Studies of cardiovascular autonomic neuropathy and mortality
| Reference | Follow-up (years) | Tests of CAN | Definition of CAN | % (Mortality/CAN+) | % (Mortality/CAN−) | Comments |
|---|---|---|---|---|---|---|
| Ewing et al. (5) | 5 |
| 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) | 5 | HRV in response to
| 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) | 3 |
| 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) | 5 |
| 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) | 8 |
| 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 |
| 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 |
| Both tests were abnormal | 28% (101/359) | 5% (6/128)§ | All subjects were candidates for pancreas transplantation. |
| Veglio et al. (16) | 5 |
| 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
| 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) | 2 | 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 |
| 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 |
| 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.