**5. What kind of relationship is between cardiac autonomic neuropathy, cardiovascular mortality, and albuminuria**

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

**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

**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)

(black box) and 25 age-matched control subjects (white box).

370 Type 1 Diabetes

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 et al. showed there was no a significant morning peak of incidence of acute myocardial in‐ farction in patients with diabetes but was obvious in control subjects; however, disappear of morning peak was not associated with duration of diabetes [49].

betic patients without silent myocardial ischemia; 3) cardiac autonomic neuropathy was sig‐ nificantly associated with an increased risk of major cardiac events. According to the Kaplan-Meier method, the increase in the risk of major cardiac events linked to cardiac auto‐ nomic neuropathy was significant after adjusting for silent myocardial ischemia, but the highest rate was found in patients who had silent myocardial ischemia and cardiac auto‐ nomic neuropathy. Authors concluded that the poor cardiovascular prognosis related to car‐ diac autonomic neuropathy in previous studies was probably associated with undetected

**of CAN**

The results were compared with those from an agematched control series

According to cutpoints previously established

According to age-related range values

Three or more of the tests were abnormal

According to the 10 point score composite autonomic severity scale (CASS)

**Results Comments**

Limited number of asymptomatic patients with predominantly T2DM

http://dx.doi.org/10.5772/52033

373

The cohort was predominantly male; no direct adjustment for use of cardio-active medications

not classified

Moderate power due to the small number of death in diabetic patients; DM was

Only one autonomic test instead of a battery

Retrospective design; limited number of subjects; symptomatic diabetic

Northern European sample; unavailable serial data obtained before and during sudden cardiac death; not all applicable risk factors could be modelled

patients

CAN was a better predictor of major cardiac events (odds ratio 4.30, 1.07-17.31) than silent myocardial ischemia (evaluated by ECG stress test, myocardial scintigraphy with dipyridamole, and 48-h ECG

Diabetic Autonomic Neuropathy and Circadian Misalignment in Type 1 Diabetes

monitoring)

1.26-5.19)

Not stated Increased all-cause mortality

associated with the lowest quintile of HR variability (hazard ratio 1.49, 1.01-2.19)

Decreased HR variability remains predictive also in diabetic patients (hazard ratio for SDNN < 50 ms 2.56,

Borderline or abnormal expiratory/ inspiratory ratio at baseline was associated with the occurrence of stroke (hazard ratio 2.3, 1.17-4.70)

Although perfusion defects remained a strong predictor of cardiac risk, CAN predicted the occurrence of death and cardiac events independent of

Sudden cardiac death relates more directly to coronary ischemia, cardiac arrhythmia, or nephropathy than it does to diabetic autonomic neuropathy

perfusion defects

silent myocardial ischemia in many patients [61].

**Sample size Tests of CAN Definition**

HR variability during deep breathing, Valsalva and lying to standing tests

HR variability during deep breathing; SBP decrease during standing

Spectral analysis of HR variability (24-h Holter

HR variability during deep breathing

Deep breathing, Valsalva manoeuvre, lying to standing, postural systolic blood pressure change, handgrip test

Quantitative sudomotor axon reflex test, HR response to deep breathing and to the Valsalva manoeuvre, BP responses during tilt and the Valsalva manoeuvre

ECG)

**Ref. Follow up (years)**

61 4.5 107 patients

62 3.5 532 patients

63 2.5 715 survivors

65 5.3 872 of 950

66 3.8 146 patients

67 15 311 patients

(of whom 17 with T1DM) and normal ECG

with DM (483 with T2DM)

of AMI (117 with DM)

patients with T2DM underwent baseline neuropathy assessment

with T2DM with suspected coronary artery disease

with T2DM and 151 patients with T1DM

Mechanisms through which cardiovascular circadian rhythms may be altered in diabetes are under current investigation. The tight crosstalk between components of circadian and meta‐ bolic cycles in mammals suggests that changes in nutrient-dependent signalling pathways such as in metabolic disorders may transmit cues that affect cardiovascular rhythmicity through transcriptional and non-transcriptional mechanisms [1, 54]. Moreover, a functional antagonism between melatonin and insulin has been supposed on the basis of animal and clinical studies. Melatonin inhibits insulin release through both the pertussis-toxin-sensitive membrane receptors MT1 and MT2 and the second messengers 3',5'-cyclic adenosine mono‐ phosphate, 3',5'-cyclic guanosine monophosphate and inositol 1,4,5-trisphosphate. In turn, increased insulin levels exert an inhibitory effect on the pineal gland and melatonin[55].

The relationship between cardiovascular prognosis and cardiac autonomic neuropathy has been investigated for a long time since the rate of deaths within a mean follow-up of 5.8 years had been found five times higher in the diabetic patients with cardiac autonomic neu‐ ropathy than in the diabetic patients free from cardiac autonomic neuropathy; most of these deaths were from cardiac causes [56]. The reasons why cardiac autonomic neuropathy af‐ fects quality and length of life are not well established, but cardiac autonomic neuropathy has been found to be associated with exercise intolerance, silent myocardial ischemia, pro‐ longation of QT interval that may cause arrhythmias, decreased myocardial perfusion re‐ serve, left ventricular hypertrophy and diastolic dysfunction [24, 57-59]. The variability of mortality rates revealed in the studies could be related to the study population, the modality for assessing cardiac autonomic neuropathy, the criteria used to define the presence of car‐ diac autonomic neuropathy, and the length of follow-up [60]. In 2003, Maser et al. examined by meta-analysis this relationship: 15 studies published from 1966 to 2001 could be included whose follow-up ranged from 0.5 to 16 years. The study-specific relative risks for individu‐ als with cardiac autonomic neuropathy ranged from 0.91 to 9.20 with a pooled relative risk for mortality of 3.45 for studies that used two or more measures to define cardiac autonomic neuropathy, and of 1.20 for those studies defining cardiac autonomic neuropathy with one measure of autonomic function [60].

Our Table 6 summarises the main studies of cardiac autonomic neuropathy and mortality/ morbidity in patients with diabetes mellitus restarting from the year 2001 onwards. In that year, a 3-7 year (mean 4.5) follow up was obtained in 107 diabetic patients with no history of myocardial infarction or angina, a normal ECG, and two or more additional risk factors, who underwent ECG stress test, a thallium-201 myocardial scintigraphy with dipyridamole, and 48-h ECG monitoring to assess silent myocardial ischemia. In addition, cardiac auto‐ nomic neuropathy was searched for by standardized tests evaluating heart rate variations [61]. The study confirmed that 1) the prevalence of type 1 silent myocardial ischemia was high (about 30%) and significant coronary stenoses were found in approximately one-third of those patients with silent myocardial ischemia; 2) there was only a trend of higher risk of major cardiac events in the diabetic patients with silent myocardial ischemia than in the dia‐ betic patients without silent myocardial ischemia; 3) cardiac autonomic neuropathy was sig‐ nificantly associated with an increased risk of major cardiac events. According to the Kaplan-Meier method, the increase in the risk of major cardiac events linked to cardiac auto‐ nomic neuropathy was significant after adjusting for silent myocardial ischemia, but the highest rate was found in patients who had silent myocardial ischemia and cardiac auto‐ nomic neuropathy. Authors concluded that the poor cardiovascular prognosis related to car‐ diac autonomic neuropathy in previous studies was probably associated with undetected silent myocardial ischemia in many patients [61].

et al. showed there was no a significant morning peak of incidence of acute myocardial in‐ farction in patients with diabetes but was obvious in control subjects; however, disappear of

Mechanisms through which cardiovascular circadian rhythms may be altered in diabetes are under current investigation. The tight crosstalk between components of circadian and meta‐ bolic cycles in mammals suggests that changes in nutrient-dependent signalling pathways such as in metabolic disorders may transmit cues that affect cardiovascular rhythmicity through transcriptional and non-transcriptional mechanisms [1, 54]. Moreover, a functional antagonism between melatonin and insulin has been supposed on the basis of animal and clinical studies. Melatonin inhibits insulin release through both the pertussis-toxin-sensitive membrane receptors MT1 and MT2 and the second messengers 3',5'-cyclic adenosine mono‐ phosphate, 3',5'-cyclic guanosine monophosphate and inositol 1,4,5-trisphosphate. In turn, increased insulin levels exert an inhibitory effect on the pineal gland and melatonin[55].

The relationship between cardiovascular prognosis and cardiac autonomic neuropathy has been investigated for a long time since the rate of deaths within a mean follow-up of 5.8 years had been found five times higher in the diabetic patients with cardiac autonomic neu‐ ropathy than in the diabetic patients free from cardiac autonomic neuropathy; most of these deaths were from cardiac causes [56]. The reasons why cardiac autonomic neuropathy af‐ fects quality and length of life are not well established, but cardiac autonomic neuropathy has been found to be associated with exercise intolerance, silent myocardial ischemia, pro‐ longation of QT interval that may cause arrhythmias, decreased myocardial perfusion re‐ serve, left ventricular hypertrophy and diastolic dysfunction [24, 57-59]. The variability of mortality rates revealed in the studies could be related to the study population, the modality for assessing cardiac autonomic neuropathy, the criteria used to define the presence of car‐ diac autonomic neuropathy, and the length of follow-up [60]. In 2003, Maser et al. examined by meta-analysis this relationship: 15 studies published from 1966 to 2001 could be included whose follow-up ranged from 0.5 to 16 years. The study-specific relative risks for individu‐ als with cardiac autonomic neuropathy ranged from 0.91 to 9.20 with a pooled relative risk for mortality of 3.45 for studies that used two or more measures to define cardiac autonomic neuropathy, and of 1.20 for those studies defining cardiac autonomic neuropathy with one

Our Table 6 summarises the main studies of cardiac autonomic neuropathy and mortality/ morbidity in patients with diabetes mellitus restarting from the year 2001 onwards. In that year, a 3-7 year (mean 4.5) follow up was obtained in 107 diabetic patients with no history of myocardial infarction or angina, a normal ECG, and two or more additional risk factors, who underwent ECG stress test, a thallium-201 myocardial scintigraphy with dipyridamole, and 48-h ECG monitoring to assess silent myocardial ischemia. In addition, cardiac auto‐ nomic neuropathy was searched for by standardized tests evaluating heart rate variations [61]. The study confirmed that 1) the prevalence of type 1 silent myocardial ischemia was high (about 30%) and significant coronary stenoses were found in approximately one-third of those patients with silent myocardial ischemia; 2) there was only a trend of higher risk of major cardiac events in the diabetic patients with silent myocardial ischemia than in the dia‐

morning peak was not associated with duration of diabetes [49].

372 Type 1 Diabetes

measure of autonomic function [60].



**Ref. Follow up (years)**

> whom 97 with T2DM

> patients of whom 77 with T2DM

74 15.5 136 diabetic

1 diabetes mellitus.

**Sample size Tests of CAN Definition**

Five autonomic function tests together with time and frequency domain parameters based on 24-hour ECG recordings

was 1.49 with a 95% confidence interval 1.01-2.19 [62].

measurements except high frequency power [63].

based on 24-hour ECG recordings

**of CAN**

**Table 6.** Studies that evaluated mortality and morbidity in patients with diabetes mellitus and cardiovascular autonomic neuropathy (CAN) from 2001 onward. AMI, acute myocardial infarction; DM, diabetes mellitus; SBP, systolic blood pressure; SDNN, standard deviation of normal RR intervals; T2DM, type 2 diabetes mellitus; T1DM, type

Wheeler et al. evaluated short-term all-cause mortality in an elderly cohort of predominant‐ ly male veteran patients with diabetes [62]. Among the 532 patients with RR variability measures (evaluated by heart rate response to timed deep breathing), subjects who died (n = 120) had significantly lower heart rat variability than survivors. The lowest quintile of heart rate variability with deep breathing was found to be associated with a 50% increase in mor‐ tality. After adjusting for age, smoking status, creatinine, pack-year of cigarettes smoked, diabetes duration, race, history of ischemic heart disease, and hypertension, the hazard ratio

Whang et al. used data from the Multicenter Post Infarction Program (MPIP, a longitudinal observational study of 715 survivors of acute myocardial infarction, including 117 diabetic patients, enrolled from 1979 to 1980) to test two hypotheses: 1) RR interval variability was lower in diabetic patients, and 2) low RR interval variability was less predictive of mortality in diabetic patients [63]. Six frequency-domain measurements and one time-domain meas‐ urement of RR interval variability were evaluated on the basis of 24-hour Holter electrocar‐ diographic recordings. Reduced RR interval variability was significantly more frequent in diabetic patients than in non-diabetic patients for all measurements except high frequency power. Moreover, in diabetic patients, the association between reduced RR interval variabil‐ ity and all-cause mortality was at least as strong as it was in non-diabetic patients for all

Since the risk of fatal and non-fatal strokes were increased in diabetic patients compared with non-diabetic patients over a 7-year follow up period [64], Cohen et al. evaluated the relation‐ ship between a number cardiovascular risk factors in normotensive and hypertensive type 2 diabetic patients (enrolled in the Appropriate Blood Pressure Control in Diabetes trial) on the incidence of stroke [65]. Cardiovascular risk factors included also autonomic function testing,

**Results Comments**

5 function tests and had an acceptable 24-hour ECG recording could be analysed, 2) ECG was recorded during normal daily activity

375

http://dx.doi.org/10.5772/52033

Sources of lower sample representativeness: 1) percentage of invited subjects who refused to participate (older than responders), 2) patients' ability to cooperate to the function tests and to have an acceptable 24-hour ECG

recording

cause mortality (estimated relative risk of death with an increase by 1 standard deviation 0.65)

Diabetic Autonomic Neuropathy and Circadian Misalignment in Type 1 Diabetes

function tests (Valsalva, 30:15, and handgrip) were superior to HR variability in predicting allcause mortality in the diabetic

Not stated Three simple autonomic

population


**Ref. Follow up (years)**

374 Type 1 Diabetes

68 10.1 388 patients

69 9.2 104 patients

70 9.0 1560 non

71 7.1 1458 patients

71 13.6 490

72 15.5 178 diabetic

73 15.5 165 diabetic

with T1DM of whom 197 with diabetic nephropathy

with T2DM of whom 51 with diabetic nephropathy

diabetic and 160 diabetic subjects (MONIKA/ KORA Study)

with T2DM

individuals from a populationbased cohort (Hoorn Study) of whom 135 with T2DM

patients of whom 110 with T2DM

patients of

**Sample size Tests of CAN Definition**

HR variability during deep breathing

HR variability during deep breathing

Time domain measures, corrected QT interval, and QT dispersion were obtained from a 12 lead resting ECG

HR variability during deep breathing, Valsalva manoeuvre and postural change

HR variability during deep breathing and standing up, 5 tests of spectral analyses of HR variability, and one baroreflex sensitivity measurement

HR variability during deep breathing, Valsalva manoeuvre, and lying to standing, postural systolic blood pressure change, diastolic blood pressure response to handgrip test

Time and frequency domain parameters **of CAN**

HR variability < 10 bpm

According to age-related reference values (total maximum CAN score of 3)

Cardiovascul ar autonomic dysfunction total score

Two or more abnormal tests

**Results Comments**

CAN determined by only one test, but well characterised population

Low patient number, but well characterised population

Short period of ECG recording (20s) without control for respiration

Lack reference values for CAN tests specific for Korean people; the effect of glycaemic control status on the development of stroke has not been assessed; limited number of

events

Moderate level of reproducibility of autonomic function parameters; CAN total score evaluated at baseline only; spectral analyses performed during 3 min; albumin/creatinine ratio measured in one urine sample only

Sources of lower sample representativeness: 1) 26% of invited subjects refused to participate (older than responders), 2) patients' ability to cooperate to the

Sources of lower sample representativeness: 1) only patients who completed all

function tests

CAN predicted cardiovascular mortality and morbidity in patients with diabetic nephropathy (hazard ratio 6.4, 1.5-26.3), but not all-cause

predicted all-cause mortality (1% increase in dipping was associated with a lower risk 0.97, 0.94-0.998); HR variability was confirmed to be a predictor also in T2DM (1 bpm increase 0.92, 0.87-0.98)

subjects with corrected QT > 440 ms increased by twofold and threefold in the non diabetic and diabetic group, respectively; prolonged QT interval predicted

cardiovascular mortality only in the non diabetic group (risk ratio 4.47, 2.44-9.22)

Hazard ratio for acute stroke events in patients with abnormal CAN scores was 2.7 compared with patients with normal scores; a CAN score of 3 was significantly associated with a new ischaemic stroke event in patients with diabetes

Both microalbuminuria and CAN are independently associated with cardiovascular mortality, and the excess mortality attributable to microalbuminuria cannot be explained by CAN

The relative risk of all-cause mortality associated with CAN was 2.85, 1.75-4.65; Valsalva ratio and handgrip had an independent predictive value

Not stated The low frequency band in the frequency domain was the most powerful predictor of all-

mortality

Not stated Non-dipping phenomenon

Not stated The relative risk of mortality in

**Table 6.** Studies that evaluated mortality and morbidity in patients with diabetes mellitus and cardiovascular autonomic neuropathy (CAN) from 2001 onward. AMI, acute myocardial infarction; DM, diabetes mellitus; SBP, systolic blood pressure; SDNN, standard deviation of normal RR intervals; T2DM, type 2 diabetes mellitus; T1DM, type 1 diabetes mellitus.

Wheeler et al. evaluated short-term all-cause mortality in an elderly cohort of predominant‐ ly male veteran patients with diabetes [62]. Among the 532 patients with RR variability measures (evaluated by heart rate response to timed deep breathing), subjects who died (n = 120) had significantly lower heart rat variability than survivors. The lowest quintile of heart rate variability with deep breathing was found to be associated with a 50% increase in mor‐ tality. After adjusting for age, smoking status, creatinine, pack-year of cigarettes smoked, diabetes duration, race, history of ischemic heart disease, and hypertension, the hazard ratio was 1.49 with a 95% confidence interval 1.01-2.19 [62].

Whang et al. used data from the Multicenter Post Infarction Program (MPIP, a longitudinal observational study of 715 survivors of acute myocardial infarction, including 117 diabetic patients, enrolled from 1979 to 1980) to test two hypotheses: 1) RR interval variability was lower in diabetic patients, and 2) low RR interval variability was less predictive of mortality in diabetic patients [63]. Six frequency-domain measurements and one time-domain meas‐ urement of RR interval variability were evaluated on the basis of 24-hour Holter electrocar‐ diographic recordings. Reduced RR interval variability was significantly more frequent in diabetic patients than in non-diabetic patients for all measurements except high frequency power. Moreover, in diabetic patients, the association between reduced RR interval variabil‐ ity and all-cause mortality was at least as strong as it was in non-diabetic patients for all measurements except high frequency power [63].

Since the risk of fatal and non-fatal strokes were increased in diabetic patients compared with non-diabetic patients over a 7-year follow up period [64], Cohen et al. evaluated the relation‐ ship between a number cardiovascular risk factors in normotensive and hypertensive type 2 diabetic patients (enrolled in the Appropriate Blood Pressure Control in Diabetes trial) on the incidence of stroke [65]. Cardiovascular risk factors included also autonomic function testing, and automated electrocardiographic measure of heart rate response to deep breathing. Expir‐ atory/inspiratory (E:I) ratio was categorised as normal (53.6%), borderline (9.5%), or abnor‐ mal (36.9%) based on age-related range values. The presence of a borderline or abnormal expiratory/inspiratory ratio at baseline was significantly associated with the occurrence of stroke in the follow up period (hazard ratio 2.3, 1.17-4.70). Thus, diabetic autonomic neuropa‐ thy was a significant independent risk factor also for the occurrence of stroke [65].

bility and rate of decline of glomerular filtration rate [68]. One year later, Astrup et al. pub‐ lished the results of a study aimed at evaluating the prognostic significance of cardiovascular risk factors, including cardiac autonomic neuropathy and 24-hour blood pressure level and rhythm, for all-cause mortality in type 2 diabetic patients (n = 104) with and without diabetic nephropathy [69]. In a Cox regression analysis, predictors of all-cause mortality included cardiac autonomic neuropathy (1 beat/min increase 0.92, 0.87-0.98) to‐ gether with age, male sex, left ventricular hypertrophy, haemoglobin A1c, daytime systolic blood pressure, glomerular filtration rate (or albuminuria, alternatively) and dipping (1% in‐ crease in dipping was associated with a lower risk 0.97, 0.94-0.998). After adjusting for tradi‐ tional cardiovascular risk factors, non-dipping of night blood pressure remained a

Diabetic Autonomic Neuropathy and Circadian Misalignment in Type 1 Diabetes

http://dx.doi.org/10.5772/52033

377

Prolonged QT corrected (QTc > 440 ms) interval was an independent predictor of mortality over 9 years in the non-diabetic (n = 1560) and diabetic (n = 160) elderly general population of the Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study, whereas QT dispersion did not predict mortality in non-diabetic or diabetic subjects. On the contrary, reduced heart rate variability appeared to be a more specific marker only in the diabetic elderly general population [70]. Ko et al. investigated whether cardiac autonomic neuropathy was associated with acute ischaemic stroke in 1458 patients with type 2 diabetes during 7.1 year follow up [71]. At follow-up, 131 patients (11.6%) had developed newly di‐ agnosed acute ischaemic stroke. Baseline cardiac autonomic neuropathy score was signifi‐ cantly associated with the development of ischaemic stroke in patients with type 2 diabetes. Indeed, the hazard ratio for acute stroke events in patients with abnormal cardiac autonomic neuropathy scores was 2.7 compared with patients with normal scores [71]. In order to in‐ vestigate whether cardiac autonomic neuropathy could explain the relationship between mi‐ croalbuminuria and cardiovascular mortality, 490 individuals from a population-based cohort (Hoorn Study) were followed for a median period of 13.6 years [72]. At baseline, were evaluated glucose tolerance status, HbA1c, and albuminuria. Cardiovascular autonom‐ ic function tests included four tests that reflected heart rate or blood pressure changes due to deep breathing or standing up, five tests of spectral analyses of heart rate variability, and one baroreflex sensitivity measurement. Both microalbuminuria and cardiac autonomic neu‐ ropathy were independently associated with cardiovascular mortality. However, after ad‐ justment for age, sex, glucose tolerance status, and other cardiovascular risk factors, microalbuminuria (relative risk 1.33, 0.83–2.13), in contrast to cardiovascular autonomic dys‐ function total score (1.52, 1.11–2.09), was not independently associated with all-cause mor‐ tality. The excess of mortality attributable to microalbuminuria could not be explained by

Finally, May and Arildsen have evaluated long-term predictive power on all-cause mortality of five function tests for cardiac autonomic neuropathy as well as of heart rate variability based on 24-hour ECG recordings (both time domain analyses and frequency domain analy‐ ses were performed) in the same sample during a 15.5-year follow up period [73-75]. When considering the five function tests for cardiac autonomic neuropathy (heart rate variability during deep breathing, Valsalva manoeuvre, and lying to standing, postural systolic blood

significant predictor of all-cause mortality [69].

cardiac autonomic neuropathy [72].

In order to investigate the prognostic value of cardiac autonomic neuropathy in relation to myocardial perfusion defects, Lee et al. evaluated 146 consecutive patients with type 2 dia‐ betes mellitus who underwent thallium-201 single photon emission computed tomography (SPECT) for suspected coronary artery disease and who tested for autonomic nerve function within three months of the single photon emission computed tomography study [66]. Car‐ diac autonomic function tests included deep breathing, Valsalva manoeuvre, lying to stand‐ ing, postural systolic blood pressure change, and handgrip test; cardiac autonomic neuropathy was defined by the presence of ≥ 3 abnormal tests. Patients were followed up for 46±24 months to record deaths and major cardiac events. Significant predictors of death were perfusion defects, cardiac autonomic neuropathy, and older age; significant predictors of cardiac events were perfusion defects, cardiac autonomic neuropathy, hypertension, and longer history of diabetes [66].

Suarez et al. investigated the risk factors for sudden cardiac death in the prospective, popu‐ lation based, Rochester Diabetic Neuropathy Study (RDNS) cohort: 462 diabetic patients (of whom 115 with type 1 diabetes) were followed up over 15 years [67]. At baseline, patients underwent 1) neuropathy assessment by the neuropathy impairment score, neuropathy symptoms and change score, nerve conduction studies, and quantitative sensation; 2) auto‐ nomic neuropathy assessment by quantitative sudomotor axon reflex test, heart rate varia‐ bility to deep breathing and to the Valsalva manoeuvre, beat to beat blood pressure responses during tilt and the Valsalva manoeuvre; 3) assessment of other putative risk fac‐ tors, metabolic control, diabetic retinopathy and nephropathy; 4) recording of a 12-lead ECG every two years. The medical records, death certificates, and necropsy reports of all deaths were reviewed and 21 cases of sudden cardiac death were identified. In bivariate analysis of risk covariates, evolving and previous myocardial infarction, bundle branch block or pacing, and nephropathy stage were stronger risk covariates than were indicators of diabetic auto‐ nomic neuropathy and HDL cholesterol. In bivariate analysis and adjusting for nephrop‐ athy, diabetic autonomic neuropathy was not statistically significant factor [67].

In a prospective observational follow up study, Astrup et al. evaluated the predictive value of cardiac autonomic neuropathy for cardiovascular mortality and morbidity (primary end point), all cause mortality and progression of diabetic nephropathy (secondary end points) in 197 patients with type 1 diabetes and diabetic nephropathy and 191 patients with long standing diabetes and normoalbuminuria who were followed for 10.1 years [68]. After ad‐ justment for cardiovascular risk factors, autonomic dysfunction was a predictor of cardio‐ vascular mortality and morbidity in type 1 diabetic patients with diabetic nephropathy (hazard ratio 6.4, 1.5-26.3), whereas the impact of heart rate variability on all-cause mortality was not significant. Moreover, there was no correlation between abnormal heart rate varia‐ bility and rate of decline of glomerular filtration rate [68]. One year later, Astrup et al. pub‐ lished the results of a study aimed at evaluating the prognostic significance of cardiovascular risk factors, including cardiac autonomic neuropathy and 24-hour blood pressure level and rhythm, for all-cause mortality in type 2 diabetic patients (n = 104) with and without diabetic nephropathy [69]. In a Cox regression analysis, predictors of all-cause mortality included cardiac autonomic neuropathy (1 beat/min increase 0.92, 0.87-0.98) to‐ gether with age, male sex, left ventricular hypertrophy, haemoglobin A1c, daytime systolic blood pressure, glomerular filtration rate (or albuminuria, alternatively) and dipping (1% in‐ crease in dipping was associated with a lower risk 0.97, 0.94-0.998). After adjusting for tradi‐ tional cardiovascular risk factors, non-dipping of night blood pressure remained a significant predictor of all-cause mortality [69].

and automated electrocardiographic measure of heart rate response to deep breathing. Expir‐ atory/inspiratory (E:I) ratio was categorised as normal (53.6%), borderline (9.5%), or abnor‐ mal (36.9%) based on age-related range values. The presence of a borderline or abnormal expiratory/inspiratory ratio at baseline was significantly associated with the occurrence of stroke in the follow up period (hazard ratio 2.3, 1.17-4.70). Thus, diabetic autonomic neuropa‐

In order to investigate the prognostic value of cardiac autonomic neuropathy in relation to myocardial perfusion defects, Lee et al. evaluated 146 consecutive patients with type 2 dia‐ betes mellitus who underwent thallium-201 single photon emission computed tomography (SPECT) for suspected coronary artery disease and who tested for autonomic nerve function within three months of the single photon emission computed tomography study [66]. Car‐ diac autonomic function tests included deep breathing, Valsalva manoeuvre, lying to stand‐ ing, postural systolic blood pressure change, and handgrip test; cardiac autonomic neuropathy was defined by the presence of ≥ 3 abnormal tests. Patients were followed up for 46±24 months to record deaths and major cardiac events. Significant predictors of death were perfusion defects, cardiac autonomic neuropathy, and older age; significant predictors of cardiac events were perfusion defects, cardiac autonomic neuropathy, hypertension, and

Suarez et al. investigated the risk factors for sudden cardiac death in the prospective, popu‐ lation based, Rochester Diabetic Neuropathy Study (RDNS) cohort: 462 diabetic patients (of whom 115 with type 1 diabetes) were followed up over 15 years [67]. At baseline, patients underwent 1) neuropathy assessment by the neuropathy impairment score, neuropathy symptoms and change score, nerve conduction studies, and quantitative sensation; 2) auto‐ nomic neuropathy assessment by quantitative sudomotor axon reflex test, heart rate varia‐ bility to deep breathing and to the Valsalva manoeuvre, beat to beat blood pressure responses during tilt and the Valsalva manoeuvre; 3) assessment of other putative risk fac‐ tors, metabolic control, diabetic retinopathy and nephropathy; 4) recording of a 12-lead ECG every two years. The medical records, death certificates, and necropsy reports of all deaths were reviewed and 21 cases of sudden cardiac death were identified. In bivariate analysis of risk covariates, evolving and previous myocardial infarction, bundle branch block or pacing, and nephropathy stage were stronger risk covariates than were indicators of diabetic auto‐ nomic neuropathy and HDL cholesterol. In bivariate analysis and adjusting for nephrop‐

athy, diabetic autonomic neuropathy was not statistically significant factor [67].

In a prospective observational follow up study, Astrup et al. evaluated the predictive value of cardiac autonomic neuropathy for cardiovascular mortality and morbidity (primary end point), all cause mortality and progression of diabetic nephropathy (secondary end points) in 197 patients with type 1 diabetes and diabetic nephropathy and 191 patients with long standing diabetes and normoalbuminuria who were followed for 10.1 years [68]. After ad‐ justment for cardiovascular risk factors, autonomic dysfunction was a predictor of cardio‐ vascular mortality and morbidity in type 1 diabetic patients with diabetic nephropathy (hazard ratio 6.4, 1.5-26.3), whereas the impact of heart rate variability on all-cause mortality was not significant. Moreover, there was no correlation between abnormal heart rate varia‐

thy was a significant independent risk factor also for the occurrence of stroke [65].

longer history of diabetes [66].

376 Type 1 Diabetes

Prolonged QT corrected (QTc > 440 ms) interval was an independent predictor of mortality over 9 years in the non-diabetic (n = 1560) and diabetic (n = 160) elderly general population of the Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study, whereas QT dispersion did not predict mortality in non-diabetic or diabetic subjects. On the contrary, reduced heart rate variability appeared to be a more specific marker only in the diabetic elderly general population [70]. Ko et al. investigated whether cardiac autonomic neuropathy was associated with acute ischaemic stroke in 1458 patients with type 2 diabetes during 7.1 year follow up [71]. At follow-up, 131 patients (11.6%) had developed newly di‐ agnosed acute ischaemic stroke. Baseline cardiac autonomic neuropathy score was signifi‐ cantly associated with the development of ischaemic stroke in patients with type 2 diabetes. Indeed, the hazard ratio for acute stroke events in patients with abnormal cardiac autonomic neuropathy scores was 2.7 compared with patients with normal scores [71]. In order to in‐ vestigate whether cardiac autonomic neuropathy could explain the relationship between mi‐ croalbuminuria and cardiovascular mortality, 490 individuals from a population-based cohort (Hoorn Study) were followed for a median period of 13.6 years [72]. At baseline, were evaluated glucose tolerance status, HbA1c, and albuminuria. Cardiovascular autonom‐ ic function tests included four tests that reflected heart rate or blood pressure changes due to deep breathing or standing up, five tests of spectral analyses of heart rate variability, and one baroreflex sensitivity measurement. Both microalbuminuria and cardiac autonomic neu‐ ropathy were independently associated with cardiovascular mortality. However, after ad‐ justment for age, sex, glucose tolerance status, and other cardiovascular risk factors, microalbuminuria (relative risk 1.33, 0.83–2.13), in contrast to cardiovascular autonomic dys‐ function total score (1.52, 1.11–2.09), was not independently associated with all-cause mor‐ tality. The excess of mortality attributable to microalbuminuria could not be explained by cardiac autonomic neuropathy [72].

Finally, May and Arildsen have evaluated long-term predictive power on all-cause mortality of five function tests for cardiac autonomic neuropathy as well as of heart rate variability based on 24-hour ECG recordings (both time domain analyses and frequency domain analy‐ ses were performed) in the same sample during a 15.5-year follow up period [73-75]. When considering the five function tests for cardiac autonomic neuropathy (heart rate variability during deep breathing, Valsalva manoeuvre, and lying to standing, postural systolic blood pressure change, diastolic blood pressure response to handgrip test) it was apparent that the relative risk of all-cause mortality associated with cardiac autonomic neuropathy was 2.85, 1.75-4.65; Valsalva ratio, heart rate response to standing up (30;15 ratio), and handgrip had an independent predictive value with regard to long-term all cause mortality [73]. When consid‐ ering separately time and frequency domain parameters of heart rate variability calculated on the basis of a 24-hour ECG recording, the power in the low frequency band was the only heart rate variability parameter with an independent predictive value on all-cause mortality [74]. When considering long-term predictive power of heart rate variability together with a battery of five autonomic function tests, the latter ones were superior to the former ones; particularly, Valsalva, 30:15 ratio, and handgrip were independent predictors of death [75].

**6.** Identifying in advance the various cardiovascular prognostic factors (how many and which ones?) to reasonably adjust for in the analysis. Risk adjustment is essential to making fair comparisons and first requires strict definition of each specific outcome, particularly in diabetic people provided the complex association of traditional, non-tra‐

Diabetic Autonomic Neuropathy and Circadian Misalignment in Type 1 Diabetes

http://dx.doi.org/10.5772/52033

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ditional and disease-specific risk factors with mortality/morbidity.

and Ottavio Giampietro\*

Department of Clinical and Experimental Medicine, Italy

*nal of Cardiology*, 57(3), 249-256.

*tion*, 80(2), 267-275.

24(4), 956-962.

\*Address all correspondence to: elena.matteucci@med.unipi.it

**Author details**

Elena Matteucci\*

**References**

press.
