Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives

Figures & data

Table 1 Summary of studies on prevalence of cardiac autonomic neuropathy

Study	Diagnostic test	Criteria	Cutoffs	Prevalence (%)	Patients, n	DM type	Population	Ethnicity	Notes
O’Brien et al^Citation10	1. HRV response to rest 2. E:I ratio 3. Valsalva maneuver 4. 30:15 ratio 5. CV of HRV	Two or more abnormal tests	HR responses below percentile 2.5 (abnormal)	17	506	T1DM	Mean age 45 years Diabetes duration 15 years	NA
Navarro et al^Citation11	1. E:I ratio 2. Valsalva ratio	Two abnormal tests	1. HRV ≥15 bpm 2. ≥1.43	65.9	545	T1DM	Mean age 33.4 years Diabetes duration 19.4 years	NA
Chen et al^Citation12	1. E:I ratio 2. HRV during six consecutive breaths 3. 30:15 ratio 4. Valsalva maneuver 5. Postural drop	Scoring 3 or more	1. HRV <8 bpm (1) 2. HRV <7 bpm (2) 3. HRV <17 bpm (1) 4. HRV <13 bpm (1) 5. SBP fall >25 mmHg or DBP fall >10 mmHg	60.6	612	T2DM	Mean age 63.1 years Diabetes duration 10.4 years	Data collected from a Taiwanese hospital	Numbers in parentheses represent score given to each CART
Kempler et al^Citation13	1. 30:15 ratio 2. SBP postural drop	One abnormal test	1. <1.04 2. Drop >20 mmHg	36	3,010	T1DM	Mean age 32.7 years Diabetes duration 14.7 years Mean HbA1c 6.7%	Data collected in European countries
Low et al^Citation14	1. Sudomotor axon-reflex test 2. HRV during Valsalva maneuver 3. SBP postural drop and 30:15 4. E:I ratio	CASS ≥1 in two domains or ≥2 in one domain (sudomotor, cardiovagal, adrenergic)	CASS is 10-point score divided into adrenergic (0–4), sudomotor (0–3), and cardiovagal (0–3) No specific cutoffs were quoted in the paper	54 (T1DM) 73 (T2DM)	68 (T1DM) 134 (T2DM)	T1DM T2DM	Mean age 59 years HbA1c 7.4% (T1DM) and 7.2% (T2DM)	T1DM – 100% white T2DM – 98% white	Recruited from Rochester Diabetic Neuropathy Study; CASS corrected for confounding effects of age and sex
Pop-Busui et al^Citation15	1. E:I ratio 2. Valsalva maneuver 3. DBP postural drop	Abnormal HRV combined with abnormal Valsalva ratio or DBP drop	1. HRV <15 bpm 2. ≤1.5 3. Drop >10 mmHg	29 (intensive-Tx group) 35 (conventional-Tx group)	620 (intensive-Tx group) 591 (conventional-Tx group)	T1DM	Mean age 47 years Diabetes duration 26 years HbA1c 7.9% (intensive), 7.8% (conventional)	NA	Primary and secondary care
Eze et al^Citation17	1. Resting HR 2. Valsalva ratio 3. HRV to deep breathing 4. 30:15 ratio 5. Postural drop	Score ≥3 out of 5 Borderline = 0.5 Abnormal = 1	1. ≥100 bpm (abnormal) 2. ≤1.1 (abnormal), 1.11–1.2 (borderline) 3. ≤10 bpm (abnormal), 11–14 bpm (borderline) 4. ≤1 (abnormal), 1.01–1.03 (borderline) 5. SBP ≥20 mmHg (abnormal), DBP ≥10 mmHg (abnormal)	44.3	70	T2DM	Mean age 55.76 years Diabetes duration 7.67 years Male 38.6%	Nigerian	Secondary care
Tahrani et al^Citation18	1. E:I ratio 2. Valsalva ratio 3. 30:15 ratio 4. Postural drop	Two or more abnormal tests	Abnormal values not given. except postural drop of SBP >20 mmHg or DBP >10 mmHg	42.2	204	T2DM	Mean age 59.5 years Diabetes duration 15 years Male 60.5% HBA1c 8.2%	White European – 43.6% South Asian – 56.4%	Secondary care
Lerner et al^Citation19	1. Valsalva maneuver 2. SBP postural drop 3. 30:15 ratio 4. E:I ratio	Two or more abnormal tests	1. <1.2 2. 10–29 mmHg (borderline), >30 mmHg (abnormal) 3. <1.03 4. HRV <10 bpm	37	384	T2DM	Mean age 57.6 years	Peru	Primary and secondary care
Mendivil et al^Citation20	1. E:I ratio 2. Valsalva maneuver 3. 30:15 ratio	One or more abnormal or borderline tests	1. HRV ≤10 (abnormal), 11–14 (borderline) 2. ≤1.1 (abnormal), 1.11–1.2 (borderline) 3. ≤1 (abnormal), 1.01–1.03 (borderline)	68	154	T2DM	Mean age 61.4 years Diabetes duration 12.2 years HbA1c 7.7%	Latin American	Secondary care
Razanskaite-Virbickiene et al^Citation21	1. E:I ratio 2. 30:15 ratio 3. SBP postural drop 4. DBP change to isometric exercise	Two or more abnormal tests	1. ≤1.1 2. ≤1.1 3. Drop ≤20 mmHg 4. Drop ≤10 mmHg	32.2	208	T1DM	Mean age 20 years Diabetes duration 15.1 years HbA1c 9.46%	Data collected from a Lithuanian–Swiss project
Menon et al^Citation22	1. E:I ratio 2. 30:15 ratio 3. SBP postural drop 4. DBP change to isometric exercise	One abnormal test = possible CAN Two abnormal tests = definite CAN	1. 20–24 years, 1.17; 25–29, 1.15; 30–34, 1.13; 35–39, 1.12; 40–44, 1.1; 45–49, 1.08; 50–54, 1.07; 55–59, 1.06; 60–64, 1.04; 65–69, 1.03; 70–75, 1.02 2. <1.03 3. Drop >30 mmHg 4. Difference between highest and resting DBP of ≤15 mmHg	31 (possible) 66.2 (definite)	74	T2DM	Mean age 61.1 years Diabetes duration 10.2 years HbA1c 8.9%	NA	Secondary care
Tahrani et al^Citation23	1. E:I ratio 2. Valsalva ratio 3. 30:15 ratio 4. SBP and DBP postural drop	Two or more abnormal tests	Abnormal values not given, except postural drop of SBP >20 mmHg or DBP >10 mmHg	40.9 in both South Asians and Caucasians	126 (South Asian) 140 (Caucasian)	T2DM	Mean age 59.5 years (South Asians), 59.2 years (Caucasians) Diabetes duration 11 years (South Asian), 10.5 years (Caucasians) HbA1c 8%	White Caucasian – 52.6% South Asian – 47.4%	Secondary care

Abbreviations: HRV, heart-rate variability; DM, diabetes mellitus; E:I, expiration:inspiration; CASS, composite autonomic severity score; CV, coefficient of variation; CART, cardiovascular reflex test; T1DM, type 1 DM; T2DM, type 2 DM; CAN, cardiac autonomic neuropathy; Tx, treatment; SBP, systolic blood pressure; DBP, diastolic blood pressure; NA, not applicable; HbA1c, glycated hemoglobin.

Figure 1 Stages of CAN.

Notes: CAN symptoms can include reduced exercise tolerance, silent ischemia, interoperative complications, and lower-limb complications. Adapted from Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. 2013;4(1):4–18. © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.⁴⁷
Abbreviations: CAN, cardiovascular autonomic neuropathy; HR, heart rate.

Table 2 Summary of Ewing tests

CART	What does it assess?	Which branch of the autonomic nervous system does it measure?	Interpretation and definition	Cutoffs (age-dependent)^Citation102	Diagnostic performance^Citation101
HR response to deep breathing (E:I ratio)^Citation103,Citation111	Assesses beat-to-beat variation (R-R variation) during paced deep breathing	Tests for defects in parasympathetic activity by assessing ability of vagal nerve to slow HR	Gives an E:I ratio: longest R-R during expiration divided by shortest R-R during inspiration	1.22–1.1 (15–65 years)	S1 = 19% S2 = 98% P=0.115 OR (95% CI) = 2.34 (1.19–4.77)
HR response to standing (30:15 ratio)^Citation103,Citation111	Assesses beat-to-beat variation (R-R variation) following standing	Tests for defects in parasympathetic activity by assessing ability of vagal nerve to slow HR	Gives the 30:15 ratio: R-R interval around 30th heartbeat divided by R-R interval around the 15th heartbeat	1.17–1.06 (15–65 years)	S1 = 96% S2 = 65% P<0.001 OR (95% CI) = 44.07 (12.68–153.25)
Valsalva maneuver (Valsalva ratio)^Citation104	Evaluates HR response during and after provoked increase in intrathoracic/abdominal pressure	Assesses both parasympathetic and sympathetic activity, but mainly parasympathetic	Gives Valsalva ratio: longest R-R interval in Phase IV divided by shortest R-R interval in Phase II and at very beginning of Phase III	1.23–1.16 (15–65 years)	S1 = 62% S2 = 92% P=0.001 OR (95% CI) = 18.56 (5.55–62.1)
BP response to standing (reduction in SBP)^Citation103,Citation106,Citation110	Assesses the baroreceptor reflex	Tests for defects in sympathetic activity by assessing ability to provide suitable HR and BP response to activity	Test result presented as difference in both SBP and DBP between sitting and standing	20 drop in SBP or 10 drop in DBP	S1 = 51% S2 = 71% P=0.061 OR (95% CI) = 2.5 (1.28–4.88)
BP response to sustained muscle contraction (rise in DBP)^Citation103,Citation105	DBP increases caused by sustained muscle contraction with the use of a handgrip dynamometer	Tests for defects in sympathetic activity by assessing ability to provide suitable HR and BP response to activity	Test result presented as difference between highest DBP during examination and average DBP at rest	Should normally be >15 mmHg	S1 = 64% S2 = 75% P=0.002 OR (95% CI) = 5.22 (2.6–10.55)

Notes: Phase I is a transient increase in BP and resulting bradycardia due to a mechanical rise in transthoracic pressure. Phase II is concomitant compensatory tachycardia due to reduced venous return and stroke volume leading to a decrease in BP. Phase III is a further transient reduction in BP and resulting tachycardia at the end of expiration due to pulmonary vasculature expansion. Phase IV is an abrupt rise in BP above baseline values with resulting bradycardia, thought to be the result of baroreceptor activation. Based on changes to hemodynamic parameters, various indices can be calculated, including the Valsalva ratio, which is derived from the longest R-R interval in Phase IV divided by the shortest R-R interval at the end of Phase II/beginning of Phase III.¹⁰⁷ Normal values for cutoffs are age-dependent; some software manufacturers (such as Ansar) also provide their own normative values. S₁ is sensitivity and S₂ is specificity.

Abbreviations: HR, heart rate; CART, cardiac autonomic reflex test; E:I, expiration:inspiration; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Figure 2 Spectral analysis of HRV.

Note: Reproduced from Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. 2013;4(1):4–18. © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.⁴⁷
Abbreviations: HRV, heart-rate variability; PS, parasympathetic; S, sympathetic ; sdNN, standard deviations of all normal beat-to-beat intervals.

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