Hypertension (HTN) is a common condition that results in damage to important target organs including the heart, kidney and brain.1,2 Low-grade inflammation has a key role in its pathogenesis and progression.3 Inflammatory processes are assumed to have particularly significant involvement in vascular remodeling of resistance arteries.4 Increasing blood pressure (BP) may progressively cause a pro-inflammatory response and thus establish a vicious cycle. Furthermore, HTN is a significant risk factor in inflammatory conditions such as atherosclerosis.5

The relationship between various cardiovascular conditions and inflammation has been investigated in previous studies.6 Elevated C-reactive protein (CRP), vascular (VCAM-1) and intercellular (ICAM-1) adhesion molecules, monocyte chemoattractant protein-1 (MCP) and plasminogen activator inhibitor-1 (PAI-1) are some of the inflammatory molecules that are increased in HTN.7,8 Along with these well-known inflammatory markers, recent studies have shown the neutrophil-to-lymphocyte ratio (NLR) to be a reliable marker of systemic inflammation.9 It has been shown to have prognostic significance in various conditions such as coronary artery disease,10,11 malignancy,12 heart failure,13 and cerebral and peripheral artery disease.14,15 Since HTN is considered a significant risk factor in most of these conditions, the relationship between NLR and HTN has also been thoroughly investigated.16 NLR is a good predictor in high-risk conditions such as resistant HTN and non-dipper HTN.17,18

Ambulatory blood pressure monitoring (ABPM) is an important tool that is frequently used by clinicians in daily practice to guide treatment and help to identify conditions such as white-coat and masked HTN.19 It is known that ABPM is a better predictor of target organ damage and cardiovascular endpoints than office BP.20 However, it may have limitations in patients with ‘high-normal’ BP.21 In view of this limitation, some authors suggest that BP load, defined as the percentage of abnormally elevated BP readings, is a better predictor.22,23

As far as we know, there are few data on the evaluation of severity of the inflammatory response in HTN using NLR, which is a simple and inexpensive method. Thus, in our study we aimed to evaluate the relationship between HTN severity and NLR using averaged ambulatory BP readings and BP load.

Three hundred hypertensive patients (47% male) were evaluated. The mean age of the population was 48.5±14 years. Patients were divided into quartiles according to NLR values (first: <1.55; second: 1.55-1.92; third: 1.92-2.48; and fourth: >2.48). There were no differences between quartiles in terms of basal demographics, cardiovascular risk factors or echocardiographic parameters (Table 1). Baseline laboratory findings are presented in Table 2. Fasting blood glucose, serum creatinine, hemoglobin, platelet count, and lipid profile were not different across NLR quartiles. White blood cell and neutrophil counts were significantly higher in upper quartiles of NLR. There was also a statistically significant trend towards lower lymphocyte count in patients in the fourth quartile.

Patients’ ABPM data are shown in Table 3. In the interquartile evaluation, daytime SBP, 24-hour DBP, daytime DBP, daytime SBP load, 24-hour DBP load and daytime DBP load were found to be significantly higher in the upper two quartiles (p<0.05 for all). The difference was more noticeable in DBP data. Dipping status and BP variability data were not significantly different between quartiles (p>0.05).

Subsequently, the relationship between mean BP and BP load values and NLR was evaluated. A positive correlation between log NLR and daytime, nighttime and 24-hour BP and BP load values was identified (p<0.05 for all). Correlations of 24-hour systolic BP (r=0.194; 95% confidence interval [CI]: 0.074-0.320, p=0.001) and 24-hour diastolic BP (r=0.197; 95% CI: 0.076-0.307, p=0.001), 24-hour systolic BP load (r=0.157; 95% CI: 0.032-0.278, p=0.006) and 24-hour diastolic BP load (r=0.181; 95% CI: 0.054-0.295, p=0.002) with log NLR are shown in Figure 1. Additionally, daytime SBP load (r=0.150, 95% CI: 0.025-0.265, p=0.009), nighttime SBP load (r=0.129, 95% CI: 0.011-0.247, p=0.026), daytime DBP load (r=0.160, 95% CI: 0.040-0.273, p=0.005) and nighttime DBP load (r=0.173, 95% CI: 0.049-0.289, p=0.003) were positively correlated with log NLR. Similarly, a significant positive correlation was observed between mean daytime SBP (r=0.173, 95% CI: 0.055-0.292, p=0.003), nighttime SBP (r=0.206, 95% CI: 0.091-0.332, p< 0.001), daytime DBP (r=0.170, 95% CI: 0.059-0.282, p=0.003) and nighttime DBP (r=0.214, 95% CI: 0.096-0.331, p<0.001) and log NLR values.

Figure 1.

Pearson's correlation analysis demonstrating correlations between NLR and (A) 24-hour systolic BP; (B) 24-hour systolic BP load; (C) 24-hour diastolic BP; and (D) 24-hour diastolic BP load. BP: blood pressure; NLR: neutrophil-to-lymphocyte ratio.

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After construction of multiple linear regression models with the four ABPM components associated with log NLR levels as independent variables, log NLR values maintained an independent association with 24-hour SBP, 24-hour DBP, 24-hour SBP load (Table 4) and 24-hour DBP load (Table 5). When 24-hour SBP was taken as a continuous variable, multivariate linear regression analysis revealed that 24-hour SBP was correlated with fasting blood glucose (β=0.160, 95% CI: 0.016-0.088, p=0.005), female gender (β=-0.114, 95% CI: -5.409-0.078, p=0.044), LVMI (β=0.194, 95% CI: 0.049-0.191, p=0.001) and log NLR (β=0.208 95% CI: 7.881-23.975, p<0.001). Similarly, multivariate linear regression analysis demonstrated significant associations between age (β=-0.197, 95% CI: -0.197-0.047, p=0.002), LVEF (β=-0.162, 95% CI: -0.837-0.149, p=0.005), log NLR (β=0.216, 95% CI: 6.119-18.741, p<0.001) and 24-hour DBP.

The results of our study show that in patients with untreated HTN, admission NLR values and ambulatory BP and BP load measurements were correlated. To our knowledge, this is the first study in the literature demonstrating such a correlation between NLR and BP severity.

Elevated NLR values are a predictor of high cardiovascular risk26 and are correlated with inflammatory activity and the severity of numerous diseases.27,28 Increased renin-angiotensin-aldosterone system activity and CRP-mediated inflammation are involved in the inflammatory response observed in hypertensive patients, and activation of peroxisome proliferator-activated receptors may protect against these effects.4 Angiotensin II triggers a series of inflammatory processes resulting in vascular remodeling and injury via endothelin-1 and NAD(P)H oxidase.29 Other than the vascular remodeling resulting from chronic HTN, there is no other evidence indicating whether low-grade inflammation level is reflected in short-term BP values. However, structural vascular alterations occurring during chronic HTN, along with some functional mechanisms, may cause acute BP alterations and inflammation.30 In previous studies it was shown that high-sensitivity CRP and leukocyte count were elevated in patients experiencing acute BP increase in conditions such as hypertensive crisis.31 Shear stress due to high BP levels may lead to an increase in inflammation in the short term by increased expression of adhesion molecules, endothelial dysfunction and NO-related mechanisms.32 It is known that ICAM-1 and interleukin-6 increase with increasing BP.33 In our study also, patients with higher NLR were found to have higher ambulatory BP measurements, particularly for DBP. Like mean BP values, the relationship of BP load with higher NLR values suggests that the inflammation observed in these patients is associated with short-term barotrauma. A higher BP load means that target organs are exposed to higher pressure for a longer duration, even if mean BP is normal. Additionally, patients with increased BP load are subject to overloading of the cardiovascular system, with consequent negative impact on related structures. Higher BP load may promote an inflammatory response to HTN. Recent studies reporting an association between BP load and target organ damage have shown that this relationship is not independent of 24-hour BP levels.34 On the contrary, Wang et al. have shown that BP load is an independent predictor of target organ damage in patients with chronic renal disease.23 Higher BP load (‘baric impact’) may cause endothelial dysfunction associated with vasopressor effects and thus may increase inflammation.35

As a probable predictor of BP severity, NLR has been the subject of antihypertensive therapy studies. Antihypertensive drugs may lead to a decrease in NLR, by both BP-lowering and anti-inflammatory effects.36,37 In previous studies non-dipping status and increased BP variability were associated with higher NLR.38,39 In our study, the lack of difference in BP variability and non-dipper status between groups made the relationship between NLR and BP/BP load clearer. Furthermore, increased pulse pressure is considered a significant marker of chronic inflammation and arterial stiffness.40 In a smaller cohort including normotensives NLR was reportedly correlated with 24-hour SBP and night-time SBP.41 In the same study, pulse pressure was also correlated positively with NLR. In our study, mean pulse pressure did not differ between quartiles and therefore did not contribute significantly to the results. Interestingly, Gang and Yanyan showed that NLR was increased in patients suffering from HTN with hyperhomocysteinemia and was positively correlated with homocysteine levels but not with BP.42 In their study, they also found no difference in NLR values between hypertensive and normotensive groups. A single office BP measurement and lack of data on antihypertensive medication could be responsible for their results.

In the present study, we found a weak correlation between ABPM data and log NLR values. There are several possible reasons for this: 24-hour ABPM provides short-term data and has limited reproducibility, which makes it difficult to clarify the severity of HTN. In addition, the selection of a relatively low-risk cohort of hypertensive patients may have meant they had only a low-grade inflammatory response, which might have weakened the correlation between NLR and severity of HTN. Nevertheless, despite other confounding factors such as the unknown chronicity of HTN and underlying subclinical end-organ damage, the available data suggest that higher NLR is associated with higher BP and BP load. Thus, our study may function as a hypothesis-generating study and lead to further research.

Our study has some limitations. Firstly, its cross-sectional design precludes drawing conclusions about causal relationships between NLR values and short-term ABPM results. Since ABPM was performed only once in each patient, the reproducibility of ambulatory BP measurements is another limitation. We think that the use of BP load as an outcome is also a limitation because its importance in cardiovascular risk stratification is debatable. In addition, it would have been better to have evaluated leukocyte activation markers, pro-inflammatory cytokines and oxidative stress markers. Exclusion of patients with severe complications of HTN from the present study prevents us from generalizing our results to the whole hypertensive patient population.

We showed for the first time a significant correlation between high BP load and NLR. Further large-scale studies are needed to assess whether NLR can be used to predict HTN severity and to guide therapy in patients with HTN.

The authors have no conflicts of interest to declare.