Serum indoxyl sulfate as a potential biomarker of aortic arterial stiffness in coronary artery disease

https://doi.org/10.1016/j.numecd.2020.07.035Get rights and content

Highlights

  • Serum indoxyl sulfate (IS) level are positive correlation with carotid–femoral pulse wave velocity (cfPWV) in CAD patients.

  • Increasing serum IS levels may be involved in the pathogenesis of aortic arterial stiffness (AAS) in CAD patients.

  • An elevated serum IS level can be a potential biomarker of AAS in CAD patients.

Abstract

Background and aims

Indoxyl sulfate (IS), a dietary tryptophan metabolite, acts as a cardiotoxin and uremic toxin. High IS levels are associated with chronic kidney disease and cardiovascular diseases. This study investigated the association between serum IS levels and aortic arterial stiffness (AAS) in coronary artery disease (CAD) patients.

Methods and results

The carotid–femoral pulse wave velocity (cfPWV) was measured by the SphygmoCor system and patients with values of >10 m/s were classified in the AAS group. The baseline characteristics were recorded and measured (including biochemical and clinical data). Serum IS levels were determined using liquid chromatography–mass spectrometry. AAS occurred in 50 (34.7%) of 144 patients with CAD. They were older, had higher IS levels and percentages of diabetes, systolic blood pressure, blood urea nitrogen, and creatinine but lower estimated glomerular filtration rates. The IS level and older age significantly correlated with AAS [odds ratio (OR) = 3.834, p = 0.031; OR = 1.095, p = 0.002, respectively]. Furthermore, the serum IS level (β = 0.167, adjusted R2 change: 0.026, p = 0.027) had a significant positive correlation with cfPWV.

Conclusions

Taken together, higher serum IS levels are potential independent biomarkers for AAS in patients with CAD. Therefore, early checking of serum IS levels may help prevent CAD progression and have clinical implications in the near future.

Introduction

Coronary artery disease (CAD) is one of the cardiovascular diseases (CVDs), which include hypertension, angina pectoris, stroke, myocardial infarction, and congestive heart failure. CAD is the leading cause of CVD mortality globally [1], particularly in developing countries [2]. Early detection and management are needed for patients with CVD or those who might have accompanying risk factors such as diabetes, high cholesterol, hypertension, or other established diseases [3].

Indoxyl sulfate (IS) is a protein-binding uremic toxin with low molecular weight. IS is generated from dietary tryptophan by gastrointestinal bacteria (primarily Escherichia coli); indole is produced from tryptophan (in food), absorbed in the intestine, and then distributed in the blood. After being metabolized in the liver through the hydroxylation and sulfation, indole will transform to IS and re-enters the circulatory system [4]. Previous studies have revealed that the chronic inflammation further caused the serum IS levels increase in the chronic kidney disease (CKD) patients [5], and approximately 90% of serum IS with serum proteins binding, which further promoted the difficulty to eliminate the uremic toxin by hemodialysis [4]. Accordingly, IS is involved in CKD progression indeed [5,6], and also activation of the inflammatory biomarkers [5,7]. In addition, IS promotes arterial calcification and higher IS levels may further increased the mortality in patients with CKD [8]. However, although IS is an well-known CKD predictor, the association between serum IS levels and AAS in patients with CAD remains unclear.

Aortic arterial stiffness (AAS) refers to changes in physical characteristics of the artery wall in terms of distensibility, compliance, and elasticity [9]. These characteristics affect the manner in which the arteries adapt to blood pressure (BP) and blood flow with each heartbeat [10], including a shorter travel time of the pulse and a higher pulse wave velocity as a result of arterial compliance [11]. Therefore, AAS can increase the risk of developing arterial obstructions [12,13]. In addition, the arterial calcification in general patients as well as in patients with CKD is a subsequent predictor of mortality in CVD beyond the established conventional risk factors. Moreover, the risk of progression of CVD complications is related to the structural and functional changes in the arterial system, similar to aging [14]. The carotid–femoral pulse wave velocity (cfPWV), a measure of AAS, is the velocity of pulse (determined as m/s) as it travels from the heart to the carotid and to the femoral arteries. It remains the most established and generally used noninvasive method for evaluating arterial stiffness and is considered as the “gold standard” [15]. Several factors may further affect cfPWV value, including age, blood pressure, and pulse pressure [16]. A previous study has indicated that cfPWV to the forward wave is an important mechanism to cause the increase of central pulse pressure which associated with arterial stiffness [17]. These factors are also associated with CVD occurrence and progression. Therefore, arterial stiffness can be clearly determined by measuring the cfPWV value as an independent prognosticator of CVD morbidity and mortality [16,18]. The 10 m/s cutoff cfPWV value is used as an influencing factor for the prognoses of CVD and hypertension by the European Society of Cardiology and the European Society of Hypertension [19]. The cfPWV value was also used as a meaningful biomarker for preventing primary and secondary CVD [11,20]. Parathyroid hormone (PTH) is a hormone involved in calcium and phosphate regulation [21]. A previous study indicated that higher levels of PTH may be promoted the arterial stiffness in untreated chronic disease patients [21]. Therefore, the levels of serum intact PTH (iPTH) also have been measured and used for comparison to the association of cfPWV.

In this study, we aimed to investigate the association between the serum IS levels and AAS in patients with CAD, and further explore whether serum IS is a potential predictive biomarker in earlier CAD prevention.

Section snippets

Participants

From January to December 2012, 144 patients with CAD were recruited from the CVD outpatient department of Tzu Chi Medical Center in Hualien, Taiwan. All participants provided informed consent before enrollment. CAD was defined as >50% stenosis in any segment determined using coronary angiography. Patients with heart failure, acute infection, malignancy, and pulmonary edema were excluded as well as patients who had nutrition supplement omega-3 fatty acids. The BP of all the participants was

Results

Baseline clinical variables of the 144 patients with CAD are described in Table 1. Among these patients, 50 (34.7%) and 94 (65.3%) were categorized into the AAS group and the control group, respectively. The AAS group had higher cfPWV values (12.05 ± 2.11 vs. 7.80 ± 1.31, p < 0.001). In addition, they were older (69.62 ± 8.30 vs. 61.67 ± 10.82, p < 0.001), had higher SBP (136.82 ± 20.15 vs. 129.38 ± 14.70, p = 0.012), BUN (18.36 ± 7.55 vs. 15.73 ± 4.21, p = 0.008), serum creatinine (1.19 ± 0.38

Discussion

A major finding of this study was the significant association of AAS with T2DM, age, SBP, BUN, serum creatinine, eGFR, and serum IS levels. Adjusting these variables in multivariable logistic regression analysis revealed that higher serum IS levels and older age had significant OR values, indicating that both were independent predictors of AAS in patients with CAD.

In previous study has already evidenced that serum IS has a significant positive correlation with aortic calcification in the CKD

Conclusions

An elevated free-form serum IS level can be an independent biomarker for AAS in patients with CAD. The cfPWV values had a significantly positive correlation with age, SBP, log-hs-CRP, and log-IS in patients with CAD. Early checking of serum IS levels may help prevent CAD progression and may have clinical implications in the near future.

Funding

This work was funded by Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, under grant number [TCMMP 104-01-04] and [TCMF-MP 107-01-01]. The funder had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Author contributions

Conceptualization, B.G.H., J.H.W., and C.H.L.; methodology, T.J.L, B.G.H., J.H.W., and C.H.L; formal analysis, T.J.L., B.G.H., J.H.W., and C.H.L.; investigation, T.J.L., Y.H.L., and R.A.D.; resources, B.G.H., J.H.W., and C.H.L.; writing—original draft preparation, T.J.L, B.G.H., R.A.D. and C.H.L.; writing—review and editing, T.J.L, B.G.H., J.H.W., Y.H.L., R.A.D. and C.H.L.

Declaration of competing interest

The authors declare no conflict of interest.

Acknowledgments

We would like to thank Dr. Jon-Son Kuo for manuscript reading and all the co-workers for their contributions in this study and the authors would like to thank Enago (www.enago.tw) for the English language review.

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