A new year’s resolution to resolve atrial fibrillation: Resolvin D1 emerges as a powerful target against post-MI atrial remodelling

This editorial refers to ‘An inflammation resolution–promoting intervention prevents atrial fibrillation caused by left ventricular dysfunction’, by R. Hiram et al., https://doi.org/10.1093/cvr/cvad175.

Atrial fibrillation (AF) is the most common arrhythmia in clinical medicine because of its close association with highly prevalent disorders such as obesity, diabetes, hypertension, coronary artery disease, and heart failure, among many others. A unifying pathophysiological feature of all these conditions is chronic inflammation, which itself has emerged as a strong predictor and likely cause of AF vulnerability.

The association between AF and inflammation was initially borne from studies revealing elevated levels of pro-inflammatory biomarkers in sera and tissue samples from AF patients. Subsequent studies in animal models and humans provided direct evidence implicating pro-inflammatory signalling from immune cells (whether resident or recruited) and myocytes in the pathogenesis of AF. Mechanistically, a vicious interplay between inflammation and oxidative stress promotes both the triggers and substrate that initiate and perpetuate AF circuits.¹

Given the mounting evidence linking inflammation to human pathophysiology, various pharmacological agents targeting pro-inflammatory pathways in general and NLRP3 signalling in particular are being actively pursued.² None of these compounds, however, have thus far shown clear efficacy in combatting AF highlighting a major unmet clinical need. This is likely due to the fact that inflammation is a highly complex and intricately choreographed process that includes distinct initiation and resolution phases that operate in concert to maintain tissue homeostasis. When the resolution phase is impeded or unsuccessful, a prolonged phase of inflammation ensues culminating in adverse remodelling.³ This is particularly relevant in the context of myocardial infarction (MI), where chronic inflammation leads to increased deposition of fibrotic lesions that disrupt myocardial conduction and alter ion channel and gap junction function via the release of cytokines and other paracrine factors. As such, therapeutics targeting the unresolved inflammatory process rather than the primary inflammation–initiation phase could be key in mitigating the arrhythmogenic substrate associated with AF, particularly in the setting of acute MI that requires a robust early inflammation phase to activate wound healing and repair processes.

1. The role of inflammation and resolution pathways in promoting cardiovascular disorders

Chronic inflammation arises when there is an imbalance between inflammation-promoting and resolving processes in favour of the former. During the resolution phase, specialized pro-resolving mediators (SPMs) that are derived from N-3 and N-6 polyunsaturated fatty acids play a key role in restoring tissue homeostasis by limiting neutrophil infiltration, promoting the activity of anti-inflammatory macrophages, and clearing cellular debris.⁴ Hence, inadequate production of SPMs, including a family of so-called Resolvins, can lead to a chronic inflammatory state marked by adverse tissue remodelling and dysfunction.⁵ In this regard, restoring the delicate balance between pro- and anti-inflammatory pathways by promoting the latter has emerged as a promising approach for a host of cardiovascular disorders, including those associated with increased afterload, either on the left ventricle (LV) vis-a-vis aortic constriction⁶ or the right ventricle in pulmonary artery hypertension (PAH).⁷ In both cases, treatment with the pro-resolving molecule Resolvin D1 (RvD1) ameliorated adverse structural remodelling and improved function by reducing pro-inflammatory cytokines. In seminal work, the Nattel group documented an impressive effect of RvD1 treatment in prevention of adverse atrial remodelling and AF propensity in a standard monocrotaline-induced model of PAH.⁷ Whether and how this intervention can improve atrial remodelling in the context of MI, however, remained unknown—at least until now.

2. Targeting the resolution of inflammation for AF prevention in MI

In this issue of Cardiovascular Research, Hiram et al.⁸ provided robust evidence linking RvD1-mediated inflammation resolution to the suppression of post-MI AF vulnerability via improvement in atrial electrical and structural remodelling. A major strength of their experimental design was the incorporation of both a prevention arm (therapy initiated 24 h before MI and maintained for 3 weeks) and a reversal arm (initiated 7 days post-MI). While the early but not late intervention groups exhibited a significant reduction in infarct size and an improvement in LV function, both treatment modalities elicited a beneficial impact on post-MI atrial remodelling, albeit to a lesser extent in the reversal group. This is a remarkable finding because it highlights direct effects of RvD1 treatment on atrial biology that are independent of improved ventricular function and overall disease burden. It also places this therapeutic strategy on a clear path towards clinical translation in cardiac catheterization procedures when the therapy can be readily applied at the time of reperfusion. As expected, the beneficial effects of RvD1 treatment were attributed to the suppression of inflammation, which in turn, resulted in a major improvement in atrial fibrosis, a hallmark of advanced AF, for which there are currently no FDA-approved treatment options.

3. Unresolved issues and future outlook

A major finding of the elegant study by Hiram et al.⁸ is the possibility to leverage RvD1-mediated inflammation resolution following acute cardiac injury to restore atrial electrophysiological properties. It is, however, surprising that the authors did not test the clinically relevant scenario of applying the therapeutic intervention as a single high dose bolus at the time of MI creation in a large animal model in order to better mimic its delivery during angioplasty. Insights from such studies would be particularly relevant because premature termination of inflammation may inadvertently interfere with reparative processes and potentially promote cardiac rupture. Although no such adverse events were seen in the early treatment group, careful optimization of both the timing and dosages of RvD1 will be required if this therapy is to successfully advance across the pipeline from rodents to preclinical models and ultimately humans.

Furthermore, the investigators did not explore the potential for RvD1 in exerting inflammation-independent effects on atrial ion channels, gap junctions, and calcium cycling proteins, an issue which will require direct investigation in future studies. Finally, assessment of this strategy against post-MI atrial remodelling and AF in the context metabolic diseases such as diabetes and obesity in which chronic inflammation as a result of impaired resolution complicates the pathophysiology of acute MI will be of major interest to the field.⁹

In summary, the study by Hiram et al.⁸ established the foundations for an exciting anti-inflammatory approach for the treatment of post-MI AF. By targeting the atria and ventricles, separately and via their bi-directional interactions with one another,¹⁰ this approach may potentially elicit synergistic benefits that are greater than the sum of the benefits to each individual chamber alone.

Funding

FGA is supported by grants from the National Institutes of Health (1R01HL149344, 1R01HL148008, 1R01 HL163092, and 1R21HL165147).