Inflammation, endothelial dysfunction, and the risk of high blood pressure: epidemiologic and biological evidence

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1 (2003) 17, & 2003 Nature Publishing Group All rights reserved /03 $ REVIEW ARTICLE Inflammation, endothelial dysfunction, and the risk of high blood pressure: epidemiologic and biological evidence Department of Preventive Medicine & Biometrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA In spite of its high impact on cardiovascular and renal disease, knowledge on risk factors for the development of high blood pressure (HBP) is limited. Mild chronic inflammation may play a significant role in the incidence of HBP. A persistent low-grade inflammation state could be associated with high but within the normal range cytokine plasma concentration. By impairing the capacity of the endothelium to generate vasodilating factors, particularly nitric oxide (NO), elevated cytokines may lead to the development of endothelial dysfunction, chronic impaired vasodilation, and HBP. These alterations in the L-arginine : NO pathway may play a major role in the development of HBP in young subjects, with inflammation-related alterations in the production of cyclo-oxygenase-derived vasoconstrictors becoming more prominent with advanced age. Cross-sectional independent associations between HBP and plasma levels of C-reactive protein, interleukin-6, and tissue necrosis factor alpha have been reported, but no prospective evidence of these associations is currently available. (2003) 17, doi: /sj.jhh Keywords: inflammation; cytokines; C-reactive protein; interleukin-6; tumour necrosis factor alpha Introduction High blood pressure (HBP) is one of the most important risk factors for cardiovascular-renal disease, because it has a high prevalence in almost all populations; it has a large impact on disease incidence, and can be controlled by early detection, and treatment. Between 24.0 and 31.1% of the adult population in the United States has HBP, 1 a condition that only in 1998 accounted for $108.0 billions in health-care spending. 2 Despite its high health impact, primary prevention of HBP is partly hampered because of a limited knowledge on risk factors. In this article, we review the epidemiological and biological evidence of a possible link between chronic mild inflammation (CMI) and HBP. Epidemiologic evidence Correspondence:, Department of Preventive Medicine & Biometrics, Uniformed Services University of the Health Sciences, Room A1039, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. lbautista@usuhs.mil This article is a United States Government work paper as defined by the US copyright act. During the last few years, several cohort studies have shown that systemic inflammation is associated with an increased risk of acute cardiovascular events. 3 5 CMI has also been associated with impaired endothelium-dependent dilatation (IEDD) of the arterial circulation, 6,7 and there is considerable cross-sectional evidence of a link between IEDD and essential hypertension. 8,9 In fact, studies in offspring and relative of hypertensive patients suggest that IEDD may precede the development of HBP. 10,11 Systemic inflammation is a state that involves many pathophysiological processes and several inflammatory markers have been used to measure CMI. Epidemiologic data support the existence of an association between different inflammatory markers and HBP. A positive association between serum level of C-reactive protein (CRP) and blood pressure has been reported in several studies (Table 1). This association is likely confounded by other risk factors, such as age, sex, and body mass index: Out of the six studies with no adjustment for potential confounders, 15 19,13 five reported a statistically significant association between CRP and blood pressure (Table 1). Also, in a group of seven studies with adjustment for potential confounders, four 24,22 24 reported a significant association between CRP and HBP. Most of these studies were not designed to test the CRP HBP association. We tested this hypothesis in a random sample of free living subjects 23 and

2 Inflammation and high blood pressure 224 Table 1 Published estimates of the association between CRP and HBP Author Year Sample size Outcome variable Significant association with CRP (Po0.05) Adjusted for Mendall et al men SBP a /DBP a No/no Age, BMI b, social class Tracy et al HBP c No None Hack et al women SBP/DBP No/no Age, BMI Koenig et al men HBP c Yes None Yudkin et al SBP/DBP Yes Age, gender Rohde et al men HBP d Yes Age Doggen et al men SBP/DBP Yes None Margaglione et al HBP e Yes None Ford and Giles men SBP Yes/no None Festa et al SBP/DBP Yes/yes Age, sex, ethnicity, smoking, BMI, insulin sensitivity Onat et al SBP/DBP No/no Age, waist perimeter, fibrinogen, total cholesterol, physical activity Yamada et al SBP/DBP Yes/no Age, BMI, fibrinogen, smoking, waist-to-hip ratio, lipid profile, blood glucose, insulin Bautista et al SBP/DBP/HBP e Yes/yes/yes Age, sex, use of antihypertensive drugs, BMI, physical activity, blood glucose, family history of HBP, alcohol use a SBP: systolic blood pressure; DBP: diastolic blood pressure. b Body mass index. c HBP, high blood pressure X160/95 mmhg. d Previous history of high blood pressure. e HBP X140/90 mmhg. found a progressive increase in blood pressure associated to higher levels of high-sensitivity CRP. In addition, subjects in the upper quartile of CRP were 1.56 times more likely to have HBP than those in the lower quartile (P ¼ 0.005), even after adjustment for other risk factors. Similarly, in a group of 89 hypertensive elderly patients without diabetes, coronary heart disease, or inflammatory disease, Bellelli et al 25 found that the proportion of nondippers (night-to-day blood pressure ratio of 100% or higher) was 2.0 and 3.1 times higher in those from the second and third as compared to those in the lowest third of CRP serum levels. As a result of the cross-sectional nature of these studies, whether the effects of CRP are the cause or the consequence of HBP has not been established. CRP production by hepatocytes is regulated by cytokines, mostly interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-a). 26 Therefore, CRP alone is unlikely to reflect all the relevant aspects of CMI, and its association with HBP may not be independent of other inflammation markers. IL-6 and TNF-a levels have also been associated to HBP in several epidemiologic studies. 16,27 34 IL-6 is a 26-kDa cytokine, produced by different cells, including monocytes, lymphocytes, and endothelial cells. IL-6 stimulates the synthesis of many acute-phase reaction proteins, including CRP, serum amyloid A, and fibrinogen. 35 In addition, IL-6 seems to counter regulate levels of TNF-a and interleukin- 1b, 36 so that higher IL-6 levels may reflect damage from other cytokines. Finally, IL-6 prolongs the IEDD associated to the administration of IL-1b and TNF-a in human volunteers. 37 Several studies show contradictory results about the association between IL-6 and HBP (Table 2). 3,16,27,28,30 32,34 Studies with adjustment for other HBP risk factors have shown a positive association, with only two exceptions. 27,34 In the only published study designed to test this hypothesis, Chae et al 32 adjusted for all main cardiovascular risk factors and found a statistically significant association between IL-6 levels and blood pressure level. Unfortunately, because of the cross-sectional nature of the data, they 32 could not sort out whether IL-6 levels were the cause or the consequence of raised blood pressure. TNF-a is a protein synthesized mainly by monocytes and macrophages and plays an essential role in the initial activation of the immune system and in lipid and glucose metabolism. Secretion of TNF-a is significantly increased in peripheral blood monocytes from patients with HBP after stimulation with lipopolysaccharide. 38 Preactivated monocytes in hypertensive patients could be the result or a causal factor triggering HBP. In fact, TNF-a induces insulin resistance, 39 and is elevated in obese subjects, 40 two conditions known to be associated with essential hypertension. Linkage and association analyses suggest that the TNF-a gene locus is associated to HBP in obese subjects. 41 In addition, the TNF-a-308 G/A promoter polymorphism, a genetic variation related to tissue TNF-a expression, has also been associated with

3 Inflammation and high blood pressure Table 2 Published estimates of the association between interleukin-6 (IL-6) and HBP 225 Author Year Sample size Outcome variable Significant association with IL-6 (Po0.05) Adjusted for Mendall et al men SBP a No Age, BMI b, smoking, occupation, alcohol Rifai et al men HBP c No None Yudkin et al SBP/DBP a Yes/yes Age, gender Ridker et al with AMI d SBP/DBP Yes/yes None 202 w/o AMI Volpato et al women HBP No None Chae et al Men SBP/DBP Yes/yes Age, AMI d, BMI b, parent AMI d, diabetes, use of alcohol/aspirin, smoking, cholesterol, physical activity Fernandez et al SBP/DBP Yes/yes e BMI Furumoto et al HBP 52 controls IL-6 No Age, sex a SBP: systolic blood pressure; DBP: diastolic blood pressure. b Body mass index. c High blood pressure: X160/95 mmhg. d Acute myocardial infarction. e Only among women. Table 3 Published estimates of the association between tumour necrosis factor (TNF-a) and HBP Author Year Sample size Outcome variable Association with TNF-a-HBP (Po0.05) Adjusted for Mendall et al men SBP a No Age, BMI, occupation, social class, smoking, alcohol use Yudkin et al SBP/DBP a Yes/yes Age, gender Ito et al women SBP/DBP Yes/no Age, menopause Furumoto et al HBP b TNF-a Yes Age, sex 52 controls Sheu et al HBP c TNF-a No None 85 controls Fernandez et al 45d controls SBP/DBP Yes/yes Age, BMI 66 DM2 e 46 DMI e a SBP: systolic blood pressure; DBP: diastolic blood pressure. b HBP, high blood pressure X140/90 mmhg. c HBP X160/95 mmhg. d Measured stnfrl/stnfr2, an indicator of TNF-a activity. e DMI=diabetes mellitus type I; DMII=diabetes mellitus type II. insulin resistance and HBP among obese people. 42 Subjects homozygous for the A allele have significantly higher systolic blood pressure than those homozygous for the G allele. 42 By stimulating the expression of the angiotensinogen gene in the liver, 43 TNF-a may also lead to high levels of angiotensin II, a potent vasoconstrictor associated to a chronic state of increased vascular resistance and HBP. 44 Moreover, TNF-a plays a fundamental role in inducing IEDD, 37 a condition that seems to play a role in the pathogenesis of essential hypertension and that is also present in offspring of hypertensive patients. 11,10 Some studies in human subjects (Table 3) have shown a positive association between TNF-a level and HBP, 16,33,34 while others have not. 27,29 However, these studies have failed to control for other risk factors for HBP. On the other hand, Fernández-Real et al 45 have shown that the ratio of soluble TNF-a receptor 1 and soluble TNF-a receptor 2 (stnfr1/ stnfr2), a correlate of the degree of activation of the TNF-a system, is positively and significantly associated with systolic and diastolic blood pressure, and that lowering blood pressure decreases the stnfr1/stnfr2 ratio. Prolonged periods of low-grade systemic inflammation may explain the higher risk of HBP observed among subjects with obesity. It is known that obesity is independently related to higher levels of CRP, TNF-a, and IL-6 in children 46 and adults. 12,14,16,27 Also, experimental studies show that TNF-a can be produced by adipocytes under physiological conditions. 40 Obesity may lead to overproduction of TNF-a, which in turn induces the synthesis of IL-6, the main regulator of CRP production by the liver. Therefore, obesity may be considered as a model of CMI, which may be the cause of the IEDD commonly observed in these patients. 47 In fact, studies in obese

4 226 people have led to believe that endothelial dysfunction may be the common antecedent factor in the clustering of dyslipidaemia, impaired fibrinolysis, and hypertension, which are attributed to insulin resistance. 16 Taken together, these findings suggest that CMI may lead to long-term impairment of the homeostatic vasodilating mechanisms aimed to regulate arterial blood pressure, becoming an independent risk factor for the development of HBP. Unfortunately, most of the available reports (Tables 1 3) do not provide an estimate of the magnitude of the association between CMI and HBP. Moreover, there is some uncertainty about the influence of environmental and genetic factors on the variability of CRP, IL-6, and TNF-a levels in healthy subjects. 42,48,49 Biological mechanisms Inflammation and high blood pressure A chronic imbalance between endothelium-derived relaxing and contracting factors could lead to an abnormal vasodilating response and to HBP. Under physiological conditions, the vascular endothelium responds to mechanical and biochemical agonists by producing antiplatelet, anticlotting, fibrynolitic, vasodilating, and vasoconstricting factors. 50 The best-known endothelium-derived relaxing factors are nitric oxide (NO), 51 endothelium-derived hyperpolarizing factor (EDRF), 52 and the prostanoid prostaglandin I 2 (prostacyclin, PGI 2 ). 53 NO is produced during the metabolism of L-arginine by NO synthase. 50,54,55 NO induces vasodilation, inhibits adhesion of platelets and white blood cells to the endothelium, prevents platelet aggregation, and inhibits growth of smooth-muscle cells. 56 Together with NO, EDHF contributes to relaxation of large conducting arteries, and appears to be a major determinant of vascular resistance in small arteries. 57 PGI 2 is a cyclo-oxygenase (COX)-derived prostanoid. It is a potent vasodilator 53 and inhibits platelet aggregation 58 and vascular smooth muscle cell growth. 59 Activation of the vascular endothelium by ageing and under pathological conditions leads to the production of contracting factors that counteract the relaxing activity of vasodilators, including endothelin (ET), the prostanoid thromboxane A 2 (TXA 2 ), and superoxide anion ( O 2 ). 60 Endothelial cells produce exclusively ET-1, the predominant form of ET, which is the most potent vasoconstrictor yet discovered. 55 At high doses, ET1 activates ET A receptors in endothelial cells promoting vasoconstriction, cell growth, platelet adhesion and aggregation, and thrombosis. 61,62 However, at low doses ET1 stimulates ET B receptors in the endothelial cell and leads to increased release of NO and PGI 2 and to vasodilation. 62,63 TXA 2 is produced mainly in platelets and is a potent platelet activator, vasoconstrictor, and smooth muscle cell mitogen. 64 O 2 is an important reactive oxygen intermediate produced mostly by phagocytic blood-borne cell, and also by endothelial cells. 65 O 2 and other oxygen free radicals, in and around vascular endothelial cells, may increase vascular resistance by inactivating NO. 66 In addition, free radicals catalyse the transformation of arachidonic acid to F 2 -isoprostanes, a family of PGF 2a -isomers. 67 One of these isomers, 8-epi PGF 2a, is a potent vasoconstrictor and mitogen 67 and has been proposed as a marker of oxidant stress in vivo. 68 A possible effect of CMI on the development of HBP may be mediated through endothelial dysfunction and alteration in the synthesis and degradation of vasodilating and vasoconstricting factors (Figure 1). 6,7,69,70 There is considerable evidence on the effect of inflammation on endothelial dysfunction. CRP levels have been associated to IEDD in patients with coronary heart disease. 6 Also, Hingorani et al 7 have shown that a mild increase in inflammatory markers, particularly IL-6, results in significant endothelial dysfunction in resistant and conduit vessels, by reducing the capacity of the endothelium to generate vasodilator factors, particularly NO. Moreover, exposure to bacterial endotoxin and inflammatory cytokines induces IEDD that last for several days, an effect that could be prevented by treatment with glucocorticoids 70 and aspirin. 37 This finding suggests that the production of locally generated inflammatory mediators contributes to endothelial dysfunction and that this abnormality is not confined to the endothelial L-arginine : NO pathway but extends to the production of COX-derived prostanoids. 70,37 In addition, COX inhibition restores NO-mediated vasodilation in patients with essential hypertension, implying that COX-dependent prostanoids can impair NO production. 71 Evidence from animal and clinical studies show that the role of COX-derived vasoconstrictors and the NO pathway on endothelial function may depend on age. Several findings support that in contrast to the role of the NO pathway, COX-derived vasoconstrictors may be more important in the incidence of HBP in older than in younger patients. First, COX-derived vasoconstrictors do not appear to be responsible for IEDD in normotensive offspring of hypertensive parents, 72 nor do they seem to increase blood pressure in animal models. 73 Second, ridogrel, a combined TXA 2 synthase inhibitor and TXA 2 receptor blocker does not lower blood pressure in hypertensive patients. 74 Third, similar to blood pressure, the production of COX-derived vasoconstrictors increases with age. 75 Therefore, it is possible that the development of HBP early in life could be mostly related to abnormalities in the L-arginine : NO pathways, and that a rising production of COX-derived vasoconstrictor prostanoids plays a greater role in the age-related increase in the incidence of HBP. Although it is currently unknown how inflammation causes IEDD, several mechanisms have been

5 Inflammation and high blood pressure 227 Figure 1 Biological mechanisms leading from chronic mild inflammation to essential hypertension. proposed 69 (Figure 1). Inflammatory cytokines may decrease the expression of the constitutive endothelial NO synthase (cnos), reducing NO availability, and predisposing to vasospasm. 7 In fact, Yoshizumi et al 76 have shown that TNF-a decreases cnos mrna level by shortening its half-life. Similarly, Verma et al 77 have recently shown that CRP, at concentrations known to predict adverse cardiovascular events, significantly reduces cnos mrna stability, downregulates the expression of cnos, and markedly attenuates NO release and bioactivity in endothelial cells, independently of ET receptor blockade or IL-6 inhibition. This could reduce the availability of NO and lead to IEDD. On the other hand, elevated endothelial production of O 2 and other oxygen-free radicals during inflammation could increase the NO degradation rate and lower its availability. 66 Actually, higher levels of oxidized LDL have been associated to endothelial-dependent vascular dysfunction in patients with coronary heart disease 6 and in patients with cardiovascular risk factors. 78 Moreover, Pleiner et al 79 have shown that IEDD induced by the administration of lipopolysaccharide in normal subjects can be restored by the local administration of high doses of Vitamin C, a free-radical scavenger. This suggests that oxidative stress may play an important role in inflammation-induced IEDD. IEDD could also be mediated by COX-derived prostanoids, which are increased during inflammation (Figure 1). In hypertensive subjects, there is an alteration of the L-arginine : NO pathway, which coexists with an increased production of COXdependent endothelial-derived contracting factors. 72 The role of inflammatory prostanoids is also supported by the finding of an independent association between activation of circulating T-lymphocytes and NO-independent blood flow changes in patients with coronary heart disease. 6 Although I have emphasized that MCI induces IEDD and precedes the development of HBP, it is possible that MCI and IEDD may both precede and follow HBP. In fact, IEDD has been considered as one of the mechanisms by which HBP contributes to the development of atherosclerosis 80 and has been associated to the risk of cardiovascular events in hypertensive patients. 81 Also, endothelial cells exposed to increased shear stress, as expected in HBP, increase their production of IL-1b, IL-6, IL-8, and TNF-a. 82,83 Finally, HBP may cause intramural hypoxia, which could increase the synthesis of free radicals and lead to IEDD. 84 However, HBP is an unlikely major determinant of MCI, because CRP level has been only weakly associated to prevalent cardiovascular disease and subclinical measures of atherosclerosis. 49,85 Results from studies in subjects taking antihypertensive drugs suggest that IEDD and MCI occur before the development of HBP. Among these subjects, blood pressure lowering does not seem to

6 228 modify the IEDD that characterizes HBP, 86,87,10 although some drugs may improve IEDD as a specific effect that goes beyond blood pressure reduction. 88,80 Therefore, IEDD may act as a causative mechanism or may become irreversible once HBP is established. Also, in an analysis of data from a previous study 23 we found that subjects with drugcontrolled HBP, without previous cardiovascular disease, had levels of CRP similar to those in noncontrolled subjects (P ¼ 0.58), after adjustment for age, sex, body mass index, smoking, and physical activity. Thus, MCI does not seem to be the consequence of elevated blood pressure, since blood pressure lowering does not lower CRP level. Unfortunately, no additional reports on the effect of antihypertensive therapy on inflammatory markers seem to be currently available. The reduced IEDD of small and large vessel observed in normotensive offspring and relative of HBP patients 10,11,72 suggests that a defect on the NO pathway precedes the onset of HBP. Unfortunately, it is not known whether inflammatory markers are also elevated in normotensive relatives of hypertensive patients. However, the level of systemic inflammatory markers such as CRP, white blood cell count, and albumin levels are at least partially (35 40%) determined by genetic factors. 49 A polymorphism of the gene that encodes IL-6 has been associated to CRP levels, 89 and a common polymorphism in the promoter region of the TNF-a gene has been associated to increased TNF-a and systolic blood pressure. 42 Since heritability seems to be an important independent determinant of the level of inflammatory markers in normal subjects, it is reasonable to argue that MCI could precede the development of HBP, even if the vascular wall also contributes to the inflammation process as a response to the blood pressure elevation. Conclusion Inflammation and high blood pressure Epidemiologic and biological evidence suggest that CMI may be an independent risk factor for the development of HBP. Elevated plasma levels of CRP, TNF-a and IL-6, within the normal range, have been associated to HBP. 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