Inflammation in hypertension: primary evidence

Cardiovascular diseases are the most common cause of hospitalization and a major contributor to mortality in the western world. Since hypertension is a major risk factor for cardiovascular disease, kidney failure and stroke, control of hypertension is an important goal of cardiovascular therapies. Hypertension is a multi-factorial trait that results from the net effect of environmental and genetic factors. Factors that may contribute to hypertension include excess dietary salt or alcohol intake, stress, age, genetics and family history, obesity, physical inactivity, and a diet rich in saturated fats. Recently however, a growing body of evidence indicates that vascular inflammation may be involved in both the initiation and development of hypertension, and these data have prompted us to reconsider the pathogenic mechanisms of hypertension.1–8 Current evidence supports a central role for inflammation in all phases of atherosclerosis.9–13 A remarkably consistent series of studies have confirmed that early- and advanced- atherosclerotic lesions are significantly paralleled by signs of both local and systemic inflammation.9 Most cardiovascular risk factors have been suggested to promote a pro-inflammatory state. Among the established risk factors for coronary artery disease, arterial hypertension has been suggested to exert pro-inflammatory actions through the increased expression of several mediators, including leukocyte adhesion molecules, chemokines, specific growth factors, heat shock proteins, endothelin-1, and angiotensin.14–22 Further support for the idea that hypertension may itself be pro-inflammatory arises from studies where treatment-induced blood pressure reduction was paralleled by a decrease in circulating inflammatory markers. Here we review the primary evidence with respect to the relationship between inflammation and hypertension for the purpose of stimulating basic as well as clinical research interest on this topic. INFLAMMATION IN HYPERTENSION Recently, vascular biologists have become increasingly interested in the role of arterial wall factors in the atherogenic process. The recognition that atherosclerosis is a special case in the general category of inflammation provides a tool to unify and simplify the understanding of complex processes. The possibility that hypertension at least in part is a product of arterial pathology similar to that of atheroslcerosis is intriguing. On the other hand, it may not be possible to separate inflammatory atherogenesis and hypertension from the injurious agents that initiate arterial inflammation. First, immunopathogenic mechanisms may be involved in the pathogenesis of hypertensive disease.14 Alterations in both humoral and cellular immunity have been described both in patients with hypertension and in animal models. Bataillard et al15 demonstrated that the in vivo administration of silica, a selective toxin to monocytes, reduced the degree of hypertension in Lyon hypertensive rats and inhibited the formation of hypertrophy of the left ventricle. Recent reports indicate that in spontaneously hypertensive rats the number of activated monocytes is significantly elevated.16 McCarron et al17 showed a significant increase of monocyte adhesion to endothelial cells after stimulation with lipopolysaccharide or pro-inflammatory cytokines in spontaneously hypertensive rats compared to normotensive Wistar-Kyoto rats. More recently, Dorffel et al5 have demonstrated the preactivation of peripheral blood monocytes in patients with essential hypertension.5 In their opinion, angiotensin II-preactivated circulating monocytes in hypertensive patients may lead to subendothelial infiltration and subsequently enhance the risk of atherosclerotic complications. Prevention of angiotensin II-mediated monocyte activation by Losartan may be a novel therapeutic approach to prevention of vascular alterations in hypertension. In addition, several studies have shown that oxidative stress and inflammation are linked to the process of hypertension, and that the immune system is also involved in this age-dependent process.23 More specifically, oxygen stress related to immune system dysfunction seems to play a key role in senescence, in agreement with the oxidation/inflammation theory of aging. From a practical point of view therefore, immune functional changes in hypertension and aging appear to be similar. A more recent animal study showed that renal oxidative stress and infiltrating immune cells may play a pathogenetic role in prenatally programmed hypertension.24 Interestingly, a large population study demonstrated that common maternal polymorphisms of genes related to immune tolerance and inflammation were associated with blood pressure regulation, urinary protein excretion and edema during pregnancy.25 This study therefore supports the hypothesis that genetically determined factors of maternal immune tolerance play a role in the pathogenesis of hypertensive disorders in pregnancy. The overall contribution of inflammation to vascular damage in patients with hypertension is still far from being clear, but research during the last decade has shed light on some aspects of this question. For example, in experimental animals, several forms of hypertension induce infiltration of monocytes/macrophages into the vessel wall and in target organs such as the kidney and the heart.14–17 Moreover, the organ protection afforded by inhibitors of either the formation or action of angiotensin II appears to be due to at least in part to reduced macrophage infiltration.18 The role of various inflammatory mechanisms, including mononuclear leukocyte infiltration, for the development of vascular damage in atherosclerosis has been increasingly acknowledged in recent years. These observations have also stimulated research on the role of vascular inflammation in hypertension. Second, the association between inflammation and hypertension parallels a similar association between low-grade inflammation and other components of the metabolic syndrome.1,2 Insulin resistance, hyperinsulinemia, or both have been implicated in the pathogenesis of hypertension. Insulin resistance recently has been linked with a pro-inflammatory state, for example, elevations of C-reactive protein (CRP), thereby leading to inclusion of a pro-inflammatory state as one of the syndrome's components.6–8 Some investigators have proposed that the inflammatory response within the arterial tree releases inflammatory cytokines that increase levels of CRP. In addition, excess adipose tissue results in further release of inflammatory cytokines that likely increase levels of CRP.8 Fatty accumulation in the liver may also stimulate hepatic cytokine production, which could further increase levels of CRP. Inflammation has also been associated with decreased endothelium-dependent relaxation, a process related to an alteration in the bioavailability of nitric oxide, and there is considerable evidence of a link between endothelial dysfunction and both essential and pregnancy-induced hypertension.26 The observed effect of CRP on hypertension may be mediated through endothelial dysfunction. Several studies have shown that increased levels of markers of inflammation such as CRP alter endothelial function. Sinisalo et al27 have shown that CRP levels are an independent determinant of endotheliumdependent vascular function among patients with coronary heart disease. This situation may also exist in patients with essential hypertension. Finally, very recent studies have focused on the relationship between inflammation and arterial stiffness in essential hypertension.28,29 In a human study, untreated hypertensive patients with low or moderate total cardiovascular risk had significantly increased blood CRP and white blood cell count and arterial stiffness, expressed as augmentation index and timing of the reflected waveform evaluated by pulse wave analysis.28 Mahmud et al29 reported that CRP was an independent predictor of pulse wave velocity and augmentation in untreated patients with hypertension. Measurement of arterial stiffness and inflammation may therefore represent an additional tool to assess cardiovascular risk in hypertensive patients. In addition, inflammatory factors play a significant role in the mechanisms that trigger and enhance remodeling of the vascular wall. Madej a et al30 reported that soluble intercellular adhesion molecule 1 (sICAM-1) and monocyte chemoattractant protein 1 (MCP-1) levels were significantly higher in patients with essential hypertension compared with normal control subjects. In conclusion, chronic inflammation is common in hypertension, is as an independent determinant of arterial blood pressure, and hypertensive patients manifest high circulating levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and CRP. C-REACTIVE PROTEIN IN HYPERTENSION The relevance of elevated levels of inflammatory markers to cardiovascular diseases is gaining increasing recognition.3 Of all the plasma markers of vascular inflammation, CRP has been the most intensively investigated in clinical studies.11 Levels of CRP have been found to predict future risk among patients with stable and unstable angina, in the chronic phase of myocardial infarction, and among patients undergoing revascularization procedures. Recently, a study has shown that plasma concentrations of CRP are elevated in pregnancy-induced hypertension.3 A cross-sectional study demonstrates for the first time a higher prevalence of hypertension linked to elevated levels of CRP.4 The unadjusted prevalence of hypertension was 58.7% in the highest quartile of CRP, but only 34.7% in the lowest quartile. This association was preserved even after adjustment for known risk factors for hypertension such as age, sex, body mass index, family history of hypertension, fasting glycemia, sedentary behavior and alcohol consumption. However, after adjustment for other determinants of blood pressure, elevated levels of CRP were associated with higher diastolic bloo pressure (P=0.002) but not with systolic blood pressure (P=0.67). The lack of statistical significance of the association between CRP and systolic blood pressure may be explained by the large variability in systolic blood pressure, which results in wide confidence intervals for the adjusted changes in systolic blood pressure when comparing CRP quartiles. Bautista et al8 found higher plasma CRP concentrations in patients with hypertension than in normotensive healthy controls, independent of the confounding influence of several CRP covariates. They have also shown a direct association of plasma CRP concentration with systolic blood pressure and pulse pressure in newly diagnosed, never-treated hypertensive patients. This relationship, despite being relatively weak, was independent of the potential confounding effect of traditional cardiovascular risk factors. Conversely, univariate and multivariate correlations between diastolic blood pressure measurements (both office and ambulatory) and plasma CRP concentrations were not significant. These results were obtained in never-treated, newly diagnosed patients with hypertension who were free of overt cardiovascular disease and had not received antihypertensive or hyperlipidemic treatment. More recently, Sesso et al7 reported a positive relationship between increased serum levels of CRP and the risk for development of incident hypertension in participants in the Women's Health Study. Their results support the hypothesis that inflammation may participate in mediation of the proatherosclerotic effects of essential hypertension actively for a median of 7.8 years, during which time approximately one fourth of the women acquired elevated blood pressure, and those with higher levels of CRP were more likely to develop hypertension. CRP levels in the upper ranges of the normal distribution are widely believed to reflect a state of low-grade chronic inflammation. Therefore, the association between higher CRP levels and new-onset hypertension led Sesso et al to suggest that hypertension may be an inflammatory disease. However, in contrast to previous data, Sonmez et al31 studied 30 nonobese young hypertensive men and 30 matched controls. They found that soluble CD40L (sCD40L) and CRP levels were not different between the two groups, and there were also no correlations between blood pressure and sCD40L or CRP, suggesting a lack of any inflammatory state in new onset hypertension.31 Interestingly, the Coronary Artery Risk Development in Young Adults (CARDIA) study was initiated in 1985–1986 to determine the factors that are associated with coronary risk development in young adults.32 CRP concentrations were measured in 3919 African American and white men and women using blood specimens from the 7 examinations. The data showed that CRP is associated with hypertension in young adults, but in contrast to the finding in older populations, the association is not longer present after adjusting for body mass index. The above studies suggest that CRP may be a more important index for new onset or young patients with hypertension. The above observations suggest that elevations of CRP may play a direct role in the cause of hypertension. CRP could enhance inflammation as a defense against injurious factors. CRP inhibits formation of nitric oxide by endothelial cells, which in turn could promote vasoconstriction, leukocyte adherence, platelet activation, oxidation, and thrombosis.11 Moreover, high levels of CRP may upregulate angiotensin receptors and enhance expression of plasminogen activator inhibitor-1 by endothelial cells.7 Both of these latter changes could raise blood pressure and promote atherogenesis. In conclusion, these findings suggest that chronic inflammation as reflected by higher levels of plasma CRP may be an independent risk factor for the development of hypertension, especially in new onset, untreated or young patients with hypertension. INFLAMMATION IN HYPERTENSIVE TARGET ORGAN DAMAGE In experimental animals, hypertensive target organ damage is almost invariably accompanied by monocyte/macrophage infiltration into the involved organs.6 This observation has been reported for all organs studied, including blood vessels, brain, heart, and kidney, and in a wide range of experimental models, including polygenic, monogenic, renovascular and mineralocorticoid hypertension.19–21 In the kidney, macrophage infiltration appears to be the most prominent in forms of hypertension with an activated renin-angiotensin-aldosterone system.19 Recently, Rodriguez-Iturbe and colleagues33 studied activation of peripheral blood leukocytes and cellular infiltration in the kidneys of Sprague-Dawley rat with coarctation of the abdominal aorta induced by banding above renal arteries. These investigators found that increased baromechanical stress is not required for accumulation of T cells and macrophages in the kidney in coarctation-induced hypertension and possibly in other hypertensive disorders. On the contrary, renal hypoperfusion and the resultant activation of the renin-angiotensin system may mediate this process by promoting local induction of chemoattractant and inflammatory cytokines. The observed tubulointerstitial inflammation in this model was associated with leukocyte activation in the systemic circulation. Moreover, therapeutic interventions, which provide organ protection, are usually accompanied by a marked reduction in macrophage infiltration. The pronounced infiltration in induced ('secondary') forms of hypertension and its response to antihypertensive treatment provide evidence that 'secondary’ activation and infiltration of macrophage does occur even if there is no primary immunological abnormality. Such a 'secondary’ immune response, once initiated, may also contribute to the maintenance of hypertension.6 However, macrophage infiltration has been surprisingly difficult to study in patients with hypertension. Analysis of macrophage infiltration in atherectomy specimens is confounded by the almost ubiquitous presence of atherosclerosis, and kidney biopsies may not be representative if the infiltration is as focal as it is in experimental hypertension.19–22 Moreover, the pathological diagnosis of hypertensive kidney disease is often doubted by pathologists, and the presence of a marked macrophage infiltration may even prompt the consideration of other, primary immunological kidney diseases. Finally, a true ‘control’ tissue without hypertension or atherosclerosis may be hard to obtain. Therefore, studies in human patients have focused on peripheral blood monocytes. These cells are activated in hypertensive patients compared to normotensive controls, exhibit increased adherence to endothelial cells in vitro and release increased amounts of cytokines, all of which suggest that hypertension is associated with an inflammatory process. IL-15 is one of the cytokines produced by neutrophils and monocyte/ macrophages, and its expression is found immunohistochemically in inflammatory cells adjacent to vulnerable atherosclerotic plaques. Recent data suggest that IL-15 might be associated with hypertensive organ damage.34 Kaibe M et al35 studied 399 patients with essential hypertension and divided them into three groups: patients with no organ damage (n=213), patients with mild organ damage (n=128), and patients with severe organ damage (n=58). They found that serum IL-15 concentrations in patients with severe organ damage was significantly higher than in those with no organ damage (P<0.01). By multiple linear logistic regression analysis, serum IL-15 concentration was an independent predictor of cardiovascular disease, suggesting that a systemic inflammatory response involving IL-15 might be involved in the development of cardiovascular disease in patients with essential hypertension. In conclusion, structural alterations in the microcirculation form a major link between hypertension and target organ damage. Other mechanisms such as oxidative stress, inflammation, or endothelial dysfunction appear to play a key role in the pathogenesis of target organ damage and therefore represent another important pathway for therapy. RESEARCH AND CLINICAL IMPLICATIONS The association between inflammation and hypertension has been clearly established, but what is lacking is an adequate causal explanation. The contribution of inflammatory processes to the etiology of hypertension is still unclear, but evidence has accumulated that inflammation is associated with hypertension, indicated that hypertension is at least related to a pro-inflammatory state. A better understanding of inflammatory mechanisms in hypertension may contribute to novel therapeutic strategies to decrease the morbidity and mortality attributable to hypertension and to alleviate hypertensive target organ damage. In addition, vascular inflammation, a possible bridge connecting hypertension with atherosclerosis, is already finding practical clinical applications. Hypertension is one of the most important risk factors for atherosclerosis, but the exact mechanism underlying the association is not fully understood. Vascular biologists are increasingly interested in the role of arterial wall factors in the atherogenic process. The recognition that atherosclerosis is a special case in the general category of inflammation provides an excellent tool to increase our understanding of a complex process. The possibility that hypertension at least in part is a product of a similar arterial pathology is intriguing. On the other hand, it is not possible to divorce inflammatory atherogenesis and hypertension from the injurious agents that initiate arterial inflammation. In another words, inflammation may be a bridge connecting hypertension with atherosclerosis. Anti-inflammatory approaches should be a promising strategy for treating both hypertension and atherosclerosis. Recent data indicate that statins have anti-inflammatory activity independent of their ability to reduce low-density lipoprotein cholesterol levels. The anti-inflammatory action of aspirin may add to its therapeutically crucial anti-platelet properties. Trials of non-steroidal anti- inflammatory drugs and macrolides are in progress, but it is premature to recommend these agents in advance of new data. Several anti-hypertensive agents like angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, or calcium channel blockers effectively reduce hypertensionassociated cardiovascular events and limit target organ damage. These agents also possess anti-inflammatory effects. Kon et al36 performed a randomized, double-blind, placebo-controlled, crossover study on 45 patients with mild or moderate hypertension to evaluate the effect of candesartan on blood pressure and inflammatory markers and found that candesartan therapy significantly reduced adiponectin levels and improved insulin sensitivity in hypertensive patients. In agreement with this study, Manabe et al37 observed that valsartan (40 to 80 mg per day for 3 months) significantly decreased systolic and diastolic blood pressure, and this was accompanied by a reduction of the inflammatory cytokines TNF-α and IL-6. Agabiti Rosei et al38 demonstrated that both nifedipine (20 mg per day) and enalapril (20 mg per day) tended to reduce E-selectin and ICAM-1. These data were also consistent with an animal study that demonstrated that calcium channel blockers have an effect on the direct anti-inflammatory and anti-oxidative role in the aorta of rats with L-argitine methylester-induced hypertension.39 CRP levels can help risk for and events in patients with coronary artery disease or hypertension. CRP levels may also patients with cholesterol who are likely to from therapy. Therefore, of inflammation may be a promising strategy for treating both hypertension and atherosclerosis. there is evidence that inflammation a role in the of hypertension, evidence is still and the of the and the inflammation hypertension and lead to hypertension, or does hypertension induce of those further Since recent studies indicate that inflammatory processes are important participants in the of both hypertension and cardiovascular disease, of the mechanisms leading to the activation of inflammation should contribute to the development of specific therapeutic approaches to in hypertension and its complications.