Editorial Comment
Inflammation, immunity and development of essential hypertension Ernesto L. Schiffrin
See original paper on page 251
T
he 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
Journal of Hypertension 2014, 32:228–229 Lady Davis Institute for Medical Research and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada Correspondence to Ernesto L. Schiffrin, CM, MD, PhD, FRSC, FRCPC, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Coˆte-Ste-Catherine Rd., #B-127, Montreal, Quebec, H3T 1E2, Canada. Tel: +1 514 340 7538; fax: +1 514 340 7539; e-mail: [email protected] J Hypertens 32:228–229 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000042
228
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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, Tregulatory 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], Volume 32 Number 2 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inflammation, immunity in prehypertension
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.
REFERENCES 1. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events in apparently healthy women. Circulation 1998; 98:731–733. 2. Blake JH, Rifai N, Buring JE, Ridker PM. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation 2003; 108:2993–2999. 3. Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R, Giugliano D. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 2003; 289:1799–1804. 4. Barzilay JI, Abraham L, Heckbert SR. The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 2001; 50:2384–2389. 5. Savoia C, Schiffrin EL. Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci 2007; 112:375–384. 6. Verlohren S, Muller DN, Luft FC, Dechend R. Immunology in hypertension, preeclampsia, and target-organ damage. Hypertension 2009; 54:439–443. 7. Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, et al. Inflammation, immunity and hypertension. Hypertension 2011; 57:132–140.
Journal of Hypertension
8. Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, et al. Arterial inflammation in patients with HIV. JAMA 2012; 308:379– 386. 9. Schillaci G, Maggi P, Madeddu G, Pucci G, Mazzotta E, Penco G, et al., for the CISAI Study Group. Symmetric ambulatory arterial stiffness index and 24-h pulse pressure in HIV infection: results of a nationwide cross-sectional study. J Hypertens 2013; 31:560–567. 10. Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and hypertension: a systematic review and meta-analysis of observational studies. J Hypertens 2013; 31:433–443. 11. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007; 204:2449– 2460. 12. Viel EC, Lemarie´ CA, Benkirane K, Paradis P, Schiffrin EL. Immune regulation and vascular inflammation in genetic hypertension. Am J Physiol Heart Circ Physiol 2010; 298:H938–H944. 13. Barhoumi T, Kasal DAB, Li MW, Shbat L, Laurant P, Fritsch Neves M, et al. T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury. Hypertension 2011; 57:469–476. 14. Julius S, Egan BM, Kaciroti NA, Nesbitt SD, Chen AK, for TROPHY investigators. In prehypertension leukocytosis is associated with body mass index but not with blood pressure or incident hypertension. J Hypertens 2014; 32:251–259. 15. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al., for the Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006; 354:1685–1697. 16. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. Creactive protein and the risk of developing hypertension. JAMA 2003; 290:2945–2951. 17. Fliser D, Buchholz K, Haller H, and for the EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis (EUTOPIA) Investigators. Anti-inflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation 2004; 110:1103–1107. 18. Touyz RM, Savoia C, He Y, Endemann D, Pu Q, Ko EA, et al. Increased inflammatory biomarkers in hypertensive type 2 diabetic patients: improvement after angiotensin II type 1 receptor blockade. J Am Soc Hypertens 2007; 1:189–199. 19. Gillum RF, Mussolino ME. White blood cell count and hypertension incidence: The NHANES I Epidemiologic Follow-up Study. J Clin Epidemiol 1994; 47:911–919. 20. Friedman GD, Selby JV, Quesenberry CP Jr. The leukocyte count: a predictor of hypertension. J Clin Epidemiol 1990; 43:907–911.
www.jhypertension.com
229
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inflammation, immunity and development of essential hypertension Ernesto L. Schiffrin
See original paper on page 251
T
he 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
Journal of Hypertension 2014, 32:228–229 Lady Davis Institute for Medical Research and Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada Correspondence to Ernesto L. Schiffrin, CM, MD, PhD, FRSC, FRCPC, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Coˆte-Ste-Catherine Rd., #B-127, Montreal, Quebec, H3T 1E2, Canada. Tel: +1 514 340 7538; fax: +1 514 340 7539; e-mail: [email protected] J Hypertens 32:228–229 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000042
228
www.jhypertension.com
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, Tregulatory 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], Volume 32 Number 2 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inflammation, immunity in prehypertension
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.
REFERENCES 1. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events in apparently healthy women. Circulation 1998; 98:731–733. 2. Blake JH, Rifai N, Buring JE, Ridker PM. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation 2003; 108:2993–2999. 3. Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R, Giugliano D. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 2003; 289:1799–1804. 4. Barzilay JI, Abraham L, Heckbert SR. The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 2001; 50:2384–2389. 5. Savoia C, Schiffrin EL. Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci 2007; 112:375–384. 6. Verlohren S, Muller DN, Luft FC, Dechend R. Immunology in hypertension, preeclampsia, and target-organ damage. Hypertension 2009; 54:439–443. 7. Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, et al. Inflammation, immunity and hypertension. Hypertension 2011; 57:132–140.
Journal of Hypertension
8. Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, et al. Arterial inflammation in patients with HIV. JAMA 2012; 308:379– 386. 9. Schillaci G, Maggi P, Madeddu G, Pucci G, Mazzotta E, Penco G, et al., for the CISAI Study Group. Symmetric ambulatory arterial stiffness index and 24-h pulse pressure in HIV infection: results of a nationwide cross-sectional study. J Hypertens 2013; 31:560–567. 10. Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and hypertension: a systematic review and meta-analysis of observational studies. J Hypertens 2013; 31:433–443. 11. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007; 204:2449– 2460. 12. Viel EC, Lemarie´ CA, Benkirane K, Paradis P, Schiffrin EL. Immune regulation and vascular inflammation in genetic hypertension. Am J Physiol Heart Circ Physiol 2010; 298:H938–H944. 13. Barhoumi T, Kasal DAB, Li MW, Shbat L, Laurant P, Fritsch Neves M, et al. T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury. Hypertension 2011; 57:469–476. 14. Julius S, Egan BM, Kaciroti NA, Nesbitt SD, Chen AK, for TROPHY investigators. In prehypertension leukocytosis is associated with body mass index but not with blood pressure or incident hypertension. J Hypertens 2014; 32:251–259. 15. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al., for the Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006; 354:1685–1697. 16. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. Creactive protein and the risk of developing hypertension. JAMA 2003; 290:2945–2951. 17. Fliser D, Buchholz K, Haller H, and for the EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis (EUTOPIA) Investigators. Anti-inflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation 2004; 110:1103–1107. 18. Touyz RM, Savoia C, He Y, Endemann D, Pu Q, Ko EA, et al. Increased inflammatory biomarkers in hypertensive type 2 diabetic patients: improvement after angiotensin II type 1 receptor blockade. J Am Soc Hypertens 2007; 1:189–199. 19. Gillum RF, Mussolino ME. White blood cell count and hypertension incidence: The NHANES I Epidemiologic Follow-up Study. J Clin Epidemiol 1994; 47:911–919. 20. Friedman GD, Selby JV, Quesenberry CP Jr. The leukocyte count: a predictor of hypertension. J Clin Epidemiol 1990; 43:907–911.
www.jhypertension.com
229
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
