In adults, hypertension (HT) is a leading precursor of cardiovascular disease and strongly associates with an increased risk for cardiovascular events, renal disease, and mortality [1
]. Rise in blood pressure (BP) is closely linked to an increase in measures of obesity, which, in turn, associate with a decline in insulin sensitivity and worsening of an atherogenic lipid profile [2
]. In addition to anthropometric measures, it is linked with factors of glucose homeostasis, a lipid profile, other metabolic markers, such as uric acid, adiponectin, and soluble receptor for advanced glycation end products (sRAGE) levels, markers of renal function, inflammation, and oxidative status associated with BP. Uric acid is considered to be a true modifying and possibly causal factor for essential hypertension, particularly in juveniles [5
]. Mechanisms comprise, among others, a reduction of nitric oxide levels in the endothelium, induction of oxidative stress, and activation of the renin–angiotensin system [6
]. The relationship between BP and the kidney is complex, and each may adversely affect the other. Essential hypertension is an initiating risk factor for future end-stage renal disease, even in adolescents, regardless of their sex, and presence or absence of obesity [7
]. On the other hand, an increase in arterial pressure is needed to maintain salt and water balance in the presence of restriction in renal perfusion, glomerular injury, and a reduced glomerular filtration rate [8
]. Adiponectin, secreted by adipocytes, plays a role in the development of obesity-associated hypertension and insulin resistance [9
]. Oxidative stress may act as a trigger for both hypertension and inflammation [10
]. Homocysteine may contribute to rise in BP via induction oxidative-damage and inflammatory-damage to vasculature [11
]. Whether inflammation is a cause or effect of hypertension remains unclear. Since this relationship is further confounded by the fact that several factors associated with hypertension, such as obesity or insulin resistance, are also associated with inflammation [10
]. A role of a cell surface multi-ligand pattern recognition receptor for advanced glycation end products (RAGE) in pathogenesis of hypertension cannot be excluded. RAGE-ligand interaction initiates downstream pathways, which results in the production of reactive oxygen species, atherogenic, and inflammatory responses, eventually potentiating vasoconstriction, peripheral vascular resistance, and arterial stiffness [13
]. Circulating sRAGE variants possess the ligand binding domain but lack the transmembrane and the signaling domain. Thus, sRAGE may exert a protective role by reducing the pool of ligands interacting with cellular RAGE.
Elevated BP (e.g., high normal BP (HNBP) and HT) associates with adverse cardiac and vascular changes such as increased left ventricular mass, carotid thickness, arterial stiffness, decreased diastolic function, and endothelial dysfunction, which are already found in children and adolescents [14
]. It is well documented that overweight-associated or obesity-associated HNBP and HT is already in juveniles accompanied with worsened markers of cardiometabolic risk, e.g., with elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), triacylglycerols, fasting plasma insulin, C-reactive protein (CRP), uric acid, reduced high-density lipoprotein cholesterol (HDL-C), adiponectin, and insulin sensitivity [3
]. We showed that, in young individuals, markers of adiposity, biochemical indicators of cardiometabolic risk, and a continuous metabolic syndrome score, increase across BP categories (normotension - NT, HNBP, HT) not only in subjects presenting cardiometabolic abnormalities but even in their peers displaying a metabolically healthy phenotype, e.g., in subjects without central obesity, insulin resistance, atherogenic dyslipidemia, microinflammation, and hyperuricemia [16
The prevalence of metabolic syndrome (MetSy), its components, and other cardiometabolic risk markers such as hyperuricemia or elevated C-reactive protein levels differs between males and females [17
]. Until about the age of 70, males have higher BP and a higher prevalence of HT than females [22
]. In our above mentioned study, about 42% of normotensive juveniles were males, Males accounted for about 81% of individuals with HNBP and 90% of hypertensive subjects [16
]. In multivariate analyses, the male sex appeared to be a significant predictor of both systolic (SBP) and diastolic BP (DBP), regardless of the presence or absence of cardiometabolic abnormalities. Former Slovak studies in young subjects document that, similarly to the prevalence of elevated BP, that of other components of metabolic syndrome or hyperuricemia differs between males and females [19
]. These lines of evidence led us to the assumption that the trends of indicators of cardiometabolic risk across BP categories differ between sexes. We hypothesized that associations would be less expressed in females since young females present lower BP values and lower prevalence of elevated BP when compared with males [19
]. To this point, we re-analyzed the trends for traditional cardiometabolic risk markers (i.e., proxy measures of obesity, glucose homeostasis, lipid profile) as well as those of oxidative status, inflammatory markers, renal function, concentrations of uric acid, adiponectin, and sRAGE across BP categories separately in males and females. We also explored whether these trends manifest similarly in the presence or absence of cardiometabolic abnormalities.
Representative data on the prevalence of HNBP and hypertension in Slovak adolescents or young adults are not available. Among medical students aged 23 years in mean, 18% of males and 2% of females presented hypertension [33
]. A study in students aged from 18 to 20 years indicated 41% prevalence of HNBP and 30% of hypertension in males, and 18% and 16%, respectively, in females [34
]. The Slovak Health Advice Centers reported about 32% prevalence of elevated BP in males aged from 10 to 25 years, and 12% among females [19
]. Recent European studies in juveniles indicated 10–16% prevalence of prehypertension (a former term for HNBP) and a 13–44% prevalence of hypertension in males, and 11–13% and 6–21%, respectively, in females [35
]. Comparison of the prevalence rates is cumbersome due to age-differences of studied cohorts and particularly due to methodological differences in classification of elevated BP. Two Slovak studies used the same methodology as we did. However, the study among students was small (n
= 122, 18% males) [34
] while the other one reported on a specific population, which involved individuals actively seeking health counseling provided by The Health Advice Centers [19
]. The study in medical students classified BP as optimal, normal, and elevated [33
]. Thus, it did not report data on the prevalence of HNBP. Other studies [35
] classified BP status according to the 2004 Working Group normative, e.g., according to sex-specific, age-specific, and height-specific percentile charts [38
]. Despite these differences, the prevalence of elevated BP was consistently higher among males when compared with females. On the other hand, in our study and the other Slovak and the Italian studies [34
], the prevalence of HNBP/prehypertension exceeded that of hypertension. However, in Portuguese and Lithuanian juveniles, the prevalence of HT was higher than that of prehypertension [36
]. Except for the prevalence of HNBP in our males, which was roughly similar to that reported in other studies, the prevalence of hypertension in males and both as well as HNBP and hypertension in females was lower in our study [35
]. Reasons are unclear. A bias imposed by voluntary participation cannot be excluded. Data on individuals who did not take part in our survey are not available. Thus, generalizability of our results to populations not represented herein remains unknown.
In our study, the majority of assessed variables differed significantly between males and females. Sex differences in anthropometric measures, HDL-C, uric acid, adiponectin concentrations, or microalbuminuria reflect biological variability, which is translated into different reference ranges for males and females. Even for variables that do not have sex-specific reference ranges, sex differences (within the reference range) are well documented. Therefore, premenopausal females present lower BP values when compared to males of similar age, higher insulin sensitivity, less proatherogenic plasma lipid profile, and higher CRP concentrations, leukocyte counts, adiponectinemia, sRAGE, and lower homocysteine concentrations [22
]. Of interest, we revealed no sex difference in insulin sensitivity, despite differences in glycemia and insulinemia. We suppose that statistically significant sex-differences in glucose and insulin concentrations, or estimated glomerular filtration rate, which manifested within their reference ranges, do not imply clinical significance and rather reflect the effects of large sets of data. Studies in a general population of older adults reported higher sRAGE concentrations in females, by about 16–25% [45
]. Thus, observed statistical significance between the sex difference of about 3% in sRAGE and cRAGE concentration should also be considered clinically insignificant. To our knowledge, data on sex-differences in esRAGE and cRAGE in an apparently healthy population are not available.
Sex-differences in measures of cardiovascular health observed in adults may not manifest in young subjects. Thus, we aimed to compare our data with those from other studies on individuals of similar age to our subjects. Consistently with our data, other studies show that females display lower SBP [47
], higher body fat percentage, lower lean mass [47
], lower glycemia, higher insulinemia [48
], higher HDL-C levels [47
], and higher CRP concentrations [52
] when compared with males. Data on sex differences in DBP, BMI, total cholesterol, LDL-C, and triacylglycerols are inconsistent [47
]. In contrast to other studies [47
], we revealed no sex differences in triacylglycerolemia, and our females showed higher concentrations of all types of cholesterol when compared with males. Lacking a difference in triacylglycerol levels might reflect a low prevalence of hypertriacylglycerolemia, which is also observed in other Slovak studies [18
]. However, as expected, our females presented a less proatherogenic lipid profile compared with males, and less severe continuous cardiometabolic score. A small study in young adults reported only a tendency towards higher sRAGE concentrations in females [53
]. Thus, regarding sex differences, our population showed only minor deviations from other data.
Changes in means may not be sensitive enough to detect variations occurring at the extremities of the distribution. These are captured by trends. Across BP categories, trends of variables associated with cardiometabolic risk differed between the sexes. Trends observed in males were largely consistent with those obtained if both sexes were analyzed together [16
]. In contrast to the whole cohort, we did not observe a significant trend in glycemia, HDL-cholesterol, microalbuminuria, and homocysteine concentrations either in males or in females. However, in both sexes, a significant upward trend in total cholesterol, and, in males, an upward trend in leukocyte counts, was revealed. [16
] Contrary to findings in the whole cohort and in males, trends in insulinemia, QUICKI, triacylglycerols, atherogenic index, uricemia, adiponectin, sRAGE, cRAGE, and esRAGE across BP categories were insignificant in females. Hence, in males, variables characterizing obesity status, insulin sensitivity, atherogenic dyslipidemia, concentrations of uric acid, adiponectin, sRAGEs, and leukocyte counts showed worsening trends across BP categories while females presented significant trends only for obesity measures, LDL-C, and non-HDL-cholesterol. These data seem to support the view that young females have more favorable risk profiles when compared with their male counterparts, not only in terms of BP but also in terms of cardiovascular risk factors and markers [54
The different outcomes in trends might have been influenced by the low prevalence of elevated BP in our females. This assumption is supported by the fact that multivariate regression models indicated that predictors of BP show only slight sex-differences. Even variables that do not display significant trends across BP categories in females (i.e., insulin resistance, atherogenic index of plasma, non-HDL-C, and uric acid) are associated significantly with higher BP in both sexes. This finding is in line with a well-known fact that hypertension frequently presents concurrently with other cardiovascular disease risk factors, such as central obesity, insulin resistance, and atherogenic dyslipidemia, constituting the MetSy [55
]. These factors individually and synergistically influence the pathophysiology of hypertension. The causes and mechanisms of the MetSy are diverse but clustering of the components in MetSy confers higher probability of manifestation of cardiovascular and renal diseases, diabetes, and mortality when compared with the manifestation of isolated components [55
]. However, the increased risk imposed by the MetSy may vary by the absence or presence of hypertension. This is reflected by lower values of a continuous cardiometabolic score calculated excluding the SBP component from the equation. A higher continuous metabolic score indicates a less favorable cardiometabolic profile.
Hypertension often occurs simultaneously with other markers of increased cardiometabolic risk, such as hyperuricemia, and low-grade inflammation, which are not part of any definition of MetSy. Uric acid, which is the end-product of purines metabolism in humans, is considered to play a role in pathogenesis of essential hypertension in juveniles [5
]. It may induce insulin resistance and higher uric acid levels increase the risk of later development of atherogenic dyslipidemia [58
]. Except for BP, uricemia also correlates with measures of obesity, glucose homeostasis, lipid profile, and inflammatory markers [60
]. The C-reactive protein, which is a non-specific marker of an inflammatory reaction, is a significant cardiovascular risk factor [64
]. CRP correlates with all components of MetSy as well as with uricemia even in children and adolescents [52
]. A significant impact of CRP in our females suggests that elevated BP-associated low-grade inflammation might be sex-specific, at least in young subjects. This is in line with the finding that CRP is associated with MetSy in females but not in males [67
]. However, a tested panel of independent variables poorly explained variability in BP, which indicated that other factors not assessed in our study, e.g., genetic background, different biochemical markers, family history, environmental and behavioral factors, such as smoking, alcohol consumption, diet, physical activity, sedentary behavior, socioeconomic status, etc., might be more robust determinants of BP. Moreover, sex-differences in BP are at least partially attributable to sex hormones and their receptors [54
About 47% of our males and 50% of females with elevated BP were cardiometabolic abnormalities-free, i.e., insulin sensitive, not presenting central obesity, atherogenic dyslipidemia, CRP > 3 mg/L, or hyperuricemia. Thus, the presence of cardiometabolic abnormalities seemed not to be a prerequisite for manifestation of HNBP or HT. Equations approximating the relationship between a continuous cardiometabolic score (calculated without the SBP component) and SBP in our study indicate that the same increase in SBP would be associated with a higher increase in risk score in females when compared with males, and that, at a given SBP value, the score is higher in females. Clinical relevance of this finding might be questioned, as premenopausal females generally present lower BP values when compared with males. However, these models indicate that a normotensive male and a normotensive female presenting SBP equal to the mean value observed for their sex in our study would score equally (i.e., 2.70). In hypertensive subjects, the cardiometabolic score would be similar (3.03 in males and 3.05 in females). Females displaying SBP equal to values presented by our males would score 2.85 and 3.28, respectively. These data raise a question whether the presence of hypertension imposes higher cardiometabolic risk in young females when compared with males.
In males, continuous cardiometabolic score increased across BP categories both in cardiometabolic abnormalities-presenting (by about 13%) and abnormalities-free subjects (about 14%). This rise was not solely on the account of increased BP. After exclusion of the SBP component, abnormalities-presenting hypertensive males displayed about a 10% higher score than their normotensive peers while, in abnormalities-free males, the difference reached about 9%. Thus, in apparently healthy young subjects with elevated BP, clinicians should pay attention even to a rise of risk factors and markers occurring within the “normal range”.
In contrast to our hypothesis, males in corresponding BP categories displayed similar mean BP values regardless of the presence or absence of cardiometabolic abnormalities. As expected, those manifesting abnormalities displayed less favorable values of almost all variables of cardiometabolic risk when compared with their abnormalities-free counterparts. Variables generally presented worsening trends across BP categories. Of interest, cardiometabolic abnormalities-free males maintained similar adiponectinemia across BP categories despite increasing trends in measures of obesity and insulin resistance. This finding is inconsistent with the data of Brambilla et al. [68
], which show that non-obese hypertensive juveniles present lower adiponectin concentrations when compared to their obese, hypertensive counterparts. Moreover, in their study, adiponectin was independently related to hypertension in the adjusted multiple logistic regression model. We observed a decreasing trend in both sRAGE variants across BP categories only in cardiometabolic abnormalities-free males. Hypertensive adults present lower sRAGE levels when compared with their normotensive counterparts and an inverse association between BP and sRAGE levels [69
]. However, virtually all components of MetSy show a significant relationship with sRAGE even in adolescents and young adults [53
]. Thus, circulating RAGE levels decline with increasing BP concurrently with worsening of other cardiometabolic risk factors and biomarkers, even before these reach the threshold risk values. In the presence of cardiometabolic abnormalities, a decline in sRAGE does not seem to be independently impacted by the rise in BP. Interaction of circulating RAGEs with RAGE ligands may ameliorate tissue injury resulting from oxidative stress generation, inflammatory, atherogenic, and diabetogenic responses [73
]. An elevated BP associated decline in sRAGE in abnormalities-free males warrants attention since low sRAGE levels indicate an increased risk of diabetes development, cardiovascular disease, or death in non-diabetic subjects [75
The strengths of our study comprise a large cohort of adolescents and young adults, representing a particularly suitable group for studies of sex differences in variables characterizing cardiometabolic risk due to a low interference of comorbidities potentially affecting these targets. The study strengths also include the ability to examine a range of measures of cardiometabolic health and the use of a multivariate model suitable for evaluating large sets of data, particularly not normally distributed, and partially correlated. Our study is limited by its cross-sectional design, which allows only for comments on associations. All variables were measured at a single occasion. The generalizability of our findings to the wider population may be limited. Other limitations are mentioned throughout the discussion.