Background
Atrial fibrillation (AF) is a common arrythmia in patients with hypertension worldwide [
1]. One-fifth of the risk factors for AF are attributable to hypertension, and the odds ratio for the development of AF in the hypertensive population is 1.4–1.5, revealing a close relationship between hypertension and AF [
2]. Hypertension is an independent risk factor for thrombosis and bleeding in AF patients, making the prognosis of AF unfavourable [
3,
4]. Additionally, effective blood pressure control using antihypertensive drugs (such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers) can prevent AF development and recurrence [
5]. Based on the fact that therapeutic interventions targeting AF risk factors have been shown to improve outcomes, it is important to identify hypertension patients at high risk of AF [
6].
The apelin receptor (APJ) was regarded as an orphan G-protein-coupled receptor when apelin/APJ signalling was first reported in 1998. Apelin/APJ signalling is widely distributed in various tissues and plays key roles in embryonic development, tumour progression and cardiovascular disease prevention [
7]. ELABELA, a novel endogenous ligand of APJ, was discovered in zebrafish embryos and promotes gastrulation movement [
8]. ELABELA-32, the mature secretory form of ELABELA, has been detected in stem cells, the kidneys, the prostate, the vascular endothelium and plasma, and has been demonstrated to have vital cardioprotective effects in cardiovascular illnesses [
9]. As reported, ELABELA plasma levels were reduced in hypertension patients [
10], and those with low levels of ELABELA tended to develop hypertension [
6]. Additionally, experimental evidence has revealed that ELABELA has positive inotropic action and plays anti-remodelling, anti-inflammatory and anti-fibrotic roles in the cardiovascular system [
9], helping to attenuate the effects of risk factors for AF development including atrial enlargement, myocardial fibrosis and inflammatory response, and to reduce the incidence and burden of AF. Unfortunately, there has been no clinical study investigating the correlation between ELABELA plasma levels and AF in patients with hypertension.
In our study, we calculated the plasma level of ELABELA in hypertension patients with and without AF, and investigated the correlative clinical factors of ELABELA to identify the underlying risk factors for AF in hypertension patients.
Discussion
ELABELA, a novel endogenous ligand of APJ and a new member of the apelinergic system, was first detected in zebrafish embryos in 2013 [
8]. The ELABELA gene is located on chromosome 4, and ELABELA-32 is its mature secretory form [
13]. In addition to promoting heart development, accumulating evidence suggests that ELABELA plays important roles in the cardiovascular system in adults, and is closely linked to some heart diseases that are similar to apelin, another well-known ligand of APJ [
14,
15]. The effects of ELABELA on the cardiovascular system include hypotensive effects, positive inotropic action, diuresis, anti-inflammatory, anti-oxidative stress, anti-fibrotic and anti-remodelling effects. The correlation between the plasma levels of ELABELA and patients with heart diseases, including hypertension and myocardial infarction, demonstrated that the protective effects of ELABELA existed not only in animal studies, but also in clinical studies [
9,
16]. It is well established that these protective effects of ELABELA can either combat hypertension or prevent the development of AF. On the other hand, evidence from previous research indicates that apelin has a close relationship with AF [
17,
18]. Given the underlying interaction among hypertension, AF and ELABELA, it is necessary to investigate the plasma levels of ELABELA in hypertensive people with and without AF.
This is the first study to date reporting that ELABELA plasma levels were lower in hypertensive patients with AF than in those without AF. We also found that ELABELA showed a close relationship with age, heart rate, BNP level and LAD. The subgroup analysis revealed that ELABELA levels were lower in the persistent AF group than in the paroxysmal AF group. These results imply that ELABELA, as a promising biomarker for hypertensive populations with AF, needs to be further investigated. According to current evidence and our findings, we proposed a hypothesis that insufficient ELABELA may partly contribute to AF development in the hypertensive population and could be a potential therapeutic target.
Both hypertension and AF are age-related diseases. Increasing age and organ ageing play a tremendous role in the development of these ailments [
19]. The apelin/APJ system directly participates in the negative regulation of senescence-associated proteins, including P16, P21 and P53 [
20]. The apelin/APJ system also alleviates the activation of the renin-angiotensin system (RAS), oxidative stress and inflammation, which are recognised inducers of senescence [
21]. ELABELA, as a new member of the apelinergic system, may have a close relationship with age and exert anti-ageing effects. In our study, the ELABELA plasma level was negatively correlated with age, which supports the hypothesis above. Although there is no study providing direct evidence on the anti-ageing effects of ELABELA, ELABELA suppresses the expression of P53 in different scenarios [
22,
23]. Both hypertension and AF progression are associated with cell senescence burden, as determined by p53 [
24,
25]. Hence, ELEBELA may suppress these age-related illnesses in a P53-dependent manner. Further, ELABELA can antagonise the effects of angiotensin II, a classic senescence inducer [
26]. These underlying anti-ageing mechanisms of ELABELA may be the bridge connecting decreased ELABELA plasma levels and hypertensive patients with AF.
The negative relationship between ELABELA and BNP may be attributed to the positive inotropic action and hypotensive effects of ELABELA [
27]. It has been well established that impaired cardiac systolic function leads to arterial hypertension, which is a key pathophysiological change in AF development [
28]. Decreased ELABELA plasma levels affect cardiac systolic function and elevate atrial pressure to increase AF incidence. On the other hand, insufficient anti-hypertensive effects also contribute to atrial remodelling and AF development. We also observed that the left atrium was enlarged in hypertension patients with AF and negatively related to ELABELA levels. This result can be interpreted by the multiple effects of ELABELA on anti-remodelling, which is the most important pathologic change in the enlarged left atrium and substrate of AF [
9]. ELABELA has been illustrated to directly suppress hypertension, RAS activation, oxidative stress and chronic low-grade inflammation, which all contribute to atrial remodelling [
29]. The diverse effects of ELABELA/APJ are derived from the activation of different downstream signalling pathways, including the inhibition of PI3K/Akt/mTOR, TGF-β1, FoxM1 and the expression of fibrosis-associated genes (
factor-β, latent TGFβ-binding protein 2, periostin and collagen 8a). Accordingly, there are reasons to believe that the decreased ELABELA plasma level may not only be an associated factor of AF, but also serve as a novel risk factor for AF. ELABELA may become a promising biomarker in identifying hypertensive patients who are at high risk of developing AF or even an intervention target for AF management in the future.
Hypertension is associated with the activation of the renin-angiotensin system, and elevated angiotensin II has been linked to AF [
30]. Angiotensin II is not only a senescence inducer but also an important pathogenesis for hypertension with AF [
31]; this induces oxidative stress, inflammatory effects, apoptosis, necrosis and fibrosis. The potent and diverse effects of angiotensin II make it a core factor in the pathogenesis of hypertension with AF. On the other hand, blocking the renin-angiotensin system can effectively prevent AF development [
30]. ELABELA has been shown to antagonise the renin-angiotensin system and to alleviate angiotensin II-induced cardiac damage [
26,
32]. Further research has revealed that ELABELA suppresses the expression of angiotensin converting enzyme, an important enzyme that helps to generate angiotensin II [
26]. Although the mechanism of interaction between ELABELA and the renin-angiotensin system is still not well known, ELABELA inhibits the renin-angiotensin system and may become a novel therapeutic target for hypertension and AF.
Another finding in this study is that ELABELA plasma levels were different in hypertensive patients with different types of AF. Patients with persistent AF had lower ELABELA levels than those with paroxysmal AF. This outcome indicates that ELABELA may also play a role in the pathological process of AF, as these two types of AF may be in different phases during disease progression [
31]. Lower ELABELA plasma levels were present in patients with persistent AF who had a larger atrial size and higher BNP levels in our study. Enlarged atria is a crucial risk factor for the maintenance of AF [
31]. Myocardial fibrosis and inflammation are two other vital AF substrates, and the severity of these pathological changes is associated with persistent AF [
33]. Interestingly, ELABELA can inhibit myocardial fibrosis, suppress inflammatory effects, reverse atrial remodelling and may finally reduce the AF burden [
34,
35]. We also found that ELABELA has a negative relationship with ESR, a traditional marker of inflammation. This outcome supports the viewpoint that ELABELA may reduce the AF burden by depressing inflammation [
35]. Although the decreased plasma levels of ELABELA had a close relationship with AF in our study, they did not correlate with persistent AF in our subgroup analysis. ELABELA might not be a confounding factor but rather a critical factor in identifying AF types. The effect of the subtle differences in ELABELA plasma levels between patients with paroxysmal and persistent AF may be diminished when significant differences in atrial size are considered together. Notably, this result was based on subgroup analysis with a limited sample size. Whether a decreased ELABELA level is an important underlying risk factor for the maintenance of AF needs further well-designed studies to provide a clear answer.
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