Continuous Positive Linear Association between the Monocyte to High-Density Lipoprotein Cholesterol Ratio and Hypertension: A Cross-Sectional Study

Background Hypertension poses a major threat to human health, and inflammation is associated with hypertension. The monocyte to high-density lipoprotein cholesterol ratio (MHR) represents a new inflammatory indicator. However, the relationship between the MHR and hypertension remains unclear. The present study investigated the association of MHR with hypertension. Method For this cross-sectional study, we continuously collected data from the Physical Examination Centre of the Second Hospital of Hebei Medical University (N = 6632). The data included patients' demographic information and clinical information including blood pressure, blood biochemical measurements, and MHR. The relationship between the MHR and hypertension was examined using different methods in univariate and multivariate logistic analysis, smooth function analysis, the threshold saturation effect analysis and subgroup analysis. Results The results showed that MHR was positively associated with hypertension without adjustment (odds ratio [OR] = 1.10, 95% confidence interval [CI]: 1.08–1.12, P < 0.001). The positive association still existed in minimally and fully adjusted models (OR = 1.08, 95% CI: 1.06–1.10, P < 0.001; OR = 1.07, 95% CI: 1.05–1.10, P < 0.001). Smooth function analysis of a generalized additive model revealed a continuous positive linear association between the MHR and hypertension throughout all MHR data (OR = 1.07, 95% CI: 1.05–1.10, P < 0.001). Subgroups analysis showed the homogeneity of the positive association among different subgroups. Conclusions A continuous positive linear association was found between the MHR and hypertension in a health examination population.


Introduction
Hypertension is a signifcant risk factor for cardiovascular and cerebrovascular diseases, and as one of the most common chronic diseases worldwide, it represents a serious threat to public health. Predicting the occurrence of hypertension in the early stage, slowing the progress of hypertension, and preventing the onset of and improving the prognosis of cardiovascular and cerebrovascular diseases are crucial issues. It is well established that infammation is associated with hypertension. Studies have shown that lowgrade infammation is a critical factor in elevated blood pressure [1]. Infammation can lead to endothelial damage, increasing the adhesion of a variety of harmful substances and the recruitment of mononuclear phagocytes to the blood vessel walls, prompting the proliferation, motility, and diferentiation of vascular smooth muscle cells, which can induce structural and functional modifcations in the blood vessel walls, such as thickening, hardening, and elasticity reduction, to cause increased blood pressure [2]. Many studies have demonstrated close relationships between infammatory markers and hypertension [3][4][5].
Most of these markers have proven to be a single action indicator with relatively poor stability, whereas the ratio of the monocyte count to the serum high-density lipoprotein cholesterol (HDL-C) level, referred to as the monocyte to HDL-C ratio and abbreviated MHR, provides a comprehensive indicator for evaluating dynamic changes in infammation by combing the indicators of monocyte count and HDL-C level. Monocytes play an essential role in the infammatory process related to hypertension. Under the action of chemokines, monocytes migrate, promote recruitment and activation of adhesion molecules, promote infammation and oxidative stress, and participate in endothelial damage. In contrast, HDL-C resists infammation and oxidative stress in addition to inhibiting the proliferation, diferentiation, and activation of monocytes [6,7]. Te MHR can represent both the antiinfammatory and antioxidative stress abilities along with the state and extent of infammation, and this combined with its stability makes the MHR more advantageous than a single indicator. Moreover, measurements of monocyte counts and serum HDL-C levels are easy and inexpensive in clinical settings. Terefore, this study investigated the clinical value of the MHR as an index. Recent research has provided evidence that the MHR is associated with infammatory conditions such as coronary artery disease [8] and stroke [9]. Notably, hypertension is also characterized by increased levels of metabolic and infammatory markers, including the serum uric acid/HDL-C ratio [10] and triglyceride/HDL-C ratio [11]. Terefore, the monocyte/HDL-C ratio may also be associated with hypertension. However, the research on MHR has mainly focused on its use for the prognosis of cardiovascular and cerebrovascular diseases caused by hypertension [12][13][14][15][16][17][18][19][20][21][22][23]. Te relationship between the MHR and hypertension has yet to characterized.
Te present study aimed to characterize the relationship between the MHR and hypertension in a health examination population. First, we selected a new comprehensive infammation indicator to explore the association with hypertension. Secondly, we selected a health examination population as the study population, as the association between the MHR and hypertension has never been explored in this particular population. Moreover, we strictly controlled confounding factors in multiple regression analyses using three adjusted models, used a generalized additive model to evaluate the relationship accurately and quantitatively, and performed subgroup analyses to further study the relationship in diferent subgroups. Altogether, we explored the relationship between the MHR and hypertension in a health examination from diferent perspectives. Te inclusion criteria included age ≥18 years and the availability of data from routine blood tests or blood lipid tests. Te exclusion criteria included (1) age ≥75 years; (2) diagnosis of diabetes, coronary heart disease, cerebrovascular disease, and severe damage to liver and kidney function; (3) recent acute or chronic infectious disease or chronic autoimmune disease; (4) malignant tumours or blood system diseases; (5) current use of hormones and nonsteroidal anti-infammatory drugs that could have an impact on the study; (6) taking an antilipemic medication that afects HDL-cholesterol levels; (7) a history of mental illness or use of psychotropic drugs; and (8) incomplete records from physical examination.

General Data Collection.
For the study, physical examination data were collected for the population from the Second Hospital of Hebei Medical University, including general demographic data (name, age, sex, height, weight, systolic blood pressure [SBP], diastolic blood pressure [DBP], etc.), clinical information regarding medical history, and blood-related indicators (routine blood test results, liver and kidney function test results, blood lipid levels, etc.).

Diagnostic Criteria and Grouping
Methods. According to the 2013 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) guidelines, hypertension was defned as a SBP ≥140 mm Hg and/or DBP ≥90 mm Hg or lower blood pressure with the administration of antihypertensive medication [24].
For measurement of routine blood counts, blood lipid levels, and other blood indicators, 5 ml samples of venous blood were drawn from the elbow of participants in the morning after overnight fasting (7:00-9:00 am after more than 8 hours without food). First, the blood samples were centrifuged for 10 min at 1912 × g in a BY-600A centrifuge (Beijing Baiyang Medical Instrument Co., Ltd., Beijing, China), and serum was extracted. Blood routine tests were performed using a Beckman Coulter UniCel DxH 800 blood cell analyser (Beckman Coulter Inc., Brea, CA, USA) provided by the Clinical Laboratory of the Second Hospital of Hebei Medical University. Biochemical indicators such as liver and kidney function indexes and blood lipid levels were detected using a Beckman Coulter AU5800 automatic biochemical analyser (Beckman Coulter, Inc., Brea, CA, USA). Te monocyte count and serum HDL-C concentration were used to obtain the MHR. Te participants were then equally divided into three groups, which corresponded to MHR < 5.21, 5.21 ≤ MHR < 7.58, and MHR ≥ 7.58, respectively.

Statistical Methods.
First the measurement data were tested for normality using the Shapiro-Wilk test. Data that followed a normal distribution were expressed as mean-± standard deviation (SD), and those that did not conform to the normal distribution were presented as median with interquartile range. Count data were expressed as percentage (%). One-way analysis of variance (ANOVA) was used to compare normally distributed clinical characteristics among the diferent MHR groups, while a nonparametric test was used to compare measurement data that did not follow a normal distribution. Te chi-square test (χ 2 ) and Fisher exact probability method were used for comparisons of classifcation variables. Univariate regression analysis was performed to analyse the relationships between general demographic data and hypertension. Ten, multivariate logistic regression analysis was applied to explore the relationship between hypertension and the MHR considered as a continuous variable, a standardized continuous variable, a categorical variable, and continuous classifcation variables (sensitivity analysis) in an unadjusted model, minimally adjusted model (adjustment: sex and age), and fully adjusted model (adjustment: sex, age group, smoking history, drinking history, anemia, renal cyst, aspartate aminotransferase [AST] group, alanine aminotransferase [ALT] group, total bilirubin [TBIL] group, uric acid [UA] group, and estimated glomerular fltration rate [eGFR] group). Furthermore, the smoothing function of the generalized additive model was used to ft the potential nonlinear relationship between the MHR and hypertension, and the threshold saturation efect was applied to analyse whether a potential threshold or saturation efect existed between the MHR and hypertension. At the same time, after adjustment for confounding factors, subgroup analyses were performed to verify the relationship between the MHR and hypertension according to each subgroup stratifcation. Diferences for which P < 0.05 were considered to be statistically signifcant. All statistical analyses were performed using the statistical software R.

Demographic and Clinical Characteristics of Participants
Stratifed by MHR Quartiles. Te study population consisted of 6632 adults with a mean age of 49.32 ± 10.96 years, including 3761 men (49.11 ± 10.87 years) and 2871 women (49.58 ± 11.07 years). Te prevalence of hypertension among all participants was 31.76%. Table 1 shows the demographic and clinical characteristics of the participants in diferent MHR groups. Signifcant diferences were observed among the diferent MHR groups for most variables (P < 0.05). Compared with that in the Q1 group, the prevalence of hypertension in the Q3 group was signifcantly higher. In contrast, SBP and DBP in the Q3 group were considerably higher than those in the Q1 group (P < 0.001; Table 1).

Univariate Regression Analysis of the Relationship between MHR and Hypertension.
On univariate analysis, the MHR was positively associated with hypertension, and the risk of hypertension increased by 10.00% with each increase in the MHR unit (odds ratio [OR] � 1.10, 95% confdence interval [CI]: 1.08-1.12, P < 0.001). Moreover, the risk of hypertension in Q3 group was 2.03 times higher than that in Q1 group (OR � 2.03, 95% CI: 1.78-2.31, P < 0.001; Table 2). Table 3, the results of multivariate regression analyses verifed the relationship between the MHR and hypertension in the unadjusted model, the minimally adjusted model, and the fully adjusted model, separately, using four forms of MHR (continuous variable, standardized continuous variable, categorical variable, and continuous classifcation variables). Te results showed that MHR was positively associated with hypertension in the crude model (OR � 1.10, 95% CI: 1.08-1.12, P < 0.001), and the positive association still was found after adjusting for confounding factors in the minimally adjusted model (OR � 1.08, 95% CI: 1.06-1.10, P < 0.001) and fully adjusted model (OR � 1.07, 95% CI: 1.05-1.10, P < 0.001). Moreover, each additional SD in MHR was associated with a 25% increase in the risk of hypertension in the fully adjusted model (OR � 1.25, 95% CI: 1.17-1.32, P < 0.001). When the MHR was converted to a categorical variable, the risk of hypertension in the Q3 group was 55% greater than that in the Q1 group (OR � 1.55, 95% CI: 1.33-1.81, P < 0.001). In all sensitivity analyses, the positive relationship still existed (P < 0.001).

Positive Linear Association between MHR and
Hypertension. Because the MHR was a continuous variable, to further ft and analyse the potential nonlinear relationship between the MHR and hypertension, a smoothing function analysis of the generalized additive model was employed in this study. After adjusting the confounding factors, a continuous positive linear association was observed between the MHR and hypertension. Analysis of the threshold efect showed that the positive linear relationship between the MHR and hypertension continued through all MHR values among the study population (Table 4, Figure 1).

Subgroup Analyses of the Relationship between MHR and
Hypertension. After an overall analysis, further subgroup analyses were performed to study the relationship between the MHR and hypertension. As shown in Figure 2, the relationship between the MHR and hypertension was analysed in diferent subgroups after adjustment of confounding factors. Te results revealed homogeneity of the positive association was in further subgroups (P < 0.01).

Discussion
Te present study comprehensively evaluated the association between the MHR and hypertension in a health examination population. Te main results of the study are as follows: (1) Te MHR was positively associated with hypertension with strict control for confounding factors. (2) A continuous International Journal of Hypertension Aydin et al. [13] confrmed that the MHR was positively associated with asymptomatic target organ damage in hypertension. Yayla et al. [25] found that the MHR in newly diagnosed and untreated hypertensive patients was signifcantly higher than that in healthy controls. Still, they did not further exclude confounding factors to analyse the actual International Journal of Hypertension relationship between the MHR and hypertension. Ji [26] investigated the MHR and asymptomatic target organ damage in patients with hypertension of varying severity, but performed only univariate analysis to analyse the relationship between the MHR and hypertension. Because the above studies focused on the MHR and target organ damage, the actual relationship between the MHR and hypertension was not studied. However, we explored the relationship between the MHR and hypertension from multiple directions and angles. Te relationship between the MHR and hypertension was analysed in univariate and multivariate analyses. In multivariate analysis, the MHR was considered according to diferent data types. At the same time, the use of diferent multivariate regression analyses gradually eliminated confounding factors to analyse the relationship between the MHR and hypertension. Moreover, we used a generalized additive model to evaluate the relationship accurately and quantitatively, and subgroup analyses to further identify the relationship in diferent subgroups. Finally, a continuous positive linear association between the MHR and the risk of hypertension was observed and continued for all values of the MHR. However, the underlying mechanism remains unclear. When an infammatory response occurs in the body, LDL-C can enter into the vascular endothelium. Te oxidized LDL-C can promote aggressive adhesion of monocytes to the vascular endothelium and can facilitate monocyte translation into macrophages, which can change into M1 and M2 phenotypes depending on infammatory status. Te M1 phenotype mainly leads to the occurrence of infammation, which will maintain and aggravate the degree of hypertension. In comparison, the M2 phenotype can adjust the process of infammation and cellular immune response, alleviating    Te red line represents the estimated probability of hypertension with increasing MHR. Blue bands represent 95% confdence intervals. Adjusted for sex, age group, alcohol drinking, smoking, anemia, renal cyst, eGFR group, UA group, AST group, ALT group, and TBIL group. tissue damage and promoting organization repair [27][28][29]. Upon the occurrence of an infammatory, M1 and M2 macrophages can switch functionally via regulation by the neuroimmune system, which causes a polarized state of macrophages that promotes permeation of cytokines into the central nervous system and stimulates the release of infammatory factors locally. Tey pass the hypothalamus and its corresponding neural pathways and then connect nerve fbers directly to stimulate sympathetic nerves, which fnally increases the blood pressure, leading to the development and progression of hypertension [30][31][32]. Tese fndings show that LDL-C and monocytes/macrophages play an essential role in the development of hypertension. Diferent from the damaging efect of LDL-C on blood vessels, HDL-C has antiinfammatory, antiapoptosis, and antiarteriosclerotic activities. Additional studies have demonstrated that HDL-C has anti-infammatory and antioxidant efects and inhibits monocyte activation, proliferation, and diferentiation, thus reducing the infammatory response caused by monocytes [6,7]. In addition, HDL-based markers play an important role in hypertension and related disorders. Te serum uric acid/ HDL ratio is associated with hypertension and other conditions that interact with hypertension, such as metabolic syndrome, type T2DM, and nonalcoholic fatty liver disease [10,[33][34][35]. Another marker, the triglyceride/HDL ratio, was found to be elevated in both hypertension and type T2DM [11,36]. In the occurrence and development of hypertension, monocytes play the role of promoting infammation and hypertension. In contrast, HDL-C acts to reduce infammation and antagonize monocytes. Because the MHR combines monocytes and HDL-C, an increased MHR can represent an enhanced infammatory response and a decrease in anti-infammatory and antioxidant abilities, which may explain the mechanism by which a higher MHR is associated with increased blood pressure.
Te present study ofers the advantages of being one of the frst studies on the MHR and hypertension at present. As a new infammatory index MHR has a certain degree of novelty. Moreover, this study was an observational study, including inevitable potential confounding factors, and therefore, rigorous statistical methods were adopted to minimize the impact of confounding factors. In the analysis, the relationship between the MHR and hypertension was frst analysed in an unadjusted model, a minimally adjusted model, and a fully adjusted model using four forms of MHR to represent the relationship between the MHR and   hypertension more comprehensively. Secondly, this study used the smoothing function analysis of the generalized additive model to ft the potential nonlinear relationship of the MHR with hypertension to discover the true relationship between exposure and outcome. Finally, subgroup analyses further verifed the relationship between the MHR and hypertension independent of a variety of clinical factors. Te present study also has some limitations and defciencies. First, this was a cross-sectional study, providing only weak evidence for the relationship between exposure and results and unable to determine the causal connection. Terefore, the causal relationship between the MHR and hypertension needs to be further verifed in prospective studies. Second, some data were missing in the data collection process, including some medication use (antihypertensives and antihyperglycemics). Te missing data could have led to a certain of results ofset, afecting the relationship between the MHR and hypertension. While we excluded individuals taking antilipemic medication (statins and fbrates antilipemic) known to afect the HDL-cholesterol level, but some other medications, including antihypertensives and antihyperglycemics, might also have infuenced the results. Moreover, this study did not include other infammatory indicators, and the efects of the MHR and other infammatory indicators on hypertension were not analysed. Data for other infammatory indicators and complete medication use will be collected in our next study to further improve this research. At last, this study was conducted in a single-centre of a health examination population, which may have led to population selection bias and limiting the extension of the results to all groups. Terefore, further verifcation by multicentre, multiethnic, and largescale clinical studies is still needed.
In conclusion, the MHR was positively associated with hypertension, and a continuous positive linear association was identifed between the MHR and the risk of hypertension for all values of MHR.

MHR:
Te monocyte to high-density lipoprotein cholesterol ratio HDL: C high-density lipoprotein cholesterol SBP: Systolic blood pressure DBP: Diastolic blood pressure AST: Aspartate aminotransferase ALT: Alanine aminotransferase TBIL: Total bilirubin UA: Uric acid eGFR: Estimated glomerular fltration rate ANOVA: One-way analysis of variance OR: Odds ratio CI: Confdence interval SD: Standard deviation.

Data Availability
Te datasets generated during and/or analysed during the current study are available from the corresponding author upon reasonable request.

Ethical Approval
Tis study was approved by the Ethics Committee of the Second Hospital of Hebei Medical University (2021-P035).