The prevalence of childhood obesity has increased over the last decade and it has become a growing health problem. Obesity in childhood commonly leads to obesity in adulthood [
Noninvasive vascular evaluation has been recently included in recommendations for cardiovascular risk assessment and prevention in children and adolescents [
In this context, this work’s aims were to evaluate whether childhood obesity associates with arterial stiffness changes and to determine (1) if the vascular impact of obesity would depend on the histological arterial type (elastic, transitional, or muscular) and/or arterial region (neck, thorax, abdomen, and upper or lower limb), (2) if the arterial stiffness changes would be associated with the increased BP found in obese children, and (3) if the vascular changes associated with obesity would depend on the children’s age. To fulfil our aims, we studied arteries from different regions and histology using a noninvasive methodological approach; we calculated local and regional arterial stiffness and we applied an analysis that allowed arterial stiffness to become BP-independent.
All procedures agreed with the Declaration of Helsinki (1975 and reviewed in 1983). All studies were approved by the Institutional Ethics Committee of the Centro Hospitalario Pereira-Rossell. Written informed consent was obtained before the examination.
CUiiDARTE Project is a Uruguayan Interdisciplinary University Program aimed at early diagnosis of arterial disease in children and adults. Children data were obtained from CUiiDARTE Database. We included 211 asymptomatic children (age range: 4–15 years old; 92 female). Children with chronic comorbidities, with cardioactive drugs use, or under treatment that could affect the cardiovascular system were excluded. Each child was assigned to one of two groups: normal weight (NW,
Before vascular evaluation, a clinical interview was performed in order to assess personal and familiar medical history and cardiovascular risk factors exposure. Children were classified as sedentary when their regular physical activity level was lower than a moderate intensity load [
Children’s height and weight were measured and the BMI was obtained by dividing body weight by height squared. Then, the
Children and adolescents were studied in a temperature-controlled room (21°–23°C); they were instructed to lie in supine position for at least 15 minutes in order to achieve a steady hemodynamic state. Heart rate and peripheral (brachial) systolic (pSBP) and diastolic (pDBP) BP measurements were obtained at fixed intervals of 8–10 minutes (HEM-433INT; Omron Healthcare Inc., Illinois, USA). Peripheral pulse pressure (pPP, pPP = pSBP − pDBP) and mean blood pressure (MBP, MBP = pDBP + pPP/3) were calculated.
Radial pulse pressure waveforms were obtained using applanation tonometry (SphygmoCor 7.01, AtCor Medical, Sydney, Australia). The pDBP and MBP were used for radial pulse waveforms calibration. The central aortic BP was obtained using a validated generalized transfer function (SphygmoCor Software) applied to the acquired peripheral waves [Figure
(a): Local (left) and regional (right) sites of arterial stiffness noninvasive evaluation. (b) Diameters border detection applied recreating common carotid artery diameter waveforms. (c) SphygmoCor Software, to determine central aortic blood pressure (levels and waveform) from radial pulse waveforms recordings. (d) SphygmoCor Software to determine arterial pulse wave velocity, from the consecutive recordings of proximal (i.e., carotid) and distal (i.e., femoral) pressure waveforms and electrocardiographic signals.
Left and right vertebral arteries, common carotid artery (CCA) and internal and external carotid arteries, common femoral artery (CFA), and left brachial arteries (BA) were analyzed to verify normal blood flow patterns. High-resolution B-mode ultrasonography (6–13 MHz linear transducer, M-Turbo, SonoSite Inc., 21919 30th Drive SE, Bothell, WA 98021, USA) was used to obtain sequences of images (videos) from transversal and longitudinal views of CCAs, CFAs, and left BA arteries, which were stored for offline analysis. Then, beat-to-beat diameter waveforms were obtained using border detection algorithm. Systolic (SD) and diastolic (DD) arterial diameters and the arterial wall intima-media thickness (posterior wall, end-diastolic value) were quantified as the average of at least 20 beats [Figure
Cross-sectional arterial distensibility (AD) was quantified as AD = ((SD − DD)/DD)/PP. Central aortic PP was considered to quantify CCA AD, while pPP was used to quantify CFA and BA distensibility.
Childhood obesity is frequently associated with increased BP levels, which in turn could determine a transient BP-dependent increase in arterial stiffness due to a passive distension of the arterial wall. Then, to account for BP dependence of arterial stiffness, three complimentary data analyses were done. First, arterial stiffness was normalized for BP calculating the
Second, the intrinsic (with independence of BP and geometry) stiffness of the arterial wall was evaluated by means of the arterial wall elastic modulus (EM). EM conceives the vessel as a hollow structure and provides information about the wall artery material regardless of its geometry and/or size [
Third, a correlation analysis between arterial stiffness and BP levels was performed for both normal weight and obese groups. To this end, nonlinear and linear regression models for each group were obtained.
Pulse wave velocity (PWV, PWV =
Data analysis was performed using SPSS software (SPSS Inc., Illinois, USA). For data analysis, both normal weight and obese children were divided into age groups: 4–8, 8–12, and 12–15 years old. Values were expressed as mean ± standard deviation or prevalence (%, 95% confidence interval [CI]). Chi squared and Student’s
Table
Anthropometrical and hemodynamic characteristics and prevalence of cardiovascular risk factors.
Total | 4–8 years old | 8–12 years old | 12–15 years old | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Normal weight | Obesity |
|
Normal weight |
Obesity |
|
Normal weight | Obesity |
|
Normal weight | Obesity |
| |
Number of subjects (% female) | 137 (39) | 84 (41) | 0.876 | 25 (40) | 18 (50) | 0.765 | 48 (40) | 40 (48) | 0.745 | 57 (40) | 21 (33) | 0.476 |
Age (years) | 10.9 ± 2.8 | 10.6 ± 2.7 | 0.465 | 6.7 ± 0.9 | 6.5 ± 0,8 | 0.389 | 10.5 ± 1.2 | 10.3 ± 1.2 | 0.265 | 13.7 ± 0.8 | 13.4 ± 1.0 | 0.111 |
Body height (m) | 1.42 ± 0.2 | 1.41 ± 0.2 | 0.502 | 1.22 ± 0.1 | 1.23 ± 0.1 | 0.555 | 1.41 ± 0.1 | 1.40 ± 0.1 | 0.359 | 1.62 ± 0.1 | 1.63 ± 0.1 | 0.234 |
Body weight (Kg) | 38.6 ± 13.4 | 58.6 ± 21.3 |
|
22.1 ± 2.5 | 34.0 ± 5.7 |
|
34.4 ± 6.9 | 54.6 ± 12.6 |
|
50.9 ± 8.8 | 83.7 ± 16.0 |
|
Body mass index (kg/m2) | 18.0 ± 2.2 | 26.8 ± 4.8 |
|
15.3 ± 0.8 | 22.0 ± 2.9 |
|
17.5 ± 1.5 | 26.4 ± 3.4 |
|
19.8 ± 1.7 | 31.1 ± 5.1 |
|
|
||||||||||||
Heart rate (b.p.m.) | 82 ± 14 | 79 ± 13 | 0.596 | 87 ± 10 | 89 ± 21 | 0.715 | 82 ± 17 | 78 ± 11 | 0.165 | 76 ± 11 | 76 ± 14 | 0.965 |
Peripheral SBP (mmHg) | 108 ± 11 | 113 ± 11 |
|
101 ± 9 | 106 ± 7 | 0.074 | 109 ± 9 | 109 ± 7 | 0.863 | 111 ± 10 | 119 ± 12 |
|
Peripheral DBP (mmHg) | 60 ± 8 | 60 ± 7 | 0.845 | 58 ± 7 | 63 ± 11 | 0.984 | 60 ± 6 | 58 ± 6 | 0.131 | 59 ± 8 | 62 ± 10 | 0.112 |
Peripheral PP (mmHg) | 48 ± 10 | 52 ± 9 |
|
43 ± 8 | 46 ± 10 | 0.228 | 48 ± 10 | 51 ± 7 | 0.118 | 52 ± 9 | 58 ± 8 |
|
|
||||||||||||
Central (aortic) SBP (mmHg) | 91 ± 9 | 94 ± 10 |
|
84 ± 8 | 88 ± 7 | 0.091 | 92 ± 8 | 92 ± 7 | 0.875 | 94 ± 9 | 104 ± 10 |
|
Central (aortic) DBP (mmHg) | 62 ± 8 | 61 ± 7 | 0.932 | 60 ± 8 | 60 ± 5 | 0.866 | 63 ± 8 | 59 ± 7 | 0.056 | 62 ± 7 | 65 ± 8 | 0.103 |
Central (aortic) PP (mmHg) | 29 ± 7 | 33 ± 8 |
|
24 ± 6 | 29 ± 8 |
|
29 ± 7 | 33 ± 6 |
|
32 ± 7 | 39 ± 9 |
|
|
||||||||||||
Hypertension (%, CI 95%) | 10 (6–16) | 32 (22–42) |
|
12 (0–25) | 39 (16–61) |
|
17 (6–27) | 25 (12–38) | 0.923 | 7 (0–14) | 43 (22–43) |
|
Dyslipidemia (%, CI 95%) | 2 (0–4) | 16 (8–23) |
|
8 (0–19) | 6 (0–16) | 0.756 | 2 (0–6) | 20 (8–32) |
|
0 (0-0) | 10 (0–22) |
|
Sedentarism (%, CI 95%) | 46 (38–55) | 66 (54–76) |
|
68 (50–86) | 67 (45–88) | 0.926 | 44 (30–58) | 70 (56–84) | 0.583 | 40 (28–53) | 57 (36–78) | 0.186 |
Values expressed as mean value ± standard deviation or percentage (prevalence) and confidence interval (95%). SBP, DBP, and PP: systolic, diastolic, and pulse blood pressure, respectively. Hypertension: diagnosed hypertension and/or hypertensive levels during study. A
Obese subjects aged twelve and older showed higher peripheral and central SBP and PP, with respect to children with normal weight. For all age groups, cPP (but not pPP) was higher in obese than in normal weight children (Table
When all the subjects were considered, the prevalence of dyslipidemia and of diagnosed hypertension and/or hypertensive peripheral BP levels during the study was higher in obese than in normal weight children. Such differences varied depending on the age group analyzed. The prevalence of sedentary life styles was higher in obese children when all the subjects were considered (Table
Table
Carotid, femoral, and brachial arteries “local” stiffness and aortic, upper-limb, and lower-limb “regional” stiffness.
Total | 4–8 years old | 8–12 years old | 12–15 years old | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Normal weight | Obesity |
|
Normal weight | Obesity |
|
Normal weight | Obesity |
|
Normal weight | Obesity |
| |
Systolic diameter left CCA (mm) | 6.3 ± 0.6 | 6.5 ± 0.7 |
|
5.9 ± 0.5 | 6.0 ± 0.6 | 0.349 | 6.3 ± 0.6 | 6.5 ± 0.5 | 0.092 | 6.4 ± 0.7 | 7.0 ± 0.4 |
|
Diastolic diameter left CCA (mm) | 5.5 ± 0.6 | 5.8 ± 0.6 |
|
5.2 ± 0.5 | 5.3 ± 0.5 | 0.281 | 5.6 ± 0.6 | 5.8 ± 0.5 | 0.140 | 5.6 ± 0.7 | 6.2 ± 0.4 |
|
Distensibility left CCA (1/mmHg × 10−3) | 4.9 ± 1.9 | 4.2 ± 1.8 |
|
6.2 ± 1.9 | 5.4 ± 2.2 | 0.211 | 4.9 ± 1.5 | 4.5 ± 1.9 | 0.317 | 4.3 ± 1.5 | 3.3 ± 0.7 |
|
3.2 ± 1.5 | 3.5 ± 1.1 | 0.118 | 2.5 ± 0.7 | 3.1 ± 1.6 | 0.104 | 3.0 ± 1.1 | 3.4 ± 1.1 | 0.095 | 3.5 ± 1.4 | 3.8 ± 0.8 | 0.325 | |
|
||||||||||||
Systolic diameter right CCA (mm) | 6.5 ± 0.7 | 6.7 ± 0.7 | 0.109 | 6.1 ± 0.7 | 6.1 ± 0.5 | 0.984 | 6.5 ± 0.6 | 6.7 ± 0.5 | 0.086 | 6.8 ± 0.6 | 7.2 ± 0.4 |
|
Diastolic diameter right CCA (mm) | 5.8 ± 0.6 | 5.9 ± 0.7 | 0.154 | 5.4 ± 0.7 | 5.4 ± 0.4 | 0.965 | 5.8 ± 0.6 | 5.9 ± 0.5 | 0.149 | 6.0 ± 0.5 | 6.4 ± 0.4 |
|
Distensibility right CCA (1/mmHg × 10−3) | 4.7 ± 1.6 | 4.2 ± 1.7 |
|
5.9 ± 2.0 | 5.4 ± 2.3 | 0.478 | 4.8 ± 1.4 | 4.3 ± 1.5 | 0.131 | 3.9 ± 1.3 | 3.2 ± 0.8 |
|
3.2 ± 1.1 | 3.6 ± 1.2 | 0.051 | 2.6 ± 0.8 | 3.0 ± 1.4 | 0.242 | 3.1 ± 1.1 | 3.6 ± 1.2 | 0.062 | 3.7 ± 1.3 | 4.1 ± 1.3 | 0.274 | |
|
||||||||||||
Systolic diameter left CFA (mm) | 6.0 ± 1.0 | 6.4 ± 1.0 |
|
5.0 ± 0.5 | 5.6 ± 0.6 |
|
5.9 ± 0.7 | 6.3 ± 0.7 |
|
6.8 ± 1.0 | 7.5 ± 0.9 |
|
Diastolic diameter left CFA (mm) | 5.6 ± 1.0 | 6.0 ± 1.0 |
|
4.6 ± 0.5 | 5.2 ± 0.6 |
|
5.4 ± 0.7 | 5.8 ± 0.7 |
|
6.3 ± 1.0 | 7.1 ± 7.1 |
|
Distensibility left CFA (1/mmHg × 10−3) | 1.8 ± 1.2 | 1.6 ± 0.8 |
|
2.3 ± 0.9 | 1.9 ± 0.8 | 0.113 | 1.9 ± 1.5 | 1.7 ± 0.8 | 0.719 | 1.4 ± 0.7 | 1.1 ± 0.4 |
|
8.7 ± 3.9 | 9.4 ± 4.0 | 0.212 | 6.5 ± 2.6 | 7.6 ± 2.5 | 0.185 | 8.7 ± 4.1 | 8.4 ± 3.2 | 0.734 | 10.3 ± 3.7 | 11.9 ± 4.5 | 0.317 | |
|
||||||||||||
Systolic diameter right CFA (mm) | 5.9 ± 1.0 | 6.3 ± 1.3 |
|
5.0 ± 0.4 | 5.4 ± 0.7 |
|
5.8 ± 0.7 | 6.3 ± 0.7 |
|
6.7 ± 0.9 | 7.5 ± 0.9 |
|
Diastolic diameter right CFA (mm) | 5.5 ± 1.0 | 5.9 ± 1.2 |
|
4.6 ± 0.4 | 5.0 ± 0.6 |
|
5.4 ± 0.7 | 5.9 ± 0.7 |
|
6.2 ± 0.9 | 7.0 ± 0.8 |
|
Distensibility right CFA (1/mmHg × 10−3) | 1.8 ± 1.0 | 1.5 ± 0.7 |
|
2.3 ± 0.8 | 2.1 ± 1.0 | 0.487 | 1.8 ± 1.3 | 1.6 ± 0.6 | 0.323 | 1.5 ± 0.7 | 1.1 ± 0.4 |
|
8.3 ± 3.8 | 9.4 ± 4.1 | 0.076 | 6.7 ± 3.9 | 7.9 ± 4.5 | 0.401 | 8.5 ± 3.8 | 9.1 ± 3.3 | 0.477 | 9.8 ± 3.8 | 11.4 ± 4.7 | 0.164 | |
|
||||||||||||
Systolic diameter BA (mm) | 2.9 ± 0.5 | 3.2 ± 0.5 |
|
2.5 ± 0.3 | 2.8 ± 0.3 |
|
2.9 ± 0.5 | 3.1 ± 0.4 | 0.156 | 3.2 ± 0.3 | 3.6 ± 0.4 |
|
Diastolic diameter BA (mm) | 2.8 ± 0.5 | 3.0 ± 0.5 |
|
2.4 ± 0.2 | 2.7 ± 0.4 |
|
2.7 ± 0.5 | 2.9 ± 0.3 | 0.221 | 3.0 ± 0.4 | 3.5 ± 0.4 |
|
Distensibility BA (1/mmHg × 10−3) | 1.5 ± 1.2 | 1.4 ± 0.8 | 0.547 | 1.7 ± 1.2 | 1.6 ± 0.8 | 0.914 | 1.6 ± 1.5 | 1.4 ± 1.0 | 0.719 | 1.4 ± 0.9 | 1.0 ± 0.3 | 0.241 |
12.8 ± 7.9 | 12.1 ± 6.8 | 0.726 | 11.4 ± 6.8 | 9.4 ± 3.8 | 0.500 | 13.1 ± 8.6 | 12.2 ± 7.6 | 0.755 | 13.3 ± 8.7 | 13.1 ± 6.1 | 0.947 | |
|
||||||||||||
Carotid-femoral PWV real (m/s) | 4.7 ± 1.4 | 4.8 ± 0.7 | 0.401 | 4.4 ± 0.6 | 4.6 ± 0.7 | 0.504 | 4.7 ± 0.6 | 4.7 ± 0.5 | 0.983 | 5.1 ± 0.6 | 5.3 ± 0.5 | 0.363 |
Femoropedal PWV (m/s) | 7.0 ± 1.1 | 7.1 ± 1.3 | 0.662 | 7.1 ± 0.9 | 7.3 ± 1.5 | 0.774 | 6.7 ± 0.8 | 6.7 ± 1.4 | 0.992 | 7.0 ± 1.3 | 7.8 ± 0.9 | 0.070 |
Carotid-radial PWV (m/s) | 7.6 ± 1.2 | 7.4 ± 1.3 | 0.283 | 7.6 ± 1.2 | 6.8 ± 1.1 | 0.075 | 7.3 ± 0.9 | 6.7 ± 0.7 | 0.074 | 7.6 ± 1.0 | 7.8 ± 0.6 | 0.317 |
Values expressed as mean ± standard deviation. CCA: common carotid artery. CFA: common femoral artery. BA: brachial artery. PWV: pulse wave velocity. A
Correlation analysis between stiffness parameters and blood pressure levels.
Normal weight | Obesity |
|
|||||||
---|---|---|---|---|---|---|---|---|---|
Model |
|
|
95% CI | Model |
|
|
95% CI | ||
Left common carotid artery distensibility |
|
0.428 | <0.001 |
|
|
0.554 | <0.001 |
|
0.232 |
Right common carotid artery distensibility |
|
0.437 | <0.001 |
|
|
0.496 | <0.001 |
|
0.672 |
Left common femoral artery distensibility |
|
0.467 | <0.001 |
|
|
0.518 | <0.001 |
|
0.502 |
Right common femoral artery distensibility |
|
0.448 | <0.001 |
|
|
0.399 | <0.001 |
|
0.700 |
Carotid-femoral pulse wave velocity |
|
0.398 | <0.001 | 0.016–0.042 |
|
0.433 | <0.001 | 0.013–0.039 | 0.744 |
Carotid-radial pulse wave velocity |
|
0.318 | <0.001 | 0.015–0.040 |
|
0.359 | <0.001 | 0.011–0.035 | 0.756 |
Analysis between arterial stiffness parameters (
In addition, with respect to those with normal weight, obese children aged 12 and older showed lower carotid and femoral distensibility (higher local arterial stiffness) (
Common carotid (a) and femoral (b) arterial wall elastic modulus for normal weight and obese children and adolescents. There were no statistical differences between normal weight and obese arteries, when comparisons were done considering the same artery and hemibody (left or right), indicating that there were no significant intrinsic arterial wall elastic alterations associated with obesity.
Correlation analysis (linear regression plots) between stiffness parameters and blood pressure levels for normal weight (NW) and obese (OB) children and adolescents. Nonstatistical differences were found when equations (for the same artery) were compared (slopes comparisons) between NW and OB groups (data shown in Table
Left common carotid artery
Right common carotid artery
Left common femoral artery
Right common femoral artery
Carotid-femoral pulse wave velocity
Carotid-radial pulse wave velocity
When regional arterial stiffness parameters were considered (PWV), there were no differences between normal weight and obese children (Table
Left and right CCA and CFA (but not BA) distensibility as well as cfPWV and crPWV (but not fpPWV) showed a negative and statistically significant correlation with BP levels (Figure
To our knowledge, this study provides for the first time data related to arterial changes associated with obesity in asymptomatic children and adolescents, analyzing different vascular territories and the role of arterial BP. The work’s main results were as follows: Hemodynamic and vascular differences between normal weight and obese subjects were mainly observed in the older-age group (subjects aged 12 and older). Compared with normal weight subjects, obese adolescents aged twelve and older had not only higher peripheral BP levels but also higher central (aortic) BP levels. Carotid and femoral distensibility, but not brachial artery distensibility, were decreased in obese adolescents aged 12 and older. Therefore, the arterial stiffness increase associated with obesity would be age- and arterial segment-dependent. When stiffness values were normalized for arterial BP ( There were no differences in regional stiffness between normal weight and obese children, which might be explained by the opposite effects on stiffness (PWV) associated with the hemodynamic (i.e., BP) and geometrical (i.e., diameters) changes observed in obese children.
Compared with normal weight subjects, the obese adolescents aged 12 and older showed similar diastolic BP levels, but higher central and peripheral SBP and PP. These findings are in agreement with previous works in which young normotensive patients were studied [
Carotid, femoral, and brachial diameters were larger in obese adolescents aged 12 and older than in normal weight adolescents from the same age group. These results could be explained by the increase in BP that would lead to a passive distension of the arterial tree. In relation with this, it has been suggested that childhood obesity may lead to hemodynamic changes, with an increased systemic blood flow that responds to changes in the ventricular function, as an adaptative mechanism that could contribute to explaining the increase in the arterial working diameters [
Obese subjects aged 12 and older showed lower carotid and femoral distensibility [Table
It is known that some of the named metabolic disturbances in childhood obesity are related to increased insulin blood levels and insulin resistance. Puberty has been studied as related with a decrease in insulin resistance, which could contribute to explaining our findings [
As it is known, arterial stiffness depends on structural components of the arterial wall, BP levels, and smooth muscle tone. In our study, while analyzing the relationship between the differences in arterial stiffness in both carotid and femoral arteries in obese children aged 12 and older, we found that once stiffness values were normalized for BP levels (
At least in theory, the excess of adipose tissue, which leads to an increased volume in the vascular system and to an inflammatory state, may contribute to initiating the vascular remodelling in which the high BP levels may have a key role. Taking into account that stated above, the increased arterial stiffness observed in obese children and adolescents could be reversed controlling BP levels [
When the regional arterial stiffness was analyzed, the results showed that there were no differences in PWV between obese and normal weight subjects. Although this finding could be thought of as paradoxical, since PWV and BP levels showed a positive (statistically significant) relationship and obese children showed higher BP levels, the result could be explained by the Moens-Korteweg equation. This equation allows analyzing hemodynamic and arterial determinants of the PWV [
As it is well known, arterial stiffness is related to increased ventricular afterload, lower cardiac systodiastolic function, impaired vascular functional capability (i.e., ability to cushion or buffer vascular pulsatility), and increased cardiovascular risk. Looking at our findings, it could be said that childhood obesity is associated with age-related arterial changes (in some vascular pathways) that could lead to cardiovascular damage and risk increase. Furthermore, this work contributes to the proposal that obesity-associated changes may progress early in life becoming evident in older children. In addition, our work gives data linking obesity-associated BP increase and vascular changes. Then, interventions aimed at controlling BP (including weight control) would result in an improvement in vascular properties.
Childhood obesity was associated with age-dependent increase in local carotid and femoral, but not brachial, arterial stiffness, which became significant in subjects aged 12 and older. Stiffness changes were not associated with intrinsic changes in the arterial wall elasticity but could be explained by BP-dependent passive arterial distension determined by the increased peripheral and central aortic BP levels observed in obese subjects.
The protocol of this project was accepted by the Ethics Committee of our institution. All procedures agreed with the Declaration of Helsinki (1975 and reviewed in 1983). Children’s responsible adults gave their signed consents in order to participate in this study.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by the Agencia Nacional de Investigación e Innovación (ANII) and Espacio Interdisciplinario (EI) and Comisión Sectorial de Investigación Científica (CSIC-Udelar) of the Republic University, Uruguay. Additionally, this work was supported by extrabudgetary funds generated by CUiiDARTE Project. Professor Dr. Yanina Zócalo and Professor Dr. Daniel Bia are the Clinical Director and General Director, respectively, of CUiiDARTE Project.