Introduction

According to World Health Organization data, cardiovascular disorders, including ischemic heart disease and cerebrovascular disorders, are the leading cause of morbidity and mortality worldwide. Especially, aging induces vascular structural changes through intimal thickening, deposition of calcium and advanced glycation end-products, endothelial dysfunction, accumulation of interstitial collagen, and extrinsic factors (Hypertension, metabolic syndrome, Diabetes, etc.)1,2,3. The reduction in compliance and elasticity of vessel walls leads to arterial stiffness. The measurement of carotid–femoral pulse wave velocity (cfPWV) is a standard diagnostic method to evaluate central arterial changes and a good predictor of increased cardiovascular risk. The cfPWV is also a strong noninvasive predictor of coronary artery disease (CAD) severity and is associated with age, sex, and BP values3. It has been shown to have an independent predictive value for all-cause mortality and cardiovascular morbidity, coronary events, and strokes in patients with uncomplicated essential hypertension4,5. Arterial stiffness induces loss of arterial elasticity and the distending force from the pressure exerted on the arterial wall. Blood pressure is elevated due to arterial stiffness and atherosclerosis status; hypertension is a high-risk factor related to cardiovascular disease6. Higher cfPWV is strongly associated with arterial stiffness and the severity of CAD3,4,5,6.

In many types of research, some serum biomarkers may predict arterial stiffness. However, these studies analyzed the patient group with chronic kidney disease, aging patients, or hypertensive patients with metabolic syndrome. There is not much discussion about cardiovascular disease, especially in CAD who need coronary bypass grafting surgery (CABG). Big endothelin-1 (BigET-1) is a 38-amino acid propeptide cleaved into the biologically active endothelin-1 (ET-1) by endothelin-converting enzyme-1. Importantly, the levels of ET-1, an endothelium-derived vasoconstrictor peptide, increase with age7,8. Both ET-1 and BigET-1 are elevated in patients with heart failure and predict the presence of elevated pulmonary pressure and mortality9. The effects of ET-1 can be observed at two sites: heart and vasculature. The actions of ET-1 include increased heart contractility; induction of hypertrophy, tissue fibrosis, and vasocontraction; vascular remodeling; increased plasma volume; and induction of systemic inflammation. High ET-1 levels have been proposed to be associated with the development of hypertension, cardiovascular disease, pulmonary hypertension, and heart failure8.

While the relationship between ET-1 and arterial stiffness, which underlie cardiovascular events, is known, few studies have investigated the link between these factors and CABG. The present study examined the association between BigET-1 levels and arterial stiffness in patients undergoing CABG. We have hypothesized that BigET-1 levels positively relate to the severity of arterial stiffness. If BigET-1 level is high in a health examination, we can inform the patient is at high risk of arterial stiffness and CAD.

Materials and methods

Participants

This single-center, cross-sectional observational study includes all participants with CAD who received CABG in the cardiovascular surgery department of Hualien Buddhist Tzu Chi General Hospital between September 1, 2018 and May 31, 2019 and followed in the outpatient clinic. Patients with the following conditions are excluded: acute infection, amputation, acute myocardial infarction, heart failure, and malignancy at the time of blood sampling. A total of 90 patients are enrolled in our study. After informing the purpose of the study, our member would keep 5 mL of blood sampling for BigET-1 levels. The patients would be divided into arterial and non-arterial stiffness groups according to the cfPWV for comparisons. The study is conducted according to the guidelines of the Declaration of Helsinki and approved by the Research Ethics Committee of Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (approval no: IRB107-120-A, July 31, 2018).

Data collection

Clinical data included medical and surgical history, body weight, body mass index (BMI), systolic and diastolic blood pressures, cfPWV, and laboratory tests. Blood samples were analyzed using an autoanalyzer (Siemens Advia 1800; Siemens Healthcare, Henkestr, Germany) to determine total cholesterol levels, triglycerides, high-density lipoprotein, and low-density cholesterol lipoprotein cholesterol, fasting glucose, blood urea nitrogen, creatinine, total calcium, and phosphorus. The serum levels of BigET-1 were measured using a commercial sandwich enzyme immunoassay (BI-20082 H; Biomedica, Wien, Austria). The blood pressure (BP) is measured in the morning by trained staff using standard mercury sphygmomanometers with appropriate cuff sizes after sitting for at least 10 min. Systolic BP (SBP) and diastolic BP (DBP) were taken three times at 5 min intervals, and the data were averaged for analysis. Hypertension was defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg for patients receiving antihypertensive medication within the past two weeks. Type II diabetes mellitus (DM) is a fasting blood glucose level of more than 126 mg/dL or treatment with antidiabetic drugs.

Measurement of arterial stiffness using CfPWV

Arterial stiffness is determined based on cfPWV, measured using pressure applanation tonometry (SphygmoCor system; AtCor Medical, New South Wales, Australia). These measurements are performed in the morning, with the participants lying supine after a minimum of 10 min rest in a quiet, temperature-controlled room. The pulse wave recordings are performed at the right common carotid and femoral arteries. The carotid–femoral distance is measured by subtracting the distance from the carotid ___location to the suprasternal notch from a distance between the suprasternal and the femoral sites. SphygmoCor version 7.1 software (AtCor Medical, Sydney, Australia) is used to process each set of pulse wave and ECG data to calculate the mean time difference between the R-wave and pulse wave on a beat-to-beat basis. Average of 10 consecutive cardiac cycles is recorded. The cfPWV is calculated using the distance and mean time difference between the two recorded points10. The present study is used cfPWV > 10 m/s to define patients with arterial stiffness. In contrast, cfPWV ≤ 10 m/s is used to determine the control group, according to the European Society of Hypertension and European Society of Cardiology guidelines3,5,6.

Statistical analysis

The data are analyzed with Statistical Package for the Social Sciences version 19.0 (SPSS, Chicago, IL, USA). Normally distributed variables are presented with medians with interquartile ranges, and comparisons are performed with the Mann–Whitney U test. The Kolmogorov–Smirnov test evaluates the continuous variables for normal distribution. Categorical data are presented as numbers and percentages and analyzed with the chi-square test. Variables that were significantly associated with arterial stiffness in patients undergoing CABG were tested for independence using multivariable logistic regression analysis. Correlation between clinical variables and cfPWV in patients undergoing CABG was evaluated using simple linear regression analysis, and variables that were significantly correlated with cfPWV were tested for independence using multivariable forward linear stepwise regression analysis. A p-value of < 0.05 was considered statistically significant.

Results

The study cohort of 90 patients who fulfilled the inclusion and exclusion criteria was categorized into the arterial stiffness (n = 30) and control (n = 60) groups based on cfPWV. The clinical characteristics of the patients are shown in Table 1. Briefly, the levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood glucose, blood urea nitrogen, creatinine, total calcium, and phosphorus were not significantly different between the two groups. The patients were especially older (p < 0.001) and had significantly lower BMI (p = 0.020) in the arterial stiffness group than in the control group. Additionally, type II DM (p = 0.037) and hypertension (p = 0.036) were significantly more frequent, and SBP (p < 0.001) and DBP (p = 0.038) were significantly higher in the arterial stiffness group than in the control group. Furthermore, cfPWV and BigET-1 were markedly higher in the arterial stiffness group than in the control group.

Table 1 Clinical variables of patients with or without arterial stiffness undergoing coronary artery bypass grafting.
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The forward multivariable logistic regression analysis, which included factors significantly associated with arterial stiffness in Table 1 (adopt factors: BigET-1, age, BMI, SBP, DBP, type II DM, and hypertension), revealed that BigET-1 was the only independent predictor of arterial stiffness in patients undergoing CABG (odds ratio 17.492, 95% CI 2.728–112.147, p = 0.003) (Table 2).

Table 2 Multivariable logistic regression analysis of factors associated with arterial stiffness in patients undergoing coronary artery bypass grafting.
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The simple linear regression analysis indicated that cfPWV was significantly correlated with age (r = 0.463, p < 0.001), BMI (r = − 0.222, p = 0.035), SBP (r = 0.409, p < 0.001), and BigET-1 level (r = 0.628, p < 0.001) (Table 3). The multivariable linear regression with forward stepwise analysis including these significant factors (age, BMI, SBP, and BigET-1) in Table 3 revealed age (β = 0.238, adjusted R2 change = 0.043, p = 0.004), SBP (β = 0.251, adjusted R2 change = 0.102, p = 0.002), and BigET-1 level (β = 0.533, adjusted R2 change = 0.387, p < 0.001) as independent predictors of arterial stiffness (Table 3). Both simple and multivariable linear regression analyses confirmed a significant association between BigET-1 levels and cfPWV and by the forward multivariate logistic regression analysis, reinforcing that a higher BigET-1 level was associated with cfPWV values and is independently associated with arterial stiffness in patients undergoing CABG.

Table 3 Correlation between carotid–femoral pulse wave velocity and clinical variables in patients undergoing coronary artery bypass grafting.
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Discussion

In the present study, our analyses indicated that the patients with arterial stiffness were significantly old age, had significantly lower BMI, and were significantly more likely to have type II DM, hypertension, and higher SBP and DBP than the controls. BigET-1 level was associated with arterial stiffness in the patient undergoing CABG.

Arterial stiffness, which is a risk factor for CVD11 is associated with oxidative stress, inflammation, vascular calcification, and cumulative effects of underlying diseases1,12,13,14. Higher cfPWV indicates more severe arterial stiffness and accelerated disease progression. Aging is a major risk factor for arterial stiffness and changes in arterial structure. Age is a key factor in arterial stiffness, as demonstrated by its strong correlation with cfPWV in this study. Aging leads to structural changes in blood vessels, such as endothelial dysfunction, increased collagen deposition, and reduced arterial elasticity, all of which contribute to stiffness14. Our findings confirm that older patients tend to have higher cfPW, highlighting age as a significant risk factor for cardiovascular disease. DM is strongly associated with increased arterial stiffness due to the accumulation of advanced glycation end-products, which cross-link collagen in the arterial wall, leading to reduced elasticity15. Elevated SBP and DBP are both causes and consequences of arterial stiffness, inducing mechanical stress on arterial walls, leading to structural changes such as increased collagen deposition and elastin degradation16. Higher BMI, indicative of overweight and obesity, is also linked to increased arterial stiffness. Obesity contributes to arterial stiffening through various mechanisms, including inflammation, insulin resistance, and activation of the renin–angiotensin–aldosterone system17. However, only BigET-1 levels remained statistically significant in multivariable logistic regression analysis. This may be due to factors such as the sample size, medication effects, selection bias, or the absence of a control group.

The endothelin family includes three isoforms—ET-1, ET-2, and ET-3. Among them, ET-1 is the most relevant to cardiovascular disease due to its strong vasoconstrictive properties. ET-1 is a principal isoform produced by the endothelium in human cardiovascular tissue and binds to two specific and distinct receptor subtypes ETA and ETB18. ET-1 induces cell fibrosis and hypertrophic growth and may also lead to vascular atherosclerosis19,20. ET-1 levels are easier to measure in healthy adults and have been reported to correlate with major and global cardiovascular risks18,21. BigET-1 is a precursor of ET-1, with a longer half-life and greater stability, making it a more reliable biomarker for predicting arterial stiffness22. We also can find some studies discussing the relationships between cardiac disease and heart failure. The action of BigET-1 is related to shear stress, neuronal stimulation, and inflammation and may induce vasoconstriction, proinflammation, prooxidative action, and cardiac remodeling23. BigET-1 remained an independent predictor of all-cause death, heart transplantation, or LVAD in patients hospitalized with heart failure24. The present study found that high BigET-1 levels were associated with arterial stiffness. Currently, no therapies directly lower BigET-1 levels. However, interventions such as endothelin receptor antagonists (e.g., bosentan), angiotensin-converting enzyme inhibitors, lifestyle modifications (diet, exercise), and control of underlying conditions like hypertension and diabetes may indirectly reduce BigET-1 activity by improving endothelial function.

CABG is associated with a higher cardiovascular mortality rate, and arterial stiffness is also linked to increased cardiovascular mortality. Serum biomarkers associated with arterial stiffness include indoxyl sulfate25 Klotho26 sclerostin27 adipocyte fatty acid binding protein10,28or resistin29. However, there has been no prior research on the relationship between BigET-1 and arterial stiffness in patients undergoing CABG. Therefore, this study identifies BigET-1 as an independent predictor of arterial stiffness in patients undergoing CABG. Mechanistically, BigET-1 is converted into ET-1, which binds to ETA and ETB receptors, leading to vasoconstriction, vascular remodeling, fibrosis, and systemic inflammation. Elevated BigET-1 levels are strongly correlated with cfPWV, a key indicator of arterial stiffness. These findings suggest that BigET-1 plays a crucial role in vascular dysfunction by promoting endothelial activation and structural changes in the arteries.

The present study has several limitations that should be acknowledged. First, this was a cross-sectional perspective, a single-center study including a limited number of patients undergoing CABG. Second, the protocol for the timing of blood sampling was not standardized. Third, given the cross-sectional nature of our study, we cannot determine the duration of elevated BigET-1 levels or how long such levels persist following interventions. Longitudinal research is needed to evaluate the temporal patterns of BigET-1 and its responsiveness to therapeutic strategies in CABG patients. Finally, the observational study design is needed to clarify the mechanism underlying the observed significant association between BigET-1 level and arterial stiffness, and further studies are warranted to confirm these findings.

This study demonstrates that BigET-1 is an independent predictor of arterial stiffness in patients undergoing CABG. This biomarker may assist in the early identification of patients at higher cardiovascular risk, enabling clinicians to consider intensified monitoring and preventive strategies tailored to vascular health. Although BigET-1 appears to be a promising biomarker for arterial stiffness, we now emphasize that further validation in larger and prospective studies is needed before it can be incorporated into clinical practice.

Conclusions

BigET-1 level was associated with arterial stiffness in patients undergoing CABG. Older age, higher SBP, and higher BigET-1 level were also positively correlated with cfPWV. Early checking of serum BigET-1 levels may help predict arterial stiffness and may have clinical use for future prevention in patients undergoing CABG.