syndromes:
- Stress cardiogram. This has low predictive accuracy especially in women, primarily because of low pretest likelihood.
- Stress cardiogram coupled with an imaging study (such as a nuclear perfusion scan or echocardiogram). This enables the assessment of inducible ischemia. There can be a problem with false positives especially in women.
- Electron Beam CT scanning. This technique is good for detecting coronary artery calcification. The score generated by the test correlates well with plaque burden but not with risk of rupture.
- Carotid artery ultrasound. This technique measures intima medial thickness and can unequivocally identify atherosclerotic plaques in the carotid arteries which, in turn, correlates strongly with coronary artery disease.
The last lecture was given by John Esdaile, M.D. from Vancouver, Canada who reviewed the evidence in systemic lupus erythematosus (SLE) linking atherosclerotic cardiovascular disease to premature death in SLE.
On Tuesday, Nov. 1, Cornelia Weyand, M.D., Ph.D. from Mayo Clinics, Rochester, MN gave a special lecture entitled "Rheumatoid Arthritis and Atherosclerotic Cardiovascular Disease: Shared Disease Mechanisms". At the Mayo Clinics, Drs. Weyand, Gabriele and others have confirmed that RA patients are at increased risk of death from cardiovascular events than age and gender-matched controls. They could not ascribe this increased risk to conventional risk factors such as hyperlipidemia. Dr. Weyands hypothesis was that RA-induced vascular injury led to an exacerbation of traditional coronary artery disease. Unstable plaques that are at high risk for rupture are characterized by infiltrates of HLADR+ macrophages and T cells. She discussed at length the presence of a peculiar CD4+/CD28null T cell that is overrepresented in both RA synovia and in non-RA coronary artery plaques. This cell overproduces interferon-gamma, recognizes MHC Class I antigens, and expresses CD161 on its surface, features that liken it to an NK cell. These CD4+/CD28null cells also exhibit decreased responses to apoptotic stimuli, and utilize unique costimulatory molecules for activation/proliferation. Having features of both T cells and NK-like cells, these cells bridge adaptive and innate immunity. One might speculate that they would respond to a broader array of stimulatory signals than conventional T cells. This cell may be responsible for macrophage activation in coronary artery plaques and in the RA synovium.
