search is a multicenter study that conducts population - based ascertainment of nongestational cases of physician - diagnosed diabetes in youth age < 20 years at diagnosis ( 15 ) .
a total of 402 search participants with type 1 diabetes , residents of colorado and ohio , who had a duration of diabetes of at least 5 years , were enrolled in the search cvd study between 2009 and 2011 . during the same time period ,
a total of 204 frequency - matched ( by age , sex , and race / ethnicity ) youth without type 1 diabetes ( control subjects ) were also recruited in the study .
control participants were enrolled from the primary - care offices in the same geographical areas from which the patients with diabetes were referred and were confirmed free of diabetes by fasting glucose levels < 126 mg / dl ( 16 ) . the study was reviewed and approved by the local institutional review boards that had jurisdiction over the local study population , and all participants provided signed informed consent or assent .
participants were invited for an outpatient research visit after an 8-h overnight fast , and medications , including short - acting insulin , were withheld the morning of the visit until after the blood draw was complete .
all participants were asked to refrain from any strenuous exercise , smoking , or consumption of any caffeinated drinks 12 h prior to the visit . race / ethnicity was self - reported , and the participants were categorized into non - hispanic white ( nhw ) and other racial / ethnic group ( including hispanic , african american , and asian / pacific islander racial / ethnic groups ) .
participants completed standardized questionnaires including medical history , medication inventory , smoking status , physical activity , daily insulin dose , and family history of diabetes and cvd .
current cigarette smoking was defined as having smoked cigarettes on one or more of the 30 days preceding the survey .
individuals who had tried smoking or smoked regularly ( at least one cigarette every day for 30 days ) but were not current smokers were considered past smokers .
participants were asked the average number of days in a typical week that they participated in physical activity for at least 20 min that made them sweat or breathe hard and were then categorized as physically inactive ( 02 days / week ) or physically active ( 37 days / week ) ( 17 ) .
height was measured in centimeters using a stadiometer and weight in kilograms using a standardized scale .
bmi was calculated as weight in kilograms divided by the square of height in meters , and age- and sex - specific bmi z - scores were derived based on the centers for disease control and prevention national standards ( 18 ) .
waist circumference was measured to the nearest 0.1 cm with the national health and nutrition examination survey protocol ( 19 ) .
resting systolic blood pressure ( sbp ) and diastolic blood pressure ( dbp ) were measured three times , using an aneroid sphygmomanometer , while the subjects were seated for at least 5 min and the average of the three measurements was taken .
laboratory samples were obtained under conditions of metabolic stability , defined , for case subjects , as no episode of diabetic ketoacidosis during the previous month . a fasting blood draw
was conducted for the assessment of the metabolic parameters ( hba1c , ldl cholesterol [ ldl - c ] , hdl cholesterol [ hdl - c ] , and triglyceride [ tg ] levels ) .
urinary albumin was measured from overnight timed urine samples by radioimmunoassay and expressed as albumin excretion rate ( aer ) .
aer levels between 20 and 199 g / min were defined as microalbuminuria ( 20 ) .
measurements of tg and hdl - c were performed enzymatically on a hitachi 917 autoanalyzer ( roche molecular biochemicals diagnostics , indianapolis , in ) .
ldl - c was calculated by the friedewald equation for individuals with tg concentration < 400 mg / dl and the beta quantification procedure for those with tg concentration 400 mg / dl . hrv was measured in the morning between 7:00 and 11:00 a.m. in a room with a stable room temperature , with the participant lying in the resting supine position for 10 min , using the sphygmocor device ( atcor medical , sydney , australia ) .
the device takes into account the normal heart beats , ignoring ectopic beats , to derive the statistical parameters of the normal r - r intervals ( n - n intervals ) of the electrocardiogram and estimates several time- and frequency - domain hrv indices ( 21 ) .
the time - domain indices of hrv used in the present analysis were sd of the r - r intervals ( sdnn ) and root mean square difference of successive normal r - r interval ( rmssd ) .
sdnn is a measure of overall hrv , so lower sdnn levels indicate reduced overall hrv .
rmssd is a measure of parasympathetic autonomic function , and reduced rmssd is a marker of parasympathetic loss .
brachial distensibility ( brachd ) was measured using a dynapulse pathway instrument ( pulse metric , san diego , ca ) , as previously described ( 22 ) .
this device derives brachial artery pressure curves using pulse dynamic analysis of arterial pressure signals obtained from a standard cuff sphygmomanometer to assess distensibility ( % /mmhg ) .
brachd was calculated using an empirical model to estimate baseline brachial artery diameter from sex , height , weight , and mean arterial pressure ( 22 ) .
pulse wave velocity ( pwv ) in the carotid to femoral segment ( pwv - trunk ) was measured with the sphygmocor device ( atcor medical ) .
pwv calculates the speed for the pressure wave generated by cardiac ejection to reach the periphery ( m / s ) ( 23 ) .
three electrocardiogram leads were applied to the torso , and the average of three distances from the lowest portion of the sternal notch to the carotid and femoral artery sites was obtained .
a pressure waveform was obtained for the proximal site ( carotid ) , and a second was recorded from the femoral artery using an applanation tonometer .
pwv - trunk is the difference in the carotid - to - femoral path length divided by the difference in r wave - to - waveform foot times , using an average of at least 10 beats to cover a complete respiratory cycle ( 23 ) .
augmentation index ( aix ) provides information concerning both wave reflections and as ( 24 ) .
the applanation tonometer was placed over the right radial artery , and three radial pulse waves were obtained , as described previously ( 5 ) .
the pressure waves were calibrated using mean arterial pressure and dbp obtained in the same arm .
the device then analyzed the pulse wave using a generalized transfer function ( 24 ) .
wave forms collected over a 10-s period were averaged to produce peripheral and corresponding central ( ascending aortic ) pressure waveforms . ascending aortic
the aix was calculated as the difference between the main outgoing wave and the reflected wave of the central arterial waveform , expressed as a percentage of the central pulse pressure . because aix is affected by heart rate
, values were adjusted to a standard heart rate of 75 bpm ( aix75 ) ( 25 ) .
all cardiac autonomic and vascular function tests were conducted fasting to prevent the possible influence of a surge in acute ambient glucose levels after a meal ( 26 ) .
statistical analyses were performed using sas for windows ( version 9.2 ; sas institute , cary , nc ) .
sdnn , tg , and aer were log - transformed to better meet model assumptions ( e.g. , homogeneity of variance ) .
comparisons of demographic and clinical characteristics between youth with and without type 1 diabetes were examined using  tests for categorical variables and t tests for normally distributed continuous variables .
the associations between sdnn ( main predictor variable ) and as outcomes were initially explored in a combined model , including both youth with and without type 1 diabetes , to test for effect modification by presence of type 1 diabetes by including an interaction term between sdnn and diabetes status .
since there was a suggestion of effect modification by presence of type 1 diabetes , subsequent analyses were stratified according to diabetes status .
multiple linear regression models were built separately for youth with and without type 1 diabetes to assess the relationships between sdnn ( independent variable ) and each of the three as measures ( dependent variables ) : peripheral ( brachd ) , central ( pwv - trunk ) , and aix75 .
separate models for each as outcome were constructed . a base model ( model 1 )
examined the relationship between sdnn and each as measure after adjustment for demographic factors  age , sex , and race / ethnicity  and was the model used for our primary test of association between sdnn and each of the as measures .
then , sequentially adjusted models explored the effect of adjustment for traditional cvd risk factors : dbp ( model 2 ) , lipid ( ldl - c , hdl - c , tg : model 3 ) , bmi ( model 4 ) , microalbuminuria ( model 5 ) , smoking status ( model 6 ) , the combined model with all cvd risk factors ( model 7 ) , and a final model with all covariates and hba1c ( model 8) .
finally , model 9 explored potential mediation of the association between hrv and as by heart rate .
similar analyses were conducted to assess the associations between rmssd and each measure of as .
search cvd is an ancillary study to the search for diabetes in youth study , conducted in colorado and ohio .
search is a multicenter study that conducts population - based ascertainment of nongestational cases of physician - diagnosed diabetes in youth age < 20 years at diagnosis ( 15 ) .
a total of 402 search participants with type 1 diabetes , residents of colorado and ohio , who had a duration of diabetes of at least 5 years , were enrolled in the search cvd study between 2009 and 2011 . during the same time period ,
a total of 204 frequency - matched ( by age , sex , and race / ethnicity ) youth without type 1 diabetes ( control subjects ) were also recruited in the study .
control participants were enrolled from the primary - care offices in the same geographical areas from which the patients with diabetes were referred and were confirmed free of diabetes by fasting glucose levels < 126 mg / dl ( 16 ) . the study was reviewed and approved by the local institutional review boards that had jurisdiction over the local study population , and all participants provided signed informed consent or assent .
participants were invited for an outpatient research visit after an 8-h overnight fast , and medications , including short - acting insulin , were withheld the morning of the visit until after the blood draw was complete .
all participants were asked to refrain from any strenuous exercise , smoking , or consumption of any caffeinated drinks 12 h prior to the visit . race / ethnicity was self - reported , and the participants were categorized into non - hispanic white ( nhw ) and other racial / ethnic group ( including hispanic , african american , and asian / pacific islander racial / ethnic groups ) .
participants completed standardized questionnaires including medical history , medication inventory , smoking status , physical activity , daily insulin dose , and family history of diabetes and cvd .
current cigarette smoking was defined as having smoked cigarettes on one or more of the 30 days preceding the survey .
individuals who had tried smoking or smoked regularly ( at least one cigarette every day for 30 days ) but were not current smokers were considered past smokers .
participants were asked the average number of days in a typical week that they participated in physical activity for at least 20 min that made them sweat or breathe hard and were then categorized as physically inactive ( 02 days / week ) or physically active ( 37 days / week ) ( 17 ) .
height was measured in centimeters using a stadiometer and weight in kilograms using a standardized scale .
bmi was calculated as weight in kilograms divided by the square of height in meters , and age- and sex - specific bmi z - scores were derived based on the centers for disease control and prevention national standards ( 18 ) .
waist circumference was measured to the nearest 0.1 cm with the national health and nutrition examination survey protocol ( 19 ) .
resting systolic blood pressure ( sbp ) and diastolic blood pressure ( dbp ) were measured three times , using an aneroid sphygmomanometer , while the subjects were seated for at least 5 min and the average of the three measurements was taken .
laboratory samples were obtained under conditions of metabolic stability , defined , for case subjects , as no episode of diabetic ketoacidosis during the previous month . a fasting blood draw
was conducted for the assessment of the metabolic parameters ( hba1c , ldl cholesterol [ ldl - c ] , hdl cholesterol [ hdl - c ] , and triglyceride [ tg ] levels ) .
urinary albumin was measured from overnight timed urine samples by radioimmunoassay and expressed as albumin excretion rate ( aer ) .
aer levels between 20 and 199 g / min were defined as microalbuminuria ( 20 ) .
measurements of tg and hdl - c were performed enzymatically on a hitachi 917 autoanalyzer ( roche molecular biochemicals diagnostics , indianapolis , in ) .
ldl - c was calculated by the friedewald equation for individuals with tg concentration < 400 mg / dl and the beta quantification procedure for those with tg concentration 400 mg / dl .
hrv was measured in the morning between 7:00 and 11:00 a.m. in a room with a stable room temperature , with the participant lying in the resting supine position for 10 min , using the sphygmocor device ( atcor medical , sydney , australia ) .
the device takes into account the normal heart beats , ignoring ectopic beats , to derive the statistical parameters of the normal r - r intervals ( n - n intervals ) of the electrocardiogram and estimates several time- and frequency - domain hrv indices ( 21 ) .
the time - domain indices of hrv used in the present analysis were sd of the r - r intervals ( sdnn ) and root mean square difference of successive normal r - r interval ( rmssd ) .
sdnn is a measure of overall hrv , so lower sdnn levels indicate reduced overall hrv .
rmssd is a measure of parasympathetic autonomic function , and reduced rmssd is a marker of parasympathetic loss .
brachial distensibility ( brachd ) was measured using a dynapulse pathway instrument ( pulse metric , san diego , ca ) , as previously described ( 22 ) .
this device derives brachial artery pressure curves using pulse dynamic analysis of arterial pressure signals obtained from a standard cuff sphygmomanometer to assess distensibility ( % /mmhg ) .
brachd was calculated using an empirical model to estimate baseline brachial artery diameter from sex , height , weight , and mean arterial pressure ( 22 ) .
pulse wave velocity ( pwv ) in the carotid to femoral segment ( pwv - trunk ) was measured with the sphygmocor device ( atcor medical ) .
pwv calculates the speed for the pressure wave generated by cardiac ejection to reach the periphery ( m / s ) ( 23 ) .
three electrocardiogram leads were applied to the torso , and the average of three distances from the lowest portion of the sternal notch to the carotid and femoral artery sites was obtained .
a pressure waveform was obtained for the proximal site ( carotid ) , and a second was recorded from the femoral artery using an applanation tonometer .
pwv - trunk is the difference in the carotid - to - femoral path length divided by the difference in r wave - to - waveform foot times , using an average of at least 10 beats to cover a complete respiratory cycle ( 23 ) .
augmentation index ( aix ) provides information concerning both wave reflections and as ( 24 ) .
the applanation tonometer was placed over the right radial artery , and three radial pulse waves were obtained , as described previously ( 5 ) .
the pressure waves were calibrated using mean arterial pressure and dbp obtained in the same arm .
the device then analyzed the pulse wave using a generalized transfer function ( 24 ) .
wave forms collected over a 10-s period were averaged to produce peripheral and corresponding central ( ascending aortic ) pressure waveforms . ascending aortic
the aix was calculated as the difference between the main outgoing wave and the reflected wave of the central arterial waveform , expressed as a percentage of the central pulse pressure . because aix is affected by heart rate
, values were adjusted to a standard heart rate of 75 bpm ( aix75 ) ( 25 ) .
all cardiac autonomic and vascular function tests were conducted fasting to prevent the possible influence of a surge in acute ambient glucose levels after a meal ( 26 ) .
statistical analyses were performed using sas for windows ( version 9.2 ; sas institute , cary , nc ) .
sdnn , tg , and aer were log - transformed to better meet model assumptions ( e.g. , homogeneity of variance ) .
comparisons of demographic and clinical characteristics between youth with and without type 1 diabetes were examined using  tests for categorical variables and t tests for normally distributed continuous variables .
the associations between sdnn ( main predictor variable ) and as outcomes were initially explored in a combined model , including both youth with and without type 1 diabetes , to test for effect modification by presence of type 1 diabetes by including an interaction term between sdnn and diabetes status .
since there was a suggestion of effect modification by presence of type 1 diabetes , subsequent analyses were stratified according to diabetes status .
multiple linear regression models were built separately for youth with and without type 1 diabetes to assess the relationships between sdnn ( independent variable ) and each of the three as measures ( dependent variables ) : peripheral ( brachd ) , central ( pwv - trunk ) , and aix75 .
separate models for each as outcome were constructed . a base model ( model 1 )
examined the relationship between sdnn and each as measure after adjustment for demographic factors  age , sex , and race / ethnicity  and was the model used for our primary test of association between sdnn and each of the as measures .
then , sequentially adjusted models explored the effect of adjustment for traditional cvd risk factors : dbp ( model 2 ) , lipid ( ldl - c , hdl - c , tg : model 3 ) , bmi ( model 4 ) , microalbuminuria ( model 5 ) , smoking status ( model 6 ) , the combined model with all cvd risk factors ( model 7 ) , and a final model with all covariates and hba1c ( model 8) . finally , model 9 explored potential mediation of the association between hrv and as by heart rate .
similar analyses were conducted to assess the associations between rmssd and each measure of as .
a total of 344 youth with type 1 diabetes and 171 healthy control subjects with complete measures of hrv and as were included in these analyses .
youth with and without type 1 diabetes had a similar age and sex distribution , though youth with diabetes were more likely to be nhw than control subjects ( 87 vs. 77% ; p = 0.004 ) .
bmi , bmi z - score , and bp were similar among youth with and without type 1 diabetes .
however , youth with type 1 diabetes had a worse metabolic profile with higher hba1c ( p < 0.0001 ) and ldl - c ( p = 0.01 ) levels and a higher prevalence of microalbuminuria ( 10 vs. 2% ; p = 0.007 ) as compared with healthy control subjects .
the heart rate was significantly higher among youth with type 1 diabetes as compared with their healthy counterparts ( p < 0.0001 ) .
finally , sdnn and rmssd were significantly lower among youth with type 1 diabetes ( 69.7 vs. 79.4 ms , p = 0.002 ; and 63.7 vs. 79.7 ms , p = 0.0003 , respectively ) as compared with their healthy counterparts . characteristics of youth with and without type 1 diabetes figure 1 displays graphically the association between sdnn and each of the vascular stiffness measures , brachd ( fig .
1c ) , in youth with and without type 1 diabetes . among youth with type 1 diabetes , reduced hrv ( marked by lower sdnn )
was significantly associated with all vascular stiffness outcomes : increased peripheral stiffness ( lower brachd , p = 0.01 ; fig .
in contrast , among control youth , the only significant association was between reduced hrv and peripheral stiffness ( brachd , p = 0.004 ; fig .
1a ) . a formal test for effect modification by diabetes status of the association between sdnn and as measures was marginally significant for central as ( pwv - trunk , p = 0.06 ; fig
. 1b ) . the associations between lower hrv and as measures ( panel a : brachd ; panel b : pwv - trunk ; panel c : aix75 ) .
the p value for interaction is in the combined sample including case and control subjects .
the  coefficients and p values are from the linear regression models shown separately for case and control subjects adjusted for age , sex , and race / ethnicity .
p value for interaction is derived from the combined model including case and control subjects .
( a high - quality color representation of this figure is available in the online issue . )
table 2 shows results of multiple linear regression analyses exploring the association between sdnn and the three as outcomes , stratified by diabetes status , in sequentially adjusted models .
associations between sdnn and measures of as ( brachd , pwv - trunk , and aix75 ) in sequentially adjusted linear regression models among youth with type 1 diabetes , lower sdnn was significantly associated with lower brachd ( p = 0.01 ) , higher pwv - trunk ( p < 0.0001 ) , and higher aix75 ( p = 0.007 ) independent of demographic variables ( model 1 ) .
these associations were unchanged on additional adjustment for dbp ( model 2 ) , lipid levels ( model 3 ) , obesity - related parameter ( bmi , model 4 ) , microalbuminuria ( aer , model 5 ) , and smoking ( model 6 ) . in the fully adjusted model ( model 7 ) , with all the covariates included , the relationships between sdnn and pwv - trunk / brachd among youth with type 1 diabetes were virtually unchanged , but the association with aix75 was reduced ( p = 0.1 ) . above and beyond
the variability included in the base model , blood pressure and obesity - related variables explained most of the variability in brachd ( change in adjusted r of 13 and 11% , respectively , from base model ) and pwv ( change in adjusted r of 7 and 4% , respectively , from base model ) .
addition of hba1c ( model 8) resulted in minimal improvement from the model with all cvd risk factors .
finally , on additional adjustment for resting heart rate in model 9 , the associations between sdnn and markers of as became nonsignificant , with resting heart rate remaining significantly associated with as in all models ( data not shown ) . among healthy control subjects ,
lower sdnn was significantly associated with brachd ( p = 0.004 ) and remained unchanged and statistically significant in the sequentially adjusted and final models ( p = 0.01 ) .
obesity - related variables explained most of the variability in brachd in youth without diabetes , with an increase of 26% in adjusted r from the base model .
supplementary table 1 shows results of multiple linear regression analyses exploring the association between rmssd and the three as outcomes , stratified by diabetes status , in sequentially adjusted models . among youth with type 1 diabetes , a significant inverse association was found between rmssd and all measures of as ( pwv - trunk , brachd , and aix75 ) .
we found that cardiac autonomic dysfunction , as measured by lower hrv , is associated with increased vascular stiffness in both central and peripheral vascular beds , among youth with type 1 diabetes .
these associations are independent of traditional cvd risk factors , including blood pressure , lipid levels , obesity - related parameters , microalbuminuria , and smoking . no associations between hrv and measures of as were found in the nondiabetic control group , except for an association between sdnn ( though not rmssd ) and peripheral stiffness ( as measured by brachd ) .
our data extend the findings from previous studies that have demonstrated an association between cardiac autonomic function and various measures of as in adults with type 1 diabetes ( 1214 ) .
ahlgren et al . ( 12 ) found that heart rate variation during deep breathing , the expiration / inspiration ratio , correlated with increased aortic stiffness in 40 women ( r = 0.49 ; p = 0.002 ) but not in 38 men ( r = 0.14 ; p = 0.4 ) with type 1 diabetes , independent of duration of diabetes .
the stockholm diabetes intervention study found , in a group of 59 adults with type 1 diabetes , that hrv correlated with arterial wall stiffness of the right common carotid artery ( 13 ) . of note , all these studies were cross - sectional and did not examine the relationship independent of the traditional cvd risk factors .
however , in the pittsburgh edc study , lower baseline expiration / inspiration ratio correlated strongly with both greater as ( measured by both aix and augmentation pressure ) and with reduced estimated myocardial perfusion ( measured by subendocardial viability ratio ) in 144 adults with type 1 diabetes some 18 years later ( 11 ) . moreover ,
although edc did not measure aix and augmentation pressure at baseline , the authors suggested , based on their findings , that cardiovascular autonomic neuropathy may play an important pathophysiological role in the development of arterial stiffening in adults with type 1 diabetes .
similarly , an association between lower hrv and progression of coronary artery calcification in both adults with type 1 diabetes and nondiabetic control subjects was recently reported by the coronary artery calcification in type 1 diabetes study ( 27 ) .
our finding of a strong correlation between reduced hrv and increased central as in youth with type 1 diabetes , but not among healthy control subjects , provides indirect support to the hypothesis of a pathophysiological role for can in the development of as .
however , given the cross - sectional design of our study , we can not directly test this hypothesis .
data from a limited number of animal ( 28 ) and human studies ( 29,30 ) suggests that the amplified sympathetic tone present in the early stage of can , also identified previously in our youth with type 1 diabetes ( 9 ) , could potentially increase the vascular tone and thus contribute to increased vascular stiffness , thus providing biologic plausibility for the above hypothesis .
indeed , on additional adjustment for resting heart rate ( elevated in youth with type 1 diabetes versus control subjects ) , the associations between sdnn and markers of as became nonsignificant , with resting heart rate remaining significantly associated with as in all models ) .
this suggests that increased resting heart rate may be on the causal pathway linking the reduced hrv with altered sympathovagal balance ( parasympathetic loss with sympathetic override ) in youth with type 1 diabetes to increased as .
we found an association between lower hrv and increased central stiffness in youth with type 1 diabetes but not in control subjects , and this association was independent of traditional cvd risk factors ( lipids , blood pressure , microalbuminuria , obesity , and smoking).these results may indicate , rather than a causal relationship , a common pathway , possibly hyperglycemia , leading in parallel to both cardiac autonomic dysfunction and increased as in individuals with type 1 diabetes .
there is ample biologic plausibility for the role of hyperglycemia as a common mediator of both abnormalities ( 31,32 ) .
hyperglycemia has been shown to promote accumulation of advanced glycation end products , causing cross - linking and polymerization of collagen molecules within the vessel wall ( 33 ) , thus resulting in loss of elasticity with subsequent reduction in arterial and myocardial compliance .
moreover , hyperglycemia was also shown to induce abnormal signaling of the autonomic neurons via accumulation of advanced glycation end products and microangiopathy , causing ischemic atrophy of the autonomic nerve fibers innervating cardiac and vascular tissue ( 34 ) .
other mechanisms , in addition to hyperglycemia , are likely to be involved . similar to edc , we also found an association between lower hrv and increased aix75 .
however , in our study , the association was attenuated on adjustment for traditional cvd risk factors .
this is not unexpected since , although cardiac autonomic dysfunction and arterial stiffening are both accelerated in the hyperglycemic environment , they likely share additional cvd risk factors . for example , elevated blood pressure levels and smoking were shown to be associated with both as and cardiac autonomic dysfunction in subjects with type 1 diabetes ( 11,3537 ) .
finally , we found a significant association between hrv and peripheral as , independent of demographic and cvd risk factors , in both youth with and without type 1 diabetes .
( 38 ) among 382 young healthy japanese men , with a significant negative association between brachial - ankle pwv and hrv parameters for parasympathetic nervous activity .
first , the cross - sectional nature of the study limits our ability to evaluate causality and order of events .
we therefore intend to prospectively follow this cohort to better understand the progression of cardiac autonomic dysfunction and vascular stiffening over time .
second , our sample of healthy control subjects was approximately half of that of youth with type 1 diabetes . however , the nonsignificant associations between hrv and as measures ( pwv - trunk and aix75 ) were not equivocal among our control sample and likely not the result of a type ii error ( lack of power ) .
finally , the hrv measure used in our study was derived from a 10-min recording of the baseline electrocardiogram .
while this is a relatively short length of recording , it is considered standard practice for clinical and research purposes , and it is advocated by the task force of the european society of cardiology and the north american society of pacing and electrophysiology ( 21 ) , as opposed to the hrv measures derived from the 24-h holter recordings .
our study also has several unique strengths : the setting of this study in a young adult contemporary population , the large and diverse sample of patients with type 1 diabetes , inclusion of a healthy control sample , and the simple noninvasive , bedside assessment of multiple measures of as , including both central and peripheral arteries . in summary
, we found a strong association between cardiac autonomic dysfunction and both central and peripheral as in youth with type 1 diabetes , independent of traditional cvd risk factors .
while lower hrv was also associated with increased peripheral stiffness in nondiabetic control youth , the association with central stiffness may be unique to individuals with type 1 diabetes .
regardless of the mechanisms responsible for this association , which need to be further explored in longitudinal studies , this association may contribute to the increased and premature cardiovascular disease burden in people with type 1 diabetes .
 objectivereduced heart rate variability ( hrv ) and increased arterial stiffness ( as ) are both present in youth with type 1 diabetes . 
 however , it is unclear whether they are associated and whether their association is independent of cardiovascular disease ( cvd ) risk factors.research design and methodsthe search cardiovascular disease ( search cvd ) study explored the cross - sectional relationships between hrv and several measures of as in youth with ( n = 344 ) and without ( n = 171 ) type 1 diabetes . the sphygmocor device ( atcor medical , sydney , australia ) 
 was used to measure hrv using sd of normal r - r interval ( sdnn ) , as well as as , using pulse wave velocity in the carotid to femoral segment ( pwv - trunk ) and augmentation index adjusted to a heart rate of 75 bpm ( aix75 ) . 
 brachial distensibility ( brachd ) , another index of as , was measured with a dynapulse instrument ( pulse metric , san diego , ca ) . 
 multiple linear regression analyses explored the associations between hrv and each of the three as measures , after adjusting for demographic characteristics and traditional cvd risk factors ( blood pressure , lipids , obesity , microalbuminuria , and smoking ) separately , for youth with and without type 1 diabetes.resultsamong youth with type 1 diabetes , lower sdnn was associated with peripheral as ( lower brachd , p = 0.01 ; r2 = 0.30 ) and central as ( higher pvw - trunk , p < 0.0001 ; r2 = 0.37 ; and higher aix75 , p = 0.007 ; r2 = 0.08 ) . 
 these associations were attenuated with adjustment for cvd risk factors , but remained statistically significant for brachd and pwv - trunk . while a similar association between hrv and brachd was present in control youth , lower hrv 
 was not associated with increased central as or with aix75.conclusionslongitudinal studies are needed to understand the pathways responsible for these associations . 
RESEARCH DESIGN AND METHODS
Participants
Anthropometric and metabolic measurements
Assessment of cardiac autonomic function
Assessment of vascular function
Statistical analyses
RESULTS
CONCLUSIONS