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Association between dehydroepiandrosterone levels and cardiovascular risk in public sector health workers in a Peruvian region

Rojas, Ricardo J.a,,b; Chávez-Sosa, Janett V.c; Gutierrez-Ajalcriña, Rosmeryd; Huancahuire-Vega, Salomóna

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Cardiovascular Endocrinology & Metabolism: March 2021 - Volume 10 - Issue 1 - p 51-55
doi: 10.1097/XCE.0000000000000219
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Abstract

Introduction

General cardiovascular risk is the probability of developing cardiovascular disease (CVD) within a defined period of time, taking into account epidemiological factors such as diabetes, dyslipidemia, hypertension and obesity [1,2]. CVD refers to the group of heart and blood vessel disorders which includes: hypertension, heart attack, stroke, peripheral vascular disease, heart failure, rheumatic heart disease, congenital heart disease and cardiomyopathies [2].Mortality from CVD has increased in recent decades in low- and middle-income countries in Latin America, including Peru [3,4].

Several studies have shown that endogenous hormones play an important etiological role in certain CVDs [5]. Alterations in the levels of testosterone, estrogens and their precursor dehydroepiandrosterone (DHEA), as well as their derivative DHEA sulfate (DHEAS) have direct and indirect effects on coronary heart disease and arterial hypertension [6]. DHEAS is the most abundant circulating hormone in humans, produced mainly by the adrenal cortex. There is evidence that low levels of DHEAS are associated with an increased risk of coronary disease and stroke [7]. Some of the cardioprotective mechanisms of this hormone include the decrease in adenosine diphosphate secretion, inhibition of platelet activation by Akt, ERK 1/2 and P38 mitogen-activated protein kinase and synergism with nitric oxide, which reduces thrombin-dependent platelet aggregation in the development of coronary heart disease [8]. Other biological protective mechanisms include anti-inflammatory effects mediated by tumor necrosis factor alpha, decrease of interleukin 8, intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and translocation of nuclear factor kappa-light-chain-enhancer of activated B cells by the activation of peroxisome proliferator-activated receptor alpha [9].

The association between plasma levels of DHEAS and cardiovascular risk in a Peruvian population has not yet been reported. The present study determines the DHEAS levels and cardiovascular risk according to the Framingham score in a group of workers at a public hospital which is part of the Ministry of Health in Lima.

Methods

An analytical cross-sectional study was carried out with workers who were either appointed or under administrative service contracts (ASC) who participated in the plan for the prevention and surveillance of communicable and noncommunicable diseases at the Hospital de Huaycán II-1, Lima, Peru. This annual assessment includes anthropometric measurements and laboratory tests of the appointed staff and ASC, totaling 368 eligible workers. The evaluation was carried out by the epidemiology unit and clinical laboratory from March to July 2019 which was attended by 316 workers. The study was approved by the hospital’s ethics committee (Ethical Committee No 023-2019), with a waiver of consent (Chairperson Dr. Juan Yafac Villanueva) on 2 July 2019. Written informed consent was obtained from all recruited workers after they were fully informed about the study.

The Framingham risk score was chosen to measure general cardiovascular risk over 10 years, because it includes significant risk factors for calculating based on the Cox proportional-hazards regression model [10]. The validity of the instrument for a Latin American population was previously shown through a multivariable analysis of receiver operating characteristics (ROC), which obtained an area under the curve (AUC) of 0.79 [11].

Participants with a history of acute myocardial infarction, chronic coronary disease, cerebrovascular disease and peripheral arterial disease were excluded from the study. The remaining 296 workers were assessed for cardiovascular risk and categorized as high (risk >20%), intermediate (risk 10–20%) and low (risk <10%) [12] and the ATP III criteria were used to identify metabolic syndrome [13].

The DHEAS competitive ELISA kit (Invitrogen, Carlsbad, California, USA) was used to quantify the plasma levels of DHEAS, and samples were processed by personnel from the Molecular Biology Research Laboratory at the Universidad Peruana Unión. For this analysis, workers from high and low cardiovascular risk groups were included, but pregnant women, breastfeeding women, those with a diagnosis of polycystic ovary, those with adrenal gland disorders, those on hypoglycemic or hypocholesterolemic drugs 3 months prior to the evaluation and those who did not sign the informed consent were excluded.

Statistical analysis

Descriptive statistics such as mean, SD, confidence intervals (CIs) and percentages were prepared for all parameters in the study. The Mann–Whitney U-test and Spearman’s rank correlation coefficient were used to find the difference and correlation between DHEAS values and cardiovascular risk in the univariate analysis. To determine the association of DHEAS with cardiovascular risk, values were grouped into high and low cardiovascular risks, then the Poisson regression analysis with robust variance was used, with the cutoff point set at the third quartile and subsequent calculation of the prevalence rate ratio (PRR) and 95% CI. P <0.05 was considered as significant. The programming language R version 3.6.2 was used for the statistical analysis.

Results

A total of 368 workers were registered at the Hospital de Huaycan II-1, Lima, Peru; 296 of them met the criteria of the study (n = 296). The population consisted of 87 men (29.4%) and 209 women (70.6%). The average age was 45.4 ± 9.3 years, most of the workers had patient care responsibilities (69.9%), had a smoking habit (88.9%) and did not have diabetes mellitus (86.8%). The variables weight, waist circumference, body fat, glucose, triglycerides, LDL-col, HDL-col, uric acid, hemoglobin, systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP) and pulse pressure (PP) showed significant differences between the male and female gender. The cardiovascular risk according to the Framingham score revealed that 67.2% of workers have a low risk, 22.3% an intermediate risk and 10.5% a high risk, with the highest risk predominating in men. Furthermore, 25.3% of all workers had metabolic syndrome with predominance in women (Table 1).

Table 1 - Characteristics of the population of health workers according to gender
Variable Total Male Female 95% CI
(n = 296) (n = 87) (n = 209)
Workers (%)
 Administrative 62 (20.9) 20 (23.0) 42 (20.1)
 Healthcare 207 (69.9) 49 (56.3) 158 (75.6)
 General services 27 (9.1) 18 (20.7) 9 (4.3)
Age (years) 45.4 ± 9.3 47.2 ± 9.2 44.7 ± 9.3 [44.4–46.5]
Weight (kg)a 68.3 ± 13.0 76.3 ± 13.2 65.0 ± 11.5 [66.8–69.8]
BMI (kg/m2) 28.2 ± 4.3 28.5 ± 4.0 28.1 ± 4.4 [27.7–28.7]
Waist circunference (cm)a 92.2 ± 10.8 96.8 ± 11.9 90.3 ± 9.7 [91.0–93.5]
Body fat (%)a 33.2 ± 6.4 27.5 ± 4.7 35.6 ± 5.5 [32.5–34.0]
Glucose (mg/dL)a 95.9 ± 30.6 100.9 ± 32.5 93.8 ± 29.6 [92.4–99.4]
Cholesterol (mg/dL) 194.0 ± 36.1 202.0 ± 36.3 192.0 ± 35.7 [190.8–199.1]
Triglycerides (mg/dL)a 162.0 ± 84.9 187.1 ± 101.9 151.7 ± 74.7 [152.4–171.8]
LDL-col (mg/dL)a 119.0 ± 79.0 121.6 ± 28.9 118.4 ± 92.2 [110.3–128.3]
HDL-col (mg/dL)a 49.3 ± 10.0 47.2 ± 8.8 50.2 ± 10.3 [48.2–50.4]
HbA1c (%) 6.1 ± 1.2 6.1 ± 1.4 6.0 ± 1.1 [5.9–6.2]
Uric acid (mg/dL)a 3.9 ± 1.1 4.6 ± 0.9 3.7 ± 1.0 [3.8–4.1]
Hemoglobin (g/dL)a 12.9 ± 1.6 14.3 ± 1.4 12.4 ± 1.2 [12.8–13.1]
SBP (mmHg)a 108.0 ± 13.1 115.2 ± 12.2 105.6 ± 12.5 [106.9–109.9]
DBP (mmHg)a 68.8 ± 10.5 73.6 ± 11.0 66.9 ± 9.7 [67.6 -70.0]
MAP (mmHg)a 82.0 ± 10.5 87.4 ± 10.3 79.8 ± 9.8 [80.8–83.2]
PP (mmHg)a 39.5 ± 9.6 41.6 ± 10.4 38.8 ± 9.2 [38.4–40.7]
Smoker (%) Yes 263 (88.9) 77 (88.5) 186 (89.0)
No 33 (11.1) 10 (11.5) 23 (11.0)
Diabetes (%) Yes 39 (13.2) 12 (13.8) 27 (12.9)
No 257 (86.8) 75 (86.2) 182 (87.1)
Diabetes familiy history (%) Yes 94 (31.8) 28 (32.2) 66 (31.6)
No 202 (68.2) 59 (67.8) 143 (68.4)
Treatment (%)b Yes 9 (3.0) 2 (2.3) 7 (3.3)
No 287 (97.0) 85 (97.7) 202 (96.7)
Cardiovascular risk (%)c
 High 31 (10.5) 19 (21.8) 12 (5.7)
 Intermediate 66 (22.3) 30 (34.5) 36 (17.2)
 Low 199 (67.2) 38 (43.7) 161 (77.0)
Metabolic syndrome (%)c Yes 75 (25.3) 14 (16.1) 61 (29.2)
No 221 (74.7) 73 (83.9) 148 (70.8)
Data are either mean ± SD or percentage.
CI, confidence interval; DBP, diastolic blood pressure; HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MAP, median blood pressure; PP, pulse pressure; SBP, systolic blood pressure.
aSignificant difference (P < 0.05) between male and female gender by U of Mann–Whitney.
bMedical treatment for high blood pressure.
cSignificant association (P < 0.05) by Pearson’s Chi square.

For the DHEAS analysis, the workers who presented a condition unrelated to the study variables that could alter the DHEAS values were discarded; 60 workers were eligible for quantification, 20 from the high-risk group and 40 from the low-risk group cardiovascular. When comparing the cardiovascular risk groups, significant differences (2156.9 vs 2814.6 ng/mL, P < 0.05) and male gender association were found (Table 2), and the relationship between DHEAS and cardiovascular risk was inversely proportional (Rho = −0.32, P < 0.05) (Fig. 1). Body weight, waist circumference, glucose, triglycerides, LDL-col, glycosylated hemoglobin (HbA1c), hemoglobin, MAP and PP presented significant differences between the high and low cardiovascular risk groups. Additionally, the multivariable analysis showed that DHEAS (PRR 0.14, 95% CI 0.04–0.53; P < 0.05), HbA1c (PRR 4.19, 95% CI 1.86–9.46; P < 0.05), PP (PRR 2.27, 95% CI 1.17–8.48; P < 0.05) and MAP (PRR 3.60, 95% CI 1.71–7.61; P < 0.05) show an independent association with high cardiovascular risk (Table 2).

Table 2 - Study variables and cardiovascular risk in health workers
Variables Cardiovascular risk Univariate analysis Multivariable analysis
High (n = 20) Low (n = 40) P value PRRa 95% CI P value
Gender (%)
 Male 12 (60.0) 5 (12.5) <0.001b
 Female 8 (40.0) 35 (27.5)
Weight (kg) 75.0 ± 11.0 68.3 ± 11.4 0.04b 1.87 0.85–4.13 0.121
Waist circunference (cm) 99.9 ± 8.9 93.9 ± 8.4 0.019b 1.22 0.56–2.68 0.614
BMI (kg/m2) 30.5 ± 4.6 29.1 ± 4.9 0.562
Body fat (%) 36.0 ± 6.8 35.7 ± 6.9 0.76
Glucose (mg/dL) 135.6 ± 52.1 87.1 ± 52.3 0.005b 1.37 0.57–3.32 0.480
Triglycerides (mg/dL) 211.4 ± 87.0 153.3 ± 88.0 0.015b 0.58 0.21–1.60 0.295
LDL-col (mg/dL) 145.2 ± 32.5 114.4 ± 32.5 0.002b 1.48 0.50–4.41 0.477
HbA1c (%) 7.7 ± 2.1 5.8 ± 2.7 0.001b 4.19 1.86–9.46 0.001c
Uric acid (mg/dL) 4.5 ± 1.2 3.9 ± 1.0 0.075
Hemoglobin (g/dL) 13.7 ± 1.6 12.7 ± 1.3 0.003b 0.52 0.21–1.27 0.152
Diabetes familiy history
 Yes 8 (40.0) 13 (32.5) 0.774
 No 12 (60.0) 27 (67.5)
MAP (mmHg) 91.2 ± 11.7 80.9 ± 11.7 0.002b 3.60 1.71–7.61 0.001c
PP (mmHg) 45.5 ± 9.2 38.0 ± 9.9 0.018b 2.27 1.17–8.48 0.023c
DHEAS (ng/mL) 2156.9 ± 773.4 2814.6 ± 773.6 0.005b 0.14 0.04–0.53 0.003c
Data are either mean ± SD or percentage. Bold values indicates statistical significance P < 0.05.
DHEAS, dehydroepiandrosterone sulfate; HbA1c, glycosylated hemoglobin; LDL, low-density lipoprotein; MAP, median blood pressure; PP, pulse pressure; PRR, prevalence rate ratio.
aStatistical significance P < 0.05 by U of Mann–Whitney or Pearson’s Chi squared.
bPrevalence rate ratio.
cStatistical significance P < 0.05 by Poisson regression analysis.

Fig. 1
Fig. 1:
Negative relationship between logarithms of DHEAS (ng/mL) and cardiovascular risk by Spearman correlation coefficient (Rho = −0.32, P < 0.05). DHEAS, dehydroepiandrosterone sulfate.

Discussion

According to the WHO/PAHO, CVDs are the main cause of death in the world, and in Peru, they are the second most common cause of death according to the results of the epidemiology department of the Peruvian Ministry of Health [14]. The identification of cardiovascular risk factors is important for the prevention of these diseases.

Cardiovascular risk assessment revealed that 67.2% of workers were at low risk, 22.3% at moderate risk and 10.5% at high risk. Similar results were reported in a study on the use of the Framingham score in Peru, as was the association with male gender [15]. The proportion of metabolic syndrome was 25.3% associated with the female gender, this being due to the fact that the female gender presents altered values of waist circumference, cholesterol and HDL over the years in the Peruvian population [16]

Our results show that in the study hospital, the workers maintain values within the normal range in most of the measured variables. Nevertheless, some presented a high cardiovascular risk. Among the health workers who were measured for DHEAS levels, those in the high cardiovascular risk group had low DHEAS levels (2156.9 vs 2814.6 ng/mL, P < 0.05), based on the Framingham score, which allows for risk adjustment according to age and gender. Values near the upper normal limit of DHEAS showed a lower probability of high cardiovascular risk; in the same way, a study in a Latin American population shows that values near the lower limit in individuals without adrenal disease are at a risk for the development of myocardial infarction [17].

The relationship between low DHEAS levels and cardiovascular risk has been reported in longitudinal studies in European, North American and Asian populations, with association to male gender. Other studies, however, have generated contradictory results [6]. Even so, laboratory research favors the role of DHEA and DHEAS in the maintenance of cardiovascular function, through interactions with ion channels, membrane and nuclear receptors, improvement of insulin resistance, prevention of the aggregation of platelets, anti-inflammatories effects and antiproliferative hormonal mechanisms [18–20]. These mechanisms could explain the association found between low DHEAS levels and high cardiovascular risk.

Additionally, the MAP and PP, used to determine the average tissue perfusion and indirect vascular elasticity, showed a positive association with cardiovascular risk. Several studies show that the increase in MAP and PP increases the risk of myocardial infarction and general cardiovascular risk, attributed to the production of oxygen-based reactions and endothelial damage [21,22]. Furthermore, HbA1c, which evaluates the proportion of glycosylated protein formation in hemoglobin, presented a positive association in this study with a higher PRR than the other factors. This environment also affects vascular endothelial proteins causing progressive damage to different tissues; such as cardiovascular, increasing HbA1c values present cardiovascular risk in both diabetic and nondiabetic people [23].

These findings could be extrapolated to groups of healthcare workers at high cardiovascular risk in a similar context to the study, evaluated by the Framingham score and conditions that do not alter DHEAS values, but studies in larger populations are needed to be able to generalize the results. However, the quantification of DHEAS is not a commonly used metabolite in cardiovascular risk assessment but in endocrine disorders. Traditionally, DHEAS measurement is used for the diagnosis and differentials of hyperandrogenism, congenital adrenal hyperplasia, premature adrenarche and adrenal carcinomas. The use of DHEAS in cardiovascular risk remains at the research study level [24].

The South American population has been poorly studied with respect to the association of DHEAS levels and cardiovascular risk as a strategy for prevention or intervention in public health [17]. The negative association of DHEAS with cardiovascular risk in the high cardiovascular risk group suggests that the probability decreases if DHEAS concentrations are higher, which could lead to treatment schemes that increase DHEAS concentrations. Unfortunately, the current approach to patients at high cardiovascular risk according to the Framingham score includes the use of statins that lower the concentration of DHEAS, probably by decreasing the prenyl components by inhibiting β-Hydroxy β-methylglutaryl-CoA reductase, for which supplementing or increasing the production of DHEAS could have an added benefit, effects that are evidenced with the use of metformin or moderate to intense exercise [25–27].

In conclusion, our findings show that among the health workers selected for DHEAS measurement, those with high cardiovascular risk had lower concentrations of the hormone, and higher levels of the hormone showed a negative association with high cardiovascular risk. Additionally, HbA1c, PP and MAP show an independent positive association with high cardiovascular risk according to the Framingham score. More studies are needed in different populations, considering additional variables in order to establish the most accurate influence of the DHEAS hormone on cardiovascular risk.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

cardiovascular diseases; dehydroepiandrosterone sulfate; risk factors

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