The Link Between Inflammation and Hypertension: Unmasking Mediators

Several pathological processes are involved in the initiation and promotion of high blood pressure1 and inflammation is believed to be one of these processes. Prospective clinical studies demonstrated an association between elevated levels of inflammatory markers and the risk of incident hypertension.2–4 In a prospective analysis of the Multi-Ethnic Study of Atherosclerosis (MESA), among 3,543 nonhypertensives at the baseline evaluation, 714 individuals developed incident hypertension during follow-up.2 Multivariable Cox proportional hazard models were used to determine the relationship between baseline levels of interleukin-6 (IL-6), C-reactive protein (CRP), and fibrinogen and future risk of hypertension. One standard deviation difference in baseline concentration of IL-6, CRP, or fibrinogen was associated with 20%–40% greater risk of incident hypertension.2 More recently, a systematic overview and meta-analysis of 14 prospective cohort studies, 2 retrospective cohort studies, and 5 nested case–control studies showed that high levels of circulating inflammation markers were significantly associated with the risk of developing hypertension.3 Specifically, the relative risk (RR) for the third vs. first tertiles of circulating CRP was 1.23 (95% confidence interval [CI]: 1.11–1.35). Similar results were obtained for other biomarkers, including high sensitive CRP (RR: 1.20, 95% CI: 1.02–1.37) and IL-6 (RR: 1.51, 95% CI: 1.30–1.71). Furthermore, the risk of hypertension increased linearly with increasing circulating inflammation markers.3 Although the associations between inflammation and hypertension have been described almost 2 decades ago, the exact pathophysiological mechanism underlying the link between increased markers of inflammation and risk of incident hypertension is complex and incompletely understood. Experimental studies have focused upon the pathophysiological role of inflammation on the initiation of hypertension and its cardiovascular complications. Systemic inflammation has been associated with increased arterial stiffness and renin–angiotensin–aldosterone system (RAAS) activity, atheroma formation, oxidative stress, and endothelial activation and dysfunction5–8 (Figure 1). The potential complex mechanism linking the association between inflammation and incident hypertension (see text for details). Abbreviations: RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system. The potential complex mechanism linking the association between inflammation and incident hypertension (see text for details). Abbreviations: RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system. In this evolving scenario of research, the new analysis of the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort published in the current issue of The American Journal of Hypertension9 adds further insights to understand the complex phenomenon linking inflammation with developing hypertension. The REGARDS Study is a national, population-based, longitudinal study of about 30,000 African American and White adults, having the main objective to build a national cohort to address ethnic differences in stroke and to determine the causes for the excess stroke mortality in the Southeastern US and among African Americans.9 Briefly, participants were randomly sampled with recruitment by mail. Then, data on cardiovascular risk factors, sociodemographic, lifestyle, and psychosocial characteristics were collected.9 Physical and physiological measures, and fasting samples were also collected during a subsequent in-home visit, and participants were followed via telephone.9 Plante et al. included in the final analytic sample 6,548 adults (26% Blacks) with a median follow-up of 9.2 years (interquartile range: 8.5–9.9 years).9 Four subgroups of patients were identified according to baseline CRP quartiles.9 Participants in the higher quartile of CRP were more likely to be smoker, female, black and with increased body mass index and waist circumference when compared with participants in the lower quartile.9 During follow-up, 3,343 (51%) participants developed incident hypertension. The incidence of hypertension was 51%, 59%, 45%, and 62% among White males, Black males, White females, and Black females, respectively.9 Higher CRP quartile was associated with a greater incidence of hypertension (adjusted RR: 1.19; 95% CI: 1.12–1.28) compared with first quartile. Furthermore, a larger proportion of adults with CRP ≥10 mg/dl developed hypertension when compared with those with CRP <10 mg/dl (P = 0.03).9 Such findings are not entirely new. Several conditions associated with inflammation, including obesity and physical inactivity tend to be more frequent in women than in men.10 Furthermore, women have higher rates of autoimmune diseases compared with men.11–13 Moreover, the association between ethnicity and inflammation has been analyzed as well, showing that Blacks often have higher CRP than Whites.14,15 It is possible to speculate that socioeconomic status may partially explain why certain ethnicities are at higher risk for inflammatory problems. The noteworthy finding in the paper from Plante et al.9 is the evidence that CRP mediated the Black–White RR for incident hypertension, attenuating a portion of the unadjusted excess risk of hypertension in Black adults. Nonetheless, this excess risk was attenuated when controlling for measures of obesity (body mass index and waist circumference) in females and diet and socioeconomic factors in males. More specifically, the new analysis of the REGARDS cohort9 highlights the mediation and catalytic role exerted by obesity in the link between inflammation and incident hypertension. In this context, studies in humans and experimental models indicate that obesity activates the sympathetic nervous system and RAAS, causing increased renal sodium reabsorption, impaired pressure natriuresis, and expansion of extracellular fluid volume1,16–18 (Figure 1). Furthermore, excess energy is stored mainly as fat in adipocytes which undergo hypertrophy and hyperplasia. Visceral adipocytes have limited hyperplastic potential and undergo hypertrophy when storing additional lipids. As these cells increase their volume (excessive adipocyte hypertrophy), they become inadequately vascularized and hypoxic, leading to activation of macrophages and secretion of inflammatory cytokines that adversely influence kidney function, vascular function (endothelial dysfunction), and metabolic homeostasis (insulin resistance, Figure 1).16,17,19 Finalizing our discussion, the paper by Plante et al.9 has some limitations which deserve to be mentioned. As acknowledged by the authors,9 CRP is the most widely studied inflammatory marker in hypertension; however, the potential inclusion of participants who had recent acute illness may have led to misclassification. Furthermore, collected data are unable to assess the contribution of genetic variants which may alter CRP levels. Finally and more importantly, ascertainment of hypertensive status during follow-up was based on self-report of antihypertensive use and on a single time measure of blood pressure9 which may have led to misclassification of normotensive status due to the masked hypertension phenomenon. Indeed and as recently documented by the Dallas Heart Study, a population study enrolling a large proportion of African Americans, prevalence of masked hypertension is far from negligible in these subjects.20 In conclusion, recent and exciting literature suggests an important role of inflammation in the pathogenesis and clinical complications of hypertension. Moreover, oxidative stress, endothelial dysfunction, SNS activation, and RAAS are associated with inflammation and contribute to hypertension by exacerbating the inflammatory response (Figure 1).8 To date, CRP is considered the inflammatory marker with the strongest association with the risk of developing overt hypertension. It has been demonstrated that hypertensive patients commonly have increased plasma CRP levels, and prehypertensive patients generally have higher plasma CRP levels than normotensive patients.2,3 Thus, circulating levels of CRP may contribute to the prognostic information regarding cardiovascular risk in hypertension, representing a potential tool to identify patients at risk, independent of other cardiovascular risk factors. Although further research will remain to elucidate the interrelationship and common mediators of these mechanisms, some specific components of inflammation pose novel therapeutic targets7,8 (by immunosuppressant drugs, vaccines that target the RAAS, blockers of HMG-CoA reductase) to enhance the effects of antihypertensive therapy by reducing the detrimental impact of oxidative stress and endothelial dysfunction. The authors declared no conflict of interest.