Cardiac autonomic neuropathy in patients with diabetes mellitus

Table 2 Observed mortality in significant studies in the last two decades

Ref.	Country	N ofsubjects	Type of DM	FUp (yr)	Diagnostic test for CAN	Criteria applied	Mortality figures(expressed in HR, RR and incidence)	Comments
Veglio et al[226]	Italy	316	T1DM	5	(1) Resting heart rate (2) HRV during deep breathing (3) BP response to standing	≥ 2 abnormal tests	Relative risk: 3.55 (1.4-8.9) and 2.21 (0.62-7.84, P = 0.22) after multivariate analysis for all-cause mortality	The mortality rates were 13% and 4% in the presence and absence of CAN respectively
Gerritsen et al[164] the Hoorn Study	Nether-lands	446	Non-DM	9	Seven parameters assessing HRV and BP response to: (1) 3-min breathing and (2) six deep breaths	Cut–off set as the lowest 25th percentile of non-diabetic group	Only E/I had a statistically significant association with mortality- Relative Risk: 2.25 (1.13–4.45) for all cause and 2.04 (0.74–5.65) for CVD mortality	An additional four parameters showed a tendency (P < 0.10) for association with acc- cause mortality: mean NN, LF power, HF power, and BRS
Chen et al[227]	Taiwan	159	T2DM	7.7	HRV response to: (1) single deep breath (2) six consecutive breaths (3) standing, (4) Valsalva manoeuvre	≥ 3 abnormal tests	All cause mortality: 29% vs 12% with and without CAN respectively CVD mortality: 9% vs 2% in pts with and without CAN	The 8-yr survival rate for pts with abnormal CAN tests was 63.6% in males and 76.4% in females, compared with 80.9% and 93.3% for patients with normal CAN tests
		612	T2DM
Wheeler et al[228]	United States	843	T1DM and T2DM		HRV response to deep breathing and postural BP	Drop in BP ≥ 30 mmHg and HRV divided into 5 quintiles HRV < 10 bpm at baseline abnormal E/I	Hazard Ratio: 1.49 (1.01-2.19) for all-cause mortality and 1.08 (0.69-1.70) for CVD mortality in the lowest quintile of HRV. Relative Risk for orthostatic hypotension: 0.65 (0.69-1.70) Relative risk: 4.9 (2.1-11.5, P < 0.0001) after adjustment for traditional CVD risk factors Hazard Ratio: 0.92 (0.87–0.98, P = 0.005) for HRV (1 beat/min increase)	Of the 142 patients for whom cause of death was available, 75 deaths (49.7%) were due to CVD. The lowest quintile of HRV was associated with a 50% increase in mortality after adjusting for other risk factors During follow-up, 33 Patients died from cardiovascular causes, During follow-up 54 of 104 patients died: 41 patients (80.4%) with diabetic nephropathy and 13 patients (24.5%) with normoalbuminuria. Thirty patients (55%) died from cardio-vascular causes
Astrup et al[229]	Denmark	388	T1DM (197 with macro-, 191 normo- albuminuria)	10.1	HRV to deep breathing
Astrup et al[230]	Denmark	104	T2DM (51 with nephropathy, 52 with normal albuminuria)	9.2	HRV to deep breathing
Soedamah- Muthu et al[115] the EURODIAB PCS	16 European countries	2787	T1DM	7	HRV response to standing and postural BP	R-R ratio of < 1.04 and drop in systolic BP ≥ 20 mmHg	Hazard Ratio: 3.61 (1.49–8.76) for CVD mortality and 2.83 (1.82–4.38) for all-cause mortality.	Autonomic neuropathy and microalbuminuria were the most important independent predictors of mortality
Lykke et al[231]	Denmark	391	T1DM	10	HRV and QTc		All cause mortality Hazard Ratio: 2.5 (0.9–6.8, P = 0.071) in pts with abnormal HRV and 2.3 (1.3-4.0, P = 0.005) in those with abnormal QT combined hazard ratio 6.7 (1.8-25, P = 0.005)	Out of 34 patients with both tests abnormal, 15 died in the 10 yr period (14 from cardiovascular causes)
Ziegler et al[232] MONICA/ KORA Augsburg Cohort study	Germany	1560	Non-DM	9	HRV, QTc interval and QTD	Group (1) Lowest quartile for SDNN, CV and max-min R-R intervals Group (2) QTc > 440, Group (3) QTD > 60 ms	All-cause mortality Relative Risk: 0.93 (0.65-1.34)/2.02 (1.29-3.17)/0.98 (0.60-1.60) in patients without DM and 1.74 (0.95-3.18)/3.00 (1.34-6.71)/0.42 (0.06-3.16) in patients with DM for group 1/2/3 respectively	Prolonged QTc interval was an independent predictor of mortality both in patients with and without DM, Low HRV trended towards an increased risk of mortality by 73% in patients with DM but not the population without DM
		160	DM
Beijers et al[233] the Hoorn Study	Nether-lands	376	Non-DM	13.6	HRV and BP response to: (1) 3-min breathing, (2) six deep breaths (3) standing	Calculated z-score for each parameter and averaged into a total CAD score	Relative risk: 2.54 (1.60–4.04) for CVD mortality and 2.11 (1.58–2.81) for all cause mortality,	CAN was associated with all-cause and CVD mortality independent to other CVD risk factors and microalbuminuria
		114	T2DM
Pop-Busui et al[29]	United States and Canada	8135	T2DM	3.5	HRV and QTI computed from 10-s resting electrocardiograms	CAN1: lowest quartile of SDNN and highest QTI quartile, CAN2: CAN1 and resting heart rate, CAN3: CAN1 and peripheral neuropathy	Hazard ratios: 1.55 (1.09-2.21)/2.14 (1.37-2.37)/2.07 (1.14-3.76) for all-cause and 1.94 (1.20-3.12)/2.62 (1.40-4.91)/2.95 (1.33-6.53) for CVD mortality in CAN1/CAN2/CAN3 respectively	CAN was independently associated with overall and CVD mortality after adjusting for baseline CVD, DM duration, traditional CVD risk factors and medications

FUP: Follow up; HR: Hazard ratio; RR: Relative risk; HRV: Heart rate variability; BP: Blood pressure; E/I: Expiration/inspiration; SDNN: Standard deviation of normally conducted R-R intervals; NN: Normal to normal R-R intervals; LF: Low frequency; HF: High frequency; BRS: Baroreflex sensitivity; CV: Coefficient of variation; QTD: QT dispersion; QTI: QT index; DM: Diabetes mellitus; T1DM: Type 1 diabetes mellitus; CAN: Cardiac autonomic neuropathy; CVD: Cardiovascular disease.