|Year : 2019 | Volume
| Issue : 6 | Page : 369-375
Endothelin-1 is a surrogate biomarker link severe periodontitis and endothelial dysfunction in hypertensive patients: The potential nexus
Sahar S Kadhim1, Salah A Al-Windy2, Hayder M Al-Kuraishy1, Ali I Al-Gareeb1
1 Department of Pharmacology, Toxicology and Medicine, College of Medicine Al-Mustansiriya University, Baghdad, Iraq
2 Department of Biology, College of Sciences, Baghdad University, Baghdad, Iraq
|Date of Web Publication||26-Nov-2019|
Prof. Hayder M Al-Kuraishy
Department of Pharmacology, Toxicology and Medicine, College of Medicine Al-Mustansiriya University, P.O. Box 14132, Baghdad.
Source of Support: None, Conflict of Interest: None
Aim and Objectives: The objective of this study was to illustrate the link between periodontitis (PO) and endothelial dysfunction in hypertensive patients. Materials and Methods: This cross-sectional study involved 53 hypertensive patients with or without PO compared with 28 healthy controls. On the basis of the study protocol, the participants were divided into three groups: Group (1): 24 patients with hypertension only, Group (2): 29 patients with hypertension and PO, and Group (3): 28 healthy controls. Lipid profile, endothelin-1 (ET-1), and high-sensitivity C-reactive protein (hs-CRP) were measured. Blood pressure and body mass index (BMI) were evaluated. Diagnostic criteria of severe PO periodontal indices including plaque index, gingival index, and community periodontal index were estimated. Data collected during the study were analyzed using analysis of variance followed by Bonferroni post hoc test and unpaired t-test (IBM SPSS Statistics for Windows, version 20.0, 2014, IBM, Armonk, NY). Results: BMI was not differed in both groups, P = 0.08. Systolic blood pressure and diastolic blood pressure were high in hypertensive patients with PO compared with hypertensive patients only, P = 0.04 and P = 0.03, respectively. Moreover, hypertensive patients with PO showed significant dyslipidemic status compared with hypertensive patients only (P < 0.05). Biomarker of endothelial dysfunction (ET-1) was elevated in patients with PO (67.54 ± 13.56 pg/mL) compared with hypertensive patients only (23.67 ± 9.63 pg/mL), P = 0.0001. hs-CRP serum level was increased patients with PO compared with hypertensive patients only, P = 0.002. PO indices were high in patients with PO compared with hypertensive patients only, P < 0.01. Conclusion: ET-1 serum level is elevated in hypertensive patients with severe PO and correlated with cardio-metabolic complications, mainly endothelial dysfunction. Therefore, ET-1 serum level is regarded as a surrogate biomarker link PO with risk of endothelial dysfunction.
Keywords: Endothelial dysfunction, hypertension, periodontitis
|How to cite this article:|
Kadhim SS, Al-Windy SA, Al-Kuraishy HM, Al-Gareeb AI. Endothelin-1 is a surrogate biomarker link severe periodontitis and endothelial dysfunction in hypertensive patients: The potential nexus. J Int Oral Health 2019;11:369-75
|How to cite this URL:|
Kadhim SS, Al-Windy SA, Al-Kuraishy HM, Al-Gareeb AI. Endothelin-1 is a surrogate biomarker link severe periodontitis and endothelial dysfunction in hypertensive patients: The potential nexus. J Int Oral Health [serial online] 2019 [cited 2021 May 18];11:369-75. Available from: https://www.jioh.org/text.asp?2019/11/6/369/271777
| Introduction|| |
Periodontitis (PO) is a group of inflammatory diseases of soft tissue and bone surrounding teeth. Periodontal diseases (PDs) include PO and gingivitis that is a common human disease after tooth decay. Long-term PO leads to destruction of tooth-supporting tissues due to accumulation of calculus and biofilms.
In addition, PO is regarded as a low-grade inflammatory disorder of tooth-supporting tissue leading to systemic inflammatory reactions. It has been reported that PO causes an increase in inflammatory biomarkers including C-reactive protein (CRP), interleukin-6 (IL-6), and other inflammatory cytokines.
Prevalence of PO is 11% of population, which is common in male around 60 years of age. The risk factors for PO are old age, smoking, diabetes mellitus, and immune deficiency.
Moreover, PO is regarded as a potential risk factor for different systemic disorders including erectile dysfunction, endothelial dysfunction, and cardiovascular disorders.
Systemic hypertension is defined as a systolic blood pressure (SBP) of 140mm Hg or more and a diastolic blood pressure (DBP) of 90mm Hg or more. Hypertension is more common in developed countries affecting 972 million people worldwide in 2000, and the number is expected to rise to 1.56 billion people by 2025.
Dental biofilms of PO release different active substances such as protein toxins, lipopolysaccharides, and chemotactic peptides, which stimulate host immune response for production of various inflammatory biomarkers such as IL-6, IL-8, prostaglandin, and tumor necrosis factor-α. Consequently, this interaction between dental biofilm products and host immune response contributes to dental mucosal inflammation as well as systemic adverse effects such as endothelial dysfunction, atherosclerosis, and hypertension. Different previous studies documented the association between hypertension and PO, which were cross-sectional studies and depended on several different variables such as hygiene practice and number of missing teeth.
Indeed, PO-induced inflammatory reactions lead to endothelial dysfunction due to induction of oxidative stress, which activates inducible nitric oxide synthase (iNOS). Activated iNOS participates into the production of free radicals in both periodontium and vascular endothelium leading to periodontal destructions and endothelial failure. Moreover, PO is associated with high concentration of CRP and IL-6, which reflect endothelial inflammations. In addition, treatment of PO significantly reduced endothelial dysfunction and concentration of inflammatory biomarkers.
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide in vascular endothelium, which also upregulated in the periodontium during PO. Likewise, Rikimaru et al. showed that ET-1 concentration is elevated during gingivitis and periodontal inflammation. Nevertheless, neither of the previous studies document the surrogate biomarker link PO with endothelial dysfunction and hypertension.
Therefore, this study aimed to illustrate a link between PO and endothelial dysfunction in hypertensive patients.
| Materials and Methods|| |
This case-controlled cross-sectional study was done in the Department of Clinical Pharmacology and Therapeutic, College of Medicine Al-Mustansiriya University in cooperation with Dental Department, College of Medicine, Baghdad University on January 2019.
This study involved 53 hypertensive patients (21 female and 32 male) with or without PO, age ranged 45–67 years that were randomly recruited from dental and cardiology departments during routine visits compared with 28 healthy controls matched with age and body weight. Full history and general physical examination as well as dental examination were done by internist physician and dentist. Written and verbal informed consents were obtained from all recruited patients according to the recommendation of the Ethical Committee No. 32AR in 22/4/2018 in College of Medicine, Al-Mustansiriyia University, Iraq, Baghdad. On the basis of study protocol, the participants were divided into three groups:
- Group (1): 24 hypertensive patients only
- Group (2): 29 hypertensive patients with PO
- Group (3): 28 healthy controls
Hypertensive patients with or without PO were included in the study. The exclusion criteria of the study were any patients with endocrine disorders, metabolic disorders, diabetes mellitus, pregnancy and lactation, psychiatric, and mental disorders.
Biochemical measurements: A fasting venous blood sample (10mL) was obtained from all enrolled subjects and recruited patients. The sample was centrifuged at 3000rpm and stored frozen until the time of analysis.
Lipid profile: Total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL) were measured by colorimetric ELISA kit method (65390, Abcam, Cambridge, Massachusetts). Very low density lipoprotein (VLDL), low-density lipoprotein (LDL), atherogenic index (AI) (AI = log [TG/HDL]), and cardiac risk ratio (CRR) (CRR = TC/HDL) were measured according to Al-Kuraishy et al.
ET-1 serum level was measured by ELISA kit method (endothelin-1 ELISA kit, ab133030, Abcam), which was expressed in pg/mL with sensitivity range (0.78–100 pg/mL). High-sensitivity C-reactive protein (hs-CRP) was measured by ELISA kit method (Cat. No. ABIN11154322; Wuhan USCN Business, shanghai, China).
Assessment of blood pressure changes and body weight: Blood pressure was measured from the left arm in the supine position by an automatic digital blood pressure monitor 2h apart. Pulse pressure = SBP–DBP and mean arterial pressure (MAP) = SBP + 2DBP/3. Body mass index (BMI) was calculated according to specific equation in kg/m2.,
Estimation and evaluation of periodontal status: Whole-mouth clinical measurements were performed with probing depth from at least of the quadrants for clinical measurements in both patients and healthy controls.
Diagnostic criteria of severe PO were done according to the method by Martin-Cabezas et al. These criteria included at least two sites on different teeth with clinical attachment level (CAL) > 6mm with probing pocket depth (PPD) > 6 mm, at least five sites with CAL > 6mm, PPD > 6mm, or CAL > 5mm.
Assessment of periodontal indices: Plaque index (PI) is used to measure the rate of plaque formation on tooth surfaces, which test the efficacy of oral care products in prevention of plaque deposits. The scores of PI were as follows: 0 = no plaque, 1 = invisible thin film of plaque adjacent to the area of tooth, 2 = visible film on tooth margin, and 3 = abundant plaque on the tooth surface.
Gingival index (GI) is used to measure the severity of gingivitis. The scores of GI were as follows: 0 = healthy gingival, 1 = mild-inflammation (red edematous gingival), 2 = moderate inflammation (bleeding on probing), and 3 = severe inflammation (spontaneous bleeding and ulceration).
Community periodontal index (CPI) is used to measure the severity of PO and gingivitis. The scores of CPI were as follows: 0 = healthy gingival, 1 = bleeding after gentle probing, 2 = calculus felt during probing, 3 = gingival margin on 3.5–5.5mm from black area of probe, and 4 = black area of probe is not visible.
Statistical analysis: Data analysis was performed by using the Statistical Package for the Social Sciences (SPSS) software (IBM SPSS Statistics for Windows version 20.0, 2014, IBM Corp, Armonk, NY). Unpaired Student’s t-test was used to test the level of significance between two study groups. Analysis of variance followed by Bonferroni post hoc test was used to compare results of different groups. The level of significance was regarded when P < 0.05.
| Results|| |
In this study, there were insignificant differences in age, BMI, and gender in hypertensive patients compared with healthy controls (P > 0.05). Smoking status and alcohol drinking were high in hypertensive patients compared with healthy controls, P < 0.01. Also, there was a significant difference in the number of teeth, which was low in hypertensive patients compared with healthy controls (P < 0.01). In addition, 54.71% of recruited hypertensive patients were associated with PO compared with 45.28% of hypertensive patients only. Also, 66.03% of recruited hypertensive patients were associated with dyslipidemia. Other characteristics of this study are shown in [Table 1].
Cardio-metabolic profile of this study illustrated that those hypertensive patients with PO demonstrated significant cardio-metabolic changes compared with hypertensive patients only. BMI was not differed in both groups, P = 0.08. SBP and DBP were high in hypertensive patients with PO compared with hypertensive patients only, P = 0.04 and P = 0.03, respectively. In addition, MAP was high in hypertensive patients with PO compared with hypertensive patients only, P = 0.03. Moreover, hypertensive patients with PO showed significant dyslipidemic status compared with hypertensive patients only. TG, VLDL, and LDL were higher, whereas HDL was low in patients with PO compared with that in hypertensive patients only, P < 0.05. Furthermore, CRR and AI were higher in patients with PO compared with hypertensive patients only, P = 0.01 and 0.0001, respectively. In this study, the biomarker of endothelial dysfunction (ET-1) was elevated in patients with PO (67.54 ± 13.56 pg/mL) compared with hypertensive patients (23.67 ± 9.63 pg/mL) only, P = 0.0001. Regarding inflammatory biomarker, hs-CRP serum level was found to be increased in patients with PO compared with hypertensive patients only, P = 0.002 [Table 2].
|Table 2: Cardio-metabolic profile in hypertensive patients with/without periodontitis|
Click here to view
Regarding PO indices, GI, PI, and CPI were high in patients with PO compared with hypertensive patients only, P < 0.01 [[Figure 1]].
|Figure 1: Periodontal indices in patients with periodontitis as compared with hypertensive patients (PI = plaque index, GI = gingival index, CPI= community periodontal index, HT = hypertensive)|
Click here to view
Indeed, this study demonstrated that PO indices were significantly correlated with most of cardio-metabolic profile. CPI was more significantly correlated with PO indices than PI and GI [Table 3].
|Table 3: Correlation of periodontitis indices with cardio-metabolic profile in hypertensive patients with periodontitis|
Click here to view
| Discussion|| |
This study illustrated that PO led to significant cardio-metabolic effects in hypertensive patients compared with hypertensive patients without PO as reported by a study by Bălan, which showed that PD is a risk factor for the development of cardiovascular complications.
Our findings also illustrated that smoking and alcohol drinking were high in hypertensive patients, which explain the association with hypertension as smoking and alcohol are regarded as a causative factors in the development of hypertension.
In addition, this study demonstrated that patients with PO were linked with high BMI as in agreement with Akram et al. who confirmed an association between PD and obesity due to pro-inflammatory changes
Moreover, this study confirmed that PO led to resistance and high blood pressure profile compared with hypertensive patients without PO despite of regular anti-hypertensive therapy. Also, the findings of this study disclosed a significant association of PO with dyslipidemia and endothelial dysfunction, which communally participated in the development of hypertension severity. Martin-Cabezas et al. confirmed that severe PO leads to resistant hypertension.
Different studies substantiated a potential nexus between chronic PO and risk of hypertension as well as other cardiovascular complications such as coronary heart disease, peripheral artery disease, and stroke due to PD-induced chronic inflammatory changes. CRP that predicts hypertension severity is highly increased in patients with PD. Also, hs-CRP is regarded as a link between chronic PO and hypertension severity. These findings correspond with results of this study as CRP serum levels were high in hypertensive patients with PO.
It has been reported that chronic PO leads to endothelial dysfunction through attenuation of endothelial vasodilatation due to systemic inflammatory changes and induction of oxidative stress. Besides, periodontal therapy reduces the risk of hypertension and endothelial dysfunction, which proofed through reduction of PO-induced inflammatory biomarkers. These pronouncements are consistent with findings of this study that confirmed a significant elevation of ET-1, which is potential biomarker of endothelial dysfunction. Khalid et al. showed that periodontal ET-1 participates in the initiation of endothelial dysfunction and subsequent hypertension. Thus, severe PO leads to induction of hypertension through induction of endothelial dysfunction.
Indeed, oxidative stress and reactive oxygen generations due to chronic PO lead to systemic lipid peroxidation and subsequent dyslipidemia, endothelial dysfunction, and hypertension. Oxidative stress is a well-known risk factor in the development of hypertension and preeclampsia., Unfortunately, biomarkers of oxidative stress were not evaluated in this study.
Therefore, oxidative stress, pro-inflammatory changes, and lipid peroxidation induce potential endothelial damage through activation of iNOS, which increases peroxynitrite instead of vasodilator nitric oxide causing endothelial failure and vasoconstriction in patients with chronic PO. Therefore, in this study high ET-1 serum levels were correlated with degrees of blood pressure and other cardio-metabolic profile.
On the other hand, bacterial biofilm of PO may play a possible role in the pathogenesis of hypertension. Recently, in a study by Czesnikiewicz-Guzik et al., illustrated that antigen of Porphyromonas gingivalis, which is the common bacterial subtype in PO leads hypertension through increasing the sensitivity of vascular endothelium to the circulating angiotensin ІІ. In addition, P. gingivalis found in 50% of atheroma samples attained from hypertensive patients with chronic PO. Likewise, P. gingivalis has potential activity to bind macrophage and augments the binding of LDL to vascular macrophage, which together activate atheroma formation, atherosclerosis, endothelial dysfunction, and hypertension severity. Furthermore, P. gingivalis induces significant endothelial dysfunction via activation the adhesion of inflammatory molecules such as ET-1, P-selectin, and E-selectin to the vascular endothelium. Regrettably, periodontal bacterial type and bacterial cultured were not performed in our study.
Moreover, this study demonstrated that patients with PO were associated with dyslipidemia (high TG, LDL, and low HDL) as revealed in a study by Lee et al., which found that PO severity is correlated with low HDL and high TG. Chronic PO leads to augmentation of plasma pro-atherogenic lipoproteins in particular LDL and TG due to chronic inflammatory changes. Similarly, amelioration of lipid profile was observed following the periodontal therapy.
Furthermore, findings of our study confirmed that periodontal indices were correlated with hypertension and cardio-metabolic profiles. However, localized inflammatory reactions increase risk of hypertension, which explains high periodontal indices in patients with PO-induced hypertension. Therefore, periodontal indices are high in patients with PO, which reflects underling PO severity. Similarly, this study revealed that periodontal indices were positively correlated with ET-1 serum levels. Chronic PO is associated with overgrowth of P. gingivalis, which has endopeptidase enzyme, which is similar to endothelin-converting enzyme, that converts preproendothelin into ET-1. Likewise, overexpression of ET-1 gene is augmented by inflammatory cytokines in PO. Also, mechanical strain upregulates ET-1 gene in patients with PO.
Therefore, high ET-1 serum is a link between PO and endothelial dysfunction in hypertensive patients with PO.
Limitations of this study were cross-sectional study, which limits follow-up of patients’ status, small sample size, IL-6, and other inflammatory biomarkers, which were not evaluated. Despite these limitations, this study is regarded as a preliminary study for future large-scale study to find the potential biomarkers that predict cardiovascular complications in patients with severe PO.
Therefore, this study conclude that, ET-1 serum level is elevated in hypertensive patients with severe PO and correlated with cardio-metabolic complications, mainly endothelial dysfunction. Therefore, ET-1 serum level is regarded as a surrogate biomarker of endothelial dysfunction in patients with severe PO.
Ethical policy and institutional review board statement
This cross-sectional study was approved by the Ethics Committee of the Research Deputy of Al-Mustansiriya University according to the reference approval 45LRT in 23/12/2018, which was coincided with declaration of Helsinki.
We would like to acknowledge Dr. Wedad A. Sami for his great support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]
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