autonomic neuropathy ( an ) has long been recognized as a significant health risk and leads to reduced quality of life ( qol ) , increased mortality and morbidity and increased health care costs ( 1 - 2 - 3 ) .
cardiovascular autonomic neuropathy ( can ) is an end - stage condition and is characterized by structural deficits due to loss of parasympathetic or sympathetic neurons that innervate the heart and blood vessels , resulting in abnormalities in heart rate ( hr ) control and vascular dynamics ( 3 ) .
can is associated with multiple cardiovascular disease states , including low ejection fraction ( 4 , 5 ) , atrial fibrillation ( 6 ) , ventricular arrhythmias ( 7 ) , cardiomyopathies ( 8 , 9 ) , symptomatic systolic heart failure ( 10 ) and myocardial ischemia ( 11 ) , as well as many of the traditional and nontraditional risk factors for heart disease ( 12 ) . in patients diagnosed with diabetes and coronary artery disease
serial an testing of a large population ( 774 ) of patients with diabetes demonstrated that 26% progressively worsened over time , despite clinical surveillance , while only 3% improved ( 13 ) .
a meta - analysis of 15 studies of patients diagnosed with diabetes and can demonstrated a relative mortality risk of 3.65 over those without can ( 3 ) .
the disease process of an is poorly understood by many clinicians and the early stages of disease are often overlooked .
the two branches of the autonomic nervous system ( ans ) , parasympathetic and sympathetic ( p&s ) , act together to maintain sympathovagal balance ( sb ) ( 14 ) . establishing and maintaining appropriate
sb slows the progression of an , reducing morbidity and mortality and improving outcomes ( 3 , 15 , 16 ) .
eta1-adrenergic agonists ( beta - blockers ) are known to reduce sympathetic activity ( 17 ) and thereby alter sb .
is known to be cardioprotective and is associated with greater longevity in geriatric and heart disease patients ( 16 , 18 ) .
propranolol and metoprolol have been studied previously for their effect on diabetic autonomic nerve dysfunction , and these drugs affect only sympathetic inhibition ( 19 , 20 ) .
the third - generation adrenergic blocker , carvedilol , has both beta - blocker and alpha - blocker effects .
the alpha - blocker acts as a vasodilator ( 21 ) , and an antioxidant and endothelin biosynthesis suppressor ( 22 ) .
thus , carvedilol has a broader affect on the ans , which may explain why it further reduces mortality ( 23 ) .
our hypotheses are that the beta - blocker , metoprolol , would inhibit sympathetic tone less than the combination alpha- and beta - blocker , carvedilol .
second , we hypothesize that carvedilol will also result in an increase in parasympathetic activity .
patients who had undergone serial autonomic p&s testing ( anx-3.0 ; ansar medical technologies , inc . ,
the registry consists of 147 arrhythmia - free patients diagnosed with noninsulin - dependent ( type 2 ) diabetes mellitus from eight ambulatory clinics located in new york , pennsylvania , new jersey , maryland and virginia .
the patient selection method and demographics , and the three noninvasive autonomic measurement methods used for screening , are described in the companion article ( 24 ) .
( + ) beta - blocker ,  are those patients who were beta - blocker nave at the beginning of the study and were started on beta - blocker during the study .
( )beta - blocker ,  consists of patients who started the study period on beta - blocker and had beta - blocker discontinued during the study
. eg3 ,  ( o)beta - blocker ,  the control group , are patients who were on stable doses of beta - blockers that did not change throughout the study .
eg3 patients were case - matched to the study population patients with respect to comorbid conditions such as hypertension ( htn ) and cardiovascular disease ( cvd ) , as well as age , gender , height and weight .
each experimental patient in the registry performed a baseline p&s study ( test n ) the day of the prescribed change to their beta - blocker . to remain in the registry ,
there needed to be documentation of the patient s compliance according to grouping , for at least 3 months , after which the patient performed a follow - up p&s study ( test n+1 ) .
all graphs consist of two curves : the broken lines represent the responses to carvedilol , and the solid lines represent the responses to metoprolol . in all figures ,
the responses are normalized to 1.0 in the baseline test to highlight the changes (  ) in response to beta - blocker titration .
the figure data present the average change (  ) in a parameter from baseline to follow - up ( test n+1 ) .
absolute values for the data in the figures are presented in the tables of the companion article ( 24 ) .
the average age , height and weight of the cohort are 61.8  12 yrs , 166.7  27 lb and 64.8  6 in , respectively , and serial tests are separated by 4.1 ( 1.2 ) months ( 24 ) .
figure 1 displays the normalized , average hemodynamic responses from the two tests for each of the three subpopulations .
similarly , figures 2 through 4 display the results from the three autonomic measurement methods : ( 1 ) p&s method results , ( 2 ) spectral - domain hrv - alone results and ( 3 ) time - domain hrv - alone results , respectively .
( a ) and ( b ) represent the experimental groups ( 1 and 2 , respectively ) and ( c ) represents the control group .
( a ) and ( b ) represent the experimental groups ( 1 and 2 , respectively ) and ( c ) represents the control group .
( please see text for details . ) in response to increasing either agent , the mean hr ( mhr ) and mean systolic bp ( sbp ) decreased . in response to increasing metoprolol
, the mhr decreases from 78 to 72 bpm and the average mhr response to increasing carvedilol decreases from 76 to 70 bpm ( both statistically significant , p<0.001 ) .
the average changes in sbp were not significant in response to increasing either agent , staying at 125 mmhg for metoprolol and changing from 122 to 121 mmhg for carvedilol .
the metoprolol - nave subpopulation demonstrates an average increase in dbp from 73 to 74 mmhg , and the carvedilol - nave subpopulation demonstrates no change . in response to discontinuing either agent , all hemodynamic measures increase
there is a statistically significant increase in mhr in response to discontinuing carvedilol ( from 73 to 77 bpm ) as compared with metoprolol ( 68 to 69 bpm ; p<0.001 ) .
the average sbp increase to discontinuing either agent ( from 115 to 116 mmhg and 122 to 123 mmhg for metoprolol and carvedilol , respectively ) is also statistically significant ( p<0.001 ) , but not clinically significant .
the average dbp increases in response to discontinuing either agent are not significant ( from 67 to 69 mmhg for metoprolol and 69 to 70 mmhg for carvedilol ) . in response to continuing either agent , none of the hemodynamic responses are significant .
the normalized data ( to highlight the respective changes in hemodynamic responses ) are displayed in figure 1 . from figure 2 ,
the results of the p&s method show that when either beta - blocker is introduced ( fig .
however , only the ( greater ) decrease for carvedilol is significant ( p<0.001 ) . a significant increase in parasympathetic activity ( fig . 2a , middle )
is measured ( p<0.001 ) in response to either agent , with the average parasympathetic increase in response to carvedilol greater than that for metoprolol . a significant decrease in sb ( fig .
2b , top ) to discontinuing either agent increases significantly ( p<0.001 for carvedilol response and p<0.010 for metoprolol response ) , and the average parasympathetic responses decrease significantly ( p<0.001 ; fig . 2b , middle ) . for both p and s , the change in response to carvedilol is greater than that for metoprolol
the average sb response to discontinuing carvedilol increases , whereas the average sb response to discontinuing metoprolol decreases . for those patients continuing beta - blocker therapy without any adjustment ( fig .
2c ) , there is very little change in p&s method results : p = 0.747 for sympathetic activity , p = 0.301 for parasympathetic activity and p = 0.275 for sb , overall .
the results of the spectral domain hrv - alone analysis [ low frequency ( lf ) , high frequency [ hf ] and lf / hf ratio ) are presented in figure 3 . the total spectral power ( tsp )
normalized lf ( lfnu ) increases in response to discontinuing carvedilol , and decreases in response to discontinuing metoprolol ( fig .
3b , middle ; p<0.010 ) in response to carvedilol , and increases in response to metoprolol .
ratio decreases in response to carvedilol , and increases in response to metoprolol ( fig .
tsp decreases in response to discontinuing either agent , with only the metoprolol change being significant ( fig .
these data show that average tsp changes to either agent are statistically significant ( see fig .
4 , top row ) . in response to increasing beta - blocker , tsp increases in response to carvedilol ( p<0.001 ) and decreases in response to metoprolol ( p<0.010 ) ( see fig .
4a , top ) . while the absolute value of the change in tsp in response to carvedilol is much greater than that for metoprolol ( 240.9 vs 42.2 ms , respectively ) , the relative changes with respect to baseline ( test n ) are similar . for patients who continued beta - blocker without adjustment ( fig .
3c ) , carvedilol further decreases the lf measure significantly ( lfnu = 0.34 , p<0.010 ) and increases the hf measure significantly ( hfnu = + 0.77 , p<0.010 ) , whereas only metoprolol decreases the hf measure significantly ( hfnu = 0.08 , p<0.010 ) .
spectral - domain hrv - alone responses to beta - blocker therapy at baseline and at follow - up .
( a ) and ( b ) represent the experimental groups ( 1 and 2 , respectively ) and ( c ) represents the control group .
the time - domain hrv - alone responses to the introduction of a beta - blocker ( fig .
4 ) were mixed and statistically significant in response to either agent ( p<0.001 ) .
rangehr ( not shown graphically , see ( 24 , table 4 ) ) and e / i ratio increase in response to carvedilol and decrease in response to metoprolol .
4a , bottom ) . the average response to introducing carvedilol ( p<0.001 ) is greater than that to metoprolol ( p<0.010 ) .
rangehr decreases significantly in response to either agent ( data not shown , see ( 24 , table 4 ) ; p<0.001 ) , while the e / i ratio increase is statistically significant for carvedilol ( fig .
4b , bottom ) to discontinuing either agent are statistically significant ( p<0.001 for both ) .
total spectral power and time - domain hrv - alone responses to beta - blocker therapy at baseline and at follow - up .
( a ) and ( b ) represent the experimental groups ( 1 and 2 , respectively ) and ( c ) represents the control group .
our study concurs with , and expands upon , previously reported effects of beta - blockers in restoration of autonomic balance ( 20 ) .
more specifically however , our study shows that carvedilol , which is both an alpha- and beta - adrenergic blocker , demonstrates a greater response than metoprolol , which is a pure beta - blocker , and demonstrates clear differences on the effects on sympathovagal balance ( sb ) .
this may be due to the fact that carvedilol contains more adrenergic blockade as compared with metoprolol .
whether hrv - alone is in the form of time - domain measures or frequency - domain measures , hrv - alone is shown in this study to not be a reliable or consistent measure to differentiate parasympathetic activity independent from sympathetic activity ( see the discussion in ( 24 ) ) .
the subpopulation of patients who continued current beta - blocker therapy without any adjustment can be considered the control group . as shown in figure 2c , no significant changes in average hemodynamic responses are demonstrated ( note the scale of the ordinate ) . similarly , as shown in figure 3c , no significant changes in average parasympathetic or sympathetic responses are demonstrated .
the changes in the p&s method are consistent with the hemodynamic changes observed for the same group ( p = 0.055 ) . as seen in figure 4c , the hrv - alone , spectral analysis method showed statistically significant responses to the continuation of beta - blockers .
carvedilol further decreased the lf measure ( assumed to represent sympathetic tone ) and increased the hf measure ( assumed to represent parasympathetic tone ) , whereas metoprolol decreased hf and produced no change to the lf measurements .
the spectral analysis of hrv - alone changes are not consistent with the hemodynamic changes observed for the same group ( p = 0.880 ) .
it is known that the sympathetic nervous system exerts major effects on mhr and the baroreceptor reflex response , which in turn contributes to the regulation of bp .
while beta - blockers cause decreases in mhr , sbp and sympathetic activity ( see figs . 2 and 3 ) , the net desired effect is an overall reduction in relative sympathetic activity .
the data demonstrate that , on average , metoprolol has less of a sympatholytic effect that carvedilol ( see fig .
these results are corroborated by the sb responses ( sb = s / p from the p&s method ) seen in figure 3a , bottom .
3a ) responses to the introduction of metoprolol are greater than that to carvedilol due to overall reduction in relative sympathetic activity , a significantly greater increase in tsp ( fig .
4a , top ) in response to carvedilol with respect to metoprolol is demonstrated . since tsp is based on the arithmetic sum of lf and hf ( 25 ) , and since the lf measure decreases , and the hf measure increases , the change in tsp indicates a relatively greater increase in the hf with carvedilol than with metoprolol .
therefore , the change in tsp would indicate a net , relative increase in parasympathetic activity .
similarly , increase in e / i ratio , rangehr and hrv , and the greater sdnn increase in response to carvedilol over metoprolol is significant .
these results suggest that carvedilol not only reduces overall sympathetic dominance , but concomitantly increases parasympathetic activity , while metoprolol only reduces relative sympathetic dominance . after weaning from beta blockers , an increase in sympathetic activity and decrease in parasympathetic activity
increases in mhr , bp and sympathetic activity increase significantly more after weaning from carvedilol than weaning from metoprolol .
significant increases in the sb response to withdrawing carvedilol indicate a shift in the autonomic balance toward a more sympathetic dominant state , as our results reflect .
the spectral domain hrv - alone ( lf and hf ) responses to discontinuing beta - blockers are mixed .
lf increases in response to discontinuing carvedilol , which is consistent with a significant increase in sympathetic activity as compared with the decrease in parasympathetic activity . however , lf decreases in response to discontinuing metoprolol .
this dichotomy may also be due to the dual alpha- and beta - adrenergic activity of carvedilol having greater sympathetic affect . given that lf is defined as a measure of sympathetic activity as modulated by parasympathetic activity ( 25 ) , the effect of discontinuing metoprolol on the lf measure may indicate a weaker sympathetic rebound and a relatively stronger decrease in parasympathetic activity .
in other words , sb ( the measure of relative sympathetic to parasympathetic activity ) increases when carvedilol is discontinued and decreases when metoprolol is discontinued . this theory is supported by the absolute p&s values of these changes ( see ( 24 ) , table 2 ) .
the subpopulation of patients who continued current beta - blocker therapy without any adjustment can be considered the control group . as shown in figure 2c , no significant changes in average hemodynamic responses are demonstrated ( note the scale of the ordinate ) . similarly , as shown in figure 3c , no significant changes in average parasympathetic or sympathetic responses are demonstrated .
the changes in the p&s method are consistent with the hemodynamic changes observed for the same group ( p = 0.055 ) . as seen in figure 4c , the hrv - alone , spectral analysis method showed statistically significant responses to the continuation of beta - blockers .
carvedilol further decreased the lf measure ( assumed to represent sympathetic tone ) and increased the hf measure ( assumed to represent parasympathetic tone ) , whereas metoprolol decreased hf and produced no change to the lf measurements .
the spectral analysis of hrv - alone changes are not consistent with the hemodynamic changes observed for the same group ( p = 0.880 ) .
it is known that the sympathetic nervous system exerts major effects on mhr and the baroreceptor reflex response , which in turn contributes to the regulation of bp .
while beta - blockers cause decreases in mhr , sbp and sympathetic activity ( see figs . 2 and 3 ) , the net desired effect is an overall reduction in relative sympathetic activity .
the data demonstrate that , on average , metoprolol has less of a sympatholytic effect that carvedilol ( see fig .
these results are corroborated by the sb responses ( sb = s / p from the p&s method ) seen in figure 3a , bottom .
3a ) responses to the introduction of metoprolol are greater than that to carvedilol due to overall reduction in relative sympathetic activity , a significantly greater increase in tsp ( fig .
4a , top ) in response to carvedilol with respect to metoprolol is demonstrated . since tsp is based on the arithmetic sum of lf and hf ( 25 ) , and since the lf measure decreases , and the hf measure increases , the change in tsp indicates a relatively greater increase in the hf with carvedilol than with metoprolol .
therefore , the change in tsp would indicate a net , relative increase in parasympathetic activity .
similarly , increase in e / i ratio , rangehr and hrv , and the greater sdnn increase in response to carvedilol over metoprolol is significant .
these results suggest that carvedilol not only reduces overall sympathetic dominance , but concomitantly increases parasympathetic activity , while metoprolol only reduces relative sympathetic dominance .
after weaning from beta blockers , an increase in sympathetic activity and decrease in parasympathetic activity is expected .
increases in mhr , bp and sympathetic activity increase significantly more after weaning from carvedilol than weaning from metoprolol .
significant increases in the sb response to withdrawing carvedilol indicate a shift in the autonomic balance toward a more sympathetic dominant state , as our results reflect .
the spectral domain hrv - alone ( lf and hf ) responses to discontinuing beta - blockers are mixed .
lf increases in response to discontinuing carvedilol , which is consistent with a significant increase in sympathetic activity as compared with the decrease in parasympathetic activity . however , lf decreases in response to discontinuing metoprolol .
this dichotomy may also be due to the dual alpha- and beta - adrenergic activity of carvedilol having greater sympathetic affect . given that lf is defined as a measure of sympathetic activity as modulated by parasympathetic activity ( 25 ) , the effect of discontinuing metoprolol on the lf measure may indicate a weaker sympathetic rebound and a relatively stronger decrease in parasympathetic activity .
in other words , sb ( the measure of relative sympathetic to parasympathetic activity ) increases when carvedilol is discontinued and decreases when metoprolol is discontinued .
this theory is supported by the absolute p&s values of these changes ( see ( 24 ) , table 2 ) .
noninvasive measures of hemodynamic and autonomic responses to changes in beta - blocker therapy were collected .
overall , the hemodynamic results are consistent with the known effects of changes in specific beta - blocker vs alpha- and beta - blocker therapy ( 21 - 22 - 23 ) . the combination of alpha- and beta - blocker decreases sympathetic tone and increases parasympathetic tone , whereas a pure beta - blocker precipitates a reflex increase in alpha - adrenergic activity , leading to less of an increase in parasympathetic tone .
the p&s method results are consistent with the hemodynamic results and with the expected autonomic effects of changes in beta - blocker therapy known to underlie the hemodynamic responses ( 13 ) .
as shown , hrv - alone measures are not always consistent with the hemodynamic responses , and are only consistent with expected variations in hr and perhaps total autonomic activity .
adrenergic - blockade is shown to reduce sympathetic activity . by providing both alpha- and beta - blockade ,
carvedilol has a more profound effect in reducing sympathetic activity as compared with the pure beta - blockade of metoprolol .
our results also suggest that carvedilol not only reduces overall sympathetic dominance , but concomitantly increases parasympathetic activity .
adrenergic antagonists may restore autonomic balance and decrease functional disturbances that can lead to early an ( 26 ) , which leads to increased morbidity and earlier mortality ( 3 , 27 ) .
a simple measure of balance ( sb ) done prospectively may add significantly to the ability to identify and predict people at risk , and the adoption of multifactorial preventive measures .
both agents block sympathetic input to the heart , reducing cardiac sympathetic tone , thereby lowering hr .
carvedilol also blocks sympathetic input to the vasculature , reducing sympathetic tone in the blood vessels , leading to vasodilation .
the importance of autonomic assessment is emphasized by the current reports from the diad study ( 28 ) and the accord study ( 29 , 30 ) .
diad demonstrates that abnormal hrv is associated with a prediction of greater increased risk of major adverse cardiovascular events ( maces ) .
the risk is greater than all traditional risk factors , including perfusion scanning ( 28 ) .
the development of ad is a multifactorial process , and maintaining sb may improve longevity and decrease morbidity and mortality . thus , it is likely that combination therapies directed at the various components of the pathogenic pathway will be needed to reduce the development of autonomic nerve fiber dysfunction .
with intensification of glycemic control , accord demonstrates a 22% increase in sudden deaths associated with ad .
establishing and maintaining normal parasympathetic and sympathetic balance may reduce morbidity risk and minimize mortality risk .
the importance of autonomic assessment is emphasized by the current reports from the diad study ( 28 ) and the accord study ( 29 , 30 ) .
diad demonstrates that abnormal hrv is associated with a prediction of greater increased risk of major adverse cardiovascular events ( maces ) .
the risk is greater than all traditional risk factors , including perfusion scanning ( 28 ) .
the development of ad is a multifactorial process , and maintaining sb may improve longevity and decrease morbidity and mortality .
thus , it is likely that combination therapies directed at the various components of the pathogenic pathway will be needed to reduce the development of autonomic nerve fiber dysfunction .
with intensification of glycemic control , accord demonstrates a 22% increase in sudden deaths associated with ad .
establishing and maintaining normal parasympathetic and sympathetic balance may reduce morbidity risk and minimize mortality risk .
 backgroundcardiovascular autonomic neuropathy ( can ) is recognized as a significant health risk , correlating with risk of heart disease , silent myocardial ischemia or sudden cardiac death . 
 beta - blockers are often prescribed to minimize risk.objectivesin this second of two articles , the effects on parasympathetic and sympathetic activity of the alpha / beta - adrenergic blocker , carvedilol , are compared with those of the selective beta - adrenergic blocker , metoprolol.methodsretrospective , serial autonomic nervous system test data from 147 type 2 diabetes mellitus patients from eight ambulatory clinics were analyzed . 
 patients were grouped according to whether a beta - blocker was ( 1 ) introduced , ( 2 ) discontinued or ( 3 ) continued without adjustment . 
 group 3 served as the control.resultsintroducing carvedilol or metoprolol decreased heart rate and blood pressure , and discontinuing them had the opposite effect . 
 parasympathetic activity increased with introducing carvedilol . 
 sympathetic activity increased more after discontinuing carvedilol , suggesting better sympathetic suppression . with ongoing treatment , resting parasympathetic activity decreased with metoprolol but increased with carvedilol.conclusioncarvedilol has a more profound effect on sympathovagal balance than metoprolol . while both suppress sympathetic activity , only carvedilol increases parasympathetic activity . 
 increased parasympathetic activity may underlie the lower mortality risk with carvedilol . 