Cardiac autonomic neuropathy in patients with diabetes mellitus

Table 1 Prevalence of cardiac autonomic neuropathy as reported in major studies

Ref.	Year	Country	N of subjects	Type of DM	Population characteristics	Diagnostic test	Criteria applied	Prevalence(%)	Comments
O’Brien et al[111]	1991	United Kingdom	506	IDDM	Mean age 45 yr, mean DM duration 15 yr, female 42%	HRV in response to (1) rest (2) single deep breath (3) Valsalva manoeuvre or (4) standing	At least two positive of the tests mentioned in the previous column	17	Prevalence of CAN was associated with the presence of other DM complications
Ziegler et al[223]	1992	Germany	130	Newly diagnosed IDDM		CV of HRV, low- and mid- frequency bands of spectral analysis, MCR, Valsalva manoeuvre or lying-to standing	At least three positive of the tests mentioned in the previous column	7.7
		Austria	647	Total IDDM				25.3
		Switzerland	524	Non-IDDM				34.3
Kennedy et al[11]	1995	United States	290	IDDM	Listed pancreas transplantation recipients	HRV Valsalva manoeuvre		90 88
DCCT research group[19]	1998	United States	1441	IDDM (1) primary prevention cohort (absence of end–organ damage such as retinopathy and microalbuminuria) (2) secondary intervention cohort (mild/ moderate retinopathy +/- microalbuminuria)	Mean age 27 yr, female 47% duration of DM 1-5 yr (mean 2.6) primary prevention cohort 1-15 yr (mean 8.8) secondary intervention cohort	HRV	R-R variation < 15	1.6-6.2	These figures represent baseline characteristics
						Valsalva manoeuvre	Valsalva ratio < 1.5	5.5-6.3
						Postural BP	Diastolic BP drop > 10 mmHg	0
Kempler et al[28] (EURODIAB IDDM)	2002	16 European countries	3250	T1DM	Mean age 32 yr, mean DM duration 14 yr, female 49%	(1) R-R response to standing (2) Postural BP	R-R ratio < 1.04 or drop > 20 mmHg in systolic BP	36	Correlation with age, DM duration and HbA1c
Gaede et al[5,224] (the Steno type 2 study)	2003	Denmark	160	T2DM	Mean age 55 yr, female 27%, HbA1C 8.8% at baseline	(1) R-R response to breathing (2)Postural BP	R-R variation < 6 or drop > 25 mmHg in systolic BP	27.5	This figure represents baseline findings
Valensi et al[27]	2003	France	245	T1DM	Mean age 39.6 yr, mean DM duration 8.6 yr, female 43%	R-R response to	Criteria for abnormal tests were based on Armstrong et al[225]		Rate of moderate/severe CAN was higher in T1DM (18.2% and 4.8%) than in T2DM (12.3% and 2.3%) (P = 0.031)
			151	T2DM		(1) deep breathing		21.2
						(2) Valsalva and		20.7
						(3) standing		33.5
							At least two positive tests (classed as moderate CAN)	20
Low et al[23]	2004	United States	83	T1DM	Mean age 59 yr, white 99%, female 48%	(1) Sudomotor axon-reflex test (2) Valsalva manoeuvre (3) BP and HR response to standing (4) R-R response to deep breathing	CASS ≥ 1 in two domains or ≥ 2 in one domain (sudomotor, cardiovagal, adrenergic)	54	This study focuses on DAN but encompasses several cardiac autonomic tests
			148	T2DM				73
Pop-Busui et al[18] (DCCT/EDIC study)	2009	United States	620	IDDM-former intensive Tx group IDDM-former conventional Tx group	Mean age 47 yr in both groups, mean DM duration 26 yr, female 49% and 46% respectively	R-R response to (1) deep breathing (2) Valsalva manoeuvre (3) postural BP	R-R < 15 or R-R 15-19.9 and Valsalva ratio < 1.5 or drop > 15 mmHg in diastolic BP	29	13/14 yr post closeout of DCCT
			591					35

DM: Diabetes mellitus; IDDM: Insulin dependent diabetes mellitus; CV: Coefficient of variation; MCR: Mean circular resultant; HRV: Heart rate variability; BP: Blood pressure; CAN: Cardiac autonomic neuropathy; CASS: Composite Autonomic Severity Score; DCCT: Diabetes Control and Complications Trial; T1DM: Type 1 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.