Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic immuno-mediated disease primarily affecting the joints, characterized by persistent high-grade systemic inflammation. Cardiovascular morbidity and mortality are significantly increased in RA, with >50% of premature deaths attributable to cardiovascular disease. In particular, RA patients were twice as likely to experience sudden cardiac death compared with non-RA subjects, pointing to an increased propensity to develop malignant ventricular arrhythmias. Indeed, ventricular repolarization (QT interval) abnormalities and cardiovascular autonomic nervous system dysfunction, representing two well-recognized risk factors for life-threatening ventricular arrhythmias in the general population, are commonly observed in RA. Moreover, large population-based studies seem to indicate that also the prevalence of atrial fibrillation is significantly higher in RA subjects than in the general population, thus suggesting that these patients are characterized by an abnormal diffuse myocardial electrical instability. Although the underlying mechanisms accounting for the pro-arrhythmogenic substrate in RA are probably intricate, the leading role seems to be played by chronic systemic inflammatory activation, able to promote arrhythmias both indirectly, by accelerating the development of ischaemic heart disease and congestive heart failure, and directly, by affecting cardiac electrophysiology. In this integrated mechanistic view, lowering the inflammatory burden through an increasingly tight control of disease activity may represent the most effective intervention to reduce arrhythmic risk in these patients. Intriguingly, these considerations could be more generally applicable to all the diseases characterized by chronic systemic inflammation, and could help elucidate the link between low-grade chronic inflammation and arrhythmic risk in the general population.

Association between chronic immune-mediated inflammatory diseases and cardiovascular risk

“…As previously described, rheumatoid arthritis showed a significant risk in all four end-points, even after adjustment for drug therapy 19. Lazzerini et al pointed out that a higher risk of rhythm disturbances, particularly tachyarrhythmias, in such individuals may significantly contribute to the high cardiovascular morbidity and mortality 20. SLE only showed a significant association with overall mortality.…”

Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease‐associated psychological morbidity

“…These data and those based on other skin inflammatory diseases indicate the central role of cytokines in driving skin pathology . Furthermore, evidence from a range of autoimmune diseases indicates that inflammatory cytokines are implicated in wider comorbidities, impacting vascular, metabolic and psychological pathways …”

Assessing QT interval in patients with autoimmune chronic inflammatory diseases: perils and pitfalls

“…In this scenario, the key mediators seem to be the inflammatory cytokines (particularly tumour necrosis factor-α, interleukin (IL)-6, IL-1β) which may affect myocardium either directly, by modulating the expression and function of specific ion channels critically involved in AP (figure 1) or indirectly, by increasing central nervous system sympathetic drive on the heart 5. Among systemic autoimmune diseases (ADs), the largest evidence has been reported for rheumatoid arthritis (RA) and connective tissue diseases (CTDs).…”

“…Given the above discussed effects of inflammatory cytokines in modulating QTc duration, particularly in RA,4 5 it is possible that the shorter QTc duration observed in patients with RA versus patients with SLE may be at least in part the result of the fact that this RA cohort did not have a sufficiently high disease activity, thus underestimating a key QT-prolonging mechanism operating in the disease (accordingly, in the present RA cohort CRP levels and DAS28-CRP score were associated with an increased QTc length). In fact, although the authors stated that their patients with RA had moderate-to-severe activity (median DAS28-CRP: 3.6, using for this definition the presence of a DAS28-CRP>3.2), current American College of Rheumatology (ACR)-recommended cut-offs (remission <2.6; low/minimal disease activity 2.6–3.2; moderate disease activity 3.2–5.1; high/severe disease activity >5.1)22 indicate that a DAS28-CRP value of 3.6 corresponds at most to a moderate disease activity.…”