Cardiovascular autonomic neuropathy in diabetes: Pathophysiology, clinical assessment and implications

Table 1 Characteristics of different studies evaluating cardiovascular autonomic neuropathy and diabetes

Study	Ref.	Sample size and type of study	CAN assessment	Main findings
Pittsburgh Epidemiology of Diabetes Complications Study III	Maser et al[49], 1990	168 participants with type 1 diabetes; Cross-sectional study	Heart rate response to deep breathing, 30:15 ratio and Valsalva maneuver	The association ofCAN with increased cardiovascular risk factors may explain the high mortality of CAN patients
EURODIAB IDDM Complications Study	Kempler et al[85], 2002	3,007 participants with type 1 diabetes; Cross-sectional study	Orthostatic hypotension test and 30:15 ratio	CAN is associated to cardiovascular disease and vascular factors may have an important role in the pathogenesis of CAN
EURODIAB Prospective Complications Study	Witte et al[86], 2005	956 participants with type 1 diabetes; Prospective cohort study (mean follow-up of 7 yr)	Orthostatic hypotension test and 30:15 ratio	Glycated hemoglobin level, hypertension, distal symmetrical polyneuropathy and retinopathy, predict the risk of CAN development
MONICA/KORA Augsburg Cohort Study	Ziegler et al[87], 2008	1720 participants (1560 non-diabetic and 160 diabetic subjects); Prospective cohort study (mean follow-up of 9 yr)	HRV, corrected QT interval and QT dispersion (difference between the longest and shortest QT intervals in 12-lead electrocardiogram)	Prolonged corrected QT interval is an independent predictor of mortality in the non-diabetic anddiabetic population, while reduced HRV appears to be a prognostic index only in the presence of diabetes
ACCORD Trial	Pop-Busui et al[54], 2010	10251 participants with type 2 diabetes; Clinical Trial	HRV, resting heart rate and QT index (observed/predicted QT duration)	CAN patients had a 1.55-2.14 increased relative risk of all-cause mortality compared to those without CAN
First Joslin Kidney Study	Orlov et al[88], 2015	370 participants with type 1 diabetes; Prospective cohort study (mean follow-up of 14 yr)	Heart rate response to deep breathing	CAN is a strong independent predictor of the long-term risk of early decline of renal function
ACCORD Trial	Tang et al[51], 2021	7725 participants with type 2 diabetes; Clinical Trial	HRV and QT index	The intensive blood pressure and glycemic control demonstrated favorable impact in patients with CAN

CAN: Cardiovascular autonomic neuropathy; HRV: Heart rate variability.

Table 2 Heart rate variability time and frequency domain measures[89,90]

	Linear indices - time domain
Parameters	Abbreviation meaning	Interpretation
MNN (ms)	Mean of NN intervals	Long RR intervals are related to a lower heart rate, while short RR intervals denote a high heart rate. It reflects SANS and PANS modulations
SDNN (ms)	Standard deviation of all NN intervals	Reflects the activity of both SANS and PANS
rMSSD (ms)	The square root of the mean squared differences of successive NN intervals	Reflects the PANS activity
NN50 (count)	Number of interval differences of successive NN intervals greater than 50 ms	Reflects the PANS activity
pNN50 (%)	Percentage of successive RR intervals that differ by more than 50 ms	The proportion of NN50 divided by total number of NN, which also represents the PANS activity
	Linear indices - frequency domain
ULF (ms², Hz, %)	Ultra low frequency	Frequency range: 0-0.003 Hz. Commonly, it is not present in HRV results
VLF (ms², Hz, %)	Very low frequency	Frequency range: 0.003-0.04 Hz. It is related to renin-angiotensin-aldosterone system, thermoregulation, peripheral vasomotor tonus and PANS activity
LF (ms², Hz, nu, %)	Low frequency	Frequency range: 0.04-0.15 Hz. It represents the SANS and PANS activity, with a predominance of SANS influence
HF (ms², Hz, nu, %)	High frequency	Frequency range: 0.15-0.4 Hz. It represents the PANS activity
LF/HF	Ratio of LF-to-HF power	So-called sympathovagal index. It represents the sympathovagal balance, the autonomic state resulting from the SANS and PANS influences
Total power (ms²)	Total power	It reflects both SANS and PANS influences, representing the components with frequency range ≤ 0.4 Hz

SANS: Sympathetic autonomic nervous system; PANS: Parasympathetic autonomic nervous system; LF: Low frequency; HF: High frequency; ULF: Ultra low frequency; VLF: Very low frequency; MNN: Mean of NN; SDNN: Standard deviation of all NN.