Hyperuricemia: A causal player or a bystander linking inflammatory signaling and atrial fibrillation?

Atrial fibrillation (AF) remains the commonest arrhythmia with an increasing prevalence worldwide [1]. Emerging evidence has demonstrated a clear association between the elevated level of serum uric acid (SUA) and the prevalence and recurrence rate of AF [2–4]. In this issue of the journal, Kuwabara et al. (2017- in this issue) validates the notion that hyperuricemia is a potential risk factor for AF in a very large cohort of Japanese patients [3]. This retrospective analysis is the first demonstration that hyperuricemia is a strong competing risk factor for AF in apparently healthy individuals with and without accompanying diseases. Although previous studies reported a positive association between SUA and AF, these studies included patients with hypertension, type-2 diabetes and diverse cardiovascular diseases but not individuals from the general population which might reflect the relationship between SUA and various cardiovascular and metabolic diseases potentially biasing the results [2,4]. Thus the major strength of the study by Kuwabara et al. (2017- in this issue) is the demonstration that hyperuricemia is a strong independent risk factor for AF even in individuals without cardiovascular and metabolic disorders [3]. However, despite the accumulating evidence linking SUA and AF, it is still unclear whether and how uric acid and/or urate (the salt or ester form of uric acid) may promote AF induction and its maintenance.

Conceptually the elevated levels of SUA/urate may contribute to the pathophysiology of AF via both inflammatory signaling-induced changes and inflammation-independent mechanisms (Fig. 1). Gicquel et al. have shown that macrophages can engulf uric acid crystal (UAC), resulting in the activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome [5]. The activated NLRP3-inflammasome in macrophages is responsible for the maturation of the cytokine interleukin-1β (IL-1β) [5]. Secreted IL-1β by macrophages promotes the proliferation and differentiation of fibroblasts to myofibroblasts, which secret a larger amount of cytokines, chemokines and growth factors including TGFβ1 [1]. Ultimately, these events increase collagen production and the deposition of extracellular matrix proteins, promoting fibrosis. In addition, the internalization of uric acid via uric acid transporter (UAT) in fibroblasts can increase the production of reactive oxidative species (ROS), which can activate the Ca²⁺-permeable transient receptor potential melastatin-related type-7 channels (TRPM7). TRPM7s are upregulated in atrial fibroblasts of AF patients and contribute to TGFβ1-induced fibroblast differentiation [6]. Thus, the increase in collagen deposition and the related fibrosis formation (structural remodeling) are expected to facilitate the development of AF-maintaining reentrant circuits by causing heterogeneously conduction slowing. Future experimental work is needed to directly test this hypothesis.

Fig. 1.

Putative mechanisms of hyperuricemia-induced atrial fibrillation. DADs, delayed afterdepolarizations; SERCA, sarcoplasmic reticulum (SR) Ca²⁺-ATPase; RyR2, ryanodine receptor type-2; UA, uric acid; pERK, phosphorylated (activated) extracellular signal-regulated kinase; ER, endoplasmic reticulum. Solid lines indicate proven mechanisms, whereas dash lines indicate putative pathways. For further details and abbreviations see text.

Uric acid/urate may also promote AF via various inflammation-independent pathways. Uric acid increases the expression of Kv1.5-channel subunits in cultured mouse atrial myocytes (HL-1 cells) [7]. Urate intake by the UATs located on cardiomyocytes can enhance the KCNA5 expression (a gene encoding Kv1.5 channels) via the activation of extracellular signal-regulated kinase (ERK) signaling pathways [7]. An upregulation of Kv1.5 proteins should increase the ultra-rapid delayed rectifier potassium current (I_Kur) [7], and abbreviate the atrial action potential. Moreover, IL-1β can suppress the L-type Ca²⁺ currents (I_Ca,L) via IL-1 receptors (IL1Rs) [8]. The augmented I_Kur and reduced I_Ca,L currents could shorten the action potential duration (APD), thereby supporting the formation of another substrate for AF-maintaining reentry [1].

Because uric acid/urate can directly activate NLRP3-inflammasome [6], the relationship between activation of NLRP3-inflammasome and development of AF appears causal. The NLRP3-inflammasome is upregulated in atrial tissue of AF patients [9] and cardiomyocyte-restricted constitutive activation of NLRP3-inflammasome promotes the development of premature atrial contractions and predisposes mice to pacing-induced AF [9]. These electrophysiological changes are associated with the development of atrial hypertrophy and fibrosis, and potentially-proarrhythmic spontaneous sarcoplasmic reticulum (SR) Ca²⁺-release events which might cause delayed afterdepolarizations and focal ectopic firing [9]. Consistent with these findings, IL-1β directly promotes triggered activity in rat myocardium [10]. Combined these results provide a strong evidence for a potential role of hyperuricemia in NLRP3-inflammasome induced atrial remodeling associated with AF development. Thus an abnormal activation of the NLRP3-inflammasome by uric acid could represent the mechanistic link between hyperuricemia and the higher incidence of AF and potentially explain why hyperuricemia may constitute an independent risk factor of AF as elegantly demonstrated in the present study of Kuwabara et al. in apparently healthy individuals from the general population [5].

Despite the substantial progress in our understanding of AF pathophysiology, the precise mechanisms leading to AF are incompletely understood [1]. Independent of the underlying cause, the clinical presentation of AF is very diverse and the complex AF pathophysiology is a big challenge for the development of novel drugs with improved efficacy and safety profiles. Since inflammatory signaling appears to contribute to both electrical and structural remodeling which typify AF, it is reasonable to speculate that allopurinol, an anti-gout drug that inhibits the synthesis of uric acid, might have beneficial effects in the prevention of AF. Prospective clinical trials in suitable patient populations are needed to establish the causative role of uric acid in AF pathophysiology and to evaluate the potential therapeutic value of allopurinol in the prevention and therapy of AF.