• heart failure
• systemic inflammatory diseases

Rheumatoid arthritis (RA) is a chronic autoimmune/autoinflammatory disorder characterised by a symmetric erosive polyarthritis, with an additive and progressive evolution leading to joint deformities and bone anchyloses. The prevalence is about 1% of the general population, and its presence is associated to a marked increased risk of cardiovascular death, particularly due to coronary artery disease (CAD) and heart failure (HF).1 RA occurs in postmenopausal women and middle-age men who often have the traditional cardiovascular risk factors; however, such risk factors cannot fully account for the increased risk observed in these patients. A combined interaction of cytokine spillover, oxidative stress, abnormal innate and specific immune adaptation and coagulation abnormalities have been considered as potential mechanisms of increased cardiovascular risk.2Systemic cytokines (especially interleukin-1β (IL-1β), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α)) and inflammatory biomarkers (such as C reactive proteins) are directly associated with the severity of CAD and the risk of atherothrombotic events.2 Patients with RA also have an increased risk of develop non-ischaemic HF.3 The underlying pathophysiological mechanisms are far from being completely understood. In addition to the traditional risk factors, antirheumatic drug therapies, especially non-steroidal anti-inflammatory drugs and glucocorticoids, and inflammatory activity may contribute to increase the cardiac vulnerability to develop covert and/or overt HF over time. It has been proposed that proinflammatory mediators (IL-1β and TNF-α) lead to direct cardiomyocyte dysfunction and injury, and, if persistent, to adverse cardiac remodelling and potentially HF.3 Whether arthritis leads to inflammation, which in turn induces cardiac dysfunction, or whether a systemic inflammation is responsible for arthritis and cardiac dysfunction remains unknown. To address this question, Pironti et al 4 report in their Heart paper for the first time how chronic inflammation of the joint(s), in a mouse model of collagen antibody-induced arthritis (CAIA), induces oxidative stress and myocardial remodelling. The mice displayed a maladaptive cardiac remodelling, characterised by ventricular hypertrophy, extracellular fibrosis, dysregulation of intracellular calcium signal pathways with an impairment of the calcium handling system and a reduced contractile capacity. All these factors lead to both systolic and diastolic dysfunction and consequently increase the susceptibility of developing HF.4

The mechanisms implicated in these abnormalities are likely to be secondary to chronic inflammation and increased oxidative stress that are closely associated pathophysiological processes, cross-promoting each other and contributing to cardiovascular disease progression even in the subacute phase of the disease. Oxidative stress is a condition of imbalance between the increased oxidant capacity and the reduced antioxidant defence of the organism. In chronic inflammatory conditions, such as RA, enhanced oxidative stress has been implicated in the pathogenesis and progression of articular and cardiovascular damages by promoting protein redox-dependent modifications,4 cytokine production and spillover that, in turn, further increase oxidant agents in a vicious circle. Pironti and colleagues show that the functional defect resides in the heart, and more specifically in the cardiomyocyte. The mice with arthritis have impaired myocardial contractility in vivo and impaired calcium handling in vitro.4

The CAIA mouse model is therefore a useful tool to study simultaneously changes in the cardiovascular system and heart function and the joints and how these systems/organs respond to targeted therapies. This may be particularly important because therapies that improve arthritis may show an unfavourable cardiovascular safety profile.

The link between inflammation and impaired cardiac contractility is reminiscent of the soluble cardiosuppressant factors in the plasma of patients with sepsis, which were sufficient to induce a reversible dysfunction.5 Two cytokines have been mainly implicated in this effect, TNF-α and IL-1β.5 Each of these cytokines, independently and synergistically, can induce a reversible myocardial dysfunction. Members of the IL-1 family of cytokines, IL-1β and IL-18, have been identified as soluble cardiosuppressant factors also in acute decompensated HF.6 TNF-α and IL-1β may not be interchangeable and their regulatory system and signalling cascade are only minimally overlapping. TNF-α inhibitors are highly effective in the treatment of RA; however, they increase the risk of HF. IL-1 blockade with anakinra showed improvement in cardiovascular function in patients with RA as early as 3 hours after the first dose, and sustained at 30 days.7 In 80 patients with RA and with (n=20) or without coronary artery disease (n=60), anakinra reduces oxidative stress and improved left ventricular contractility and relaxation as measured by tissue Doppler echocardiography.8 Anakinra also appears to improve cardiorespiratory fitness in patients with systolic HF.6 A recent large phase III clinical trial of IL-1β in patients with prior acute myocardial infarction showed reduced recurrent cardiovascular events as well as reduced incidence of arthritis, further strengthening this link.9

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Figure 1

Cytokines and reactive oxygen species (ROS)-mediated effect of rheumatoid arthritis on cardiac function. Inflammatory arthritis, as recapitulated in the collagen antibody-induced arthritis mouse model, is characterised by joint inflammation and a systemic increase in proinflammatory cytokines, leading to an oxidative stress to the heart, myocardial remodelling and dysfunction.