Inflammation, immunity and development of essential hypertension

The role of inflammation and immunity in cardiovascular disease and in hypertension has been increasingly recognized as evidence of inflammatory markers and mediators [1,2], and innate and adaptive immune dysregulation has accumulated [3–5]. The same is true for obesity, metabolic syndrome, and diabetes [6,7]. Patients with HIV-associated disease (HIV-AIDS) who have evident immune imbalance do not exhibit more incident hypertension; however, inflammation of the aorta has been demonstrated by PET-computed tomography (CT) scans, and shown to correlate with activation of macrophages [8]. HIV-AIDS patients exhibit increased vascular stiffness and pulse pressure [9], which could be the result of immune dysregulation. In many conditions associated with immune changes such as dermatological and rheumatological diseases, as shown recently for psoriasis [10], prevalence of hypertension is increased, reinforcing the hypothesis of inflammatory and immune contribution to blood pressure elevation. This has been further supported by evidence from experimental models of hypertension, in which immune mechanisms have been implicated [11–13]. In this issue of the Journal, Julius et al.[14] have examined the correlation of white blood cell count (WBCC) and blood pressure elevation as well as metabolic syndrome in patients with prehypertension, who were part of a trial of prevention of development of hypertension with treatment with the angiotensin receptor blocker (ARB) candesartan [15]. These authors suggest that because in the cohort studied with prehypertension, 64% of whom developed hypertension within 4 years, there was no correlation between WBCC and blood pressure, and WBCC did not predict incident hypertension among those who did develop blood pressure elevation, that inflammation does not precede hypertension. Because these parameters correlated with BMI and the metabolic syndrome, the authors conclude that overweight and obesity are the common denominators driving the hemodynamic, metabolic, and inflammatory abnormalities. Furthermore, they cannot show a reduction of WBCC with candesartan, concluding that the anti-inflammatory action of ARB may be more easily demonstrated in advanced hypertension with higher degrees of inflammation, but cannot be shown in prehypertension or early in hypertension. As the authors recognize, a 4-year study may be too short to allow prediction of incident hypertension, whereas in previous studies, follow-up was 6–10 years. Furthermore in this study, only 62% of participants on placebo developed hypertension. Thus this study confirms previous ones showing the association of WBCC with obesity and other components of the metabolic syndrome, but not with hypertension or effect of ARBs. These data, however, are insufficient to allow the conclusions of the authors. In fact, their conclusion that inflammation does not seem to precede hypertension or that renin–angiotensin inhibitors do not reduce inflammation on the basis of WBCC responses is not strong evidence. Many studies have shown that high-sensitivity C-reactive protein and many other inflammatory biomarkers correlate with blood pressure [2] and predict incident hypertension [16], strongly supporting the hypothesis that this study purports to negate, and others have demonstrated that ARBs reduce biomarkers of inflammation [17,18]. When one considers that this population had small levels of blood pressure elevation or variation, it is not surprising that correlations were not significant. On the contrary, it is also not surprising that there should be a correlation with BMI since the spread of the latter was greater. The authors measured WBCC, which can vary in response to numerous conditions (infectious and inflammatory noninfectious). The authors would be more able to conclude regarding cellular components of inflammation if they had looked at effector memory T lymphocytes, T-regulatory lymphocytes, and so on in a more sophisticated manner, evidently impossible at this stage with their study that ended many years ago. In conclusion, although in the study by Julius et al.[14] in contrast to many others [19,20], WBCC did not correlate with incident hypertension, the limitations pointed out here do not allow it to be stated that these results are incompatible with the hypothesis that inflammation and immune dysregulation indeed do contribute to incident hypertension or that ARB treatment may suppress inflammatory responses. ACKNOWLEDGEMENTS The work of the author was supported by Canadian Institutes of Health Research grants 37917, 82790, and 102606, a Canada Research Chair (CRC) on Hypertension and Vascular Research from the CIHR/Government of Canada CRC Program, and the Canada Fund for Innovation. Conflicts of interest There are no conflicts of interest.

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