all patients participated in the identification of early mechanisms in the pathogenesis of diabetic late complications ( ideal ) study launched in 2003 as a substudy of the nationwide finnish diabetic nephropathy study ( finndiane study ) ( 3 ) . a total of 125 patients participated at baseline in 20032004 , and 80 patients agreed to take part in the follow - up visit in 20082009 . the study protocols were approved by the ethics committee of helsinki university hospital . both at baseline and follow - up , patients underwent a clinical examination , resting electrocardiogram ( ecg ) , laboratory testing , one 24-h urine collection , ambulatory blood pressure monitoring ( abpm ) , and assessment of spontaneous brs and autonomic function tests . each participant completed a detailed questionnaire on lifestyle , smoking habits , and family history . the autonomic tests were performed in a quiet room at a temperature between 19 and 23c between 8:00 a.m. and 2:00 p.m. under standardized conditions as previously described ( 3 ) . the autonomic testing was postponed in cases of hypoglycemia within 24 h of the test . continuous blood pressure was measured with finapres 2300 digital plethysmograph ( ohmeda , louisville , co ) from the middle finger of the right arm held at heart level . recorded signals were digitized with 12-bit resolution at a sampling rate of 200 hz ( winacq data acquisition system ; absolute aliens , turku , finland ) . the subsequent off - line signal processing was performed using wincprs software ( absolute aliens ) . the autonomic function was evaluated in line with the recommendations of the recent european diabetic neuropathy study group ( neurodiab ) expert panel ( 15 ) by a set of four cardiovascular autonomic function tests : 1 ) the expiration - to - inspiration ratio of rr interval ( rri ) during slow deep breathing , 2 ) the maximum - to - minimum 30-to-15 ratio of rri during active standing , 3 ) the sbp response to standing , and 4 ) the maximum - to - minimum ratio of rri during valsalva maneuver . each test was scored ( 0 if normal and 1 if abnormal ) according to finnish age - specific reference values ( 16 ) , giving a total autonomic score between 0 and 4 . the participants with type 1 diabetes were grouped as follows : can-0 ( autonomic score = 0 ) , can-1 ( autonomic score = 1 ) , and can-2 ( autonomic score > 1 ) . the timing of breathing ( controlled and deep breathing ) was given by a signal from the wincprs software and verbal instructions by the technician . at the prospective visit , the respiration was monitored with respiratory inductance plethysmography ( zrip ; pro - tech services , mukilteo , wa ) . ecg and continuous blood pressure were recorded in the supine position during 5 min of spontaneous breathing and 2 min of controlled breathing ( 15 breaths per min ) and during 1 min of slow deep breathing ( 6 breaths per min ) . time series of the rri and the sbps were constructed and saved for further analysis . power spectral analysis of sbp and rri was performed with fast fourier transformation to obtain the power in the low - frequency ( 0.040.15 hz ) and high - frequency ( 0.150.40 hz ) bands . brs was determined from the spontaneous fluctuations in the rri and sbp during spontaneous , controlled , and deep breathing by six different methods and the average of these six methods ( brsaverage ) . the sequence methods ( brs and brs ) are based on identification of sequences of three or more consecutive heartbeats in which the sbp and the subsequent rris changed in the same direction at the minimum of 1 mmhg or 5 ms . the slopes of the regression lines between sbp and rr intervals were calculated for valid sequences with the correlation coefficient > 0.85 , and average was taken as a measure of brs and brs , correspondingly . -coefficients were calculated as the square root of the ratio of the spectral powers of rris and sbp in the low - frequency range ( brs-lf ) ( 0.040.15 hz ) and high - frequency range ( brs-hf ) ( 0.150.4 hz ) . transfer function brs was determined as the average of the sbp - rri cross - spectrum divided by the sbp spectrum in the frequency range of 0.040.15 hz , when coherence exceeded 0.5 . furthermore , we used a new method ( brs - sd ) ( 17 ) , based on the calculation of the ratio between the sd of the rri divided by the sd of sbp as a measure of brs . finally , we determined the average of all six methods because none of the individual methods proved superior to the others ( 17 ) . because controlled breathing by forcing the patient to breathe 15 breaths per min is likely to induce sympathetic activation in some patients , the brs during spontaneous breathing was used as the resting level . deep breathing reduces sympathetic activity ( 18 ) , and therefore we calculated the increase in brs as a response to deep breathing . ambulatory blood pressure monitoring ( abpm ) was performed in a subset of 71 participants with a spacelabs 90207 monitor ( spacelabs , redmond , wa ) . during the monitoring , patients were asked to avoid vigorous physical exercise and to keep their arm relaxed during measurements . blood pressure readings were obtained every 20 min during the day ( 7:00 a.m.11:00 p.m. ) and every 30 min at night ( 11.00 p.m.7:00 a.m. ) . patients with a nocturnal decrease of systolic or diastolic blood pressure < 10% of the corresponding daytime value were defined as nondippers . the change in blood pressure over time was calculated as the baseline value subtracted from the follow - up value . venous blood samples were obtained after a light breakfast and analyzed for hba1c , lipids , and serum creatinine . hba1c concentrations were determined by immunoturbidimetric immunoassay ( medix biochemica , kauniainen , finland ) . serum lipids ( total cholesterol , triglycerides , and hdl cholesterol ) and creatinine were measured by enzymatic methods . differences between groups were analyzed with  ( for qualitative variables ) or unpaired student t test ( for quantitative variables ) . statistical significance was defined as p value  0.05 . from our database , we selected all available data on spontaneous breathing obtained in healthy subjects with an age range of 1660 years ( n = 425 ) , and we calculated age regression curves for each brs index , sd of all normal rris ( sdnn ) , and mean rri . for the autonomic function tests ( e - to - i ratio , 30-to-15 ratio , valsalva ratio , and lying - to - standing change in sbp ) , we obtained similar age regression slopes from a previous study in 120 healthy subjects aged 2292 years ( 19 ) . using equations obtained in healthy subjects , we calculated the physiologic age - dependent deterioration for each subject over the individual follow - up period . to obtain age - adjusted values , we added the age - dependent brs deterioration value to the value of the follow - up result . thus , the difference between baseline and age - adjusted follow - up value reflected changes not due to aging . to evaluate the change in brs over time , we performed a paired t test between baseline brs and both the measured brs and age - adjusted brs at follow - up . the autonomic tests were performed in a quiet room at a temperature between 19 and 23c between 8:00 a.m. and 2:00 p.m. under standardized conditions as previously described ( 3 ) . the autonomic testing was postponed in cases of hypoglycemia within 24 h of the test . continuous blood pressure was measured with finapres 2300 digital plethysmograph ( ohmeda , louisville , co ) from the middle finger of the right arm held at heart level . recorded signals were digitized with 12-bit resolution at a sampling rate of 200 hz ( winacq data acquisition system ; absolute aliens , turku , finland ) . the subsequent off - line signal processing was performed using wincprs software ( absolute aliens ) . the autonomic function was evaluated in line with the recommendations of the recent european diabetic neuropathy study group ( neurodiab ) expert panel ( 15 ) by a set of four cardiovascular autonomic function tests : 1 ) the expiration - to - inspiration ratio of rr interval ( rri ) during slow deep breathing , 2 ) the maximum - to - minimum 30-to-15 ratio of rri during active standing , 3 ) the sbp response to standing , and 4 ) the maximum - to - minimum ratio of rri during valsalva maneuver . each test was scored ( 0 if normal and 1 if abnormal ) according to finnish age - specific reference values ( 16 ) , giving a total autonomic score between 0 and 4 . the participants with type 1 diabetes were grouped as follows : can-0 ( autonomic score = 0 ) , can-1 ( autonomic score = 1 ) , and can-2 ( autonomic score > 1 ) . the timing of breathing ( controlled and deep breathing ) was given by a signal from the wincprs software and verbal instructions by the technician . at the prospective visit , the respiration was monitored with respiratory inductance plethysmography ( zrip ; pro - tech services , mukilteo , wa ) . ecg and continuous blood pressure were recorded in the supine position during 5 min of spontaneous breathing and 2 min of controlled breathing ( 15 breaths per min ) and during 1 min of slow deep breathing ( 6 breaths per min ) . time series of the rri and the sbps were constructed and saved for further analysis . power spectral analysis of sbp and rri was performed with fast fourier transformation to obtain the power in the low - frequency ( 0.040.15 hz ) and high - frequency ( 0.150.40 hz ) bands . brs was determined from the spontaneous fluctuations in the rri and sbp during spontaneous , controlled , and deep breathing by six different methods and the average of these six methods ( brsaverage ) . the sequence methods ( brs and brs ) are based on identification of sequences of three or more consecutive heartbeats in which the sbp and the subsequent rris changed in the same direction at the minimum of 1 mmhg or 5 ms . the slopes of the regression lines between sbp and rr intervals were calculated for valid sequences with the correlation coefficient > 0.85 , and average was taken as a measure of brs and brs , correspondingly . -coefficients were calculated as the square root of the ratio of the spectral powers of rris and sbp in the low - frequency range ( brs-lf ) ( 0.040.15 hz ) and high - frequency range ( brs-hf ) ( 0.150.4 hz ) . transfer function brs was determined as the average of the sbp - rri cross - spectrum divided by the sbp spectrum in the frequency range of 0.040.15 hz , when coherence exceeded 0.5 . furthermore , we used a new method ( brs - sd ) ( 17 ) , based on the calculation of the ratio between the sd of the rri divided by the sd of sbp as a measure of brs . finally , we determined the average of all six methods because none of the individual methods proved superior to the others ( 17 ) . because controlled breathing by forcing the patient to breathe 15 breaths per min is likely to induce sympathetic activation in some patients , the brs during spontaneous breathing was used as the resting level . deep breathing reduces sympathetic activity ( 18 ) , and therefore we calculated the increase in brs as a response to deep breathing . ambulatory blood pressure monitoring ( abpm ) was performed in a subset of 71 participants with a spacelabs 90207 monitor ( spacelabs , redmond , wa ) . during the monitoring , patients were asked to avoid vigorous physical exercise and to keep their arm relaxed during measurements . blood pressure readings were obtained every 20 min during the day ( 7:00 a.m.11:00 p.m. ) and every 30 min at night ( 11.00 p.m.7:00 a.m. ) . patients with a nocturnal decrease of systolic or diastolic blood pressure < 10% of the corresponding daytime value were defined as nondippers . the change in blood pressure over time was calculated as the baseline value subtracted from the follow - up value . venous blood samples were obtained after a light breakfast and analyzed for hba1c , lipids , and serum creatinine . hba1c concentrations were determined by immunoturbidimetric immunoassay ( medix biochemica , kauniainen , finland ) . serum lipids ( total cholesterol , triglycerides , and hdl cholesterol ) and creatinine were measured by enzymatic methods . differences between groups were analyzed with  ( for qualitative variables ) or unpaired student t test ( for quantitative variables ) . statistical significance was defined as p value  0.05 . from our database , we selected all available data on spontaneous breathing obtained in healthy subjects with an age range of 1660 years ( n = 425 ) , and we calculated age regression curves for each brs index , sd of all normal rris ( sdnn ) , and mean rri . for the autonomic function tests ( e - to - i ratio , 30-to-15 ratio , valsalva ratio , and lying - to - standing change in sbp ) , we obtained similar age regression slopes from a previous study in 120 healthy subjects aged 2292 years ( 19 ) . all age regressions were significant except that with rri . using equations obtained in healthy subjects , we calculated the physiologic age - dependent deterioration for each subject over the individual follow - up period . to obtain age - adjusted values , we added the age - dependent brs deterioration value to the value of the follow - up result . thus , the difference between baseline and age - adjusted follow - up value reflected changes not due to aging . to evaluate the change in brs over time , we performed a paired t test between baseline brs and both the measured brs and age - adjusted brs at follow - up . from our database , we selected all available data on spontaneous breathing obtained in healthy subjects with an age range of 1660 years ( n = 425 ) , and we calculated age regression curves for each brs index , sd of all normal rris ( sdnn ) , and mean rri . for the autonomic function tests ( e - to - i ratio , 30-to-15 ratio , valsalva ratio , and lying - to - standing change in sbp ) , we obtained similar age regression slopes from a previous study in 120 healthy subjects aged 2292 years ( 19 ) . using equations obtained in healthy subjects , we calculated the physiologic age - dependent deterioration for each subject over the individual follow - up period . to obtain age - adjusted values , we added the age - dependent brs deterioration value to the value of the follow - up result . thus , the difference between baseline and age - adjusted follow - up value reflected changes not due to aging . to evaluate the change in brs over time , we performed a paired t test between baseline brs and both the measured brs and age - adjusted brs at follow - up . table 1 shows the clinical characteristics and abpm data of the participants at baseline and follow - up . duration at baseline was 8.8  0.2 years and 13.8  0.2 years at follow - up with a mean follow - up time of 5.0  0.0 years . of the 5 patients with antihypertensive treatment ( aht ) at baseline , 1 terminated the medication and 17 new patients started aht . thus , a total of 21 patients were using aht at the time of the follow - up visit , whereas none used -blockers . office sbp did not change over time , but the patients with aht had higher blood pressure both at baseline and follow - up . the patients who started aht were older ( 35.6  0.9 vs. 30.8  0.7 years ; p < 0.001 ) and had a later age at onset of diabetes ( 21.3  1.0 vs. 17.2  0.7 years ; p < 0.05 ) . the lipid concentrations remained unchanged , but 10 patients started lipid - lowering medication during follow - up . clinical characteristics and ambulatory blood pressure in patients with type 1 diabetes and according to antihypertensive treatment at follow - up data are means  sem or median ( range ) . aht , antihypertensive treatment at follow - up ; aht , no antihypertensive treatment at follow - up ; uaer , urinary albumin excretion rate . * significant at p < 0.05 . * * significant at p < 0.01 for baseline vs. follow - up . 68 patients had no signs of can ( can-0 ) , whereas 11 patients had borderline ( can-1 ) and one had evident ( can-2 ) can . at follow - up , one of the patients progressed to can-2 , and in 12 patients the can score worsened . the single patient with can-2 at baseline reversed to can-1 , and seven patients improved their autonomic score . brs indices at baseline did not differ when patients were grouped by can score at follow - up . when all patients were analyzed together , the e - to - i ratio , sdnn , and all but one of the brs indices declined significantly during follow - up , but after age adjustment only one brs method ( brs-hf ) showed a significant decline ( p < 0.01 ) ( table 2 ) . in the group with aht , there was a significant drop with time in e - to - i ratio , 30-to-15 ratio , sdnn , brs-hf , brs , and brsaverage , but the changes in e - to - i ratio , 30-to-15 ratio , and brs-hf were significant even after age adjustment ( p < 0.01 ) . in those without aht , e - to - i ratio and four of six brs indices declined significantly during follow - up , but none of these changes were significant anymore after age adjustment . autonomic function tests and spontaneous baroreflex sensitivity at baseline and follow - up data are means  sem . aht , antihypertensive treatment at follow - up ; aht , no antihypertensive treatment at follow - up . * significant at p < 0.05 . * * significant at p < 0.01 for baseline vs. follow - up . significant at p < 0.01 for baseline vs. follow - up adjusted for follow - up time . the association between spontaneous brs and 24-h ambp and office blood pressure at baseline were analyzed in patients with ambp data available . overall brs correlated negatively with 24-h and daytime ambp , predominantly with diastolic blood pressure ( dbp ) and mean arterial blood pressure ( map ) . all brs variables except brs correlated with 24-h dbp ( r 0.238 to 0.331 ; p < 0.05 ) and daytime dbp ( r 0.295 to 0.400 ; p < 0.05 ) , whereas the correlations with nighttime ambp were nonsignificant . furthermore , office blood pressures ( sbp , dbp , and map ) correlated significantly with brs-lf ( r 0.234 to 0.275 ; p < 0.05 ) , and transfer function brs ( r 0.251 to 0.281 ; p < 0.05 ) . the correlations between baseline spontaneous brs - variables and change in nighttime sbp are shown in fig the lower brs at baseline , the more the nighttime sbp increased over time ( r = 0.348 to 0.381 ; p < 0.05 ) . in addition to resting brs , we also calculated the increase in brs induced by deep breathing at baseline ( data not shown ) . two of the brs methods showed a significant correlation with the increase in blood pressure over time , mainly with 24 h ( brs-lf r = 0.3230.346 , p < 0.05 ; brs - sd r = 0.3520.454 , p < 0.05 ) and nighttime ( brs-lf r = 0.3030.434 , p < 0.05 ; brs - sd r = 0.3330.481 , p < 0.05 ) indices and with daytime map ( brs-lf r = 0.302 , p < 0.05 ; brs - sd r = 0.339 , p < 0.05 ) . with the other brs methods the correlations between the response in brs and blood pressure variables were nonsignificant . correlations between baseline spontaneous brs and change in nighttime sbp during 5-year follow - up . at baseline , 68 patients had no signs of can ( can-0 ) , whereas 11 patients had borderline ( can-1 ) and one had evident ( can-2 ) can . at follow - up , one of the patients progressed to can-2 , and in 12 patients the can score worsened . the single patient with can-2 at baseline reversed to can-1 , and seven patients improved their autonomic score . brs indices at baseline did not differ when patients were grouped by can score at follow - up . when all patients were analyzed together , the e - to - i ratio , sdnn , and all but one of the brs indices declined significantly during follow - up , but after age adjustment only one brs method ( brs-hf ) showed a significant decline ( p < 0.01 ) ( table 2 ) . in the group with aht , there was a significant drop with time in e - to - i ratio , 30-to-15 ratio , sdnn , brs-hf , brs , and brsaverage , but the changes in e - to - i ratio , 30-to-15 ratio , and brs-hf were significant even after age adjustment ( p < 0.01 ) . in those without aht , e - to - i ratio and four of six brs indices declined significantly during follow - up , but none of these changes were significant anymore after age adjustment . autonomic function tests and spontaneous baroreflex sensitivity at baseline and follow - up data are means  sem . aht , antihypertensive treatment at follow - up ; aht , no antihypertensive treatment at follow - up . * significant at p < 0.05 . * * significant at p < 0.01 for baseline vs. follow - up . significant at p < 0.01 for baseline vs. follow - up adjusted for follow - up time . the association between spontaneous brs and 24-h ambp and office blood pressure at baseline were analyzed in patients with ambp data available . overall brs correlated negatively with 24-h and daytime ambp , predominantly with diastolic blood pressure ( dbp ) and mean arterial blood pressure ( map ) . all brs variables except brs correlated with 24-h dbp ( r 0.238 to 0.331 ; p < 0.05 ) and daytime dbp ( r 0.295 to 0.400 ; p < 0.05 ) , whereas the correlations with nighttime ambp were nonsignificant . furthermore , office blood pressures ( sbp , dbp , and map ) correlated significantly with brs-lf ( r 0.234 to 0.275 ; p < 0.05 ) , and transfer function brs ( r 0.251 to 0.281 ; p < 0.05 ) . the correlations between baseline spontaneous brs - variables and change in nighttime sbp are shown in fig . 1 . the lower brs at baseline , the more the nighttime sbp increased over time ( r = 0.348 to 0.381 ; p < 0.05 ) . in addition to resting brs , we also calculated the increase in brs induced by deep breathing at baseline ( data not shown ) . two of the brs methods showed a significant correlation with the increase in blood pressure over time , mainly with 24 h ( brs-lf r = 0.3230.346 , p < 0.05 ; brs - sd r = 0.3520.454 , p < 0.05 ) and nighttime ( brs-lf r = 0.3030.434 , p < 0.05 ; brs - sd r = 0.3330.481 , p < 0.05 ) indices and with daytime map ( brs-lf r = 0.302 , p < 0.05 ; brs - sd r = 0.339 , p < 0.05 ) . with the other brs methods the correlations between the response in brs and blood pressure variables were nonsignificant . correlations between baseline spontaneous brs and change in nighttime sbp during 5-year follow - up . the association between spontaneous brs and 24-h ambp and office blood pressure at baseline were analyzed in patients with ambp data available . overall brs correlated negatively with 24-h and daytime ambp , predominantly with diastolic blood pressure ( dbp ) and mean arterial blood pressure ( map ) . all brs variables except brs correlated with 24-h dbp ( r 0.238 to 0.331 ; p < 0.05 ) and daytime dbp ( r 0.295 to 0.400 ; p < 0.05 ) , whereas the correlations with nighttime ambp were nonsignificant . furthermore , office blood pressures ( sbp , dbp , and map ) correlated significantly with brs-lf ( r 0.234 to 0.275 ; p < 0.05 ) , and transfer function brs ( r 0.251 to 0.281 ; p < 0.05 ) . the correlations between baseline spontaneous brs - variables and change in nighttime sbp are shown in fig . 1 . the lower brs at baseline , the more the nighttime sbp increased over time ( r = 0.348 to 0.381 ; p < 0.05 ) . in addition to resting brs , we also calculated the increase in brs induced by deep breathing at baseline ( data not shown ) . two of the brs methods showed a significant correlation with the increase in blood pressure over time , mainly with 24 h ( brs-lf r = 0.3230.346 , p < 0.05 ; brs - sd r = 0.3520.454 , p < 0.05 ) and nighttime ( brs-lf r = 0.3030.434 , p < 0.05 ; brs - sd r = 0.3330.481 , p < 0.05 ) indices and with daytime map ( brs-lf r = 0.302 , p < 0.05 ; brs - sd r = 0.339 , p < 0.05 ) . with the other brs methods the correlations between the response in brs and blood pressure variables were nonsignificant . correlations between baseline spontaneous brs and change in nighttime sbp during 5-year follow - up . in a representative sample of patients with type 1 diabetes , we demonstrated that although the brs is reduced at baseline , the decline in brs during a 5-year follow - up is similar to that seen in healthy subjects . the low brs at baseline does not progress to evident can but predicts an increase in nighttime sbp . cross - sectional studies have shown that cardiovagal brs deteriorates with age in healthy subjects ( 14 ) . as expected , there was a decline in the majority of the autonomic indices in patients with diabetes , but when the age - dependent deterioration was eliminated the decline , which could have been ascribed to the presence of diabetes , was no longer significant . however , in patients with aht there was a significant drop in the e - to - i ratio , 30-to-15 ratio , and brs-hf even after age correction . although these patients were older this is further supported by increased prevalence of laser - treated retinopathy in this group . in the current study , all but one of the brs - variables correlated inversely with 24-h dbp and daytime dbp at baseline  in agreement with previous data ( 20 ) . importantly , baseline brs predicted an increase in nighttime blood pressure at follow - up . moreover , the brs response to deep breathing correlated with the increase in 24-h blood pressure indices overall . a recent meta - analysis confirmed that nighttime sbp is a stronger predictor of cardiovascular and noncardiovascular mortality than daytime sbp both in hypertensive patients and in randomly selected populations ( 21 ) . in contrast to some ( 12 ) but not all ( 22 ) previous studies , we could not detect any relationship between the increase in nocturnal blood pressure and the albumin excretion rate . moreover , the nondipping status was not related to baseline brs and did not predict an increase in blood pressure or albumin excretion rate . this might be explained by the fact that future microalbuminuric patients are most likely those already on aht . it is of note , though , that the predictive value of the nondipping phenomenon for microalbuminuria or especially in normotensive patients is still not clear . whereas spontaneous brs was associated with an increase in nighttime blood pressure , the brs ( sd and lf ) , i.e. , the brs response to deep breathing , correlated with a general increase in blood pressure . during sleep , the renin - angiotensin system plays a more important role in blood pressure regulation than the sympathetic nervous system unless the sympathetic system is activated ( 23 ) . it can be argued that nighttime blood pressure is better standardized than daytime blood pressure , and thus an increase in nighttime blood pressure may also be a more sensitive marker of sympathetic activation . slow breathing is an intervention that reduces muscle nerve sympathetic activity and consequently increases brs in patients with chronic heart failure , hypertension , and chronic obstructive pulmonary disease ( 18,24 ) . thus , the magnitude of improvement after an intervention aimed to reduce the sympathetic activation could reflect the level of functional impairment . the fact that the brs response predicts an increase in nighttime blood pressure underlines the importance of a functional deficiency of the autonomic regulation . potential differences in the prognostic information that the different brs methods provide are inadequately studied . in the current study , the deep breathing interestingly , a recent study demonstrated that reduced brs in hypertension was most evident using the noninvasive brs-lf method ( 25 ) . the similar behavior of brs - sd and brs-lf is not surprising given that they are tightly correlated ( 17 ) . nonetheless , the single method that showed a persistent decline over time even after age adjustment was the brs-hf . this decline could be explained by reduced respiratory sinus arrhythmia in the high - frequency region due to diabetes . yet , a more prominent change over time than the reduced high - frequency component of rri ( lnhf - rri ) ( spontaneous breathing 6.21  0.13 vs. 5.77  0.15 ms , p < 0.001 ; controlled breathing 6.00  0.11 vs. 5.99  0.16 ms , p = ns ) was the marked increase in the hf component of the sbp ( lnhf - sbp ) ( spontaneous breathing 0.17  0.08 vs. 0.59  0.07 mmhg , p < 0.001 ; controlled breathing 0.21  0.08 vs. 0.83  0.08 mmhg , p < 0.001 ) . whether the decline in brs-hf is a cause or a consequence of the increase in sbp - hf remains unclear , but the ability of the brs to buffer blood pressure changes in the hf region is obviously reduced . furthermore , the association between baseline brs indices and the change in blood pressure over time was studied only in patients not treated with aht , and thus the current study was not designed to assess the association between brs and albuminuria . in conclusion , although the decline in brs over time appears to be physiological , a reduced brs at baseline predicts an increase in blood pressure . the assessment of brs could help to identify those patients with type 1 diabetes who would benefit from early interventions aiming to reduce sympathetic overactivity and to delay the development of hypertension .
objectivewe have recently demonstrated that early autonomic dysfunction , defined as low baroreflex sensitivity ( brs ) , could be functional and reversible . 
 however , potential temporal changes in brs have not yet been addressed by longitudinal studies in type 1 diabetes . 
 moreover , it is not known whether low brs predisposes to hypertension or other nonfatal diabetes complications.research design and methodswe conducted a 5-year prospective study including 80 patients with type 1 diabetes . 
 we measured ambulatory blood pressure and autonomic function tests . 
 brs was assessed by six different methods during spontaneous , controlled , and slow deep breathing at baseline and follow-up.resultsspontaneous brs declined over time ( brsaverage 16.2  0.8 vs. 13.2  0.8 ms / mmhg ; p < 0.01 ) , but the change was not significant when adjusted for time of follow - up . 
 low brs at baseline did not progress to cardiac autonomic neuropathy but predicted an increase in the nighttime systolic blood pressure ( brsaverage r = 0.37 ; p < 0.05 ) . additionally , brs response to deep breathing at baseline predicted an increase in 24-h ambulatory blood pressure ( brs-lf r = 0.3230.346 ; p < 0.05).conclusionsthe decline in spontaneous brs over time in patients with type 1 diabetes seems to be due to normal aging , which supports a functional etiology behind early autonomic derangements 
 . decreased resting brs and the magnitude of improvement by deep breathing may be due to sympathovagal imbalance , a well - known mechanism in the development of hypertension . 
 early interventions aiming to reduce sympathetic overactivity in patients with low brs might delay the development of hypertension .