**4. Diagnostic tests of cardiovascular autonomic neuropathy**

The presence of cardiac autonomic neuropathy may be indicated by resting tachycardia (heart rate > 100 bpm) that is due to an imbalance of the sympathetic/parasympathetic tone. Because neuropathy is seen first in the longest fibres, early in the natural history of diabetes there is impairment of parasympathetic function, followed later by sympathetic denervation that progresses from the apex of the ventricles towards the base of the heart and increases the propensity to dysrhythmias [10, 25]. Moreover, cardiac autonomic neuropathy reduces exercise tolerance by impairing heart rate, blood pressure, and cardiac output responses to exercise. Indeed, subjects with diabetes and suspected cardiac autonomic neuropathy should perform a cardiac stress test before undertaking an exercise program. The assump‐ tion of upright posture results in gravity-mediated displacement of blood into the veins of the pelvis and lower limbs, reducing venous return to the heart. In healthy people, this leads to a reflex increase in sympathetic nervous system activity, increasing peripheral vascular resistance and heart rate such that arterial pressure is maintained [26]. In diabetic people, sympathetic vasomotor denervation may lead to orthostatic hypotension that is aggravated when combined with orthostatic bradycardia [25]. Moreover, a large proportion of diabetic patients receive multi-drug therapy that potentially contributes to the fall in blood pressure on assuming the upright posture [24]. Table 3 provides a list of drugs, which may interfere with autonomic function tests.

tervals (that is, all intervals between adjacent QRS complexes resulting from sinus node

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**5.** Frequency domain measures of heart rate variability evaluate how power (variance) distributes as a function of frequency using power spectral density (PSD) analysis (Ta‐ ble 5) [43]. Vagal activity is thought to contribute mainly to the high frequency (HF, 0.15-0.4 Hz) component, which is related to respiratory activity, while the sympathetic system is thought to modulate the lower-frequency heart rate variability components. The very low frequency (VLF, <0.04 Hz) components are related to fluctuations in vaso‐ motor tone associated with thermoregulation, and the low frequency (LF, 0.04-0.15 Hz)

components are considered to be associated with the baroreceptor reflex [10, 44].

**6.** QT interval prolongation in the ECG has been used to diagnose cardiac autonomic neu‐ ropathy with reasonable sensitivity, specificity and positive predictive value [12, 45] al‐ though there is no universal agreement on 1) QT measurement and correction techniques, and 2) normality range [46]. Age dependency of cardiovascular autonomic responses is exemplified in Figure 3. Figures 4-6 show the heart rate variability with deep breathing, lying to standing, and Valsalva manoeuvre, respectively, in patients

**Figure 1.** The linear relationship between age and heart rate response to deep breathing expressed as expiratory/ inspiratory (E:I) ratio and systolic blood pressure (SBP)midline estimate statistic of rhythm (MESOR) in 20 patients with

depolarisations) or the instantaneous heart rate is determined.

with type 1 diabetes and control subjects.

type 1 diabetes and 25 age-matched control subjects.

In diabetes, analysis of 24-h ambulatory blood pressure monitoring (ABPM) showed altered characteristics of blood pressure rhythm [1]. In particular, diabetic patients had a high prev‐ alence of increased night time blood pressure or non-dipping profile [27-32] that could re‐ flect a) the presence of autonomic neuropathy [32-33] resulting in sympathetic predominance during sleep, but also b) the circadian misalignment due to obstructive sleep apnoea in obese subjects with type 2 diabetes [34]. Chronobiologically interpreted ambulato‐ ry blood pressure monitoring uncovered that midline estimate statistic of rhythm (MESOR) and mean of systolic blood pressure and diastolic blood pressure were higher in diabetic pa‐ tients than in healthy subjects [35-42]. Figures 1-2 show the relationship between heart rate response to deep breathing and the circadian blood pressure rhythm parameters midline es‐ timate statistic of rhythm and acrophase.

Abnormalities in respiration-related heart rate variability can be evaluated in a number of different ways, from the simple bedside tests of short-term heart rate differences previously listed to the spectral analysis of heart rate variability, taking into account that normative val‐ ues of heart rate variability indices are affected mainly by age [10]:


tervals (that is, all intervals between adjacent QRS complexes resulting from sinus node depolarisations) or the instantaneous heart rate is determined.

**4. Diagnostic tests of cardiovascular autonomic neuropathy**

with autonomic function tests.

364 Type 1 Diabetes

timate statistic of rhythm and acrophase.

The presence of cardiac autonomic neuropathy may be indicated by resting tachycardia (heart rate > 100 bpm) that is due to an imbalance of the sympathetic/parasympathetic tone. Because neuropathy is seen first in the longest fibres, early in the natural history of diabetes there is impairment of parasympathetic function, followed later by sympathetic denervation that progresses from the apex of the ventricles towards the base of the heart and increases the propensity to dysrhythmias [10, 25]. Moreover, cardiac autonomic neuropathy reduces exercise tolerance by impairing heart rate, blood pressure, and cardiac output responses to exercise. Indeed, subjects with diabetes and suspected cardiac autonomic neuropathy should perform a cardiac stress test before undertaking an exercise program. The assump‐ tion of upright posture results in gravity-mediated displacement of blood into the veins of the pelvis and lower limbs, reducing venous return to the heart. In healthy people, this leads to a reflex increase in sympathetic nervous system activity, increasing peripheral vascular resistance and heart rate such that arterial pressure is maintained [26]. In diabetic people, sympathetic vasomotor denervation may lead to orthostatic hypotension that is aggravated when combined with orthostatic bradycardia [25]. Moreover, a large proportion of diabetic patients receive multi-drug therapy that potentially contributes to the fall in blood pressure on assuming the upright posture [24]. Table 3 provides a list of drugs, which may interfere

In diabetes, analysis of 24-h ambulatory blood pressure monitoring (ABPM) showed altered characteristics of blood pressure rhythm [1]. In particular, diabetic patients had a high prev‐ alence of increased night time blood pressure or non-dipping profile [27-32] that could re‐ flect a) the presence of autonomic neuropathy [32-33] resulting in sympathetic predominance during sleep, but also b) the circadian misalignment due to obstructive sleep apnoea in obese subjects with type 2 diabetes [34]. Chronobiologically interpreted ambulato‐ ry blood pressure monitoring uncovered that midline estimate statistic of rhythm (MESOR) and mean of systolic blood pressure and diastolic blood pressure were higher in diabetic pa‐ tients than in healthy subjects [35-42]. Figures 1-2 show the relationship between heart rate response to deep breathing and the circadian blood pressure rhythm parameters midline es‐

Abnormalities in respiration-related heart rate variability can be evaluated in a number of different ways, from the simple bedside tests of short-term heart rate differences previously listed to the spectral analysis of heart rate variability, taking into account that normative val‐

**1.** Heart rate response to deep breathing, which measures sinus arrhythmia during quiet

**2.** Heart rate response to standing up induces reflex tachycardia followed by bradycardia

**3.** Valsalva manoeuvre evaluates cardio-vagal function in response to a standardized in‐

**4.** Time domain measures of heart rate variability are summarised in Table 4[43]. In a con‐ tinuous ECG record, each QRS complex is detected, and the normal-to-normal (NN) in‐

crease in intrathoracic pressure, primarily parasympathetic mediated.

ues of heart rate variability indices are affected mainly by age [10]:

respiration and primarily reflects parasympathetic function.

and is both vagal and baroreflex mediated.


**Figure 1.** The linear relationship between age and heart rate response to deep breathing expressed as expiratory/ inspiratory (E:I) ratio and systolic blood pressure (SBP)midline estimate statistic of rhythm (MESOR) in 20 patients with type 1 diabetes and 25 age-matched control subjects.

**Drug class Medication Effect on heart**

Calcium channel blockers diltiazem x

Cardiac glycosides digoxin x

Psychoactive drugs x

SDNN ms Standard deviation (SD) of all normal-to-normal (NN) intervals

segments of the entire recording

the second interval is longer)

minute segments of the entire recording SDSD ms SD of differences between adjacent normal-to-normal (NN) intervals

**Variable Units Description**

**STATISTICAL MEASURES**

Diuretics furosemine, thiazides x

Benzodiazepines alprazolam x x

lorazepam

Tricyclic antidepressants amitriptyline x x

**Table 3.** Drug classes which may interfere with autonomic function tests and some examples of medications [12].

SDANN ms Standard deviation (SD) of the averages of normal-to-normal (NN) intervals in all 5-minute

NN50 count ms Number of pairs of adjacent normal-to-normal (NN) intervals differing by more than 50 ms

in the entire recording (counting all such NN intervals pairs or only pairs in which the first or

RMSSD ms Root-mean square of the differences of successive normal-to-normal (NN) intervals SDNN index ms Mean of the standard deviations (SDs) of all normal-to-normal (NN) intervals for all 5-

pNN50 % NN50 count divided by the total number of all normal-to-normal (NN) intervals

**rate**

Diabetic Autonomic Neuropathy and Circadian Misalignment in Type 1 Diabetes

nifedipine x verapamil x

spironolactone x

diazepam x

midazolam x

carbamazepine x

desipramine x x doxepin x x fluvoxamine x x imipramine x x nortriptyline x x

**Effect on blood pressure**

367

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**Figure 2.** The linear relationship between age and heart rate response to deep breathing expressed as expiratory/ inspiratory (E:I) ratio and diastolic blood pressure (DBP) acrophase in the same subjects as in Figure 1.



**Table 3.** Drug classes which may interfere with autonomic function tests and some examples of medications [12].

**Figure 2.** The linear relationship between age and heart rate response to deep breathing expressed as expiratory/

enalaprin x lisinopril x quinalapril x trandolapril x

losartan x

bisoprolol x metoprolol x nebivolol x

**rate**

**Effect on blood pressure**

inspiratory (E:I) ratio and diastolic blood pressure (DBP) acrophase in the same subjects as in Figure 1.

**Drug class Medication Effect on heart**

Anti-inflammatory drugs acetylsalicylic acid x Angiotensin converting enzyme inhibitors captopril x

366 Type 1 Diabetes

Angiotensin II type 1 receptor blockers eprosartan x

β-blockers atenolol x

α-adrenoceptor antagonists doxazosin x



**Table 4.** Time domain measures of heart rate variability described by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. The four measures marked in grey were recommended for time domain heart rate variability assessment [43].

**Figure 3.** The linear relationship between age and heart rate response to deep breathing expressed as expiratory/

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369

**Figure 4.** Two-way box percentile plots of heart rate response to deep breathing expressed as expiratory/inspiratory

(E:I) ratio in 20 patients with type 1 diabetes (black box) and 25 age-matched control subjects (white box).

inspiratory (E:I) ratio.


**Table 5.** Frequency domain measures of heart rate variability described by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology [43].

**Variable Units Description**

**Variable Units Description ANALYSIS OF SHORT-TERM RECORDINGS**

seconds)

recommended for time domain heart rate variability assessment [43].

VLF ms2 Power in very low frequency (VLF) range LF ms2 Power in low frequency (LF) range

HF ms2 Power in high frequency (HF) range

LF/HF ms2 Ratio LF [ms2]/HF[ms2]

VLF ms2 Power in the VLF range LF ms2 Power in the LF range HF ms2 Power in the HF range

**ANALYSIS OF ENTIRE 24 HOURS**

LF norm nu LF power in normalized units LF/(total power-VLF)x100

HF norm nu HF power in normalized units HF/(total power-VLF)x100

α Slope of the linear interpolation of the spectrum in a log-log scale

Cardiology and the North American Society of Pacing and Electrophysiology [43].

**Table 5.** Frequency domain measures of heart rate variability described by the Task Force of the European Society of

Total power ms2 Variance of all normal-to-normal (NN) intervals ULF ms2 Power in the ultra low frequency (ULF) range

Total number of all normal-to-normal intervals divided by the height of the histogram of all normal-to-normal (NN) intervals measured on a discrete scale with bins of 7.8125 ms (1/128

ms Baseline width of the minimum square difference triangular interpolation of the highest

ms Difference between the widths of the histogram of differences between adjacent normal-

ms Coefficient ϕ of the negative exponential curve k · e-ϕt, which is the best approximation of

the histogram of absolute differences between adjacent NN intervals

ms2 The variance of normal-to-normal (NN) intervals over the temporal segment

**Table 4.** Time domain measures of heart rate variability described by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. The four measures marked in grey were

peak of the histogram of all normal-to-normal (NN) intervals

to-normal intervals measured at selected heights

**GEOMETRIC MEASURES**

Heart rate variability triangular index

368 Type 1 Diabetes

Triangular interpolation (TINN)

Differential index

Logarithmic index

5-min total power

**Figure 3.** The linear relationship between age and heart rate response to deep breathing expressed as expiratory/ inspiratory (E:I) ratio.

**Figure 4.** Two-way box percentile plots of heart rate response to deep breathing expressed as expiratory/inspiratory (E:I) ratio in 20 patients with type 1 diabetes (black box) and 25 age-matched control subjects (white box).

**5. What kind of relationship is between cardiac autonomic neuropathy,**

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Chronic misalignment between the endogenous circadian timing system and the behaviou‐ ral cycles may increase the risk of diabetes, obesity, cardiovascular disease and cancer [5] as well as the presence of diseases may affect circadian rhythms. While cardiovascular events generally occur in the early morning hours [47-48], abnormalities in the circadian pattern of cardiovascular events in the diabetic population has been attributed to differences in the du‐ ration of diabetes and supposedly the variable extent of underlying diabetic autonomic neu‐ ropathy [6-9, 49]. In 1989 Hjalmarson et al. observed two peaks of symptom onset of acute myocardial infarction for patients with diabetes: a peak, 28%, was discernible between 6:01 AM and 12:00 noon and a secondary peak, 25%, between 6:01 PM and midnight. In patients over 70 years of age, smokers, diabetics, those receiving β-blockers, and women, the morn‐ ing and the evening peaks were of the same size [6]. Moreover, angina has long been consid‐ ered an unreliable index of myocardial infarction in diabetic patients with coronary artery disease [50-51]. The prolonged anginal perception threshold in diabetic patients was sug‐ gested to be partly the result of damage to the sensory innervation of the heart [52]. In the same 1990, to investigate the incidence and mechanism of painless myocardial ischemia on exercise testing in diabetic patients, Murray et al. performed two studies: 1) retrospectively, all exercise tests carried out in the hospital during the past 5 years were reviewed for silent ischemia; 2) prospectively, diabetic patients with known or suspected coronary artery dis‐ ease underwent autonomic function testing and a second exercise test. They concluded that silent myocardial ischemia on exercise testing was common among patients with diabetes

**cardiovascular mortality, and albuminuria**

mellitus and was associated with severe autonomic dysfunction [53].

Ambulatory electrocardiographic monitoring in 60 patients with diabetes and coronary ar‐ tery disease, 25 of whom underwent also autonomic nervous system testing, evidenced that 1) silent ischemia was highly prevalent since 91% of all ischemic episodes were silent, and 2) time of onset of ischemia followed a circadian distribution with a peak incidence in the morning hours, except in patients with moderate to severe autonomic nervous system dys‐ function who did not demonstrate such a peak [7]. Using harmonic regression model to evaluate the circadian variation of myocardial infarction symptom onset in patients (n = 3882) who were enrolled in the Onset Study, it was then confirmed that patients with type 1 diabetes and those with type 2 diabetes for 5 or more years had an attenuation of the morn‐ ing peak in acute myocardial infarction [9]. Authors concluded that inconsistency in obser‐ vation of such an effect in patients with diabetes in the past might well have been due to differences in the duration of diabetes and thus the variable extent of underlying autonomic dysfunction [9]. To exemplify inconsistencies among clinical observations, the time of onset of ischemic pain in patients enrolled in the Thrombolysis in Myocardial Ischemia (TIMI) III Registry Prospective Study and in the TIMI IIIB trial showed a circadian variation with a peak in the morning hours between 6 AM and 12 noon. This circadian variation was ob‐ served both in patients with unstable angina and in those with evolving non-Q-wave acute myocardial infarction and in all subgroups tested, diabetics included [8]. On the contrary, Li

**Figure 5.** Two-way box percentile plots of heart rate response to standing upcalculated as the ratio of the longest R-R interval around the 30th beat to the shortest R-R interval around the 15th beat in 20 patients with type 1 diabetes (black box) and 25 age-matched control subjects (white box).

**Figure 6.** A two-way box percentile comparison plot of heart rate response to Valsalva manoeuvre expressed as the ratio of the longest R-R interval shortly after the manoeuvre to the shortest R-R interval during the manoeuvre in 20 patients with type 1 diabetes (black box) and 25 age-matched control subjects (white box)
