Table 3—

Studies of CAN and mortality

Follow-up (years)Tests of autonomic functionDefinition of CAN% Mortality/ CAN+% Mortality/ CANNotes
Reference
 Ewing et al. (31)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. (82)10–15
  1. HRV during deep breathing

  2. Valsalva maneuver

  3. Heart rate and sBP response to standing

Based on HRV and the presence or absence of symptomatic autonomic neuropathy27% (20/73)11% (4/38)Mortality in asymptomatic individuals with an isolated abnormality in autonomic function tests was not increased. Excess mortality was restricted to those with symptomatic CAN (18/49 vs. 4/38).
 O’Brien et al. (36)5HRV in response to
  1. supine rest

  2. single deep breath

  3. Valsalva maneuver

  4. standing for 60 s

Two or more of the four tests were abnormal27% (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. (83)3
  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 borderline31% (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. (84)5
  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 subjects were older and had more complications at baseline.
 Rathmann et al. (85)8
  1. Coefficient of variation of R-R intervals with normal respiration

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

Both tests abnormal23% (8/35)3% (1/35)*Subjects with advanced renal disease, proliferative retinopathy, and CVD were excluded.
 Hathaway et al. (86)2–5 (case-control study)
  1. HRV during deep

  2. Valsalva maneuver

Both tests abnormal31% (4/13)0% (0/16)*Case-control study of transplant recipients (pancreas-kidney or kidney alone). Case subjects (n = 4) died of sudden cardiac death within 3.5 years posttransplant. Control subjects survived 2–5 years posttransplant.
 Orchard et al. (87)21. HRV during deep breathingAbnormal E:I ratio9% (8/88)2% (9/399)Relative risk decreased from 4.03 to 1.37 after controling for duration, renal disease, hypertension, and coronary heart disease.
 Sawicki et al. (88)5–131. R-R variation between supine and standing positionR-Rsupine/R-Rstanding <1.0362% (16/26)29% (17/59)All subjects with overt diabetic nephropathy
 Navarro et al. (89)1–11.5
  1. HRV during deep breathing

  2. Valsalva maneuver

Both tests abnormal28% (101/359)5% (6/128)All subjects were candidates for pancreas transplantation.
 Toyry et al. (90)10
  1. HRV during deep breathing

  2. sBP decrease during standing

Parasympathetic neuropathy = abnormal E:I ratio50% (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, follow-up predicted CVD mortality at 10-year, follow-up even after adjusting for conventional CVD risk factors.
 Sawicki et al. (91)15–161. R-R variation between supine and standing positionR-Rsupine/R-Rstanding <1.0369% (58/84)76% (100/132)Consecutive patients (31% male) enrolled over a 2-year period for improvement in metabolic control.
 Veglio et al. (92)5
  1. Heart rate (resting)

  2. HRV during deep breathing

  3. BP response to standing

Two or more of the tests abnormal13% (10/75)4% (10/241)QTc prolongation was associated with increased mortality risk.
 Gerritsen et al. (93)0.5–9.21. E:I differenceNot availableNot availableRelative risk = 2.25 (1.13–4.45); diabetic subjects (n = 159) identified through a population survey
 Chen et al. (94)7.7HRV 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 more29% (106/371)12% (29/241)CAN+ associated with increased mortality even in the absence of postural hypotension
Total§400/1,316212/1,584
  • BP, blood pressure; CVD, cardiovascular disease; E:I difference = mean expiration to inspiration difference in R-R intervals over six consecutive breaths; R-R interval, time interval between successive ECG R-waves; sBP, systolic blood pressure.

  • *

    * P < 0.05;

  • P < 0.01;

  • P < 0.001;

  • §

    § Mantel-Haenszel estimate for the pooled relative risk for mortality = 2.14 (95% CI 1.83–2.51, P < 0.0001). Adapted from Maser et al. (94a).