|Year : 2021 | Volume
| Issue : 4 | Page : 274-278
Hypertension Severity and Inflammatory Burden as Evaluated by Neutrophil–Lymphocyte Ratio: Role of Telmisartan
Esraa H Fahad1, Marwa S Al-Niemi2, Nawar R Hussain2, Hayder M Al-Kuraishy3, Ali I Al-Gareeb3
1 Department of Clinical Pharmacy, College of Pharmacy, Al-Mashreq University, Bagdad, Iraq
2 Department of Clinical Pharmacology, College of Pharmacy, Al-Farahidi University, Bagdad, Iraq
3 Department of Clinical Pharmacology, Medicine and Therapeutic, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq
|Date of Submission||13-Jul-2021|
|Date of Decision||16-Aug-2021|
|Date of Acceptance||30-Aug-2021|
|Date of Web Publication||26-Oct-2021|
MBChB, MRCP, FRCP Hayder M Al-Kuraishy
Professor in Department of clinical Pharmacology, Medicine and Therapeutic, Medical Faculty, College of Medicine, Al-Mustansiriyah University, P.O. Box 14132, Baghdad
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Different studies implicated inflammation as associative or causative factor in the development of hypertension (HT). It has been reported that low-grade inflammation enhances development of HT, as high blood pressure is linked with high neutrophils, lymphocytes, C-reactive protein, and interleukin 6. Neutrophil–lymphocyte ratio (NLR) may reflect underlying chronic low-grade inflammation in different inflammatory disorders and cardiovascular diseases including HT. Telmisartan (TLS), which is an angiotensin II receptor type 1 blocker that used in the management of HT, may reduce the associated inflammatory disorders. Thus, the aim of the present study was to assess the level of NLR in relation to the HT severity in patients treated with TLS. Methods: Forty-four patients with severe HT compared with matched 20 patients with mild HT as controls were recruited. Anthropometric and biochemical variables as well as NLR were measured. Results: Blood pressure and lipid profile were higher in patients with severe HT on antihypertensive therapy other than TLS. TLS treatments had improved blood pressure; lipid profile and low NLR compared to patients with severe HT not were on TLS treatment. Conclusion: TLS reduces HT severity through reduction of NLR; therefore, it regarded the optimum angiotensin receptor blocker (ARB) drug in the management of HT. Thus, preclinical and prospective studies are warranted in this regards.
Keywords: Hypertension, neutrophil–lymphocyte ratio, telmisartan
|How to cite this article:|
Fahad EH, Al-Niemi MS, Hussain NR, Al-Kuraishy HM, Al-Gareeb AI. Hypertension Severity and Inflammatory Burden as Evaluated by Neutrophil–Lymphocyte Ratio: Role of Telmisartan. Int J Nutr Pharmacol Neurol Dis 2021;11:274-8
|How to cite this URL:|
Fahad EH, Al-Niemi MS, Hussain NR, Al-Kuraishy HM, Al-Gareeb AI. Hypertension Severity and Inflammatory Burden as Evaluated by Neutrophil–Lymphocyte Ratio: Role of Telmisartan. Int J Nutr Pharmacol Neurol Dis [serial online] 2021 [cited 2022 Jan 25];11:274-8. Available from: https://www.ijnpnd.com/text.asp?2021/11/4/274/329205
| Introduction|| |
Hypertension (HT) is a medical disorder characterized by persistent high blood pressure and regarded as a potential risk factor for various cardio-metabolic diseases including heart failure (HF), acute coronary syndrome (ACS), atrial fibrillation (AF), stroke, chronic kidney disease, and peripheral arterial disorders. HT might be primary or essential in 95% of cases due to unidentified causes, and secondary HT in 5% due to different secondary causes such as chronic kidney disease, endocrine diseases, chronic alcoholism, drugs such as contraceptive, cyclosporine, and nonsteroidal anti-inflammatory drugs (NSAIDs). HT is mainly asymptomatic though it may be associated with headache, tinnitus, anxiety, and fainting episodes. HT is defined when systolic and diastolic blood pressure more than 130/80, respectively, as measured from brachial site at sitting position; however, ambulatory blood pressure is more accurate than single measuring.
Different studies implicated inflammation as associative or causative factor in the development of HT. However, prolong use of anti-inflammatory NSAIDs and immunosuppressive drug cyclosporine is linked with development of HT. Nevertheless, many experimental studies exposed that abnormal adaptive immune response and lymphocyte activation in viral diseases are linked with progression of HT. It has been reported that low-grade inflammation enhances development of HT, as high blood pressure is linked with high neutrophils, lymphocytes, C-reactive protein, and interleukin 6 (IL-6). It has been shown that neutrophil–lymphocyte ratio (NLR) may reflect underlying chronic low-grade inflammation in different inflammatory disorders and cardiovascular diseases including ACS, AF, and HF. Thus, NLR is a simple reliable biomarker and can be used as a predictive factor for progression of HT.
On the other hand, telmisartan (TLS), which is an angiotensin II receptor type 1 (AT1) blocker that used in the management of HT, diabetic nephropathy and HF may reduce the associated inflammatory disorders. Guerra et al. observed that TLS has anti-inflammatory effects through inhibition release of pro-inflammatory cytokines mainly IL-6 and tumor necrosis factor alpha. Hence, TLS may affect inflammatory burden, recruitment of inflammatory cells, and so NLR in the hypertensive patients.
Thus, the aim of the present study was to assess level of NLR in relation to the HT severity in patients treated with TLS.
| Material and Methods|| |
In the present case–control study, 46 hypertensive patients aged 49 to 68 years were recruited from consultation unit in the Department of Internal Medicine compared with matched 20 patients with mild HT as controls. This study was approved by Scientific and Ethical Committee in College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq 2019 in cooperation with Department of Pharmacy, Bagdad University and College of Pharmacy, Al-Farahidi University according ethical clearance number MYT12, March 21, 2019. The recruited patients and enrolled controlled after full medical history and clinical examination were divided accordingly into:
Group I: Hypertensive (mild–moderate HT) controls aged 54.94 ± 4.31 years (n = 20); Group II: Patients with severe HT on TLS therapy aged 55.65 ± 4.55 years (n = 22); and Group III: Patients with severe HT on other antihypertensive therapies aged 55.65 ± 4.12 years (n = 24). Selection of patients with severe HT was carried out according to the guideline and diagnostic criteria. Mild–moderate HT 140 to 159 mmHg systolic and 90 to 99 mm Hg diastolic, severe HT >160 mmHg systolic and >100 mmHg diastolic.
Any patient with HT on TLS and/or other antihypertensive therapy was included.
Any patient with diabetes mellitus, chronic kidney disease, chronic liver disease, connective tissue disease, cardiovascular complications, pregnancy, lactation, mental, and psychiatric disorders were excluded.
Measurements of anthropometric parameters
Both systolic and diastolic blood pressures were estimated from left arm of each patient at supine position and repeated 15 minutes after to take the precise reading by automated sphygmomanometer. Pulse pressure (PP) and mean arterial pressure (MAP) were calculated by specific equation according to the previous study. As well, body mass index (BMI) was measured by specific equation, BMI = Weight (kg)/Height (m2).
Measurements of biochemical and hematologic parameters
Ten milliliter of blood was drawn from recruited patients and healthy controls after an over-night fasting, 5 mL for biochemical variables that centrifuged at 3000/rpm and stored at −20°C till time of analysis. The second 5 mL was used immediately for measurement of complete blood count (CBC) by automated analyzer.
Determination of lipid profile including total cholesterol (TC), high-density lipoprotein (HDL), and total triglyceride (TG) was estimated by enzyme-linked immunosorbent assay kit method. Though, low-density lipoprotein (LDL) was calculated by Friedwald equation. Similarly, very low-density lipoprotein (VLDL) was calculated by Al-Kuraishy et al. method, VLDL = TG/5. Besides, cardiac risk ratio (CRR) was calculated by specific equation, CRR = TC/HDL.
From CBC, neutrophil and lymphocyte counts were measured, as well NLR was estimated, and normal NLR is 1 to 3.
Data of the present study were analyzed by SPSS version 24.00 (SPSS 24.0, 2019, IBM Corp., NY, USA) and presented as mean ± standard deviation, percentages, and numbers. One-way analysis of variance and unpaired Student t test were applied to detect significance of differences; P < 0.05 was regarded as level of significance.
| Results|| |
In the beginning of the study, 50 patients were recruited, and 6 patients had been excluded due to HF, stroke, and chronic kidney disease. Forty-four patients continued the study without loss at end of the study as revealed in the consort flow diagram [Figure 1].
Characteristics of the present study illustrated that most of the patients with severe HT have underlying high BMI and dyslipidemia when compared with the patients with mild–moderate HT. Gender ratio, age, and duration of HT were insignificant between two groups. Other characteristics were revealed [Table 1].
Furthermore, SBP, MAP, PP, CRR, NLR, and lipid profile were higher in patients with severe HT on antihypertensive therapy other than TLS. Indeed, patients with severe HT on TLS treatments had improved blood pressure; lipid profile and low NLR compared to patients with severe HT not were on TLS treatment [Table 2].
|Table 2 Differences in the lipid profile, blood pressure, and neutrophil–lymphocyte ratio in hypertensive patients regarding telmisartan therapy|
Click here to view
| Discussion|| |
In the present study, there was significant dyslipidemic status with high blood pressure profile in patients with severe HT compared to the patients with mild–moderate HT as dyslipidemia is correlated with risk of severe HT.
Inflammation and oxidative stress are involved in the progression of severe HT due to endothelial injury and proliferation of vascular smooth muscle with increment of peripheral vascular resistance. NLR reflects underlying inflammation and oxidative stress; therefore, high NLR is regarded as a prognostic and diagnostic tool for inflammation-induced HT as well it correlated with HT severity. These findings are in agreement with findings of the present study as high NLR is observed in patients with severe HT. High NLR in severe HT might be due to dyslipidemia-induced inflammation and oxidative stress as revealed by Dilek et al. study.
It has been reported that elevation of neutrophils and lymphocytes is correlated with incidence and severity of HT due to release of different mediators from the neutrophils, including myeloperoxidase, elastase, and free radicals leading to plague injury and tissue damage. Besides, free radicals from the neutrophils are linked with the pathogenesis of severe HT through development of oxidative stress injury. However, biomarkers of oxidative stress were not evaluated in the present study.
Likewise, lymphocytes play an important role in the development of HT, as infusion of activated lymphocytes is associated with progression of severe HT, though inhibition of adaptive immunity by immunosuppressive drugs reduces risk for development of HT.
Into the bargain, NLR reflects activity of both neutrophils and lymphocytes; thus, it is more accurate and simple to be a surrogate indicator for severity of HT.
On the other hand, TLS in the present study reduced HT severity significantly when compared with severe HT in patients on other types of antihypertensive treatments. It has been observed that TLS has long half-life, large volume of distribution, and high lipid solubility, hence, producing a higher potency and efficacy in blocking AT1R compare to the other angiotensin receptor blockers, thus it is effective in the management of severe HT. Indeed, TLS is regarded as a partial agonist of peroxisome proliferator activator receptor gamma (PPARγ), by which it has antifibrotic and anti-inflammatory effects. Al-Hejjaj et al. confirmed that TLS has anti-inflammatory effect in rats. As well, TLS has antioxidant effects through enhancement of free radical scavenging activity. Therefore, the anti-inflammatory and antioxidant properties of TLS might be the chief mechanism in attenuation of HT severity.Moreover, TLS inhibits neutrophil activity with suppression release of pro-inflammatory cytokines in rat model of ulcerative colitis. Likewise, through activation of PPARγ inhibits migration of lymphocyte migration and development of inflammation-induced HT. Therefore, TLS indirectly reduces NLR, by which inhibits inflammation-mediated HT as in consistent with findings of the present study.
Despite of enormous findings, the present study has several limitations including small sample size, not prospective. Pro-inflammatory cytokines were not evaluated, though the present study to our knowledge this is the first study evaluate the potential effect of TLS on NLR in HT patients.
| Conclusion|| |
The TLS reduces HT severity through reduction of NLR; therefore, it regarded the optimum angiotensin receptor blocker (ARB) drug in the management of HT. Thus, preclinical and prospective studies are warranted in this regards.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
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. [Full text]
Al-Maiahy TJ, Al-Gareeb AI, Al-Kuraishy HM. Prolactin and risk of preeclampsia: a single institution, cross-sectional study. Asian Pac J Reprod 2019;8:112-7. [Full text]
Hoeper MM, Pausch C, Grünig E et al.
Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry. J Heart Lung Transp 2020;39:1435-44.
Ferreira NS, Tostes RC, Paradis P, Schiffrin EL. Aldosterone, inflammation, immune system, and hypertension. Am J Hypertens 2021;34:15-27.
Marienhagen K, Lehner F, Klempnauer J, Hecker H, Borlak J. Treatment of cyclosporine induced hypertension: results from a long-term observational study using different antihypertensive medications. Vascu Pharmacol 2019;115:69-83.
Guzik TJ, Touyz RM. Oxidative stress, inflammation, and vascular aging in hypertension. Hypertension 2017;70:660-7.
DiGangi C. Neutrophil‐lymphocyte ratio: predicting cardiovascular and renal complications in patients with diabetes. J Am Assoc Nurse Pract 2016;28:410-4.
Huber G, Ogrodnik M, Wenzel J et al.
Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior. J Cereb Blood Flow Metab 2021;41:2356-69.
Guerra GC, Araújo AA, Lira GA et al.
Telmisartan decreases inflammation by modulating TNF-α, IL-10, and RANK/RANKL in a rat model of ulcerative colitis. Pharmacol Rep 2015;67:520-6.
Nerenberg KA, Zarnke KB, Leung AA et al.
Hypertension Canada’s 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children. Can J Cardiol 2018;34:506-25.
Rasheed HA, Al-Kuraishy HM, Al-Gareeb AI, Hussien NR, Al-Nami MS. Effects of diabetic pharmacotherapy on prolactin hormone in patients with type 2 diabetes mellitus: Bane or Boon. J Adv Pharm Technol Res 2019;10:163-8.
] [Full text]
Al-Nami MS, Al-Kuraishy HM, Al-Gareeb AI. Impact of thioctic acid on glycemic indices and associated inflammatory-induced endothelial dysfunction in patients with type 2 diabetes mellitus: a case control study. Int J Crit Illn Inj Sci 2020;10:21-7. [Full text]
Palmer MK, Barter PJ, Lundman P, Nicholls SJ, Toth PP, Karlson BW. Comparing a novel equation for calculating low-density lipoprotein cholesterol with the Friedewald equation: a VOYAGER analysis. Clin Biochem 2019;64:24-9.
Al-Kuraishy HM, Al-Gareeb AI, Alblihed M, Cruz-Martins N, Batiha GE. COVID-19 and risk of acute ischemic stroke and acute lung injury in patients with type ii diabetes mellitus: the anti-inflammatory role of metformin. Front Med 2021;8:644295.
Dikalova AE, Pandey A, Xiao L et al.
Mitochondrial deacetylase Sirt3 reduces vascular dysfunction and hypertension while Sirt3 depletion in essential hypertension is linked to vascular inflammation and oxidative stress. Circ Res 2020;126:439-52.
Abd-Alazim M, Mohammad AH, Radwan MS, Shokr AA. Is neutrophil/lymphocyte ratio a useful marker to predict the severity of pre-eclampsia? Egypt J Hosp Med 2018;73:6621-5.
Dilek TD, Gayret OB, Kilinc S, Erol M, Yigit O, Mete F. The assessment of the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in dyslipidemic obese children. Bagcilar Med Bull 2019;4:56-61.
Taylor S, Dirir O, Zamanian RT, Rabinovitch M, Thompson AA. The role of neutrophils and neutrophil elastase in pulmonary arterial hypertension. Front Med 2018;5:217.
Small HY, Migliarino S, Czesnikiewicz-Guzik M, Guzik TJ. Hypertension: focus on autoimmunity and oxidative stress. Free Radic Biol Med 2018;125:104-15.
Zhang J, Crowley SD. Role of T lymphocytes in hypertension. Curr Opin Pharmacol 2015;21:14-9.
Hirvensalo P, Tornio A, Launiainen T et al.
UGT1A3 and sex are major determinants of telmisartan pharmacokinetics—a comprehensive pharmacogenomic study. Clin Pharmacol Ther 2020;108:885-95.
Villapol S. Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell Mol Neurobiol 2018;38:121-32.
Al-Hejjaj WK, Numan IT, Al-Sa’ad RZ, Hussain SA. Anti-inflammatory activity of telmisartan in rat models of experimentally-induced chronic inflammation: comparative study with dexamethasone. Saudi Pharm J 2011;19:29-34.
Surendrakumar R, Idhayadhulla A, Alarifi S, Ahamed NA, Sathish Kumar C. Antioxidant activity of telmisartan–Cu (II) nanoparticles connected 2-pyrimidinamine and their evaluation of cytotoxicity activities. BioMed Res Int 2020; 2020;8872479.
Guerra GC, Araújo AA, Lira GA et al.
Telmisartan decreases inflammation by modulating TNF-α, IL-10, and RANK/RANKL in a rat model of ulcerative colitis. Pharmacol Rep 2015;67:520-6.
Walcher D, Hess K, Heinz P et al.
Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-γ. Hypertension 2008;51:259-66.
[Table 1], [Table 2]