Dysglycemic states and hypertension : A relationship dependent on low-grade inflammation

Hypertension (HTN) is a prominent cardiovascular risk factor, Background: affecting over 1 billion people worldwide. Identification of closely associated cardiometabolic conditions may be crucial for its early detection. The objective of this study was to identify factors associated with HTN and prehypertension (PHT) in an adult population sample from Maracaibo City, Venezuela. A randomized multi-staged sampling cross-sectional study was Methods: performed in 2230 individuals from Maracaibo City Metabolic Syndrome Prevalence Study database. PHT and HTN were defined according to JNC-7 criteria. Multiple logistic regression analysis was used to assess the main risk factors for each condition. 52.6% (n=1172) of the subjects were female, the prevalence of HTN Results: was 32% (n=714), while the prevalence of PHT was 31.1% (n=693). The main risk factors for HTN were age ≥60 years (odds ratio [OR]: 40.99; 95%CI: 16.94-99.19; p<0.001) and the local indigenous ethnic group (OR: 3.06; 95%CI: 1.09-8.62; p=0.03). Adjustment for high sensitivity C-reactive protein levels increased the OR of these factors and diminished the impact of other factors. Meanwhile, age ≥60 years (OR: 3.39; 95%CI: 1.41-8.18; p=0.007) and alcohol consumption (OR: 1.49; 95%CI: 1.06-2.00; p=0.02) were the main risk factors for PHT. There are significant differences in the risk factor profiles for HTN Conclusion: and PHT. Additionally, low-grade inflammation appears to link multiple metabolic factors and preexisting vascular characteristics. 1 1,2 1 2

Hypertension (HTN) is the leading risk factor contributing to mortality worldwide, associated with approximately 9.4 million deaths every year 1 .In addition, it is the main modifiable risk factor for the development of cardiovascular disease (CVD) 2 , which causes the greatest numbers of death globally, with 17.5 million deaths in 2012 3 and projections of up to 23.3 million deaths annually by 2030 4 .Given its complex etiology, HTN has been classified as primary when appearing without any identifiable cause (90% of all cases) and secondary HTN when resulting as a direct consequence of another known preexisting condition, such as cardiovascular or kidney disease 5 .
Research on primary HTN has focused on identifying different risk factors, which could help define its specific etiology 6 .Various genetic and environmental conditions have been categorized as modifiable and non-modifiable risk factors: Family history of HTN is considered to be one of the main nonmodifiable risk factors 7 , along with age, sex and race 8 .On the other hand, high sodium intake, hypercaloric diets, smoking, alcohol consumption, obesity, and a sedentary lifestyle all represent modifiable risk factors 9,10 .
Likewise, low-grade inflammation has been suggested to play a great role in the pathophysiology of HTN, due to the stimulation of the proliferation of endothelial vascular smooth muscle cells in addition to vascular remodeling and endothelial dysfunction 11 .
Several epidemiological studies have reported high levels of inflammatory markers, such as C-reactive protein (CRP) and proinflammatory cytokines in patients with HTN.Furthermore, these findings correlate with a higher risk of developing HTN, as well as target organ damage in healthy individuals 12 .
Considering the high prevalence of HTN in the Venezuelan population 13 , it becomes imperative to identify the conditions associated with both HTN and prehypertension (PHT) in order to aid in early diagnosis.The objective of this study was to determine the main associated risk factors for HTN and PHT in adult patients from Maracaibo City, Venezuela.

Ethical considerations
This study was approved by the Bioethics Committee of the Endocrine and Metabolic Research Center -University of Zulia (approval number: BEC-006-0305).All participants enrolled in the study signed a written consent before any questioning, intervention, or physical examination.This ethical approval includes all future studies using this data set.Maracaibo City is divided into parishes, where each parish was proportionally sampled through a multi-staged cluster selection method.In the first stage, clusters were represented by sectors from each of the 18 parishes with proportional representation.Four sectors were selected from each parish by simple randomized sampling.In the second phase, the clusters were represented by city blocks within each sector, which were selected by simple randomized sampling using a random number generator.From the overall population, 2,026 individuals were selected on the basis of availability of insulin determination.Further details of the sampling process have been previously published 14 .

Subject evaluation
A full medical history and blood samples for biochemical evaluation were obtained from each participant by trained personnel.A full physical examination was also performed.Collected data included age, gender, ethnic group, socioeconomic status (according to the method of Graffar modified by Mendez Castellano 15 ), smoking habit and family history of HTN.High risk alcohol intake was defined as those consuming ≥1 gram of alcohol daily.
Physical activity (PA) was measured using the International PA Questionnaire-Long Form (IPAQ-LF) 16 .Each domain of the questionnaire was clustered in quintiles according to the calculated metabolic equivalents (METs) and classified according to the PA pattern in one of six categories: very low, low, moderate, high, and very high in addition to a category for inactive individuals or those whose METs equaled zero.
In addition, an anthropometric evaluation was performed: weight was determined using a digital scale (Tanita, TBF-310 GS Body Composition Analyzer, Tokyo-Japan) while height was measured with a previously calibrated stadiometer on a flat surface.Body Mass Index (BMI) was calculated with the Quetelec's formula [Weight/(Height) 2 ] and individuals were categorized based on the World Health Organization (WHO) classification 17 .Waist circumference was measured with a plastic measuring tape graduated in centimeters and millimeters, taking an equidistant point between the costal margin and the anterior superior iliac spine as an anatomical reference, according to the protocol proposed by the US National Health Institute (NHI) 18 .
Blood pressure measurement Blood pressure (BP) was taken through auscultation with subjects sitting down and feet on the floor following 15 minutes of rest, determined with a calibrated mercury sphygmomanometer.Korotkoff's phases I and V were identified as systolic and diastolic BP, respectively.BP was determined 3 times with 15 minutes intervals between each registration on two different days.BP was categorized according to the Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of Hypertension (JNC-7) criteria 19 .PHT is classified as systolic BP between 120 mmHg and 139 mmHg or diastolic BP between 80 mmHg to 89 mmHg.HTN is classified as systolic BP greater than 140 mmHg or diastolic BP over 90 mmHg.

Definitions
HOMA2-IR was utilized for the evaluation of insulin resistance (IR) as proposed by Levy et al. 20 computed with the HOMA-Calculator v2.2.2 software application with IR defined as HOMA2-IR ≥2 21 .Elevated hs-CRP was defined as levels ≥0.765 mg/L 22 ; hypertriacylglyceridemia was defined as fasting TAG ≥150 mg/dL; and low HDL-C as fasting HDL-C <50 mg/dL in females or <40 mg/dL in males 23 .Regarding glycemic state, subjects were classified as: a) Normoglycemic, individuals with fasting glucose <100 mg/dL; b) Impaired Fasting Glucose (IFG), those with fasting glycemia between 100-126 mg/dL; and c) Type 2 diabetes mellitus (DM2), those with fasting glycemia >126 mg/dL or a previously established diagnosis 24 .Likewise, waist circumference cutoff points ≥90 cm (females) and ≥95 cm (males) for the definition of abdominal obesity were used 25 .
We followed the methods similar to previous analyses with other risk factors 26 .

Statistical analysis
Variables with non-normal distribution underwent logarithmic transformation, showing a normal distribution after the Geary test, qualitative variables were expressed in absolute and relative frequencies, evaluating association through the χ 2 test.Multiple logistic regression analysis was used to study the risk factors associated with PHT and HTN.Two models were devised for the latter, where the first model was adjusted by sex, age groups, ethnic groups, family history of hypertension, smoking, alcohol consumption, household physical activity, leisure time physical activity, hypertriglyceridemia, low HDL-C, glycemic status, BMI categories and elevated waist circumference.The second model was adjusted for all these factors and high serum hs-CRP levels.The multiple logistic regression model for PHT was adjusted for the same factors as the second model.Results were shown in Odds Ratios (95%CI) being statistically significant when p<0.05.Data analysis was performed using the Statistical Software SPSS v. 19 for Windows (IBM inc.Chicago, IL).

Prevalence of hypertension and prehypertension
Normotensive individuals comprised 36.9% of the sample (n=823).The prevalence of PHT was 31.1% (n=693), while 32% (n=714) of the subjects were hypertensive.Therefore, a combined total of 63.1% of the sample showed altered BP levels (Figure 1).

General characteristics of the population
Table 1 and Table 2 show the distribution of subjects according to the presence of PHT and HTN.Age (χ 2 =438.82;p<0.0001) and home PA (χ 2 =39.53 p<0.001) were the main sociodemographic and psychobiologic factors associated with these conditions, respectively; whereas BMI was the main clinical-metabolic factor associated with HTN and PHT in the univariate analysis (χ 2 =264.36;p<0.0001).

Risk factors for hypertension
In the first model (

Discussion
HTN represents the main modifiable risk factor for the development of CVD 2 , which is why it is alarming that only 4 of 10 individuals in this sample exhibit normal BP levels.According to the WHO, the prevalence of HTN in the Americas is 35% 27 , similar to those in our study at 32%.In a cross-sectional study by Wang and Wang 28 , based on the data obtained in the 1999-2000 National Health and Nutrition Examination Survey (NHANES) and using JNC-7 classification, the prevalence of HTN was slightly lower than ours (27.1%), while also reporting a similar prevalence for PHT (31%).Following the same methodology, Erem et al. 29 assessed a population of 4809 individuals in Turkey and reported results markedly differing from ours, with a prevalence of 44% for HTN and 14.5% for PHT.Lastly, another study by Do et al. 30 on a population of 17,199 Vietnamese individuals described a vastly different picture, where the prevalence of HTN was lower than PHT (20.7% vs 41.8%), which illustrates the heterogeneous distribution of this disease around the world.In regards to the non-modifiable risk factors for HTN, our multivariate models showed that men had a higher risk of developing this disease, similar to several studies in Turkey 29 , China 31 and Guatemala 32 .However, age appears to be the main risk factor in our sample.In this context, a cross-sectional study by Awoke et al. 33 on 679 adult individuals aged ≥35 years ascertained greater HTN risk for individuals aged ≥55 years in comparison to those aged 35-44 years.Similarly, Katulanda et al. 34 and Mc Donald Posso et al. 35 found higher risk in individuals aged ≥70 years and ≥60 years, respectively.This association could be explained by the development of atherosclerosis with age 36 .Family history of HTN was also a significant risk factor in our study.Other studies around the world, such as the one published by Ranasinghe et al. 37 , have reported a higher risk in adult individuals with family history of HTN, similarly to Awoke et al. 33 ; these findings support the relevance of the genetic component in the pathogenesis of HTN 7 .
Among the modifiable risk factors assessed, both hypertriacylglyceridemia and dysglycemic states showed a close link with HTN, in harmony with previous reports 38 .Nevertheless, it should be noted that both of these factors lost significance in the multivariate models after adjusting for hs-CRP, underlining the dependent relationship between low-grade inflammation and HTN in regards to alterations of carbohydrate and lipid metabolism.This link was ascertained notwithstanding adjustment for IR, the hallmark etiopathogenic mechanism found in the metabolic syndrome 39 .
Concerning obesity, BMI-classified obese and overweight individuals.as well as those with increased waist circumference.showed a higher risk for HTN even after adjustment for hs-CRP.Similarly, Guwatudde et al. 40 studied 3906 individuals in sub-Saharan Africa and reported BMI as the only modifiable risk factor for HTN with a higher risk for overweight and obese individuals.Indeed, the predictive value of waist circumference as a risk factor for HTN tends to vary in a population-specific fashion.In a Croatian cohort of 9070 subjects, Ivičević Uhernik et al. 41 ascertained greater HTN risk in individuals with waist circumference ≥94 cm for males, and ≥88 cm for females.These results coincide with previous investigations that show the propensity of HTN to present alongside other cardiometabolic  disorders 42,43 .In this regard, IR has been suggested to play a paramount role as the common denominator connecting the pathophysiology of these conditions 44 , promoting vascular alterations independently of the impact of concurrent low-grade inflammation, including increased expression of vascular cell adherence molecules, oxidative stress, and a decrease in nitric oxide availability 45 .On the other hand, an increase in adiposity has also been associated with higher angiotensin II and aldosterone levels 46,47 , postulating obesity as a state of inappropriate activation of the renin angiotensin aldosterone system; thus, participating in conjunction with IR in the pathogenesis of HTN and other associated cardiometabolic diseases 46 .
The link between immunity, inflammation, and the development of HTN has been a subject of intense research in recent decades 12 .Increased levels of inflammatory biomarkers, such hs-CRP, have been independently associated with higher cardiovascular risk 48 .In this study, after adjusting for hs-CRP levels and several other variables, indigenous populations were shown to be at a higher risk for HTN in contrast with the data analyzed by NHANES 2011-2012 49 .Afro-Venezuelan individuals had the highest prevalence for HTN when compared to non-Hispanic white individuals, Hispanic, and Asian groups.This may be explained by the fact that this ethnic group often suffer from lower socioeconomic status in addition to chronic stress, worse healthcare, or discrimination 50 .
IR also behaved as a risk factor after adjusting for hs-CRP, comparable to results of El Bcheraoui et al. 51 , reported after studying 10,735 individuals aged ≥15 years where subjects with DM2 had a higher risk for HTN.The risk in prediabetes, however, was not significant.Similarly, a study by Sung et al. 52 in 8347 individuals showed that increased hs-CRP levels were an independent risk factor for the development of HTN, analogous to our findings.CRP is involved in the innate immune response with diverse functions that include stimulating monocytes for the  release of pro-inflammatory cytokines, such as interleukin(IL)-6, IL-1β and tumor necrosis factor alpha, as well as the expression of intercellular adhesion molecules (ICAM-1) and vascular cell adherence molecules 53 .These effects underlie the link between inflammation and the development of HTN.
Age, alcohol consumption and low HDL-C were identified as risk factors for PHT in this study, echoing the findings by Wu et al. 54 where individuals with PHT were older and had low HDL-C.Furthermore, Singh et al. 55 reported a higher risk for PHT with older age in both males and females, while the risk associated with alcohol consumption was only significant for men.On the other hand, PA at home was determined to be a protective factor for PHT according to our model, in contrast to the higher risk reported for sedentary individuals 56 .Poor lifestyle habits have been previously highlighted as the main determinants of PHT 19 , possibly able to modify early pathophysiologic alterations found in these subjects, such as high levels of IL-17 57 .
Our findings reflect the importance of focusing efforts towards decreasing the presence of various risk factors in the adult population of Maracaibo City, particularly considering the high prevalence of PHT and HTN and the differences in risk profiles for each state.The key modulating role of low-grade inflammation was also prominent in our study.
The limitations of this study include its cross-sectional design, which prevents the assessment of causality.However, the data analysis is comparable to current literature and provides important information about non-communicable diseases in Latin American communities -allowing for the design and implementation of primary care programs to detect individuals at risk of PHT and HTN in this context.
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Figure 1 .
Figure 1.Prevalence of hypertension and prehypertension in adult individuals from Maracaibo, Venezuela.2016.
14is report is part of the Maracaibo City Metabolic Syndrome Prevalence Study14, a cross-sectional study whose purpose is to identify metabolic syndrome and cardiovascular risk factors 14 the adult population of Maracaibo, the second largest city of Venezuela.The study sample was calculated based on city population estimates by the National Institute of Statistics: (1,428,043 inhabitants for the year 2007), amounting to 1,986 individuals.An additional 244 subjects (12%) were included for oversampling in order to increase accuracy of the estimates obtained from smaller subgroups within the overall sample, totaling 2,230 individuals14.
HTN= Hypertension¥ Drinker defined as intake ≥1 gram of alcohol per day.

Table 3 . Risk factors for hypertension in adult individuals from Maracaibo, Venezuela. 2016
.
a Confidence Interval (95%); b Significance level; c Triglycerides ≥150 mg/dL; d HOMA2-IR≥2 * Model 1: Adjusted for sex, age groups, ethnic groups, socioeconomic status, family history of hypertension, smoking habit, alcohol intake, home physical activity per the IPAQ-LF, leisure physical activity per the IPAQ-LF, low HDL-C, hypertriacylglyceridemia, glycemic status, BMI categories, insulin resistance, elevated waist circumference (≥95cm for males; ≥90cm for females).** Model 2: Adjusted for sex, age groups, ethnic groups, socioeconomic status, family history of hypertension, smoking habit, alcohol intake, home physical activity per the IPAQ-LF, leisure physical activity per the IPAQ-LF, low HDL-C, hypertriacylglyceridemia, glycemic status, BMI categories, insulin resistance, elevated waist circumference (≥95cm for males; ≥90cm for females); AND elevated hs-CRP levels.

Table 4 . Risk factors for prehypertension in adult individuals from Maracaibo, Venezuela. 2016
.
a Confidence Interval (95%); b Significance level; c Triglycerides ≥150 mg/dL; d HOMA2-IR≥2 Model adjusted for sex, age groups, ethnic groups, socioeconomic status, family history of hypertension, smoking habit, alcohol intake, home physical activity per the IPAQ-LF, leisure physical activity per the IPAQ-LF, low HDL-C, hypertriacylglyceridemia, glycemic status, BMI categories, insulin resistance, elevated waist circumference (≥95cm for males; ≥90cm for females); AND elevated hs-CRP levels.