Markers or Makers: Inflammatory Cytokines in Treatment-Resistant Hypertension

Between 7% and 20% of the hypertensive population exhibits resistance to treatment, defined as blood pressure that is poorly controlled with 3 drugs or requiring 4 drugs for control. The diagnosis of resistant hypertension requires exclusion of poor compliance, secondary causes, and white coat effect. A possible cause of resistant hypertension that has been previously investigated in small studies is inflammation. In this issue of Hypertension, Chen et al report a previously undefined relationship between some biomarkers of inflammation and apparent treatment-resistant hypertension (ATRH) in patients with chronic kidney disease. The investigators analyzed 1359 subjects with ATRH from the Chronic Renal Insufficiency Cohort and 2008 subjects without ATRH. They found that resistant hypertension was associated with a rather marked increase in the inflammatory markers TNF (tumor necrosis factor)-α and IL (interleukin)-6 (odds ratios, 1.49 and 1.29, respectively) and a reduction in levels of TGF (transforming growth factor)-β1. In contrast, blood levels of hsCRP (high-sensitivity C-reactive protein), fibrinogen, IL-1β, and IL-1RA (IL-1 receptor antagonist) were not associated with resistant hypertension. The authors created an inflammatory score, based on the levels of each of these biomarkers and found that higher scores were associated with resistant hypertension. Moreover, participants were followed for an average of 6.7 years and hazard ratios associated with ATRH were 1.49 for cardiovascular diseases and 1.27 for death after adjustment for confounding variables. Why would the Chen et al choose to study the role of inflammatory markers in ATRH? Studies during the past decade, largely in experimental animals, have established a role of the immune system in the development of hypertension and its attendant end-organ damage. It is now clear that cells of both the innate and adaptive immune system accumulate in kidneys and vessels of hypertensive animals and humans. These cells release inflammatory cytokines, including IL-17A, TNF-α, IFN (interferon)-γ, IL-6, and others that promote vascular and renal dysfunction and ultimately tissue damage. Of relevance to the Chen et al study, Filho et al have shown that neutralizing circulating TNF-α reduces blood pressure in spontaneously hypertensive rats. Likewise, Guzik et al showed TNF-α blockade lowers blood pressure and reduces vascular superoxide production in Ang II (angiotensin II)–infused mice. Mice lacking IL-6 exhibit reduced hypertension and less reduction of renal blood flow during Ang II infusion. Thus, the finding of elevated IL-6 and TNF-α in patients with chronic kidney disease and ATRH are in keeping with prior studies in experimental animals. Prior studies have examined the association of hsCRP, IL-6, and TNF-α with hypertension. Like Chen et al, Bautista et al found a significant association between blood pressure and plasma levels of TNF-α and IL-6, but no relationship to hsCRP in 196 otherwise healthy subjects. hsCRP has been also been shown to be predictive of the development of hypertension. In smaller cohorts of hypertensive subjects, Yu et al showed higher levels of TNF-α and IL-6 in hypertensive patients, whereas studies from our group showed higher TNF-α and hsCRP levels, but no differences in IL-6 levels in hypertensive and resistant hypertensive subjects compared with normotensive. The Chen et al study adds to these prior reports in several ways. First, it was a study not simply of hypertension, but of resistant hypertension, a special subset that is of particular clinical interest. It is very rare to have such a large population of patients with resistant hypertension. Second, it involved patients with chronic kidney disease, a condition where inflammation is common. Among the subjects studied by Chen et al, those with resistant hypertension had higher urinary protein and significantly lower glomerular filtration rate as compared to the patients without resistant hypertension, possibly reflecting more severe kidney disease. Multivariate analysis showed a significant relationship between the inflammatory cytokines and resistant hypertension even after correcting for renal function. Although drugs that modify immune responses would unlikely ever be used in humans with easily controlled hypertension, agents like anti– IL-6 or anti–TNF-α might be employed in a high-risk population such those with resistant hypertension. At least 4 of biomarkers studied by Chen et al, IL-6, IL-1β, CRP, and TNF-α are intimately related (Figure). IL-1β can signal IL-6, which in turn signals production of CRP. Moreover, TGF-β and IL-6 act in concert to stimulate T cells to produce IL-17. TNF-α can also stimulate production of CRP. It is therefore somewhat surprising that these 3 biomarkers did not track in parallel in the study of Chen et The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. This article was sent to Karen A. Griffin, Guest Editor, for review by expert referees, editorial decision, and final disposition. Correspondence to David G. Harrison, Betty and Jack Bailey Professor of Medicine, Pharmacology and Physiology, Director of Clinical Pharmacology, Room 536, Robinson Research Bldg, Vanderbilt University, Nashville, TN 37232. Email david.g. harrison@vumc.org Markers or Makers Inflammatory Cytokines in Treatment-Resistant Hypertension