there are similarities between children and adults suffering from heart failure ( hf ) , such as the preferred pharmacological treatment ( 1 ) , the use of pace - makers and heart transplants ( 2,3 ) , the inability of the patient to reach the predicted heart rate for the patient 's age during cardiopulmonary exercise testing ( 4,5 ) , and the ergoespirometric response under similar clinical conditions ( 5 ) . in adults , endothelial dysfunction is related to the development of diastolic dysfunction ( 6,7 ) , chagas disease , left ventricular hypertrophy ( 8) , ischemic cardiomyopathy , hf ( 8,9 ) , obesity , type 1 diabetes , hyperlipidemia , arterial hypertension ( 10 ) , peripheral arterial disease , chronic kidney disease ( 11 ) and atherosclerosis ( 12 ) because the dysfunction predisposes the vasculature to vasoconstriction , leukocyte adherence , platelet activation , and vascular inflammation ( 13 ) . nevertheless , there is a lack of data regarding endothelial function in children with cardiomyopathy . the severity of endothelial dysfunction is related to the cardiovascular risk ( 14 ) , the severity of cardiovascular symptoms ( 15 ) , and the inability to exercise ( 11 ) and represents a predictor for cardiac transplant and death ( 16 ) . it is known that diseases , such as kawasaki 's disease ( 8) , hyperlipidemia ( 10 ) , obesity , and type 1 diabetes , play important roles in systemic inflammation and endothelial dysfunction ( 17 ) . these diseases may increase the likelihood of cardiovascular events ( 18 ) and may predispose children to the development of cardiomyopathy . based on these considerations , we reviewed the published literature on endothelial function in pre - pubertal children to evaluate the endothelial function in pre - pubertal children with cardiomyopathy or children at risk of developing cardiomyopathy , and we conducted an analysis of the data from the relevant studies . this analysis was undertaken to help clarify the role of endothelial impairment in children at risk of suffering from cardiomyopathy . endothelial function can be analyzed by noninvasive methods , including ultrasonography ( us ) ( 19 ) and peripheral artery tonometry ( pat ) ( 20 ) . during a us examination , the baseline rest image of the subject 's brachial artery is acquired , and a 5-min arterial occlusion is performed using cuff inflation to at least 50 mm hg suprasystolic pressure . the subsequent cuff deflation induces reactive hyperemia that results in an increase in flow or , more precisely , shear stress by dilating the brachial artery ; this phenomenon is designated flow - mediated dilatation ( fmd ) . after returning to the baseline , a second brachial artery image is recorded after the administration of nitroglycerine ( ntg ) ; this image corresponds to the contribution of the intima muscle relaxation to the dilation and is known as the endothelium - independent vasodilatation ( 19 ) . in contrast to us , the pat evaluation is a method that does not require the administration of drugs , and it combines the assessment of the flow - mediated dilatation after the same 5-min arterial cuff occlusion , with the arterial pulse wave amplitude measurement taken using a pneumatic fingertip probe ( 20 ) . a search of the pubmed , bireme , and scielo databases was conducted to perform a systematic review , according to the recommendations of prisma ( 21 ) . the search was performed using the following keywords : endothelial , child , pediatrics , and infant . the results were limited to human studies published in english , spanish , and portuguese . the initial selection was based on the title and abstract , and those deemed relevant were retained for further analysis . the exclusion criteria included the following : analyses of the endothelial function in animals , cadavers , adolescents or adults ; reviews ; analyses of either the coronary or pulmonary arteries or the neurological or osteomuscular systems ; if the patients had rheumatic , oncohematological , splenic or hepatic diseases ; or if the studies were trials related to markers , genetics and interventions . the list of potential trials to include was verified by the authors of the present study . we note that there may be a risk of bias across the studies because not all of the trials published have been indexed in the selected databases . the following data were collected for analysis : the number of patients enrolled in the study ; the patient 's age ; whether sexual maturity had been reached ; any diseases involved ; the protocol used for the endothelial function evaluation and the fmd , ntg , and pat values . collected data in all tables were expressed following disease order , in order to better clarify data presentation and analysis . the values of endothelial function were expressed as the mean  standard deviation ( sd ) , as collected from the original trials . the data from healthy children were compared with the data for unhealthy children , and the differences were analyzed using the student t - test . a total of 559 articles were retrieved after the preliminary search , and 21 articles were considered potentially relevant based on the title and abstract . a careful analysis of these articles was performed , and ten trials were excluded for several reasons . table 1 presents the general descriptions of the included studies and provides information regarding the participants , their ages , their diseases , the endothelial evaluation method used and whether there were differences between genders ( table 1 ) . all eleven of the selected studies provided data for healthy children for comparison , and , with the exception of one study ( 22 ) , all of the studies compared healthy children to ill children . four of the studies evaluated obese children ( 23 - 26 ) , one evaluated children with obesity and type 1 diabetes ( 27 ) , three studied children with type 1 diabetes ( 28 - 30 ) , and two evaluated children with kawasaki 's disease ( 31 - 32 ) . these reviewed studies reported a mean age of 9.81.8 years old , and only four articles investigated the sexual maturation of the group of pre - pubertal children ( 23,25,26,29 ) . forty - five percent of all of the studies found no difference in the endothelial function between genders , and 55% of the reports did not provide these data ( table 1 ) . most of the studies used ultrasound to determine the percent diameter changes for the fmd and ntg assessments ( 22 - 29,31,32 ) . only one study used reactive hyperemia  peripheral artery tonometry ( rh - pat ) for the same purpose ( 30 ) , showing that the endothelial function was impaired in diabetic children relative to that in healthy children ( 1.630.5 vs. 1.950.3 for diabetic children vs. healthy children ) ( 30 ) . the fmd response values from all of the other articles for obese and diabetic children were significantly lower than those for healthy children ( 5.91.29% for obese children , 4.50.7% for diabetic children , and 9.81.8% for healthy children ; p<0.0008 ) . the obese children had a 39% lower fmd response than the healthy children , and the diabetic children had a decrease in their fmd of 25% ( table 2 ) . the children with kawasaki 's disease had 27% lower fmd responses than the healthy children ( 7.11.27% vs. 9.81.8% , respectively ) , but this difference was not statistically significant ( p  =  0.26 ) . the fmd data for the obese children , diabetic children , and children with kawasaki 's disease exhibited no statistically significant differences ( p<0.38 ) ( table 2 ) . the ntg response ( table 2 ) also showed no significant difference among the groups ( 22.77.1% for healthy children , 19.62.0% for obese children and 16.65.9% for diabetic children ; p<0.19 ) . among the excluded studies , one contained no data on endothelial function ( 33 ) , and most of the excluded studies did not list the data for pre - pubertal children , post - pubertal children ( 34 - 39 ) and adults ( 40,41 ) separately . another study ( 42 ) published data for the same patients as used in a previously published study ( 32 ) . ultrasound is the most frequently used method to evaluate endothelial function because it has a low cost , is safe and is sufficiently reproducible . however , some limitations of this method are that the fmd response can be influenced by both temperature and age , and ultrasound requires drug administration and the recording of images for posterior analysis ( 19 ) . another technique for the assessment of endothelial function is the pat method , which has been proposed to be more practical and precise ( 20 ) , and pat results are moderately significantly correlated with us results ( 43 ) . the pat method combines the traditional flow - mediated dilatation measurement with pneumatic fingertip probes to measure the arterial pulse wave amplitude ( 20 ) . one study ( 31 ) chose pat over us and confirmed that diabetic children have endothelial dysfunction , as do adults ( 44,45 ) . in five studies ( 22,24,25,28,32 ) , the gender of the individual did not correlate with the endothelial function , as has been found for adults ( 60 ) and adolescents ( 61 ) . pre - pubertal children show lower responses to beta - adrenergic receptors and have lower levels of circulating catecholamines ( adrenaline and noradrenaline ) than adolescents and adults ( 46 ) . the obese children exhibit accelerated growth and , therefore , earlier puberty ( 47 ) , which is evidenced by an advancement of menarche by 2.2 years ( 11.2 vs. 13.4 years , respectively ) ( 48 ) because fat mass influences the levels of hormones ( 49,50 ) . these data reinforce the need for the evaluation of sexual maturation in studies involving children . the extent of sexual maturation is widely accessed using the tanner - whitehouse scale , which is based on secondary sexual characteristics , such as breast development and menarche in girls , standards for penis development in boys , and pubic hair development in both sexes ( 51 ) . this lack of sexual maturity assessment explains why those trials that combined information for children , adolescents ( 33 - 39 ) , and adults ( 40,41 ) were excluded in the present study and explains the elevated fmd data from one study ( 24 ) , which included a higher mean age of obese children of 124 years old . the evaluation of sexual maturity also explains why three of the included studies ( 23,25,26 ) that assessed the pubertal stage by clinical examination yielded similar fmd data . diabetic and obese individuals have hyperinsulinemia , and both diabetes and obesity are related to the higher hormone ( 50 ) and inflammation levels ( 52 ) that contribute to increased arterial stiffness and vascular lesions , which are related to both endothelial function and structural arterial changes ( 53 ) and may explain the endothelial dysfunction results for these groups ( 23 - 30 ) . in addition to some methodological disparities , all of the studies showed significantly impaired endothelial function ( fmd response ) in the obese and diabetic children despite the lack of a difference in the ntg response , a result that was reported for adults ( 54 ) when compared with healthy subjects ( 55 ) . however , fmd impairment seems to be greater in adults than in children ( 44% in obese adults and 55% in diabetic adults ) ; similarly , adults show no difference in ntg responses ( 54,56 ) . the collected fmd values in children with kawasaki 's disease are lower than those in healthy children ( 31,32 ) , which can indicate a low , but persistent , level of inflammation ( 57 ) , as evidenced by higher c - reactive protein ( crp ) levels ( 52,53,58 ) . only one study ( 32 ) included ntg data , and this lack of data limits the discussion of the information provided . the fmd values suggest that the major dysfunctions in these children occur as a result of the local nitric oxide ( no ) bioavailability in the endothelium ( no production ) because the shear stress induced by reactive hyperemia activates endothelial no production ( 59 ) . the ntg response also suggests that the vascular smooth muscle cell function is preserved ( 19 ) . yet , one study showed significantly lower gt values in obese children than in healthy children ( 27 ) , and two other studies did not publish values for the ntg response ( 22,24 ) . some reports ( 20,25,28 ) did not describe how long the subjects were at rest , according to corretti et al . ( 22 ) , > 10 min is recommended , between the collections of the fmd and ntg response images , which might have contributed to the reported outcomes . it is also worth noting that three of the trials ( 24,27,29 ) allowed the arteries to return to the basal condition and that two of these studies ( 24,29 ) did not yield statistically significant data . in spite of the statistically significant differences in some of the endothelial function responses , the number of trials regarding this subject remains limited . another limitation of the data search for pre - pubertal children is that the studies list the results for adults , teenagers , and children together , and do not divide the data by group according to the puberty state and age . the small number of studies in children may also be due to the use of the us method because drug administration is required . however , the new method of endothelial function evaluation , the pat method , might help increase the number of trials using this population . although endothelial dysfunction has been identified in adults as a predictor of cardiac transplant and death , the clinical implications of endothelial dysfunction were not presented in the selected trials , nor were they the focus of the current study ; however , this correlation should be further evaluated in children . lastly , even though the number of pre - pubertal children with endothelial dysfunction is unknown , there is a great number of children who suffer from this condition . thus , the barriers in the pediatric field must be broken , and more studies on this topic should be performed to understand this population better . in conclusion , endothelial function is an important clinical feature because it may indicate the severity of cardiovascular symptoms , prognosis , and mortality . children at risk of developing cardiomyopathy exhibit endothelial dysfunction ; however , the prevalence of endothelial dysfunction in cardiomyopathic children remains unknown because of the lack of data . we suggest that attention should be paid to the consequences of endothelial function in this group . a search of the pubmed , bireme , and scielo databases was conducted to perform a systematic review , according to the recommendations of prisma ( 21 ) . the search was performed using the following keywords : endothelial , child , pediatrics , and infant . the results were limited to human studies published in english , spanish , and portuguese . the initial selection was based on the title and abstract , and those deemed relevant were retained for further analysis . the exclusion criteria included the following : analyses of the endothelial function in animals , cadavers , adolescents or adults ; reviews ; analyses of either the coronary or pulmonary arteries or the neurological or osteomuscular systems ; if the patients had rheumatic , oncohematological , splenic or hepatic diseases ; or if the studies were trials related to markers , genetics and interventions . the list of potential trials to include was verified by the authors of the present study . we note that there may be a risk of bias across the studies because not all of the trials published have been indexed in the selected databases . the following data were collected for analysis : the number of patients enrolled in the study ; the patient 's age ; whether sexual maturity had been reached ; any diseases involved ; the protocol used for the endothelial function evaluation and the fmd , ntg , and pat values . collected data in all tables were expressed following disease order , in order to better clarify data presentation and analysis . the values of endothelial function were expressed as the mean  standard deviation ( sd ) , as collected from the original trials . the data from healthy children were compared with the data for unhealthy children , and the differences were analyzed using the student t - test . a total of 559 articles were retrieved after the preliminary search , and 21 articles were considered potentially relevant based on the title and abstract . a careful analysis of these articles was performed , and ten trials were excluded for several reasons . table 1 presents the general descriptions of the included studies and provides information regarding the participants , their ages , their diseases , the endothelial evaluation method used and whether there were differences between genders ( table 1 ) . all eleven of the selected studies provided data for healthy children for comparison , and , with the exception of one study ( 22 ) , all of the studies compared healthy children to ill children . four of the studies evaluated obese children ( 23 - 26 ) , one evaluated children with obesity and type 1 diabetes ( 27 ) , three studied children with type 1 diabetes ( 28 - 30 ) , and two evaluated children with kawasaki 's disease ( 31 - 32 ) . these reviewed studies reported a mean age of 9.81.8 years old , and only four articles investigated the sexual maturation of the group of pre - pubertal children ( 23,25,26,29 ) . forty - five percent of all of the studies found no difference in the endothelial function between genders , and 55% of the reports did not provide these data ( table 1 ) . most of the studies used ultrasound to determine the percent diameter changes for the fmd and ntg assessments ( 22 - 29,31,32 ) . only one study used reactive hyperemia  peripheral artery tonometry ( rh - pat ) for the same purpose ( 30 ) , showing that the endothelial function was impaired in diabetic children relative to that in healthy children ( 1.630.5 vs. 1.950.3 for diabetic children vs. healthy children ) ( 30 ) . the fmd response values from all of the other articles for obese and diabetic children were significantly lower than those for healthy children ( 5.91.29% for obese children , 4.50.7% for diabetic children , and 9.81.8% for healthy children ; p<0.0008 ) . the obese children had a 39% lower fmd response than the healthy children , and the diabetic children had a decrease in their fmd of 25% ( table 2 ) . the children with kawasaki 's disease had 27% lower fmd responses than the healthy children ( 7.11.27% vs. 9.81.8% , respectively ) , but this difference was not statistically significant ( p  =  0.26 ) . the fmd data for the obese children , diabetic children , and children with kawasaki 's disease exhibited no statistically significant differences ( p<0.38 ) ( table 2 ) . the ntg response ( table 2 ) also showed no significant difference among the groups ( 22.77.1% for healthy children , 19.62.0% for obese children and 16.65.9% for diabetic children ; p<0.19 ) . among the excluded studies , one contained no data on endothelial function ( 33 ) , and most of the excluded studies did not list the data for pre - pubertal children , post - pubertal children ( 34 - 39 ) and adults ( 40,41 ) separately . another study ( 42 ) published data for the same patients as used in a previously published study ( 32 ) . ultrasound is the most frequently used method to evaluate endothelial function because it has a low cost , is safe and is sufficiently reproducible . however , some limitations of this method are that the fmd response can be influenced by both temperature and age , and ultrasound requires drug administration and the recording of images for posterior analysis ( 19 ) . another technique for the assessment of endothelial function is the pat method , which has been proposed to be more practical and precise ( 20 ) , and pat results are moderately significantly correlated with us results ( 43 ) . the pat method combines the traditional flow - mediated dilatation measurement with pneumatic fingertip probes to measure the arterial pulse wave amplitude ( 20 ) . one study ( 31 ) chose pat over us and confirmed that diabetic children have endothelial dysfunction , as do adults ( 44,45 ) . in five studies ( 22,24,25,28,32 ) , the gender of the individual did not correlate with the endothelial function , as has been found for adults ( 60 ) and adolescents ( 61 ) . pre - pubertal children show lower responses to beta - adrenergic receptors and have lower levels of circulating catecholamines ( adrenaline and noradrenaline ) than adolescents and adults ( 46 ) . the obese children exhibit accelerated growth and , therefore , earlier puberty ( 47 ) , which is evidenced by an advancement of menarche by 2.2 years ( 11.2 vs. 13.4 years , respectively ) ( 48 ) because fat mass influences the levels of hormones ( 49,50 ) . these data reinforce the need for the evaluation of sexual maturation in studies involving children . the extent of sexual maturation is widely accessed using the tanner - whitehouse scale , which is based on secondary sexual characteristics , such as breast development and menarche in girls , standards for penis development in boys , and pubic hair development in both sexes ( 51 ) . this lack of sexual maturity assessment explains why those trials that combined information for children , adolescents ( 33 - 39 ) , and adults ( 40,41 ) were excluded in the present study and explains the elevated fmd data from one study ( 24 ) , which included a higher mean age of obese children of 124 years old . the evaluation of sexual maturity also explains why three of the included studies ( 23,25,26 ) that assessed the pubertal stage by clinical examination yielded similar fmd data . diabetic and obese individuals have hyperinsulinemia , and both diabetes and obesity are related to the higher hormone ( 50 ) and inflammation levels ( 52 ) that contribute to increased arterial stiffness and vascular lesions , which are related to both endothelial function and structural arterial changes ( 53 ) and may explain the endothelial dysfunction results for these groups ( 23 - 30 ) . in addition to some methodological disparities , all of the studies showed significantly impaired endothelial function ( fmd response ) in the obese and diabetic children despite the lack of a difference in the ntg response , a result that was reported for adults ( 54 ) when compared with healthy subjects ( 55 ) . however , fmd impairment seems to be greater in adults than in children ( 44% in obese adults and 55% in diabetic adults ) ; similarly , adults show no difference in ntg responses ( 54,56 ) . the collected fmd values in children with kawasaki 's disease are lower than those in healthy children ( 31,32 ) , which can indicate a low , but persistent , level of inflammation ( 57 ) , as evidenced by higher c - reactive protein ( crp ) levels ( 52,53,58 ) . only one study ( 32 ) included ntg data , and this lack of data limits the discussion of the information provided . the fmd values suggest that the major dysfunctions in these children occur as a result of the local nitric oxide ( no ) bioavailability in the endothelium ( no production ) because the shear stress induced by reactive hyperemia activates endothelial no production ( 59 ) . the ntg response also suggests that the vascular smooth muscle cell function is preserved ( 19 ) . yet , one study showed significantly lower gt values in obese children than in healthy children ( 27 ) , and two other studies did not publish values for the ntg response ( 22,24 ) . some reports ( 20,25,28 ) did not describe how long the subjects were at rest , according to corretti et al . ( 22 ) , > 10 min is recommended , between the collections of the fmd and ntg response images , which might have contributed to the reported outcomes . it is also worth noting that three of the trials ( 24,27,29 ) allowed the arteries to return to the basal condition and that two of these studies ( 24,29 ) did not yield statistically significant data . in spite of the statistically significant differences in some of the endothelial function responses , the number of trials regarding this subject remains limited . another limitation of the data search for pre - pubertal children is that the studies list the results for adults , teenagers , and children together , and do not divide the data by group according to the puberty state and age . the small number of studies in children may also be due to the use of the us method because drug administration is required . however , the new method of endothelial function evaluation , the pat method , might help increase the number of trials using this population . although endothelial dysfunction has been identified in adults as a predictor of cardiac transplant and death , the clinical implications of endothelial dysfunction were not presented in the selected trials , nor were they the focus of the current study ; however , this correlation should be further evaluated in children . lastly , even though the number of pre - pubertal children with endothelial dysfunction is unknown , there is a great number of children who suffer from this condition . thus , the barriers in the pediatric field must be broken , and more studies on this topic should be performed to understand this population better . in conclusion , endothelial function is an important clinical feature because it may indicate the severity of cardiovascular symptoms , prognosis , and mortality . children at risk of developing cardiomyopathy exhibit endothelial dysfunction ; however , the prevalence of endothelial dysfunction in cardiomyopathic children remains unknown because of the lack of data . we suggest that attention should be paid to the consequences of endothelial function in this group . guilherme v guimares ( cnpq # 304733/2008 - 3 ) was supported by conselho nacional de pesquisa .
although it is known that obesity , diabetes , and kawasaki 's disease play important roles in systemic inflammation and in the development of both endothelial dysfunction and cardiomyopathy , there is a lack of data regarding the endothelial function of pre - pubertal children suffering from cardiomyopathy . in this study 
 , we performed a systematic review of the literature on pre - pubertal children at risk of developing cardiomyopathy to assess the endothelial function of pre - pubertal children at risk of developing cardiomyopathy . 
 we searched the published literature indexed in pubmed , bireme and scielo using the keywords  endothelial ' ,  children ' ,  pediatric ' and  infant ' and then compiled a systematic review . 
 the end points were age , the pubertal stage , sex differences , the method used for the endothelial evaluation and the endothelial values themselves . 
 no studies on children with cardiomyopathy were found . 
 only 11 papers were selected for our complete analysis , where these included reports on the flow - mediated percentage dilatation , the values of which were 9.801.80 , 5.901.29 , 4.500.70 , and 7.101.27 for healthy , obese , diabetic and pre - pubertal children with kawasaki 's disease , respectively . 
 there was no significant difference in the dilatation , independent of the endothelium , either among the groups or between the genders for both of the measurements in children ; similar results have been found in adolescents and adults . 
 the endothelial function in cardiomyopathic children remains unclear because of the lack of data ; nevertheless , the known dysfunctions in children with obesity , type 1 diabetes and kawasaki 's disease may influence the severity of the cardiovascular symptoms , the prognosis , and the mortality rate . the results of this study encourage future research into the consequences of endothelial dysfunction in pre - pubertal children .