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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2011  |  Volume : 22  |  Issue : 1  |  Page : 97-103
Endothelial dysfunction and inflammation in different stages of essential hypertension

1 Department of Nephrology, Jawaharlal Nehru Medical College (JNMC), Aligarh Muslim University (AMU), Aligarh, UP, India
2 Department of Community Medicine, Jawaharlal Nehru Medical College (JNMC), Aligarh Muslim University (AMU), Aligarh, UP, India

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Date of Web Publication30-Dec-2010


The objective of this study was to assess the various factors affecting endothelial function in essential hypertensives and to establish a relation between them in a regression model. Also, the micro-inflammatory state that is known to exist in essential hypertension was evaluated. Sixty newly detected patients of essential hypertension not on any prior treatment and classified into Stage-1 or Stage-2 hypertension according to the JNC-VII criteria were recruited in the study. After a detailed history and physical examination, investigations including blood urea, serum creatinine, blood sugar (F), S. lipid profile (F), urine for albumin, sugar and sediments, X-ray of the chest, ECG and fundus examination were carried out. Urine for microalbuminuria, Hs-CRP and brachial artery reactivity were tested as markers of endothelial dysfunction and inflammation. The CRP levels, taken as a marker of inflammation in hypertension, were significantly elevated in a majority of the study subjects. Endothelial dysfunction was significantly more quantified in Stage-2 hypertension as compared with Stage-1 hypertension (P < 0.01). The Hs-CRP levels were consistently found to be elevated in both the stages of hypertension in our study, with an insignificant difference between the two groups. A significant association was noted with the stage of hypertension, triglycerides, microalbuminuria, CRP, LDL cholesterol and age, with the stage of hypertension emerging as the most powerful predictor variable (P < 0.0001) followed closely by microalbuminuria (P < 0.0001) in a multiple regression analysis model. The present study reinforces the view that hypertension is in part an inflammatory disorder. Endothelial dysfunction is an important component of essential hypertension, the severity being determined by the stage of hypertension, microalbuminuria, LDL-cholesterol, triglycerides, age and Hs-CRP levels independently. The undesirable inflammatory response can be cost-effectively prevented at various levels by targeting the potentially modifiable risk factors elucidated in the study.

How to cite this article:
Gupta V, Sachdeva S, Khan AS, Haque SF. Endothelial dysfunction and inflammation in different stages of essential hypertension. Saudi J Kidney Dis Transpl 2011;22:97-103

How to cite this URL:
Gupta V, Sachdeva S, Khan AS, Haque SF. Endothelial dysfunction and inflammation in different stages of essential hypertension. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2021 May 17];22:97-103. Available from: https://www.sjkdt.org/text.asp?2011/22/1/97/74368

   Introduction Top

Although the exact pathophysiology of essen­tial hypertension is still not completely eluci­dated, endothelial dysfunction is considered to play a pivotal role in the natural history of disease. Initially regarded as an inert barrier bet­ween blood and blood vessels, the vascular endothelium is now recognized as an impor­tant center of vascular control. The seminal work of Furchgott and Zawadzki [1] has also em­phasized on the crucial role of endothelium in vascular homeostasis. The endothelium parti­cipates importantly in the regulation of vas­cular tone, nutrient delivery and waste remo­val, inflammation, thrombosis and coagulation. [2] It is widely postulated that most of the dys­function of the endothelium occurring in hy­pertension is a consequence rather than a cause of hypertension. [3],[4] However, whether these fun­tional abnormalities are the primary cause or effect of hypertension is uncertain. The study investigates the micro-inflammatory state in hypertension and analyses the various deter­minants of endothelial dysfunction in patients with different stages of essential hypertension with an attempt to establish their relative im­portance in a linear regression model. The same could have an important bearing on the conclusions and cast light, particularly on the preventive modalities, toward the development of essential hypertension.

   Methodology Top

Sixty newly detected patients of essential hy­pertension not on any prior treatment and cla­ssified into Stage-1 or Stage-2 hypertension according to JNC-VII criteria 4a were recrui­ted in the study. Informed consent was taken from all subjects prior to the study. The ex­clusion criteria were patients with secondary hypertension of any etiology, including chro­nic kidney disease, smokers, diabetics; those afflicted with acute or chronic inflammatory conditions including collagen vascular diseases, acute or chronic infections, familial dyslipide­mias, acute coronary syndromes and cerebro­vascular accidents; and patients on statins or lipid-lowering therapy as well as women on hormone-replacement therapy. Detailed history and physical examination were carried out for each study individual. A thorough general phy­sical examination, assessment of vital parame­ters, anthropometry (height, weight) and systemic examination were performed for clues to the markers, complications and possible se­condary etiology to hypertension. Patients were investigated on the lines of hypertension and tests including blood urea, serum creatinine, fasting blood sugar, fasting serum lipid profile, urine for albumin, sugar and sediments were conducted. Chest X-ray, ECG, ocular fundus examination, estimation of microalbuminuria, Hs-CRP and brachial artery reactivity were chosen to serve as markers of endothelial dys­function and inflammation.

Blood Pressure Measurement

Patients were asked to rest for at least 5 min. The blood pressure was measured in patients in both the upper extremities in the sitting, supine and standing positions (for at least 2 min). An average of two readings on two dif­ferent visits was taken before assigning an individual value to a specific category of the JNC-VII classification.

Hs-CRP Measurement

Estimation of C-reactive protein was carried out by the enzyme-linked immunosorbant assay (ELISA) technique (UBI MAGIWEL CRP ELISA kit supplied by UNITED BIOTECH INC.).

Estimation of Microalbuminuria

Urinary albumin was quantitatively determined using an Immunotech Albumin RIA kit (Immu­notech Company Prague, Czech Republic) based on the principle of competitive immunoanaly­tical determination.

Color Doppler of the Brachial Artery

The ultrasound system was equipped with vascular software for two-dimensional (2D) imaging, color and spectral Doppler and a high­frequency vascular transducer. The brachial artery was imaged below the antecubital fossa in the longitudinal plane. A segment with clear anterior and posterior intimal interfaces bet­ween the lumen and the vessel wall was se­lected for continuous 2D grayscale imaging. Flow-mediated vasodilatation (FMD) was re­corded and expressed as change in post-stimulus diameter as a percentage of the baseline diameter. An exogenous nitic oxide (NO) donor, such as a single high dose (0.4 mg) of nitro­glycerin (NTG) spray or sublingual tablet was given to determine the maximum obtainable vasodilator response, and served as a measure of endothelium-independent vasodilation (EID) reflecting vascular smooth muscle function. Peak vasodilation occurred 3-4 min after NTG administration and images were continuously recorded during this time. The difference bet­ween the two percentages (FMD and EID) was taken as a marker for gauging endothelial dys­function (ED).

   Statistical Analysis Top

Analysis was performed using SPSS version 10.0 statistical package for windows (SPSS, Chicago, IL, USA). Continuous variables were expressed as mean ± standard deviation (Gaussian distribution) or range and qualitative data were expressed as percentages. Unpaired t-test for independent samples was used in compa­ring continuous data between the two groups. Stepwise multivariate regression analysis was used to study the association between endo­thelial dysfunction as a dependant variable and various clinical and biochemical parameters as the independent variables.

   Results Top

The study group comprised of 60 essential hypertensive subjects, 36 males and 24 females, categorized into Stage-1 or Stage-2 hyperten­sion. While males were equally distributed in both the categories, females were more skewed toward the higher stage of hypertension [Table 1]. Most cases were in the 50-60-year age group (n = 21), while they were more or less equally distributed in the other age groups. Headaches were the most common clinical feature, present in 46% of the cases in Stage-1 hypertension and 59% of the cases in Stage-2 hypertension. Other clinical features in Stage-1 and Stage-2 hypertension, respectively, were: dyspnea on exertion (30% and 35%), blurring of vision (33% and 50%), dizziness (23% and 29%) and palpitations (19% and 29%). Fourteen patients in the study were overweight while eight were obese. There was greater prevalence of dyslipidemia with increasing BMI. Systolic, diastolic and mean arterial pressures differed significantly (P < 0.05) between the normal and the overweight subjects. ECG showed left atrial enlargement (LAE) as the most common iso­lated abnormality detected in 17% (n = 10) of the patients. It was followed in order by left ventricular hypertrophy (LVH) in 10% (n = 6), ST-T wave changes suggestive of ischemia in 8% (n = 5) and combined LAE with LVH in 5% (n = 3) of the subjects. Fundus examination revealed hypertensive retinopathy in 18 pa­tients, of whom six had Stage-1 and 12 had Stage-2 hypertension [Table 1]. There were 20 dyslipidemics (79.6%) in Stage-1 hypertension and 25 (83.3%) in Stage-2 hypertension. Urinary microalbuminuria (albumin-creatinine ratio; ACR) was unevenly distributed through-out the study subjects irrespective of the stage of hypertension. The mean ACR values in Stage­1 hypertension were 17.15 ± 21.55 mg/g as compared with 20.76 ± 28.78 mg/g in Stage-2 hypertension, the difference between the two means not being significant (P > 0.05). The Hs­CRP levels were consistently found to be ele­vated in both the stages of hypertension. The mean value of endothelial dysfunction (quan­tified as stated above) in Stage-1 hypertension was 7.45 ± 1.52% as compared with 10.21 ± 2.46% in Stage-2 hypertension. Applying the t-test for independent samples, the difference between the two was highly significant (P < 0.001) [Table 2]. A significant association of endothelial dysfunction was noted with the stage of hypertension (P < 0.001), triglyceride levels (P < 0.05), microalbuminuria (P < 0.01), CRP (P < 0.05), LDL cholesterol (P < 0.01) and age (P < 0.05) [Table 3]. On multivariate regression analysis, the stage of hypertension (P < 0.001), C-reactive protein level (P < 0.05), triglyceride level (P < 0.01), presence of micro­albuminuria (P < 0.01), LDL-cholesterol level (P < 0.01) and age (P < 0.01) were found to be significant predictors of endothelial dysfunc­tion [Table 4]. The cumulative predictive accu­racy of the regression equation was 86.9%.

   Discussion Top

Ours is a cross-sectional prospective obser­vational study on newly diagnosed patients of essential hypertension carried out over a span of 18 months in a tertiary care setting. This study recruited 34 males and 26 females, of whom 24 subjects were in Stage-1 and 36 subjects were in Stage-2 of hypertension. The gender distribution in the two stages was dif­ferent. While males were equally distributed in both the categories, females were more skewed toward the higher stage of hypertension. This could be due to the recruitment of a significant number of post-menopausal elderly women in the study group as the prevalence of hyperten­sion in females is closely related to age, with a substantial increase occurring after 50 years. [5] This increase is presumably related to hormo­nal changes of menopause, although the me­chanism is unclear. Another important charac­teristic of the study population was the inclu­sion of a good number of young hypertensive males as compared with females, the ratio being 9:1 in the 20-30 years age group. This might not just be an incidental finding but may actually represent a rising trend of hyperten­sion in the young population, [6],[7],[8] with the males being affected more than females [9],[10],[11] due to their greater involvement in stressful activities in life. Headache followed by blurring of vision and dyspnea on exertion were the most fre­quent clinical features among our study sub­jects. These symptoms underscore the impor­tance of the chronic effects of hypertension on the heart, eyes and the brain. In our study, diastolic blood pressure and mean arterial pre­ssures were found to differ significantly bet­ween normal-weight and over-weight indivi­duals. These results reinforce the strong rela­tion between BMI and hypertension, which, in part, is due to impaired microvascular function in obesity [12],[13] and associated insulin resistance in these subjects.

Highly Sensitive C-Reactive Protein

Hs-CRP levels were found to be elevated in both the stages of hypertension in our study. This is consistent with the recent view that hy­pertension is in part an inflammatory disorder. [14] Hs-CRP levels were found to predict future hypertension in a large study of initially nor­motensive women, even in subjects with low baseline blood pressure levels. [15] In another study, [16] there was a greater prevalence of ele­vated Hs-CRP in patients with systolic or dias­tolic blood pressure in the pre-hypertensive/ hypertensive range than people with normal blood pressure. Also, Hs-CRP was found to predict endothelial dysfunction in the multi­variate regression model illustrated above [Table 4], although the association was found to be weak. This provides support to the hyp­thesis that inflammatory cytokines like Hs­CRP, by disturbing endothelial function, may result in chronic impaired vasodilatation and hypertension. Similar results were also ob­served by Fransesco Perticone et al [17] in their study. Microalbuminuria has been associated with hypertension in a number of studies, although the exact cause or effect relationship is unclear. In a number of follow-up studies, urinary albumin excretion in previously nor­motensive patients has been associated with an increased risk of hypertension and blood pre­ssure progression. [18] While these findings are in favor of a causative association, an alternative hypothesis deserves mention; i.e., elevated uri­nary albumin excretion may reflect prior expo­sure of the glomeruli and kidneys to elevated blood pressure. In our study, urinary micro­albuminuria (albumin-creatinine ratio, ACR) was unevenly distributed throughout the study subjects irrespective of the stage of hyperten­sion. Although the mean ACR values were higher in Stage-2 hypertension as compared with Stage-1 hypertension, the difference was not statistically significant. However, micro­albuminuria was significantly associated with endothelial dysfunction and was an important predictor of endothelial dysfunction in the lo­gistic regression model. These observations go more in favor of the hypothesis that micro­albuminuria reflects generalized endothelial dysfunction leading to systemic hypertension rather than just being a manifestation of high blood pressure.

Endothelial dysfunction was extensively ana­lyzed in our study with respect to its asso­ciation with hypertension stage, microalbumi­nuria, inflammation (Hs-CRP) and lipid pro­file. Among them all, the stage of hypertension was found to be the strongest predictor, with a predictive power of 55.6% in multivariate re­gression analysis. This was further strengthened by the presence of a strong correlation between endothelial dysfunction and hypertension stage using Pearson's correlation, with P <0.05. Our observations were supported by a similar study [19] in which endothelial dysfunction was signifi­cantly correlated with mean blood pressure (P < 0.0001) and age (P < 0.0002) in a multivariate regression model. While endothelial dysfunc­tion is known to occur in essential hyperten­sion, the cause and effect relationship is still not clearly established. Indeed, experimental studies suggest that most of the alterations in endothelial function in hypertension are a con­sequence rather than the cause of high blood pressure. [14] The other important predictors of endothelial dysfunction in decreasing order of significance were micro-albuminuria, age, S. triglycerides, >LDL and Hs-CRP. While age, microalbuminuria and Hs-CRP have already been discussed above, the role of lipids in end­othelial dysfunction deserves a note, particu­larly in relation to the natural history of hyper­tension and atherosclerosis. The fact that HMGCoA reductase inhibitors (statins) reduce cholesterol levels and improve endothelial dys­function has been established in a number of studies, lending support to our findings. [20] Be­sides, another important approach of lowering cholesterol by the inhibition of systemic Acyl­COA: cholesterol acyl transferase improved the vascular function and circulating TNF-α levels. [21]

Thus, the factors found directly or indirectly to be responsible for endothelial dysfunction were hypertension, inflammation, hyperlipide­mia, age, obesity and oxidative stress, all inter­ related by diverse mechanisms.

We conclude from the study that there is a strong association between BMI, hypertension and abnormal lipids. Hs-CRP levels are elevated in essential hypertension, reinforcing the view that hypertension is in part an inflammatory disorder. Endothelial dysfunction is an important component of essential hypertension, the severity being determined by stage of hyper­tension, microalbuminuria, LDL-cholesterol, triglycerides, age and Hs-CRP levels, indepen­dently.

   References Top

1.Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in relaxation of arterial smooth muscles by acetylcholine. Nature 1980; 290:373-6.  Back to cited text no. 1
2.Faxon DP, Fuster V, Libby P, et al. Athero­sclerotic vascular disease conference: Writing group III: Pathophysiology. AHA Conference Proceedings Circulation 2004;109(21):2617-25.  Back to cited text no. 2
3.Vanhoutte PM. Endothelial dysfunction in hypertension. J Hypertens Suppl 1996;14(5): S83-93.  Back to cited text no. 3
4.Luscher TF. The Endothelium in Hypertension: bystander, target or mediator? J Hypertens Suppl 1994;12(10):S105-16.  Back to cited text no. 4
5.Izumi Y, Matsumoto K, Ozawa Y, et al. Effect of age at menopause on blood pressure in post­menopausal women. Am J Hypertens 2007;20 (10):1045-50.  Back to cited text no. 5
6.WHO: World Health Statistics Annual. 1984.  Back to cited text no. 6
7.Gupta R, Goyle A, Kashya P, et al. Prevalence of atherosclerosis risk factors in adolescent school children. Indian Heart J 1998;50:511-5.  Back to cited text no. 7
8.Kusuma Y, Das P. Hypertension in Orissa, India: a cross-sectional study among some tribal, rural and urban populations. Public Health 2008;122(10):1120-3.  Back to cited text no. 8
9.Ishikawa S, Nakamura Y, Kario K, et al. Two decades of prevalence of hypertension and isolated systolic hypertension in Japanese popu­lation. Am J Hyperten 2004;17(5):S199-200.  Back to cited text no. 9
10.Yekeen LA, Sansui RA, Ketiku AO. Preva­lence of obesity and high level of cholesterol in hypertension. Afr J Biomed Res 2003;6(3): 129-32.  Back to cited text no. 10
11.Safdar S, Omair A, Faisal U, Hasan H. Prevalence of Hypertension in a low income settlement of Karachi, Pakistan. J Pak Med Assoc 2004;54(10):506-9.  Back to cited text no. 11
12.de Jongh RT, Serne EH, IJzerman RG, de Vries G, Stehouwer CD. Impaired microvas­cular function in Obesity. Implications for obesity-associated microangiopathy, hyperten­sion, and insulin resistance Circulation 2004; 109:2529-35.  Back to cited text no. 12
13.de Jongh RT, Serne EH, Eringa EC, Richard G IJzerman RG, Stehouwer CD. Does micro­vascular dysfunction link obesity with insulin resistance and hypertension? Exp Rev Endo­crinol Metab 2006;1(2):181-7.  Back to cited text no. 13
14.Li JJ, Fang CH, Hui RT. Is hypertension an inflammatory disease? Med Hypotheses 2005; 64(2):236-40.  Back to cited text no. 14
15.Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. Metabolic syndrome - - Abstract. JAMA 2003;290:2945-51.  Back to cited text no. 15
16.King DE, Egan BM, Mainous AG 3rd, Geesey ME. Elevation of C-reactive protein in people with prehypertension. J Clin Hypertens 2004;6 (10):562-8.  Back to cited text no. 16
17.Perticone F, Maio R, Tripepi G, Zoccali C. Endothelial dysfunction and mild renal insu­fficiency in essential hypertension. Circulation 2004;110:821-5.  Back to cited text no. 17
18.Pedrinelli R, Giampietro O, Carmassi F, et al. Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet 1994;344:14-8.  Back to cited text no. 18
19.Panza JA, Quyyumi AA, Brush JE, Epstein SE. Abnormal endothelium dependant vascular relaxation in patients with essential hyperten­sion. N Engl J Med 1990;323:22-7.  Back to cited text no. 19
20.Mehta JL, Li DY, Chen HJ, Joseph J, Romeo F. Inhibition of LOX-1 by statins may relate to upregulation of eNOS. Biochem Biophys Res Commun 2001;289:857-61.  Back to cited text no. 20
21.Kharbanda RK, Wallace S, Walton B, Donald A, Cross JM, Deanfield J. Systemic Acyl-CoA: Cholesterol acyltransferase inhibition reduces inflammation and improves vascular function in hypercholesterolemia. Circulation 2005;111: 804-7.  Back to cited text no. 21

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Sandeep Sachdeva
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