In recent years, the incidence rate and mortality of coronary artery disease (CAD) have risen significantly, posing a growing threat to human health and safety [1], as well as increasing the economic burden on patients and society [2]. While percutaneous coronary intervention (PCI) technology advancements have revolutionized CAD management [3], some patients still experience adverse clinical outcomes [4]. Therefore, recent studies have focused on prognosis prediction and finding new post PCI markers. Some of the emerging PCI markers include apolipoprotein E (ApoE) [5], plasminogen activator inhibitor-1 (PAI-1) [6], and anti-apolipoprotein B-100 autoantibody (anti-apoB-100 Ab) [7]. Additionally, metrics including the neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, systemic inflammation response index, systemic immune-inflammation index offer insights into a patient’s inflammatory and immune status [8, 9, 10, 11, 12, 13, 14, 15, 16].

The role of ecto-5${}^{\prime }$-nucleotidase (5${}^{\prime }$-NT) has recently garnered increasing attention. The 5${}^{\prime }$-NT enzyme was identified 60 years ago, and is found in skeletal muscle and heart tissue [17]. Also known as CD73 (Ecto-5’-nucleotidase—eN, also known as CD73, is a glycosylated protein bound to the outer surface of the plasma membrane by a glycosylphosphatidylinositol anchor (1) and co-localizes with detergent-resistant and glycolipid-rich membrane subdomains called lipid rafts [18]), 5${}^{\prime }$-NT is an intrinsic membrane glycoprotein widely present on mammalian cells [19, 20]. It can anchor and bind to glycosyl phosphatidylinositol located on the outer surface of the plasma membrane, allowing colocalization with detergent-resistant and lipid-rich membrane subdomains [18, 21, 22]. Functionally serum 5${}^{\prime }$-NT catalyzes 5${}^{\prime }$-nucleotides with the ability to hydrolyze the corresponding nucleosides [18]. Dixon and Purdon et al. [23] were the first to point out the clinical significance of serum 5${}^{\prime }$-NT levels for liver, gallbladder, and bone disease diagnostics. Although evidence has implicated 5${}^{\prime }$-NT with cardiovascular disease development, these results remain controversial [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32]. Some animal studies have suggested it exerts protective effect against ischemia, but other recent studies implicate 5${}^{\prime }$-NT in promoting atherosclerosis [33, 34, 35]. Thus, the relationship between 5${}^{\prime }$-NT and clinical outcomes in patients after PCI remains unclear. Given this uncertainty, we conducted a study involving 6555 patients with CAD after PCI to examine possible correlations between serum 5${}^{\prime }$-NT levels and clinical outcomes.

In this study, we propose that elevated 5${}^{\prime }$-NT levels serve as a prognostic risk marker, indicating poor long-term outcomes in patients with CAD after PCI. More specifically, the results of this empirical analysis establish a significant positive correlation between higher serum 5${}^{\prime }$-NT level and increased risks of long term mortality, as well as adverse cardiovascular and cerebrovascular events. As serum 5${}^{\prime }$-NT levels rise, the incidence of ACD, CD, MACE and MACCE also increase, providing new insights into the role of 5${}^{\prime }$-NT in CAD management.

While the role and mechanism of 5${}^{\prime }$-NT in cardiovascular diseases are controversial, animal studies have suggested it may have a cardioprotective function [21, 22, 23, 24, 25, 26, 27, 28, 29]. Specifically, increased 5${}^{\prime }$-NT activity and adenosine release have been shown to limit the scope of myocardial infarction in rodents [28]. Elevated 5${}^{\prime }$-NT may protect against CAD development by promoting adenosine production in ischemic myocardium [27, 28]. Adenosine, in turn, may protect the myocardium by activating K-ATP channels [21, 24, 25, 26, ]. Kitakaze et al. [28] also suggested that the short-term and high-dose administration of adenosine in dog hearts can activate 5${}^{\prime }$-NT, and thereby limit the scope of infarction, owing to adenosine’s cardioprotective properties mediated through 5${}^{\prime }$-NT [21, 22, 23, 24, 25, 26, 27, 28, 29].

Some studies challenge the purported cardioprotective role of 5${}^{\prime }$-NT. While CD73+ regulatory T cells (Tregs) have been implicated in heart injury after ischemia/reperfusion, their role in repair after myocardial infarction (MI) remains unconfirmed [30, 31]. Contradicting previous findings, a recent study reported that inactivating the CD73 gene did not impact the infarct size during ischemic preconditioning in mouse hearts either in vitro or in vivo [32]. This suggests that extracellular adenosine, generated by 5${}^{\prime }$-NT, may not contribute to the cardioprotective effects of adenosine during early ischemic preconditioning [32]. Thus, the role of 5${}^{\prime }$-NT in cardiovascular health is far from settled.

It has been reported [33] that CD73 knockout led to arterial calcification, a ubiquitous pathological process of atherosclerosis [34]. This underscores the influence of CD73 on the occurrence and progression of atherosclerosis. In a study using ApoE-/- mice, CD73 inactivation inhibited the migration, proliferation and foam cell transformation of vascular smooth muscle cells (SMCs), thereby attenuating both AS and hyperlipidemia [35]. This led to the proposal that CD73 is an important regulator in the development of atherosclerosis (AS). In their experiment, CD73 siRNA was used to downregulate CD73 expression [35]. They mainly explain the role of CD73 in the rupture of atherosclerotic plaques through the following mechanisms: First, deactivating CD73 led to carotid artery ligation injuries, which affected parameters such as the neointimal area, the neointimal/medial thickness ratio, and the number of proliferative SMCs [35]. Second, the downregulation of CD73 (at both the mRNA and protein levels) through siRNA significantly inhibited both the migration and growth of human umbilical artery smooth muscle cells (HUASMCs) [35]. Furthermore, the knockdown of CD73 significantly reduced cyclin D1 levels, impacting the cell cycle [35]. This indicates that CD73 can inhibit the release and migration of inflammatory factors in HUASMCs, promoting their proliferation ability [35]. Third, administration of CD73 siRNA significantly reduced lipid accumulation, implying a role for CD73 in lipid metabolism [35]. Fourth, CD73 appears to promote plaque formation by increasing blood lipid levels, specifically triglycerides, TC, and plasma LDL-C [35]. The mechanism for these increases may be related to CD73’s regulatory impact on hepatic mRNA expression genes coding for hepatic lipase, peroxisome proliferator-activated receptor $\alpha$, peroxisome proliferator-activated receptor $\gamma$, farnesyl diphosphate synthase, lecithin-cholesterol acyltransferase, and cytochrome p450 family 7 subfamily A member 1 in the liver [35]. Stenosis of the vascular lumen caused by abnormal lipid metabolism is the main cause of myocardial ischemia. Triglycerides, TC and LDL-C can be considered important risk factors for CAD [36].

Another study suggested impaired CD73-derived adenosine production contributes to the development of atherosclerosis in mice and humans, leading to calcification of human lower limb arteries [37]. When compared to the age-matched healthy control group, peripheral artery disease (PAD) patients had significantly higher CD73 activity in the blood [37]. They suggest that the high CD73 activity observed in the circulation of PAD patients appears to be a result of the shedding and loss of CD73 expression in mature occlusive plaques [37]. Müller et al. [38, 39] proposed that signal-induced glycosylphosphatidylinositol-anchored CD73 was upregulated by lysosomal degradation (LD)-mediated lipid synthesis in adipose tissue via diacylglycerol (DIG) transfer from the adipose body to adipocytes. They found that adipocytes release microbubbles containing CD73, which enter immature or small adipocytes through gaps or blood circulation and adhere to the surface of lipid droplets [38, 39]. Once attached, the enzymes facilitate the breakdown cAMP (cyclic adenosine monophosphate) on the lipid droplet surface [38, 39]. The decrease in cAMP levels impact lipid metabolism enzymes dependent on cAMP phosphorylation, such as hormone-sensitive lipase (HSL) and glycerol-3-phosphate acyltransferase (GPAT), thereby enhancing esterification, inhibiting lipolysis and promoting lipid synthesis [38, 39]. Furthermore, they described the release of specific transcripts and microRNAs induced by stimulation [40]. These molecules control lipid synthesis and lipid droplet biogenesis from primary and differentiated rat adipocytes to microbubbles containing Gce1 and CD73 [40]. During their transfer and expression in small adipocytes, lipid synthesis is upregulated [40]. This suggests a potential mechanism for regulating lipid metabolism and adipocytes size, facilitated by microcapsules containing a specific set of GPI (glycolphosphatidylinositol)-anchored proteins and RNA [40]. In a separate study, Müller et al. [38] found that the esterification effects triggered by audiogenic stimulants could be nullified by depleting CD73-containing microvesicles secreted from adipocytes.

In our study, after adjusting for potential confounding variables, we found that the serum 5${}^{\prime }$-NT level could serve as an independent risk factor for long-term mortality in CAD patients after PCI. These findings suggest possible mechanisms explaining the role elevated serum 5${}^{\prime }$-NT levels play in the onset and progression of CAD.

This study has limitations, both subjective and objective in nature. First, it does not account for the influence of dietary habits, nutritional status, and other related factors in patients with CAD. Second, we did not measure serum 5${}^{\prime }$-NT activity in this study. Patients were only tested for 5${}^{\prime }$-NT levels on admission, without subsequent dynamic monitoring. Finally, this was a single-center cohort study. Although the sample was large, the patient population source was relatively narrow, undermining the study’s generalizability. Due to limited geographical representation of the population, unidentified confounding variables may affect the validity and reliability of the study findings. For a more comprehensive understanding, future research should aim for a larger, multicenter study design and include basic mechanistic experiments to better elucidate the relationship between serum 5${}^{\prime }$-NT levels and long-term outcomes in CAD patient following PCI. This would provide improved guidance for the comprehensive diagnosis and treatment of CAD.

This was the first study to investigate the relationship between elevated serum 5${}^{\prime }$-NT and long-term clinical outcomes in CAD patients following PCI treatment. The findings suggest that serum 5${}^{\prime }$-NT level can function as an independent prognostic marker for predicting adverse outcomes after PCI. Incorporating this biomarker into routine clinical practice could enhance decision-making in the treatment of coronary heart disease.

Reasonable requests to access the data used in these analyses can be made to the first authors.

XX and YZ designed this study. TW and XX conducted research. XH, HY and YY provided assistance and suggestions for ELISA experiments. MA, XX and TW analyzed the data and wrote the paper. All authors have contributed to the editing and revision of the manuscript. All authors have read and approved the final manuscript. All authors have fully participated in this work and agree to be responsible for all aspects of the work.

This study was approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University (Ethical approval number: K201909-02). It is based on the standards of the Helsinki Declaration. All patients provided written informed consent and were explicitly allowed to collect relevant clinical data.

Not applicable.

This research was funded by the National Natural Science Foundation of China (82000238 and 82170345).

The authors declare no conflict of interest. Xiang Xie and Ying-Ying Zheng are serving as Guest Editors of this journal. We declare that Xiang Xie and Ying-Ying Zheng had no involvement in the peer review of this article and have no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Ezra Abraham Amsterdam.