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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 3  |  Page : 119-125

Assessment of biomarkers of endothelial dysfunction in patients with angiographically proven coronary artery disease


1 Department of Biochemistry, MGM Medical College, Aurangabad, Maharashtra, India
2 Department of Biochemistry, MGM Medical College, Navi Mumbai, Maharashtra, India
3 Department of General Medicine, MGM Medical College, Aurangabad, Maharashtra, India
4 Department of Mathematics, ICLES Motilal Jhunjhunwala College, Navi Mumbai, Maharashtra, India

Date of Submission29-Apr-2020
Date of Acceptance10-May-2020
Date of Web Publication18-Aug-2020

Correspondence Address:
Dr. Zunjarrao G Badade
Department of Biochemistry, MGM Medical College, Navi Mumbai, Maharashtra.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_41_20

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  Abstract 

Introduction: The endothelium plays an important role in vascular homeostasis. Endothelial dysfunction leads to vasospasm, vasoconstriction, excessive thrombosis, and abnormal vascular proliferation. Endothelial dysfunction may be present in asymptomatic individuals, those could later develop hypertension, diabetes mellitus, and heart-related problems, which is one of the major causes of morbidity and mortality in India. The markers of endothelial dysfunction studied in this work are high-sensitivity C-reactive protein (hs-CRP), urine microalbumin creatinine ratio, and associated other markers such as lipid profile and fasting plasma sugar. Aims and Objective: The primary aim of this study was to assess biomarkers of endothelial dysfunction in patients with angiographically proven coronary artery disease (CAD). The secondary aim of this study was to estimate the levels of serum hs-CRP, urine microalbumin creatinine ratio, lipid profile, and fasting plasma sugar level in patients with angiographically proven CAD. Materials and Methods: This cross-sectional descriptive study was carried out from May 1, 2017 to April 30, 2019, at MGM Medical College, Aurangabad on approval of the Institutional Ethics Committee. A total of 231 patients with CAD of both sexes aged 21–80 years were included in the study. Serum hs-CRP was estimated by immunoturbidimetry, lipid profile by microslide method on VITROS 5600 (Ortho Clinical Diagnostics, Raritan, NJ, USA), urine microalbumin by immunoturbidimetry, urine creatinine by enzymatic reaction, and urine microalbumin creatinine ratio is calculated. Results and Discussion: hs-CRP was elevated in smokers, especially in triple vessels as compared to single and double vessels in patients with CAD, whereas the difference was nonsignificant between two- and three-vessel disease groups. In this study, we found an increased association between patients with microalbuminuria and abnormalities in serum lipoproteins. These lipid abnormalities include a lower high-density lipoprotein (HDL) level as well as higher values for low-density lipoprotein (LDL) and total triglycerides. Conclusion: This study showed that hs-CRP and urine microalbumin creatinine ratio levels were higher especially in smoker patients with CAD. There was an increase in levels of serum triglycerides, hs-CRP, LDL, and reduced HDL cholesterol levels in patients with CAD.

Keywords: Coronary artery disease, endothelial dysfunction, biomarkers


How to cite this article:
Guddetwar SG, Badade ZG, Bhale DV, Talib SH, Badade VZ. Assessment of biomarkers of endothelial dysfunction in patients with angiographically proven coronary artery disease. MGM J Med Sci 2020;7:119-25

How to cite this URL:
Guddetwar SG, Badade ZG, Bhale DV, Talib SH, Badade VZ. Assessment of biomarkers of endothelial dysfunction in patients with angiographically proven coronary artery disease. MGM J Med Sci [serial online] 2020 [cited 2020 Sep 28];7:119-25. Available from: http://www.mgmjms.com/text.asp?2020/7/3/119/292375




  Introduction Top


The endothelium is one of the largest organs in the body composed of up to trillion cells, weighing over 1kg, and covering approximately 3 m2 in a 70-kg man. It interacts with almost every system in the body and implicated in end-organ diseases of systems such as renal, hepatic, neurologic, vascular, dermatologic, immunologic, and cardiac.

The endothelium is a single-vessel layer standing as the ultimate layer between blood and vascular supply to other tissues, and serving multiple purposes like a hemostatic balance between thrombosis and anticoagulation. In addition, endothelium regulates vascular tone, carefully balancing vasoconstriction and vasodilation to provide adequate perfusion pressure to target organs.

Coronary artery disease (CAD) is an incidence of atherosclerosis described as a chronic vascular event with risk factors such as hypertension, diabetes mellitus, smoking, obesity, hypercholesterolemia, and positive family history of cardiovascular (CV) risk assessment. There are several biomarkers, such as high-sensitivity C-reactive protein (CRP), serum nitrite, urine microalbumin (mALB) creatinine ratio, and other associated markers such as lipid profile, and fasting plasma glucose has been studied to be related to adverse CAD prognosis. Physical and biochemical injuries and immune-mediated changes lead to damage in endothelial cells.

The endothelium plays an important role in the regulation of vasomotor tone via the synthesis and liberates vasodilator substance release nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor, as well as by the release of vasoconstrictor substances such as endothelin-1 and platelet-activating factor. NO derived from L arginine or related compound may account for biological activity of endothelium derived releasing factor.[1],[2]

Dysfunction of endothelial cells is the earliest event in the process of lesion formation; hence, the concept that assessment of endothelial function may be a useful prognostic tool for CAD. Endothelial dysfunction (ED) is defined as a change toward injurious processes and it contributes to vasospasm, vasoconstriction, excessive thrombosis, and abnormal vascular proliferation.[3] ED can be established by the depletion of the endothelium-derived vasodilators by local increases in challengers to these substances.

hs-CRP is a member of the pentraxin family of proteins. It is an acute-phase reactant manufactured mainly by the liver. Serum CRP levels are increased in response to acute infections, inflammatory conditions, and trauma. The inflammatory biomarker hs-CRP is an independent predictor of future CV events.[4] Studies from Europe and the United States indicate that increased levels of hs-CRP with apparently healthy men and women are a strong predictor of future CV events.[5],[6] hs-CRP has been stated to be an independent significant predictor and a risk factor of cardiometabolic risk, with an additive value to metabolic syndrome components.[7]

Microalbuminuria (MA) is defined as the presence of albumin in the urine above the normal range (<30 mg per day). MA is not only a predictor of diabetic complications but also independent risk factors of CV disease.[8],[9],[10],[11] MA predicts the development of ischemic CV events related to the development of atherosclerosis. Several clinical studies in individuals with either Type 1 or Type 2 diabetes or MA show a higher CVD mortality.[12],[13] The measurement of urine microalbumin-creatinine ratio (UMCR) in random spot urine has become a widely accepted clinical tool for assessing urinary albumin excretion.[11]

The aim of our study was to assess the biomarker of ED in CAD patients with angiographically proven CAD. We have estimated levels of serum lipid profile, serum hs-CRP, plasma sugar, and urine mALB creatinine ratio in patients with CAD and compared the results of various biochemical markers for the detection of ED in relation to the severity of patients with CAD viz. single-vessel, double vessels, and triple vessel diseases.


  Materials and methods Top


This is a cross-sectional descriptive study and includes 231 patients with angiographically proven CAD admitted to MGM Medical College and Hospital, Aurangabad. The study was conducted on 231 CAD subjects’ and 50 healthy individuals aged 20–80 years from May 1, 2017 to April 30, 2019. Health controls were nondiabetic, nonhypertensive, nonsmokers, nonalcoholic, and nontobacco chewer volunteers.

Informed consent was obtained from all subjects before participation in the study. Fasting plasma and random urine samples from each participant were collected and processed in a central laboratory. Patients with a history of primary cardiac disease, rheumatic diseases, intestinal diseases, parenchymal liver and kidney diseases, and sepsis were excluded from this study. Ethical approval for the study was obtained by the Institutional Ethics Committee of MGM Medical College, Aurangabad.

Serum hs-CRP was estimated at immunoturbidimetry VITROS 5600 (Ortho Clinical Diagnostics, Raritan, NJ, USA). mALB was estimated by immunoturbidimetry and urine creatinine by the enzymatic method. Urinary mALB creatinine ratio was calculated. Serum lipid profile was estimated by microslide method, whereas low-density lipoprotein (LDL) was a calculated parameter. Fasting plasma sugar was estimated by glucose oxidase-peroxidase method on VITROS 5600.

Statistical analysis

Data were compiled in an Excel sheet and the master chart was prepared. Data were analyzed using Statistical Package for the Social Sciences (SPSS) software program, version 25.0. Data were presented by visual impressions such as bar diagram, pie diagram, and in the form of values. A value of P ≤ 0.0001 was considered as highly significant and was calculated using an independent sample t test at a 95% confidence interval.


  Results Top


A total 231 angiographically proven CAD subjects of both sexes aged 20-80 years (189 males and 26 females) and 50 healthy control subjects (26 males and 24 females) are included in present study. We compared hs-CRP, UMCR, total cholesterol, triglycerides, LDL cholesterol levels between control group and CAD groups according to vessel disease in all CAD patients.

[Table 1] shows distribution of patients according to age group, 21-30, 31-40, 41-50, 51-60, 61-70 and 71-80 years. The mean age group is 56.27 ± 9.93 years. [Table 2] shows baseline clinical and demographic characteristics of CAD patient and healthy controls. [Table 3] shows distribution according to vessel disease vs various markers. They were grouped as single, double and triple vessels disease. The maximum patients were single vessels disease and minimum are with triple vessels.
Table 1: Distribution of patients with CAD according to age groups

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Table 2: Baseline clinical and demographic characteristics of patients with CAD (study group) and healthy subjects (control)

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Table 3: Distribution of patients according to vessel disease vs. various markers

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  Discussion Top


An increase in pressure on health resources worldwide led to the emphasis on preventive measures against the global pandemic of CAD. Indians are at higher risk of developing CAD than others, which cannot be explained by traditional risk factors alone. Multiple blood parameters in proven CAD have shown the risk assessment. The endothelium’s central role provides not only insights into pathophysiology, but also a possible clinical opportunity to detect early disease, stratify CV risk, and assess response to treatments. The endothelium is a highly selective barrier and metabolically active organ, which plays crucial roles in the maintenance roles in the maintenance of vascular homeostasis[14] by keeping a delicate balance between vasodilatation and vasoconstriction.[15]

This study of assessment of biomarkers of ED in patients with angiographically proven CAD contributes to study risk of CAD. This enables the identification of high-risk patients who may benefit from early intervention.

[Table 1] shows a total of 231 patients with angiographically proven CAD of both sexes (189 men and 42 women) and 50 healthy individuals (26 men and 24 women) aged 20–80 years are included in this study. [Table 1] shows the distribution of patients with CAD according to age group, in which the mean age group was 56.27 ± 9.93 years and in healthy 50.77 ± 8.78 years. Aging is an important determinant of CV risk in both men and women, and increasing age has been considered as one of the main factors that predispose people to ED.[16]

[Table 2] shows the baseline clinical and demographic characteristics of patients with CAD and healthy individuals. Traditional risk factors, viz. diabetes, hypertension, and lipid profiles, were studied. In our study, diabetes was present in 57 (24.7%) and hypertension in 91 (39.4%) of patients with CAD. Of 231 patients with CAD, 91 (39.4%) were smokers, 73 (31.6%) alcoholic, and 64 (28.6%) tobacco chewers. Our study group included 217 (93.9%) patients with chest pain and 133 (57.6%) patients were obese. According to our study, the mean of total cholesterol was significantly high in CAD than control, that is, 202.49 ± 64.74 mg/dL and 139.01 ± 30.50 mg/dL, respectively (P ≤ 0.0001). Serum triglycerides were significantly higher in CAD 181.98 ± 68.77 mg/dL in comparison with control 95.4 ± 20.96 mg/dL (P ≤ 0.0001). LDL cholesterol was also significantly high, that is, 132.49 ± 62.46 mg/dL and high-density lipoprotein cholesterol (HDL-C) was significantly low, that is, 33.08 ± 8.45 mg/dL (P ≤ 0.0001). Inflammatory markers such as hs-CRP were significantly high at 8.91 ± 4.49 mg/L (P ≤ 0.0001). Mean fasting plasma sugar was significantly high at 137.4 ± 34.18 mg/dL (P ≤ 0.0001). Urine mALB creatinine ratio was significantly high at 31.25 ± 7.6 (P ≤ 0.0001). The body mass index (BMI) of 231 patients was 26.33 ± 4.41. No significant difference was observed in systolic and diastolic blood pressure in patients with CAD and control.

In this study, hs-CRP, UMCR, and lipid profiles showed a significant correlation with smoking. Cigarette smoke contains many free radicals and delivers free radicals directly to the wall of the blood vessel. Besides being the supplier of free radicals, cigarette smoke facilitates the endogenous release of reactive oxygen species (ROS) through the activation of inflammatory cells. Smoking is associated with oxidative stress, inflammation, and release of circulating factors that are associated with endothelial injury and ED.

Generally, diabetes is an independent risk factor for the development of atherosclerosis and CV disease. In addition, it has been known that hyperglycemia impairs endothelial function. Hyperglycemia also leads to the generation of advanced glycation end products (AGEs), which are the products of the nonenzymatic glycation of proteins and lipids. AGEs accumulate in the vessel wall, alter the structural integrity of the endothelium and basement membrane, and can impede NO activity. This contributes substantially to the ED.[17] High levels of LDL cholesterol and low levels of HDL-C are independently associated with ED and inflammation.[18] In patients with CAD and dyslipidemia, the increased degradation of NO by ROS has been suggested because the infusion of the L-arginine (substrate of NO) partially normalized the impaired coronary endothelial function.[19] Possible mechanisms underlying dyslipidemia-induced ED include (1) the upregulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, oxidative stress, and increased O2 production, (2) increased plasma levels of asymmetric dimethylarginine (ADMA), and (3) the oxidation of LDL. ADMA is an endogenous inhibitor of endothelial NO synthase (eNOS) and competes with L-arginine for the same binding site on eNOS, which results in eNOS uncoupling. As a result, O2 production is increased and NO production is decreased.[20]

The main risk factors are increased levels of total cholesterol, triglycerides, LDL cholesterol fasting plasma sugar, lowered level of HDL-C, and other risk factors such as hypertension, smoking, insulin resistance with or without overt diabetes mellitus, age, and family history of premature coronary heart disease (CHD). Modifiable risk events account for 85% of the elevated CHD risk, of which the most important is serum cholesterol. Total cholesterol levels of <160 mg/dL can decrease CHD risk, even if other risk factors are present.[21] According to meta-analyses, triglycerides were independent risk factors for CHD, even after adjustment with HDL-C, which is strongly and inversely correlated with triglycerides.[22] Clinical studies based on extensive literature support the inverse relationship between HDL-C levels and atherosclerosis. HDL enhances reverse cholesterol transport and has antioxidative, anti-inflammatory, antithrombotic, and vasoprotective effects.[23]

Kumar and Das[24] in their study found that the lipid profile of patients with CHD showed significant variation when compared to that of the control group. The total cholesterol (P < 0.05) and LDL (P < 0.05) were significantly higher in the cases, whereas the HDL-C were significantly lower (P < 0.05) from that of the controls. Serum triglycerides were increased among cases than that of the controls but were not found to be statistically significant.

Our findings show that serum hs-CRP level in the patient at high risk for CAD was an independent predictor of future CV events. The results also clarify the roles of various other biomarkers involved in the process of ED, which showed considerable increase in their levels with respect to the hs-CRP. We found that most of the CAD cases had significantly higher mean values of hs-CRP (8.91 ± 4.49).

[Table 3] shows the distribution of patients with CAD according to vessel disease (single, double, and triple vessel disease). The study comprised 120 (51.94%) single-vessel disease, 52 (22.51%) double-vessel disease, and 59 (25.54%) triple-vessel disease patients. The maximum patients were single-vessel disease and minimum were with triple-vessel diseases. The table shows that hs-CRP was 8.9 ± 2.91 and UMCR was 22.9 ± 6.85 in single-vessel disease. hs-CRP was 9.2 ± 3.79 and the mean of UMCR was 31.69 ± 7.46 in double-vessel disease. hs-CRP was 9.77 ± 7.85 and UMCR was 38.64 ± 8.69 in triple-vessel disease. Mean serum hs-CRP, UMCR, total cholesterol, triglyceride, LDL, very low density lipoprotein (VLDL), total chol/HDL-C ratio, and fasting plasma sugar values are lowest in single-vessel disease. In double-vessel disease, mean hs-CRP, UMCR, total cholesterol, triglyceride, LDL, VLDL total chol/HDL-C ratio, and fasting plasma sugar are more than a single-vessel disease. In the case of triple-vessel disease, the mean serum hs-CRP, UMCR, total cholesterol, triglyceride, LDL, VLDL total chol/HDL-C ratio, and fasting plasma sugar values are maximum.

A significant increase in values of mean serum UMCR, total cholesterol, triglyceride, LDL, VLDL, and total chol/HDL-C ratio is observed in a double-vessel as compared with a single-vessel disease. Also, a significant increase in the values of mean serum UMCR, total cholesterol, triglyceride, LDL, VLDL, and total chol/HDL-C ratio is observed in triple-vessel disease as compared to single- and double-vessel disease, respectively (P ≤ 0.0001).

As regards, hs-CRP and fasting plasma sugar rise is not significant in a double vessel on comparing with a single-vessel disease and triple vessel disease in comparison with a single and double vessel, respectively. In our study, the increase in the levels of serum hs-CRP is not significant in patients with double vessel disease as compared to single vessel disease. Similarly, no significant differences in serum hs-CRP were seen in triple vessel disease in comparison with single and double vessel diseases.

Numerous studies have shown the association between hs-CRP and measurement of coronary disease as follows.

Habib et al.[25] studied 87 patients with angiographically evaluated CAD (57 men and 30 women). These results suggest that patients with angiographically evaluated CAD have significantly higher levels of hs-CRP as compared to healthy individuals and are correlated with the presence and severity of CAD. A comparison of lipid profile between control and patients with CAD showed that patients with CAD had significantly higher triglycerides and significantly lower HDL-C levels as compared to control subjects. Triple-vessel disease patients had significantly higher hs-CRP levels than single- and double-vessel diseases, whereas the difference was nonsignificant between single- and double-vessel disease groups. Our findings coincided with this study.

In our study, MA showed distribution according to vessel disease. They were grouped single-, double-, and triple-vessel disease. The mean of UMCR was 22.9 ± 6.85 in single-vessel disease. The mean of UMCR was 31.69 ± 54.08 in double-vessel disease. The mean of UMCR was 38.64+8.69 in triple-vessel disease. Mean serum UMCR was the maximum in triple-vessel diseases as compared to single- and double-vessel diseases. Urinary mALB creatinine ratio in the spot urine sample was used to detect MA as it was shown to be equally sensitive. Thus, we found urine mALB creatinine ratio elevated in CAD by angiographically proven cases. Our findings coincided with Habib et al.

Lohani et al.,[26] in their cross-sectional analytical study carried out on 120 patients with IHD, observed that all 40 patients of group I had significant CAD. In total, 57 (71.2%) patients of group II had significant CAD and 23 (28.8%) patients had no significant CAD. The difference was highly significant (P < 0.001). Single-vessel involvement was significantly more frequent in subjects of group II than group I (35.0% vs.15.0%, P = 0.022). Double-vessel involvement was high in group I than group II, but the difference was not statistically significant (36.8% vs. 32.40%, P = 0.641). Triple-vessel involvement was significantly more frequent in subjects of group I than group II (50.0% vs.10.7%, P < 0.001). The mean stenosis score of group I was significantly higher than group II (95% CI 4.966 to 2.809, P < 0.001). The mean ± standard deviation (SD) total coronary vessel score of group I was 16.60 ± 4.75 with a range of 7.0–21.0 and the mean ± SD total coronary vessel score of group II was 8.26 ± 6.24 with a range of 0.0–21.0. The mean total score of group I was significantly higher than group II (95% CI 10.558–6.117, P < 0.001). Patients with MA have more extensive and complex angiographic CAD as compared to those without MA. These findings correlate with our study as regards the relationship between MA and angiographic severity of CAD.

Thus, UMCR has been associated with vascular inflammation and is a useful predictor of CV events. Endothelial function deteriorates; vascular homeostasis becomes impaired and leads to reduced antioxidant and anti-inflammatory effects, increased vascular permeability to lipoproteins, and the increased expression of inflammatory cytokines and adhesion molecules. Generally, diabetes is an independent risk factor for the development of atherosclerosis and CV disease. In addition, it has been known that hyperglycemia impairs endothelial function.

The functional integrity of the endothelium is a fundamental element for vascular health. Many studies have established that ED could be an early integrated index of all atherogenic and atheroprotective indicators present in an individual. Until now, several biochemical markers and functional studies have led to the development of early detection and therapeutic interventions for ED. However, further research with large randomized controlled trials is necessary to aim at guiding the evaluation and treatment of ED. Ultimately, this effort could lead us to the prevention of atherosclerosis and the changing of CV disease outcomes.[27]


  Conclusion Top


The direct measurement of endothelial function has been an important clinical tool in diagnosing and predicting the development of the CV disease. Our data indicate that patients with angiographically proven CAD have higher serum levels of hs-CRP, total cholesterol, serum triglycerides, LDL, VLDL, UMCR, plasma sugar, and lower HDL.

The introduction of endothelial function testing into clinical practice might enable to innovate individualized CV medicine.[28] Thus, the current patient-specific risk assessment may be insufficient to identify individual risk. In addition, most of the prevailing therapies are targeted for traditional risk factors rather than atherosclerosis itself.

Endothelial function is an integrated index of all atherogenic and atheroprotective factors present in an individual including nontraditional and unknown factors, and has the significant predictive value for future CV events in addition to traditional risk factors.

Moreover, the endothelial function has a pivotal role in all phases of atherosclerosis, from initiation to atherothrombotic complication, and is reversible at every phase, indicating the utility of endothelial function-guided therapies. Further research, including large-scale randomized controlled trials, is necessary to determine whether noninvasive endothelial function assessment can be useful to guide treatment and to change outcomes.

Financial support and sponsorship

This project was sponsored and supported by MGM Medical College and Hospital, Aurangabad, India.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3]



 

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