Association of white blood cell counts with left ventricular mass index in hypertensive patients undergoing anti‑hypertensive drug therapy
- Authors:
- Published online on: February 10, 2017 https://doi.org/10.3892/etm.2017.4119
- Pages: 1566-1571
Abstract
Introduction
The incidence of hypertension is increasing year by year and may cause severe organ damage and increase the risk of patient mortality (1,2). Hypertensive heart disease (HHD) may be associated with diastolic and systolic heart dysfunction, and eventually lead to heart failure (3,4).
The primary pathological characteristic of HHD is left ventricular hypertrophy (LVH), which is independently associated with a number of cardiovascular endpoints, including coronary heart disease and stroke (5). Therefore, hypertensive patients with LVH have an increased risk of experiencing cardiovascular events compared to hypertensive patients without LVH (6,7).
There is a strong correlation between high blood pressure and LVH (8,9). However, it has been indicated that nonhemodynamic factors, including transforming growth factor β1, the renin-angiotensin system and tumor necrosis factor α may induce profibrotic effects and proinflammation, thus contributing to LVH (10,11). Furthermore, studies using animal models have demonstrated that macrophage, T cell and monocytic fibroblast precursors serve important roles in angiotensin II infusion-induced or pathological cardiac remodeling (12–15).
Although studies using animal models have demonstrated that nonhemodynamic factors, including inflammatory cells and cytokines, contribute to left ventricular hypertrophy (LVH) (12,14), there is little clinical data to confirm this association. Based on the aforementioned results, the present study aimed to determine whether circulating leukocyte subtypes are associated with LVH in hypertensive patients treated with anti-hypertensive drugs.
Patients and methods
Patients
A total of 144 consecutive hypertensive patients currently taking anti-hypertensive drug therapy were enrolled in the current study between January 2012 and December 2014 in the Department of Cardiology, Beijing Friendship Hospital, Capital Medical University (Beijing, China). All enrolled patients had a 5–20 year history of hypertension and had all previously taken anti-hypertensive drugs. Exclusion criteria included secondary hypertension, heart failure symptoms, idiopathic cardiomyopathy, ischemic heart disease and the presence of other heart diseases. Blood pressure (BP) was measured at an office at the Beijing Friendship Hospital on two separate occasions. A calibrated mercury sphygmomanometer was used while patients were seated following a 10 min rest. Normal BP was defined as systolic BP (SBP) of 90–140 mmHg or diastolic BP (DBP) of 60–90 mmHg (16,17). Patients were excluded from the current study if they had secondary hypertension, heart failure symptoms, idiopathic cardiomyopathy, ischemic heart disease or other heart diseases. Patient characteristics are summarized in Table I. The protocol of the current study was approved by the Institutional Committee of the Capital Medical University (Beijing, China) and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was given by all patients.
Laboratory analyses
Baseline clinical data was collected for all patients. Counts for total white blood cells (WBC) and differentiated subtypes (neutrophils, lymphocytes, monocytes, eosinophils and basophils) were measured immediately following presentation using peripheral venous blood in an automated blood cell counter (ADVIA 2120: Siemens Healthcare Diagnostics, Camberley, UK). The WBC count was treated as a continuous and categorical variable and was classified as low (<6.65×109/l, <33th percentile), intermediate (6.65–10.11×109/l, 33th-66th percentiles) or high (>10.11×109/l, >66th percentile) (18,19). Alanine transaminase, creatinine, blood urea nitrogen, cholesterol, triglycerides, uric acid and glucose were measured using an established immunoassay (Biosite Inc., San Diego, CA, USA). Quantitative C-reactive protein determination was performed with the BN II Nephelometer (Siemens Healthcare Diagnostics). Cardiac troponin T was measured on the Elecsys 10/10 (Roche Diagnostics, Indianapolis, IN, USA).
Evaluation of cardiac structure and function
Echocardiographic examination of the patients was performed by two experienced cardiologists using a VIVID 7 cardiovascular ultrasound system (GE Healthcare Life Sciences, Uppsala, Sweden) with an M4S 1.5–4.0-MHZ matrix array probe (GE Healthcare Life Sciences) according to the guidelines of the American Society of Echocardiography (20). Echocardiographic examination was performed with patients in the left lateral decubitus position breathing slowly. The cardiologists were blinded to the patients' other data. The echocardiograph measurements included left ventricular end-diastolic diameter (LVEDD), left ventricular posterior wall thickness in diastole (LVPWT) and inter-ventricular septal wall thickness in diastole (IVST). Left ventricular systolic function was assessed using the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). Left ventricular mass was calculated using the ASE-recommended formula: Left ventricular mass (g) = 0.8 × {1.04[(IVST + LVEDD + LVPWT)3 - (LVEDD)3]} (21). Left ventricular mass was divided by body surface area to obtain the left ventricular mass index (LVMI). Body surface (m2) was calculated using (0.0061 × height + 0.0124 × weight - 0.0099). LVH was defined as previously described (22,23). Patients were divided into two different groups according to LVMI. One group consisted of patients with lower LVMI (≤100 g/m2) and the other group consisted of patients with higher LVMI (>100 g/m2).
Statistical analysis
Data analysis was performed using the SPSS statistical package ver. 16.0 for Windows (SPSS Inc., Chicago, IL, USA). Differences in the distribution of demographics, laboratory parameters and medical characteristics among hypertensive patients with lower LVMI, compared with those who had higher LVMI, were examined using the χ2 test for categorized variables and either one-way analysis of variance for continuous variables, or non-parametric tests if distribution was skewed. Multivariate logistic regression analyses were performed to examine the associations of total white blood cell and other potentially confounding prognostic factors with LVMI. Other factors included in the multivariate analyses were age, gender, hypercholesterolemia, diabetes mellitus and medication (aspirin, β-blockers, calcium-channel blockers, angiotensin converting enzyme inhibitor and aldosterone receptor blocker). All P-values were the results of two-tailed tests. A value of P<0.05 was considered to indicate a statistically significant difference.
Results
White blood cells are increased in patients with LVMI
Clinical characteristics of all patients are presented in Table I. At baseline, the 41% of the study population were male and the mean age was 53.7 years [range 44–66 years, standard deviation (SD) 5.8 years]. Out of all the patients, 10% had diabetes mellitus and 28% had hyperlipidemia. The mean SBP and DBP (mmHg) were 121.2 (SD 18.8) and 74.0 (SD 11.3). Blood platelet, hemoglobin, serum creatinine, urea nitrogen and uric acid levels did not significantly differ between the two groups. The drug treatments received by patients in the two groups were not significantly different.
Cardiac remodeling caused by hypertension is accepted as an inflammatory response (14,15) in which inflammatory cells play a critical role. Therefore the current study measured levels of WBC. The LVMI of the study population by tertiles of total WBC level is presented in Fig. 1. In the middle tertile (Tertile 2, n=44), 16% of patients had higher LVMI, indicative of myocardial hypertrophy (MH), which was lower than that in the highest tertile (Tertile 3, n=51; P=0.012). Notably, in the lowest tertile (Tertile 1, n=49) 22.4% of patients had MH, higher than in the middle tertile (Tertile 2), however, this difference was not statistically significant (22.4% vs. 39.2%, P=0.425).
Neutrophil counts correlate with LVMI
To determine which specific leukocyte types have a critical role in hypertension-induced MH, different WBC subtypes were measured. The LVMI of the study population by tertile of neutrophil counts is presented in Fig. 2. A high LVMI indicates the presence of MH. The proportion of patients with MH in both the lowest (n=48) and middle tertile (n=48) was 18.8%. However, a larger proportion (39.6%) of patients in the highest tertile had MH (18.8% vs. 39.6%, P=0.012) compared with the middle and lowest tertiles.
As presented in Fig. 3, other subtypes of WBC were detected. A slightly higher proportion of patients had MH (31.3%) in the middle tertile (n=48) compared with the other tertiles; the percentages in the lowest tertile (n=46) and highest tertile (n=50) were 25.0 and 22.0% respectively (P=0.582; Fig. 3A). As presented in Fig. 3B for the monocyte count, a marked increase (37.8%) of MH in the highest tertile (n=45) was observed, while the proportion of patients with MH in the other two tertiles were 19.6% and 22.6% respectively. However, none of these differences were statistically significant.
Table II presents the results from the logistic analysis. Total WBC counts differed significantly between the two LVMI groups (the lowest and the highest; P=0.013). Additionally, accompanied by an increase in total WBCs particularly over the middle tertile, the percentage of patients with higher LVMI (or MH) was significantly increased (P=0.008). Furthermore, Table II indicated that older patients (>65 years old) had higher LVMI than those ≤65 years (P=0.042). However, there were no significant differences in gender, DM, hypercholesterolemia and cardiovascular drug treatment between the groups.
 | Table II.Multivariate logistic regression analyses for left ventricular mass index in hypertensive patients. |
Discussion
In the present study, a correlation was detected between white blood cell count and LVMI in hypertensive patients undergoing anti-hypertensive drug therapy. Hypertension is an important risk factor for cardiovascular diseases including atherosclerosis and myocardial hypertrophy, and is independent of age, gender and ethnicity (24,25). The incidence of hypertension is an important basis for the progress of cardiovascular diseases, which itself is a result of many interacting factors. There is evidence that nonhemodynamic factors, which possibly lead to profibrotic effects and proinflammation, may influence LVH (10,11).
Hypertension is a chronic disease (26,27). Active drug therapy may reduce and delay the organ damage caused by hypertension (27). Excluding the impact of other factors, there are significant differences in LVH among patients receiving the same drug therapy (28,29). LVH is closely associated with the plasma levels of white blood cells in patients, which gives an indication of hypertension (17,19). Thus practitioners can focus on the level of white blood cell intervention required, further reducing the patient's long-term target organ damage.
The current study detected a strong correlation between white blood cell counts (particularly neutrophil counts) and LVMI in hypertensive patients undergoing anti-hypertensive drug therapy. It demonstrates that modulating neutrophil number to a moderate level for hypertensive patients alongside anti-hypertensive drug therapy may benefit the long-term prognosis of patients. Inflammation is an indicator for the progression of myocardial remodeling underlying the pathogenesis of LVH (30–34). Inflammatory factors are typically derived from white blood cells, particularly neutrophils (35–39). Myocardial expression of inflammatory mediators, including monocyte chemoattractant protein-1 or fractalkine, is significantly increased in experimental myocarditis or dilated cardiomyopathy (40,41). The infiltrating inflammatory cells and/or cardiomyocytes may account for enhanced LVH. Inflammatory cells and cytokines participate in the pathological process of cardiovascular remodeling and are a double-edged sword; they can clear necrotic cells and foreign antigens and promote angiogenesis and scar repair (42). However, excessive inflammatory cell infiltration may seriously upset the balance of the body microenvironment, causing organ damage (42–44).
To the best of our knowledge, the present study is the first to demonstrate that circulating specific types of leukocyte may be associated with LVH in hypertensive patients currently taking anti-hypertensive drugs and thus may provide a novel preventative strategy for LVH by modulating myocardial inflammation.
Acknowledgements
The present study was supported by the National Natural Science Foundation of China (nos. 81300209, 81400263, 81230007 and 81200147) and Basic-Clinical Cooperation Project of Chinese Capital Medical University (no. 13JL59).
References
|
Westerlund E, Brandt L, Hovatta O, Wallén H, Ekbom A and Henriksson P: Incidence of hypertension, stroke, coronary heart disease, and diabetes in women who have delivered after in vitro fertilization: A population-based cohort study from Sweden. Fertil Steril. 102:1096–1102. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Veloso HH: Incidence of sudden cardiac death in congestive heart failure: Chagas disease versus systemic arterial hypertension. Int J Cardiol. 175:175–176. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Kim W, Park CS, Kim HJ, Kim KH, An HM, Kim YH, Lim CH, Kang WY, Hwang SH and Kim W: Hypertensive heart failure associated with middle aortic syndrome reversed dramatically by endovascular management. J Cardiovasc Ultrasound. 19:144–147. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Maskali F, Poussier S, Louis H, Boutley H, Lhuillier M, Thornton SN, Karcher G, Lacolley P and Marie PY: Assessment of the early stage of cardiac remodeling of spontaneously hypertensive heart failure rats using the quantitative 3-dimensional analysis provided by acipimox-enhanced FDG-PET. Int J Cardiovasc Imaging. 30:449–456. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Sosner P, Cabasson S, Hulin-Delmotte C, Saulnier PJ, Gand E, Torremocha F, Piguel X, Miot A, Maréchaud R, Herpin D, et al: Effect of Cornell product and other ECG left ventricular hypertrophy criteria on various cardiovascular endpoints in type 2 diabetic patients. Int J Cardiol. 175:193–195. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Seto S: Left ventricular hypertrophy, ischemic heart disease and the incidence of cardiovascular events in Japanese high-risk hypertensive patients. Circ J. 73:1014–1015. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH and Mogensen CE: Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients with left ventricular hypertrophy and diabetes. J Nephrol. 21:566–569. 2008.PubMed/NCBI | |
|
Pai AU, Chakrapani M, Bhaskaran U and Kamath P: Study of home-monitored night blood pressure and its correlation with left ventricular hypertrophy in treatment-naive hypertensive patients. Singapore Med J. 53:95–98. 2012.PubMed/NCBI | |
|
Nathwani D, Reeves RA, Marquez-Julio A and Leenen FH: Left ventricular hypertrophy in mild hypertension: correlation with exercise blood pressure. Am Heart J. 109:386–387. 1985. View Article : Google Scholar : PubMed/NCBI | |
|
de Simone G, Pasanisi F and Contaldo F: Link of nonhemodynamic factors to hemodynamic determinantsof left ventricular hypertrophy. Hypertension. 38:13–18. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Bauwens FR, Duprez DA, De Buyzere ML, De Backer TL, Kaufman JM, Van Hoecke J, Vermeulen A and Clement DL: Influence of the arterial blood pressure and nonhemodynamic factors on left ventricular hypertrophy in moderate essential hypertension. Am J Cardiol. 68:925–929. 1991. View Article : Google Scholar : PubMed/NCBI | |
|
Rateri DL, Howatt DA, Moorleghen JJ, Charnigo R, Cassis LA and Daugherty A: Prolonged infusion of angiotensin II in apoE(−/−)mice promotes macrophage recruitment with continued expansion of abdominal aortic aneurysm. Am J Pathol. 179:1542–1548. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Ismahil MA and Prabhu SD: Cardiac immune cell remodeling after myocardial infarction. J Mol Cell Cardiol. 62:142–143. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Lee AA and McCulloch AD: Multiaxial myocardial mechanics and extracellular matrix remodeling: Mechanochemical regulation of cardiac fibroblast function. Adv Exp Med Biol. 430:227–240. 1997. View Article : Google Scholar : PubMed/NCBI | |
|
Ngu JM, Teng G, Meijndert HC, Mewhort HE, Turnbull JD, Stetler-Stevenson WG and Fedak PW: Human cardiac fibroblast extracellular matrix remodeling: dual effects of tissue inhibitor of metalloproteinase-2. Cardiovasc Pathol. 23:335–343. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Orme S, Ralph SG, Birchall A, Lawson-Matthew P, McLean K and Channer KS: The normal range for inter-arm differences in blood pressure. Age Ageing. 28:537–542. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Chue CD, Edwards NC, Ferro CJ, Steeds RP and Townend JN: Reduction of blood pressure already in the normal range further regresses left ventricular mass. Heart. 96:10802010. View Article : Google Scholar : PubMed/NCBI | |
|
Colquitt JL and D'Orazio JA: Intracranial hemorrhage and a white blood cell count of almost 1 million cells/muL. J Pediatr. 162:2142013. View Article : Google Scholar : PubMed/NCBI | |
|
Twig G, Afek A, Shamiss A, Derazne E, Tzur D, Gordon B and Tirosh A: White blood cells count and incidence of type 2 diabetes in young men. Diabetes Care. 36:276–282. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Troianos CA, Hartman GS, Glas KE, Skubas NJ, Eberhardt RT, Walker JD and Reeves ST: Councils on Intraoperative Echocardiography and Vascular Ultrasound of the American Society of Echocardiography: Guidelines for performing ultrasound guided vascular cannulation: Recommendations of the american society of echocardiography and the society of cardiovascular anesthesiologists. J Am Soc Echocardiogr. 24:1291–1318. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, et al: Recommendations for chamber quantification: A report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 18:1440–1463. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, Vargiu P, Simongini I and Laragh JH: Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol. 19:1550–1558. 1992. View Article : Google Scholar : PubMed/NCBI | |
|
Koren MJ, Devereux RB, Casale PN, Savage DD and Laragh JH: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med. 114:345–352. 1991. View Article : Google Scholar : PubMed/NCBI | |
|
Lin KC, Tsao HM, Chen CH and Chou P: Hypertension was the major risk factor leading to development of cardiovascular diseases among men with hyperuricemia. J Rheumatol. 31:1152–1158. 2004.PubMed/NCBI | |
|
Kováčová M and Kiňová S: Arterial hypertension in gravidity-a risk factor for cardiovascular diseases. Vnitr Lek. 58:922–927. 2012.(In Czech). PubMed/NCBI | |
|
Azancot MA, Ramos N, Moreso FJ, Ibernon M, Espinel E, Torres IB, Fort J and Seron D: Hypertension in chronic kidney disease: the influence of renal transplantation. Transplantation. 98:537–542. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Barreto MS, Reiners AA and Marcon SS: Knowledge about hypertension and factors associated with the non-adherence to drug therapy. Rev Lat Am Enfermagem. 22:491–498. 2014.(Article in English, Portuguese, Spanish). View Article : Google Scholar : PubMed/NCBI | |
|
Hachamovitch R, Sonnenblick EH, Strom JA and Frishman WH: Left ventricular hypertrophy in hypertension and the effects of antihypertensive drug therapy. Curr Probl Cardiol. 13:375–421. 1988.PubMed/NCBI | |
|
Eselin JA and Carter BL: Hypertension and left ventricular hypertrophy: is drug therapy beneficial? Pharmacotherapy. 14:60–88. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Mehta SK, Rame JE, Khera A, Murphy SA, Canham RM, Peshock RM, de Lemos JA and Drazner MH: Left ventricular hypertrophy, subclinical atherosclerosis and inflammation. Hypertension. 49:1385–1391. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Tsai WC, Lin CC, Huang YY, Chen JY and Chen JH: Association of increased arterial stiffness and inflammation with proteinuria and left ventricular hypertrophy in non-diabetic hypertensive patients. Blood Press. 16:270–275. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Xu Y, Chen Y, Li D, Li J, Liu X, Cui C and Yu C: Hypertension, fluid overload and micro inflammation are associated with left ventricular hypertrophy in maintenance hemodialysis patients. Ren Fail. 35:1204–1209. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Salles GF, Fiszman R, Cardoso CR and Muxfeldt ES: Relation of left ventricular hypertrophy with systemic inflammation and endothelial damage in resistant hypertension. Hypertension. 50:723–728. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Cottone S, Nardi E, Mulè G, Vadalà A, Lorito MC, Riccobene R, Palermo A, Arsena R, Guarneri M and Cerasola G: Association between biomarkers of inflammation and left ventricular hypertrophy in moderate chronic kidney disease. Clin Nephrol. 67:209–216. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Fanning NF, Kell MR, Shorten GD, Kirwan WO, Bouchier-Hayes D, Cotter TG and Redmond HP: Circulating granulocyte macrophage colony-stimulating factor in plasma of patients with the systemic inflammatory response syndrome delays neutrophil apoptosis through inhibition of spontaneous reactive oxygen species generation. Shock. 11:167–174. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Scapini P, Morini M, Tecchio C, Minghelli S, Di Carlo E, Tanghetti E, Albini A, Lowell C, Berton G, Noonan DM and Cassatella MA: CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A. J Immunol. 172:5034–5040. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Droemann D, Hansen F, Aries SP, Braun J, Zabel P, Dalhoff K and Schaaf B: Neutrophil apoptosis, activation and anti-inflammatory cytokine response in granulocyte colony-stimulating factor-treated patients with community-acquired pneumonia. Respiration. 73:340–346. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Tanabe J, Watanabe M, Mue S and Ohuchi K: Leukocyte-derived neutrophil chemotactic factor-2 produced by infiltrated leukocytes in allergic inflammation model in rats is macrophage inflammatory protein-2. Immunol Invest. 24:757–764. 1995. View Article : Google Scholar : PubMed/NCBI | |
|
Tavares-Murta BM, Lefort J, Cunha FQ, Ferreira SH and Vargaftig BB: Interference of a neutrophil recruitment inhibitory factor upon the accumulation of inflammatory cells and airway hyperreactivity in sensitized guinea-pigs after intranasal antigen challenge. Br J Pharmacol. 108:538–543. 1993. View Article : Google Scholar : PubMed/NCBI | |
|
Shen Y, Zhang FQ and Wei X: Truncated monocyte chemoattractant protein-1 can alleviate cardiac injury in mice with viral myocarditis via infiltration of mononuclear cells. Microbiol Immunol. 58:195–201. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Ning J, Li YH and Zhang CB: Expression of monocyte chemoattractant protein-1 in sudden death due to viral myocarditis and its medicolegal significance. Fa Yi Xue Za Zhi. 25:334–336. 2009.(In Chinese). PubMed/NCBI | |
|
Halaris A: Inflammation, heart disease, and depression. Curr Psychiatry Rep. 15:4002013. View Article : Google Scholar : PubMed/NCBI | |
|
Huston JM and Tracey KJ: The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J Intern Med. 269:45–53. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Luttmann-Gibson H, Suh HH, Coull BA, Dockery DW, Sarnat SE, Schwartz J, Stone PH and Gold DR: Systemic inflammation, heart rate variability and air pollution in a cohort of senior adults. Occup Environ Med. 67:625–630. 2010. View Article : Google Scholar : PubMed/NCBI |
