Physical activity (PA) is any movement produced by the skeletal muscles that raises energy expenditure above resting metabolic rate, and is performed to improve or maintain the components of physical fitness and health (1). Since PA is widely recognized as a primary contributor to overall health protection (2), the World Health Organization recommends ≥1 h/day of PA (3). In parallel, inactivity and sedentary time should be reduced because they promote obesity and diabetes (3). Sedentary time is characterized by any sitting, reclining, or lying posture with an energy expenditure ≤1.5 metabolic equivalents (4).

Nowadays, there is a growing prevalence of metabolic disorders in children that may place a child at a high risk of developing a cardiovascular disease (CVD) later in life. CVD are the most common cause of death globally, accounting for 17.8 million deaths worldwide (5). For instance, known metabolic risk markers such as insulin resistance (HOMA-IR) and high sensitivity C-reactive protein (hsCRP) are considered to induce detrimental effect on cardio-metabolic health (6). Increased HOMA-IR, together with increased total body adiposity and fat accumulation were related to increased epicardial fat (EF) in adult population (5, 7). Additionally, hsCRP was related to cardiac remodeling and diastolic dysfunction in hypertensive patients (8). Similar associations have been identified in children with insulin resistance, hypertension and CVD (9–11). However, to the best of our knowledge, no previous studies explored these associations in relation to PA in healthy children.

High blood pressure, especially diastolic-to-systolic blood pressure ratio (D/S BP ratio) has been proposed as a relevant cardiovascular risk marker because of its relation to systemic vascular resistance (12). EF, interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) are heart-related cardiovascular risk markers, and potential therapeutic targets for maintenance of cardiovascular health (13–15). Previous studies have shown that EF causes local inflammation and has direct effects on coronary atherosclerosis (13), while IVST and LVPWT predict all-cause death in patients with coronary artery disease (14), and cardiac events (15), respectively.

Since PA has been reported to be beneficial for the overall health (2), we hypothesize that there will be differences in the cardio-metabolic profile of the children according to their level of PA, and that more PA may relate to a better cardio-metabolic profile. Therefore, our objectives are: (1) To compare metabolic and cardiovascular risk markers in children according to the level of PA; (2) to explore the associations of metabolic and cardiovascular risk markers with PA and sedentary time; and (3) to identify the associations between metabolic and cardiovascular risk markers in less and more active children (below and above 50th percentile for PA).

Descriptive characteristics, as well as a comparison of the cardio-metabolic profile according to the level of PA of the children are presented in Table 1. Based on the results, more physically active children had lower values for BMI SDS (27.51% less, p = 0.040), insulin (30.72% less, p = 0.013), HOMA-IR (34.15% less, p < 0.001), hsCRP (61.54 less, p < 0.001) and D/S BP ratio (7.02% less, p < 0.0001) compared to less physically active children. Worthy to note is that we identified sex differences among the groups of more and less physically active children, thus we corrected the observed differences for any potential confounding variables such as age, sex and BMI. Interestingly, all differences remained significant in analysis of covariance correcting for the previously mentioned confounding variables (Table 1).

Bivariate associations of metabolic and cardiovascular risk markers with PA and sedentary time are presented in Table 2 and Figure 1. On the one hand, PA was negatively associated with HOMA-IR (r = −0.142, p = 0.044), EF (r = −0.133, p = 0.040) (Table 2), hsCRP (r = −0.157, p = 0.016) and D/S BP ratio (r = −0.211, p < 0.001) (Figure 1A). On the other hand, sedentary time was positively associated with insulin (r = 0.221, p < 0.001), HOMA-IR (r = 0.210, p = 0.003), EF (r = 0.197, p < 0.002) (Table 2), hsCRP (r = 0.227, p < 0.001) and D/S BP ratio (r = 0.202, p = 0.002) (Figure 1B). Worthy to note is that the negative association of D/S BP ratio with PA, as well as its positive association with sedentary time, remained significant after correcting for age, sex and BMI (Figure 1). The positive association between sedentary time and hsCRP also remained significant after correcting for age, sex and BMI (Figure 1B).

Bivariate associations between metabolic and cardiovascular risk markers are presented in Table 3 and Figure 2. D/S BP ratio was positively associated with insulin (r = 0.196, p = 0.005) and HOMA-IR (r = 0.185, p = 0.008) in the studied children (Table 3). Furthermore, IVST and LVPWT were positively associated with hsCRP (r = 0.171, p = 0.008 and r = 0.186, p = 0.004) (Table 3), while EF was positively associated with insulin (r = 0.292, p < 0.0001) and hsCRP (r = 0.298, p < 0.0001) (Figure 2) in the same children. Interestingly, when we analyzed the same associations in groups according to the level of PA of the children, all previously mentioned associations were present only in less physically active children (r = 0.179 to r = 0.367, p = 0.049 to p < 0.0001), while they were not observed in more physically active children (Table 3 and Figure 2). Worthy to note is that the positive associations of EF with insulin and hsCRP remained significant after correcting for age, sex and BMI in the studied children, especially in less physically active children (Figure 2).

Main findings of this study indicate that school-aged children who are more physically active have a better cardio-metabolic profile than those who are less physically active. Metabolic and cardiovascular risk markers are negatively related to PA and positively related to sedentary time in these children. Finally, metabolic risk markers were positively related to cardiovascular risk markers in the same children. Interestingly, PA seems to modulate the latter associations in a volume-dependent manner, as they were identified in less physically active children and were not present in more physically active children.

Children who are more physically active have lower insulin, HOMA-IR, hsCRP and D/S BP ratio, than less physically active children. This outcome allows us to accept the postulated hypothesis of the present study. Even if previous studies did not focus on comparing the metabolic and cardiovascular profile in healthy children depending on their PA levels, existing evidence in adult population is in line with our findings (29). For instance, previous studies reported that HOMA-IR, hsCRP and blood pressure were significantly lower in adults who perform a minimum of 150 min/week of PA, in comparison to those who performed less PA (29, 30). A recent meta-analysis confirmed that increased blood pressure in childhood is associated with higher risk for CVD and mortality in adulthood (31). However, subjects with increased blood pressure during childhood, but normal blood pressure during adolescence, were not at risk for developing a CVD (31). This evidence raises the need to develop an effective non-medication based strategy to reduce blood pressure in pre-pubertal children, with the aim to prevent CVD in adulthood. Results obtained in our study indicate that PA may be such strategy even in apparently healthy children, which emphasizes the importance for children to be physically active in order to maintain their cardiovascular health. As it has been previously suggested, PA may confer beneficial effects on metabolic and cardiovascular health by enhancing insulin sensitivity in the muscles and the liver (30). Moreover, PA helps reducing the amount of adipose tissue, which may prevent from obesity-driven insulin resistance and inflammation (30). In addition, our results reinforce the idea of benefits on cardiovascular health depending on the PA levels, which may be explained by a higher increase in the blood flow and a higher reduction in the vascular resistance due to the demand induced by higher PA levels (32).

Present findings also indicate that HOMA-IR, hsCRP, D/S BP ratio and EF are related to sedentary time in school-aged children. On the other hand, all these metabolic and cardiovascular risk markers were inversely related to PA. In line with the associations of metabolic and cardiovascular risk markers with PA and sedentary time in our study, previous evidence suggest that sedentary time is associated with altered metabolic profile (33), while PA was inversely related to BMI, fat percentage and HOMA-IR, thus lowering the risk for obesity in children (34). Additionally, higher levels of PA were related to lower hsCRP concentration (35). In the same line, cardiovascular markers were also negatively associated with PA. More precisely, the associations between D/S BP ratio and PA obtained in the present study are in accordance with previous reports suggesting that a lowered risk for hypertension was related to more PA and less sedentary time (36). In general, PA is associated with a lower heart rate on a long-term scale that could allow for sufficient time for diastolic left ventricular filling and coronary flow, therefore improving arterial compliance and lowering blood pressure (30, 37). Furthermore, it is worthy to emphasize that the World Hypertension League and the European Society of Hypertension recommended regular PA across the lifespan (including childhood) because of its well-established antihypertensive effects, as well as its favorable impact on other modifiable CVD risk factors (38). Moreover, they highlighted an inverse dose–response relationship between PA levels and CVD, i.e., the incidence of stroke, coronary artery disease and overall mortality (38). Finally, EF was negatively related to PA in our study suggesting that more PA will potentially contribute to less EF. To the best of our knowledge, no previous studies in healthy children have explored this association. However, in line with our findings, PA was related to lower visceral fat in Japanese female adults (39). One possible physiological mechanism explaining the inverse association between EF and PA may be the lipid mobilization triggered by increased catecholamine production during PA, leading to increased lipolysis rate in the EF cells (39).

Metabolic risk markers were related to cardiovascular risk markers in the present study, leading to the premise that any metabolic alterations in these children may potentially induce alterations in their cardiovascular health as well. Even though studies reporting associations between metabolic and cardiovascular risk markers in healthy children are scarce, previous studies have obtained similar results in adults (5, 7, 40), and in children at risk for developing a cardiovascular disease (9–11). For instance, increased body mass, insulin concentration and higher HOMA-IR in children with obesity were related to higher EF (9, 41). Increased hsCRP in hemodialysis patients was related to higher IVST (42), while higher BMI in children with hypertrophic cardiomyopathy was related to higher LVPWT (11). As discussed previously, studies in healthy children exploring the associations of metabolic risk markers with IVST and LVPWT, and in relation to PA, are missing to the best of our knowledge. However, we suggest that the associations between metabolic and cardiovascular risk markers identified in healthy children may be a result of the interplay between multiple underlying mechanisms. Higher insulin levels may lead to reduction of the sodium excretion rate and increased blood pressure (43). In addition, higher insulin levels may also promote fatty acid synthesis (44) which may end up in excessive lipid accumulation, therefore directly contributing to the formation of ectopic fat (45), such in this case - EF. Furthermore, hsCRP stimulates the production of adhesion molecules that enhance the infiltration of monocytes and lymphocytes resulting in fibrosis and cardiac remodeling (8), such as increased IVST and LVPWT. It is worthwhile to note that the results in our study were obtained in apparently healthy school-aged children, and thus indicate the importance of the early assessment of metabolic and cardiovascular profile in children.

Finally, it is also important to mention that the positive associations of D/S BP ratio with insulin and HOMA-IR, the positive associations of hsCRP with IVST and LVPWT, and the positive associations of EF with insulin and hsCRP identified in less physically active children, were not observed in more physically active children at the present study. More precisely, our results are indicative on a potential modulatory role of PA on the associations between the metabolic and cardiovascular risk markers because none of the associations identified in less physically active children was present in more physically active children. Moreover, current findings are pointing toward a dose-dependent modulatory effect of PA, propounding the idea that PA may modulate cardio-metabolic health in these children in a volume-dependent manner. Even though studies in healthy children that report volume-dependent PA-induced cardio-metabolic health benefits are scarce, in support to our findings previous studies in adult hypertensive population reported that higher PA levels provided superior cardio-metabolic benefits (38, 46). Additionally, the authors of the previous works argued that higher PA levels did not show any adverse effects among individuals diagnosed with hypertension, contradicting and disproving the hypothesis that there might be a threshold beyond which high PA levels could become harmful or counterproductive, especially for individuals with hypertension (38, 46). Remarkably, they demonstrated that higher PA levels are superior in reducing the risk for CVD and may serve as a beneficial approach in reducing the mortality rates among hypertensive population (38, 46). Indeed, prior findings in adult hypertensive population are in line with the findings of the present study in apparently healthy school-aged children. Therefore, taking in consideration previous and current findings, we suggest that encouraging higher levels of PA, even from pediatric age, could contribute to improved cardio-metabolic health outcomes in children, and potentially prevent the development of CVD in the future (38, 46).

More PA is associated with a better cardio-metabolic profile in school-aged children. PA appears to modulate the associations between metabolic and cardiovascular risk markers in a volume-dependent manner, thus reinforcing the idea that fostering PA in children and encouraging an active lifestyle from an early age, could potentially reduce the risk for future cardio-metabolic diseases and improve overall health outcomes in adulthood.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Institutional Review Board of Dr. Josep Trueta Hospital, Girona, Spain. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

FV: Conceptualization, Formal analysis, Investigation, Methodology, Software, Writing – original draft. GC-B: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Writing – review & editing. JB: Data curation, Funding acquisition, Project administration, Writing – review & editing. JS-F: Formal analysis, Methodology, Software, Writing – review & editing. RF-L: Methodology, Software, Supervision, Writing – review & editing. VL-R: Methodology, Software, Writing – review & editing. IO: Data curation, Methodology, Software, Writing – review & editing. JM-C: Data curation, Methodology, Software, Writing – review & editing. MS: Methodology, Writing – review & editing. AL-B: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – review & editing. AP-P: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Supervision, Writing – review & editing.