Due to abundant common risk factors, the coexistence of coronary heart disease (CAD) and atrial fibrillation (AF) is prevalent, resulting in worse prognoses and increased healthcare burdens (1, 2). Approximately 6–21% of patients with CAD are complicated with AF (3), while CAD is estimated to occur in 20–30% of patients with AF (4–6). It's well-established that inflammation, endothelial dysfunction, atrial and ventricular remodeling play important roles in the occurrence and progression of CAD and AF. Endothelin-1 (ET-1), a peptide derived from endothelial cells, has been indicated to be associated with endothelial dysfunction and inflammation (7, 8). Meanwhile, as an autocrine and paracrine mediator, ET-1 is associated with myocardial remodeling involving cardiac hypertrophy, dilatation, and fibrosis (9–11).

Big ET-1 is the precursor of ET-1 with no biological function but a longer half-life in the peripheral circulation. In clinical settings, big ET-1 is more easily measured and widely used to evaluate the activity of the endothelial system (7, 8). Several studies have demonstrated that elevated big ET-1 is a risk factor for adverse outcomes in patients with heart failure (12), CAD (13–16), AF (17), and hypertrophic cardiomyopathy (18). However, the association between plasma big ET-1 levels and long-term outcomes in patients with AF and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) has not been evaluated before. Therefore, we conducted a post-hoc analysis of a cohort study in Chinese patients with AF and ACS or undergoing PCI to explore this issue.

In the present cohort, patients with high plasma big ET-1 levels tended to have more comorbidities, impaired cardiac function, elevated inflammatory levels, and worse prognosis. Factors reflecting activated inflammation and cardiac dysfunction were related to big ET-1 ≥ 0.54 pmol/l. In patients with AF and ACS or undergoing PCI, big ET-1 ≥ 0.54 pmol/l was an independent predictor of all-cause death, NACE, cardiovascular death, MACE, BARC class ≥ 3 bleeding, and BARC class ≥ 2 bleeding. The results of subgroup analysis were consistent with the overall results for these patients.

Risk stratification based on clinical and laboratory variables is essential in prognosis evaluation and management guidance for patients with AF and ACS or undergoing PCI (1, 2).

In the present study, patients in the high big ET-1 group tended to have more comorbidities, impaired cardiac function, and elevated inflammatory levels. Factors reflecting inflammation (white blood cell count, red cell distribution width, platelet count, free fatty acid) and cardiac function (N-terminal pro-B type natriuretic peptide, left ventricular ejection fraction) were detected to be independently associated with plasma big ET-1 levels, which were consistent with previous reports (17). This relationship indicated that big ET-1 ≥ 0.54 pmol/l might be a useful marker of activated inflammation state and impaired cardiac function. Previous researches have revealed that ET-1 plays a crucial role in endothelial dysfunction, inflammation, and myocardial remodeling (7, 8, 22). Accordingly, big ET-1 might contribute to the occurrence and progression of AF and CAD through facilitating these processes.

Plasma concentrations of ET-1 and big ET-1 have been detected to be related to the prognosis of abundant cardiovascular diseases (12–15, 17, 18). Yip et al. (23) found that ET-1 was a strong predictor of 30-day mortality and major adverse cardiovascular events in ST segment-elevation myocardial infarction patients undergoing primary PCI. A cohort of 110 first-acute myocardial infarction patients undergoing primary PCI showed that higher ET-1 level was related to increased incidences of cardiogenic shock and cardiac death (24). Several studies have also detected a significant correlation between ET-1 and long-term mortality in patients with acute myocardial infarction (13, 16). As to stable CAD, big ET-1 was also an independent predictor of 2-year cardiovascular outcomes (15). Another study including 6,150 patients with three-vessel disease indicated that big ET-1 was independently associated with long-term mortality (14). Wu et al. (17) enrolled 716 patients with AF and found that the elevated big ET-1 level was an independent predictor of long-term mortality and major adverse events during a median follow-up of 3 years. Additionally, the correlations between plasma big ET-1 levels and prognosis of other cardiovascular diseases [such as heart failure (12), hypertrophic cardiomyopathy (18)] have also been identified by abundant studies.

To the best of our knowledge, our study indicated that elevated plasma big ET-1 levels were associated with an increased risk of adverse outcomes in patients with AF and ACS or undergoing PCI for the first time. Potential mechanisms for the association between big ET-1 and prognosis in these patients have not been fully elucidated and might be manifold. Firstly, elevated levels of ET-1 and big ET-1 are practical markers for the activation of inflammation (7, 8, 22). Besides endothelial cells, inflammatory cells such as polymorphonuclear leukocytes and macrophages are also important sources of ET-1 (25, 26). It's well-established that inflammation plays an important part in the initiation and progression of AF and CAD (27). ET-1 could induce the adherence of neutrophils to vascular endothelial and myocardium cells by upregulating adhesive molecule expression (28). Meanwhile, elevated plasma ET-1 levels are related to the enhancement of oxidative stress and activation of various inflammatory factors in the inflammation cascade. All of these have been indicated to participate in the formation and aggravation of artery atherosclerotic and myocardial fibrosis, which might contribute to the unsatisfactory prognosis of patients with AF and CAD (29, 30). Secondly, ET-1 is closely related to endothelial dysfunction (31, 32). ET-1 is a potent vasoconstrictor (32) and is associated with decreased synthesis and increased degradation of nitric oxide (7, 8, 22). Accordingly, ET-1 plays an important role in maintaining a balance between vasoconstriction and vasodilatation (32). Abundant studies have demonstrated that endothelial dysfunction participated in the development of CAD and AF (23, 33, 34). Thirdly, ET-1 is an autocrine and paracrine mediator with mitogenic and inotropic effects in the myocardium. Previous researches have detected the relationship of ET-1 with vascular and myocardial remodeling (9–11). Several studies demonstrated that ET-1 was related to the modulation of post-infarct left ventricular remodeling (11) and reduced left ventricular ejection fraction (13). On the other hand, Mayyas et al. found that ET-1 was positively associated with left atrial size, heart failure, AF persistence, and severity of mitral regurgitation (9). Structural remodeling and electrical remodeling have been verified to be essential in the occurrence, maintenance, recurrence, and progression of AF (35). ET-1 has been indicated to carry arrhythmogenic effects (36) and play an essential role in the initiation and perpetuation of AF (37). In patients with AF and ACS or undergoing PCI, elevated plasma ET-1 levels might contribute to a worse prognosis through facilitating atrial and ventricular remodeling (9–11). Finally, ET-1 has been indicated to be associated with coronary artery calcification, reperfusion injury, no-reflow, and stent thrombosis (7, 8, 13, 38, 39). Additionally, previous researches have detected a relation of ET-1 with promoted platelet aggregation and activated prothrombotic state (7, 40). All of these might contribute to increased thromboembolic risk and unfavored prognosis. In this study, subgroup analysis indicated a consistent relationship between plasma big ET-1 levels and all-cause mortality in patients with AF and ACS or undergoing PCI. The positive correlation between elevated big ET-1 and prognosis might be of great value in clinical routine practice. The plasma big ET-1 level could act as a useful biomarker for risk stratification, prognosis evaluation, and management guidance in patients with AF and ACS or undergoing PCI. Identification of high-risk patients and adoption of intensified management strategies might do a favor in improving these patient's prognosis (1, 2).

Several limitations should be mentioned in this study. First, due to inherent defects of observational studies, a definite causal association between big ET-1 and clinical endpoints could not be inferred. On the other hand, although multivariable regression analysis has been performed to adjust for potential confounders, the list of relevant variables for adverse outcomes could hardly be exhaustive. The results should be interpreted cautiously. Second, this study only tested plasma big ET-1 levels at baseline and lacked serial data of plasma big ET-1 levels during the follow-up. Dynamic monitoring of plasma big ET-1 levels might provide more information for prognosis prediction. In the present study, big ET-1 rather than ET-1 levels, plasma rather than cardiac levels were measured. These might influence the accuracy of our results. The exact association between ET-1 and prognosis in patients with AF and ACS or undergoing PCI might be explored in the future. Third, this study was conducted in a single center in China. The homogeneity of participants and management strategies might limit the generalizability of our conclusions to other populations. Finally, the sample size was relatively small in this study, which might limit the statistical power. Further well-designed prospective studies with a larger sample size would provide more evidence for this issue.

In patients with AF and ACS or undergoing PCI, the elevated big ET-1 level was an independent predictor of all-cause death, NACE, cardiovascular death, MACE, BARC class ≥ 3 bleeding, and BARC class ≥ 2 bleeding.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of Fuwai Hospital. The patients/participants provided their written informed consent to participate in this study.

S-qL: collected the data, performed the statistical analysis, drafted, and wrote the manuscript. Y-mY and JZ: designed and revised the manuscript. SW, JW, HZ, and X-hS: collected the data. All authors read and approved the final manuscript.

This work was supported by Capital's Funds for Health Improvement and Research (No. 2018-2-4031) and Capital‘s Funds for Research and Application of Clinical Diagnosis and Treatment Technology (Z191100006619121).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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