https://orcid.org/0000-0003-1598-2652
Atrial fibrillation (AF) is the most common arrhythmia and one of the major cardiovascular problems which is associated with severe morbidity and complications such as stroke, heart failure, and sudden death. It affects 2–3% of the European population, 0.5–2% of the Asians and accounts for about 1–3% of the American health-care expenditure [Citation1, Citation2]. As AF is seen to occur more commonly in those above 60 years of age, the incidence of AF and stroke (five-fold increased risk with AF) are expected to rise worldwide in the coming decades with progressive aging of the population. The incidence of AF among patients with valvular heart disease (VHD), particularly rheumatic heart disease (RHD), is further common, occurring in a much younger age group of 20–30 years and poses a great challenge to the treating physician [Citation3, Citation4].
Nerve growth factor (NGF), the first neurotrophin (NT) to be discovered, is a homodimer composed of two non-covalently bound chains that exerts its actions through two structurally unrelated transmembrane receptors—the TrkA receptor tyrosine-kinase, which is specific for NGF, and the p75NTR receptor, a tumor necrosis factor receptor family member that is shared among all NTs [Citation5]. NGF is known to be the main contributor to cardiac sympathetic innervation density. It has been previously shown that ET-1 (Endothelin-1) signaling pathway contributes to an increase in NGF expression, while Cn-NFAT (Calcineurin-Nuclear Factor of Activated T Cells) signaling pathway significantly depresses NGF expression. However, the molecular mechanisms involved in atrial fibrillation, still remain unclear [Citation6].
Our knowledge gap in this regard appears to now have been bridged with a novel study that shows that NGF-TrkA-Akt-GSK3β pathway may indeed be involved in the occurrence of valvular AF. Herein, a comparative tissue analysis from right atrial appendage from 15 patients each with and without AF, not only showed markedly elevated NGF expression, but also, expression of TrKA, GSK3β, p-Akt, and p-GSK3β were seen to be decreased [Citation7].
It is well known that GSK3β is the downstream regulator of Akt and TrkA is a specific trk receptor that binds to NGF which is crucial for maintaining sympathetic neuron health and stimulating axon regeneration. Activation of Akt inhibits GSK-3β expression by increasing its phosphorylation and leads to hypertrophy and/or fibrosis. In the aforementioned study, Akt/GSK3β phosphorylation was remarkably reduced in AF patients. Akt activity is enhanced in myofibrosis associated with AF, which suggests that phosphorylation of Akt may be integral to the occurrence of myofibrosis in AF [Citation7].
Today, our armamentarium in the management of AF comprises predominantly of drugs targeting the heart rate and rhythm. These pharmacological modalities of treatment of AF are suboptimal and incomplete as we still do not have any drug that addresses the molecular pathways directly involved in the pathogenesis of AF. Hence, we have not been able to control or cure the very cause of AF medically, without transcatheter interventions or surgical ablation. This new understanding in the molecular pathophysiology of AF therefore, opens up a whole new exciting avenue for both a targeted therapy as well as lead to a better understanding about the pathophysiology of AF. Furthermore, monitoring of NGF levels post surgery or transcatheter ablation may provide us with valuable insights into prognosis pertaining to freedom from AF or AF recurrence or persistence. More studies are needed however, to tap further into this understanding of the role of NGF/TrKA signaling pathway in the occurrence of AF.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
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