A signature of aberrant immune responsiveness identifies myocardial dysfunction in rheumatoid arthritis.

Heart failure (HF) is an important complication of rheumatoid arthritis (RA) that leads to the premature death of many patients. Until recently, this complication has been overshadowed by the increased risk of coronary heart disease and myocardial infarction in RA. Since 2004, epidemiological studies have confirmed a significantly increased risk of incident HF among people with RA unexplained by traditional cardiovascular risk factors or coronary heart disease (1, 2). HF has a grim prognosis in patients with RA, with up to 35% mortality in the first year after diagnosis—a rate of HF death that is two-fold higher than the analogous rate for persons in the general population (3). How rheumatoid disease leads to HF is unknown. Several indicators of disease activity or severity predict incident HF, including rheumatoid factor, elevated acute phase reactants, high disability and global severity scores, as well as extra-articular manifestations such as interstitial lung disease, scleritis, and vasculitis (1, 2, 4). A prevailing theory is that chronic, systemic immune activation with elaboration of inflammatory mediators, including cytokines such as TNF-α, IL-1, and IL-6, leads to microvascular dysfunction and ultimately to myocardial remodeling and fibrosis (5). A recent study reported higher expression of adhesion molecules, HLA molecules, and inflammatory cytokines by cardiac endothelial cells and cardiomyocytes in patients with inflammatory rheumatic disease as compared to controls, suggesting immune activation contributes to cardiovascular disease in the RA population (6). Yet, it remains unclear how immune mechanisms conspire in the pathogenesis of myocardial disease in RA. The unique effect of RA on myocardial function appears to be impairment of diastolic filling, relaxation, or compliance, known as diastolic dysfunction (5). Numerous case-control echocardiography studies have reported an increased prevalence of impaired diastolic function in RA patients even without clinical cardiovascular disease (7–14). When HF occurs, persons with RA are more likely to have preserved systolic function compared to persons without arthritis (3), suggesting RA-related immune mechanisms incite myocardial injury in a manner that tends to culminate in diastolic dysfunction. Notably, isolated diastolic dysfunction in the general population is associated with increased mortality (15). Thus, improved understanding of the clinical and biological determinants of diastolic dysfunction may explicate the pathogenesis of HF with preserved systolic function and illuminate new targets for therapy, with the ultimate goal of impacting the high mortality of HF in patients with RA. Further, the identification of biomarkers reflecting immune events early in the pathogenesis of myocardial injury, prior to the development of clinical HF, may enable recognition of patients at future risk for myocardial dysfunction. In attempt to meet this aim, we have devised an approach to identify complex biomarkers based on ex vivo cytokine production, reflecting the responsiveness of the peripheral innate and adaptive immune systems (16). We have shown that profiles of ex vivo cytokine release in response to broad stimulation, summarized as an multi-cytokine prediction score, may have utility in differentiating patients at high risk for disease complications (16). The objective of this study was to identify an “immune signature” of myocardial dysfunction in RA by testing the hypothesis that distinct ex vivo cytokine profiles correlate with the degree of left ventricular diastolic dysfunction (LVDD) after adjusting for cardiovascular risk factors and RA disease characteristics.