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Table 1—

Studies of cardiovascular autonomic neuropathy and mortality

ReferenceFollow-up (years)Tests of CANDefinition of CAN% (Mortality/CAN+)% (Mortality/CAN)Comments
Ewing et al. (5) 
  1. Valsalva maneuver

  2. Handgrip

  3. Postural fall in BP

 
 53% (21/40) 15% (5/33)* Subjects who complained of symptoms suggestive of autonomic neuropathy comprised the study cohort. CAN+ subjects had more complications at baseline. Half of the deaths for the CAN+ subjects were attributed to renal failure. 
Sampson et al. (9) 10–15 1. HRV during deep breathing Based on abnormal HRV and the presence of symptomatic autonomic neuropathy 37% 18/49 11% (4/38)* Mortality in asymptomatic individuals with an isolated abnormality in HRV was not increased (2/24 vs. 4/38). Excess mortality restricted to those with symptomatic CAN. 
O’Brien et al. (10) HRV in response to
  1. supine rest

  2. single deep breath

  3. Valsalva maneuver

  4. standing for 60 seconds

 
Two or more of the four tests were abnormal 27% (23/84) 8% (7/84)* Those with CAN had greater prevalence of other complications, but in multivariate analysis, CAN was the most important predictor of mortality. 
Ewing et al. (11) 
  1. HRV during deep breathing

  2. Valsalva maneuver

  3. 30:15 ratio

  4. BP response to standing

  5. BP response to handgrip

 
Normal = all tests normal or one borderline; early = one of the three heart rate tests abnormal or two borderline; definite = two or more of the heart rate tests abnormal; severe = at least two of the heart rate tests abnormal and one or both of the BP tests abnormal or both borderline 31% (10/32) 8% (3/39) Included men <60 years old. CAN+ subjects who died (n = 10) had longer QT intervals than those who did not. 
Jermendy et al. (12) 
  1. HRV during deep breathing

  2. Valsalva maneuver

  3. 30:15 ratio

  4. SBP response to standing

 
Results of parasympathetic tests (1, 2, 3) were scored 0 = normal, 1 = borderline, 2 = abnormal. Those with a score of 0–1 = without CAN; score of 2–3 = early CAN; score of 4–6 = definitive CAN 40% (12/30) 4% (1/23)* No patients had an abnormal SBP response to standing. Deceased were older and had more complications at baseline. 
Rathmann et al. (13) 
  1. Coefficient of variation of R-R intervals with normal respiration

  2. Coefficient of variation of R-R intervals with deep respiration

 
Both tests abnormal 23% (8/35) 3% (1/35) Subjects with advanced renal disease, proliferative retinopathy, and CVD were excluded. 
Hathaway et al. (14) 2–5 case-control study 
  1. HRV during deep breathing

  2. Valsalva maneuver

 
Both tests abnormal 31% (4/13) 0% (0/16) Case-control study of transplant recipients (pancreas-kidney or kidney alone). Cases (n = 4) died of sudden cardiac death within 3½ years posttransplant. Control subjects survived 2–5 years posttransplant. 
Navarro et al. (15) 1–11.5 
  1. HRV during deep breathing

  2. Valsalva maneuver

 
Both tests were abnormal 28% (101/359) 5% (6/128)§ All subjects were candidates for pancreas transplantation. 
Veglio et al. (16) 
  1. Heart rate (resting)

  2. HRV during deep breathing

  3. BP response to standing

 
Two or more of the tests were abnormal 13% (10/75) 4% (10/241)* QTc prolongation associated with increased mortality risk. 
Chen et al. (17) 7.7 HRV in response to
  1. single deep breath

  2. six consecutive breaths

  3. supine to standing

  4. Valsalva maneuver BP change sitting to standing

 
Unique diagnostic criteria defined by scoring 3 or more 29% (106/371) 12% (29/241)§ CAN+ associated with increased mortality even in the absence of postural hypotension. 
Total for studies with CAN defined by 2 or more abnormalities#    313/1,088 66/878  
Orchard et al. (6) 1. HRV during deep breathing Abnormal E/I (expiration/ inspiration) ratio 9% (8/88) 2% (9/399)* Relative risk decreased from 4.03 to 1.37 after controlling for duration, renal disease, hypertension, and coronary heart disease. 
Sawicki et al. (18) 5–13 1. RR variation between supine and standing position RRsupine/RRstanding <1.03 62% (16/26) 29% (17/59)* All subjects with overt diabetic nephropathy. 
Toyry et al. (19) 10 
  1. HRV during deep breathing

  2. SBP decrease during standing

 
Parasympathetic neuropathy = abnormal E/I (expiration/inspiration) ratio 50% (3/6) 17% (20/116) Mortality rates for CVD mortality only. Subjects were newly diagnosed with diabetes. In multivariate analysis, sympathetic CAN+ at 5-year predicted CVD mortality at 10 years, even after adjusting for conventional CVD risk factors. 
Sawicki et al. (20) 15–16 1. RR variation between supine and standing position RRsupine/RRstanding <1.03 69% (58/84) 76% (100/132) Consecutive patients (31% male) enrolled over a 2-year period for improvement in metabolic control. 
Gerritsen et al (21) 0.5–9.2 
  1. Spectral analysis during spontaneous breathing for 3 minutes

  2. EI difference and baroreflex sensitivity during six deep breaths for 1 min

 
EI difference NA NA Relative risk = 2.25 (1.13–4.45) for EI difference. Diabetic subjects (n = 159) identified through a population survey. 
Total for studies with CAN defined by a single measure    85/204†† 146/706  
ReferenceFollow-up (years)Tests of CANDefinition of CAN% (Mortality/CAN+)% (Mortality/CAN)Comments
Ewing et al. (5) 
  1. Valsalva maneuver

  2. Handgrip

  3. Postural fall in BP

 
 53% (21/40) 15% (5/33)* Subjects who complained of symptoms suggestive of autonomic neuropathy comprised the study cohort. CAN+ subjects had more complications at baseline. Half of the deaths for the CAN+ subjects were attributed to renal failure. 
Sampson et al. (9) 10–15 1. HRV during deep breathing Based on abnormal HRV and the presence of symptomatic autonomic neuropathy 37% 18/49 11% (4/38)* Mortality in asymptomatic individuals with an isolated abnormality in HRV was not increased (2/24 vs. 4/38). Excess mortality restricted to those with symptomatic CAN. 
O’Brien et al. (10) HRV in response to
  1. supine rest

  2. single deep breath

  3. Valsalva maneuver

  4. standing for 60 seconds

 
Two or more of the four tests were abnormal 27% (23/84) 8% (7/84)* Those with CAN had greater prevalence of other complications, but in multivariate analysis, CAN was the most important predictor of mortality. 
Ewing et al. (11) 
  1. HRV during deep breathing

  2. Valsalva maneuver

  3. 30:15 ratio

  4. BP response to standing

  5. BP response to handgrip

 
Normal = all tests normal or one borderline; early = one of the three heart rate tests abnormal or two borderline; definite = two or more of the heart rate tests abnormal; severe = at least two of the heart rate tests abnormal and one or both of the BP tests abnormal or both borderline 31% (10/32) 8% (3/39) Included men <60 years old. CAN+ subjects who died (n = 10) had longer QT intervals than those who did not. 
Jermendy et al. (12) 
  1. HRV during deep breathing

  2. Valsalva maneuver

  3. 30:15 ratio

  4. SBP response to standing

 
Results of parasympathetic tests (1, 2, 3) were scored 0 = normal, 1 = borderline, 2 = abnormal. Those with a score of 0–1 = without CAN; score of 2–3 = early CAN; score of 4–6 = definitive CAN 40% (12/30) 4% (1/23)* No patients had an abnormal SBP response to standing. Deceased were older and had more complications at baseline. 
Rathmann et al. (13) 
  1. Coefficient of variation of R-R intervals with normal respiration

  2. Coefficient of variation of R-R intervals with deep respiration

 
Both tests abnormal 23% (8/35) 3% (1/35) Subjects with advanced renal disease, proliferative retinopathy, and CVD were excluded. 
Hathaway et al. (14) 2–5 case-control study 
  1. HRV during deep breathing

  2. Valsalva maneuver

 
Both tests abnormal 31% (4/13) 0% (0/16) Case-control study of transplant recipients (pancreas-kidney or kidney alone). Cases (n = 4) died of sudden cardiac death within 3½ years posttransplant. Control subjects survived 2–5 years posttransplant. 
Navarro et al. (15) 1–11.5 
  1. HRV during deep breathing

  2. Valsalva maneuver

 
Both tests were abnormal 28% (101/359) 5% (6/128)§ All subjects were candidates for pancreas transplantation. 
Veglio et al. (16) 
  1. Heart rate (resting)

  2. HRV during deep breathing

  3. BP response to standing

 
Two or more of the tests were abnormal 13% (10/75) 4% (10/241)* QTc prolongation associated with increased mortality risk. 
Chen et al. (17) 7.7 HRV in response to
  1. single deep breath

  2. six consecutive breaths

  3. supine to standing

  4. Valsalva maneuver BP change sitting to standing

 
Unique diagnostic criteria defined by scoring 3 or more 29% (106/371) 12% (29/241)§ CAN+ associated with increased mortality even in the absence of postural hypotension. 
Total for studies with CAN defined by 2 or more abnormalities#    313/1,088 66/878  
Orchard et al. (6) 1. HRV during deep breathing Abnormal E/I (expiration/ inspiration) ratio 9% (8/88) 2% (9/399)* Relative risk decreased from 4.03 to 1.37 after controlling for duration, renal disease, hypertension, and coronary heart disease. 
Sawicki et al. (18) 5–13 1. RR variation between supine and standing position RRsupine/RRstanding <1.03 62% (16/26) 29% (17/59)* All subjects with overt diabetic nephropathy. 
Toyry et al. (19) 10 
  1. HRV during deep breathing

  2. SBP decrease during standing

 
Parasympathetic neuropathy = abnormal E/I (expiration/inspiration) ratio 50% (3/6) 17% (20/116) Mortality rates for CVD mortality only. Subjects were newly diagnosed with diabetes. In multivariate analysis, sympathetic CAN+ at 5-year predicted CVD mortality at 10 years, even after adjusting for conventional CVD risk factors. 
Sawicki et al. (20) 15–16 1. RR variation between supine and standing position RRsupine/RRstanding <1.03 69% (58/84) 76% (100/132) Consecutive patients (31% male) enrolled over a 2-year period for improvement in metabolic control. 
Gerritsen et al (21) 0.5–9.2 
  1. Spectral analysis during spontaneous breathing for 3 minutes

  2. EI difference and baroreflex sensitivity during six deep breaths for 1 min

 
EI difference NA NA Relative risk = 2.25 (1.13–4.45) for EI difference. Diabetic subjects (n = 159) identified through a population survey. 
Total for studies with CAN defined by a single measure    85/204†† 146/706  

EI difference = mean expiration-inspiration difference in R-R intervals over six consecutive breaths; R-R interval = time interval between successive electrocardiogram R-waves.

*

P < 0.01;

P < 0.05;

§

P < 0.001.

Postural hypotension (>20 mmHg fall in SBP) was present for 67% of the patients with symptomatic CAN (i.e., abnormal HRV). Additional tests for CAN, not performed at baseline, were included in this study during the follow-up years.

A small number of affected individuals (n = 15) were considered to have early CAN, defined as having 2 to 3 borderline test results, 1 abnormal and 1 borderline test, or a single abnormal test.

#

Mantel-Haenszel estimate for the pooled relative risk for mortality = 3.45 (95% CI: 2.66− 4.47; P < 0.001) for studies with CAN defined by two or more abnormalities.

Mantel-Haenszel estimate for the pooled relative risk for mortality = 1.20 (95% CI: 1.02–1.41; P = 0.03) for studies with CAN defined by a single measure.

††

The study by Gerritsen et al. (21) was not included in the calculation of these rates (or in the pooled relative risk estimate) because raw numbers were not provided.

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