Journal of Human Hypertension (2006) 20, 310–312 & 2006 Nature Publishing Group All rights reserved 0950-9240/06 $30.00 www.nature.com/jhh
COMMENTARY
White blood cell count and hypertension VJ Karthikeyan and GYH Lip Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK Journal of Human Hypertension (2006) 20, 310–312. doi:10.1038/sj.jhh.1001980; published online 26 January 2006
Hypertension is a major global health problem and public-health challenge, demanding a vast proportion of health care resources directly and indirectly because of its high and increasing prevalence and the concomitant risks of cardiovascular and kidney disease, disability-adjusted life-years and mortality.1,2 Various risk factors have been implicated in the development of hypertension, some of which include genetic, environmental, psychosocial, and inflammatory factors.3,4 Links between inflammation and hypertension have been suggested in the past, with mounting evidence of more than a mere putative link between the two, with implications in the development of complications and the management of hypertension per se.4,5 Indeed, various inflammatory markers including high-sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-a) and white blood cell (WBC) count have been studied and found to be associated with hypertension and its complications.5–11 Certainly, there has been an enormous interest in the identification of these measurable indices even in persons at risk of, but without overt hypertension or complicating cardiovascular disorders. However, most of these studies have been cross-sectional in design, making it difficult to understand whether inflammation, chronic or mild, with an increase in the inflammatory markers, is a cause or an effect of high blood pressure (Table 1).12–14 With respect to the relationship between WBC count and hypertension, one population-based study12 found an association between elevated WBC count and incident hypertension in a predominantly white population, with the risk ratio of hypertension being directly related in a dose-dependant manner to increasing tertiles of WBC count (WBC count tertiles 1–3 has relative risks (RR) of hypertension of 1.0, 1.2, 1.7; Po0.01). This association appeared to be independent of smoking and other cardiovascular Correspondence: Professor GYH Lip, Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, UK. E-mail:
[email protected] Published online 26 January 2006
risk factors. Two longitudinal studies13,14 investigating the association between WBC count and incidence of hypertension noted an increased incidence of hypertension with ‘high normal’ WBC count compared to lower WBC counts. Again both these studies involved a predominantly white population, with small numbers of Afro-Caribbeans. In this issue of the Journal of Human Hypertension, Orakzai et al.15 add further weight to data on the relationship between WBC count and rising systolic blood pressure (SBP) within the normotensive range. In this cross-sectional study, blood pressures and WBC counts were measured in 3484 white asymptomatic low-risk subjects (mean age 43 years, predominantly males) attending a primary prevention clinic, after assessments for cardiovascular risk factors. A linear relationship between elevated WBC count and higher SBP was found, with particularly high WBC count among subjects with SBP 130–139 mmHg when compared to those with SBP o120 mmHg (P ¼ 0.02). This study involved a predominantly white Brazilian population, and again, the relationship in nonwhite subjects remains unclear. Is the association of WBC count with hypertension plausible? It has been hypothesized that elevated WBC counts cause a chronic low-grade inflammation that alters endothelial function, affecting nitric oxide and prostacyclin production and consequently, a loss of vasodilator, antithrombotic and antiatherogenic properties of the vascular endothelium. Other postulated mechanisms include increased adherence of the stimulated leukocytes to the vascular endothelium, causing capillary leukocytosis and subsequent increased vascular resistance; a raised WBC count may therefore indicate increased catecholamine levels or enhanced sympathetic nervous system activity, thus causing an increase in blood pressure and eventually resulting in sustained hypertension.12 In addition, inflammation may play a key role in the initiation and development of hypertension via the proinflammatory actions of mediators such as adhesion molecules, chemokines, growth factors, heat shock proteins, endothelin-1 and angiotensin. Certainly, a persistent low-grade inflammatory state could result in high normal levels of inflammatory cytokines.15
White blood cell count and hypertension VJ Karthikeyan and GYH Lip 311
Table 1 Examples of studies investigating the relationship between WBC count and hypertension Study
Number (n)
Findings
Comments Initial WBC count related to the development of hypertension; WBC predictive of incident hypertension (?). Further evidence of a possible relationship between WBC count and incident hypertension.
Friedman et al.13
2062
RR of hypertension 40% (95% CI) in persons in the highest quartile of WBC count
Gillum et al.14
6456
Shankar et al.12
2459
RR of hypertension 50% over a 10-year period in white men with WBC 48600 vs WBC o6200 cells/mm3 Increased risk ratio of hypertension related to increasing tertiles of WBC count (WBC count tertiles 1–3; RR 1, 1.2, 1.7; Po0.01)
How relevant is WBC count in prehypertensive and hypertensive populations? The Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure (JNC 7) report16 has redefined a SBP of 120–139 mmHg or a diastolic blood pressure of 80–89 mmHg as ‘prehypertensive’ with suggestions to health promoting lifestyle modifications to prevent cardiovascular disease. This study by Orakzai et al.15 furthers our current, albeit limited, understanding of a possible relationship between WBC count and high blood pressure. Of note, even in the high normal SBP categories (currently classified as the ‘pre-hypertensive range’), the WBC count was still high. Further prospective studies investigating such an association in large population cohorts and involving other racial groups, as well as looking for evidence of a drop in the WBC count with reduction in blood pressure by nonpharmacological as well as pharmacological means, are probably required. Also, relevant would be the exploration of other ‘noninflammatory, noninfective’ causes of leukocytosis, such as pregnancy (e.g., in the context of hypertension in pregnancy), corticosteroid therapies, haematological malignancies and their role, if any, in the pathogenesis of hypertension. It is also difficult to predict or speculate if treatments aimed at reducing inflammation and WBC count would be beneficial in blood pressure control per se. In view of a predominantly thrombotic nature of the complications of hypertension, various rheological and haemostatic factors have been hypothesized to play a role in the pathogenesis of hypertension and cardiovascular disease.17,18 Whether high WBC counts have any role in the complex rheological abnormalities (including whole blood and plasma viscosity, von Willebrand factor, platelet activation and aggregation, fibrinogen, etc) seen in hypertension remains to be determined.
3 4
5
6
7
8
9
10
11
12
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13 14
Consistent evidence of relationship between WBC count and incident hypertension.
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