Factors involved in cardiac autonomic neuropathy in diabetic patients

ELSFVIER

Factors Involved in Cardiac Autonomic Neuropathy in Diabetic Patients P. Valensi J.-P. Huard C. Giroux J.-R. Attali

ABSTRACT The role cardiac autonomic neuropathy (CAN) plays in diabetes is not well known. The aim of this study was to identify the factors involved in CAN in diabetic patients. One hundred patients, 44 insulindependent (IDDM) and 56 non-insulin-dependent (NIDDM), were investigated, using five standard tests. Three of these tests were for parasympathetic control (cardiac response to the lying-to-standing, deep breathing, and Valsalva tests), and the other two measured sympathetic control (testing for orthostatic hypotension and evaluating heart and blood pressure response to the handgrip test). Results were compared to those found in a series of 40 healthy volunteers. An age-adjusted comparison with the controls, showed that 34 patients had one abnormal parasympathetic test, 23 had two, and 6 patients had three. Cardiac parasympathetic neuropathy was thus present in 63% of the patients. The handgrip test was completed by 84 diabetic patients. There was evidence of orthostatic hypotension and/or an abnormal cardiac response to the handgrip in 15 of these patients, who all had a parasympathetic abnormality as well. There was no significant association between the type of diabetes and the presence of CAN. The duration of diabetes was significantly longer in patients with CAN (9.3 rt

0.9 years) (p < 0.01) than in those with all three parasympathetic tests normal (5.8 t 0.9 years) (p < 0.01). The HbA,, level was also higher in patients with CAN than in those with three normal parasympathetic tests (9.95 2 0.35% versus 8.17 t 0.42%, p < 0.005). There was a significant association between the presence of retinopathy, observed by angiofluorography, and the presence of peripheral neuropathy confirmed by the electrophysiological investigation and the presence of CAN (p < 0.001). However, more than half the patients without retinopathy or nephropathy had CAN, and 11 of the 31 patients with a normal electrophysiological investigation also had CAN. Eighteen patients (6 IDDM) without retinopathy and nephropathy, who had been diabetic for less than 2 years, also had CAN. This study shows that CAN occurs early and is frequently found in a population of unselected diabetic patients. Metabolic factors may play an important role in its occurrence. CAN is significantly associated with the presence of retinopathy, which suggests that an impairment of autonomic peripheral blood flow control might be a contributing factor in the formation of microvascular lesions. (Journal of Diabetes and Its Complications 11;3:180-187, 1997.) 0 Elsevier Science Inc., 1997

INTRODUCTION Department of Endocrinology-Diabetology-Nutrition, Jean Verdier Hospital, Paris-Nord University, Bond, France Reprint requests to be sent to: Prof. P. Valensi, Service d’Endocrinologie-Diabetologie-Nutrition, Hopital Jean Verdier, avenue du 14 Juillet, 93143 Bond, Cedex, France. Journal of Diabetes and Ifs Complications 11:180-l 87 0 Elsevier Science Inc., 1997 655 Avenue of the Americas, New York, NY 10010

E

vidence of subclinical impairments of cardiac autonomic control can be easily found by carrying out standard bedside tests. Reproductibility of these tests is excellent, as intrasubject

1056-8727/97/$17.00 PII SlO56-8727(97)00005-O

] Diub Camp 1997; 21:280-287

CARDIAC

variation coefficients are not above ll%.‘,’ These tests have shown that cardiac autonomic neuropathy (CAN) is frequently found in diabetic subjects, ranging from 20% to 70%.‘~~-~ It is important to identify this complication of diabetes because of its prognostic value, as three studies have shown that impairments revealed by the tests are a prelude to high mortality rates due to cardiovascular disease and to other complications as well, such as kidney failure or infectious complications.M The role played by CAN in the course of diabetes is not altogether clear. It usually occurs several years after the onset of the disease, but it has been detected in many cases as early as the first 2 years after diagnosis.“,‘” The results for these tests, repeated 6 years3 or 10 years’ later, have shown no change regardless of the duration of diabetes. The association of CAN with the other chronic complications is still a controversial point. It has been suggested that CAN is not frequently associated with retinopathy or nephropathy.” In a previous study we found that this complication can precede patient nephropathy and retinopathy diagnosed by eye fundus.12 In this study, we attempted to determine in a larger group of diabetics the influence that age, duration of diabetes and degree of glycemic control have over autonomic cardiac control, and the relationship between CAN and microangiopathic complications detected by means of more sophisticated techniques and peripheral neuropathy confirmed by electrophysiological assessment. METHODS Patients. One hundred diabetic patients (63 men and 37 women), 44 insulin-dependent (type I, IDDM) and 56 non-insulin-dependent (type II, NIDDM), were studied. The mean age t SEM was 44.3 -t 1.3 years (range, 17-65 years). The diabetes had been known for 7.9 t- 0.7 years (range, 6 months-30 years). The HbA’, level, 9.29 -C 0.26%, determined by microcolumn chromatography (N < 5.8%), showed that glycemic control was poor. Six of the patients had clinical signs of autonomic neuropathy: gastroparesis, nocturnal diarrhea, or neurogenic bladder. The 100 patients were selected, after excluding patients with a pathologic condition likely to disturb the cardiac autonomic function tests (coronary heart disease, heart failure, respiratory disease, anemia, fever, or high blood pressure) as well as patients taking vasodilators, antihypertensives, neuroleptics, or antidepressants, and patients having other cause of neuropathy (uremia, chronic alcoholism, hypothyroidism, or neoplasia). The tests were conducted at a time when no ketosis or hypoglycemia was apparent, and at least 2 h after coffee or tobacco consumption, and after 1 h of rest.13 The results were compared with a group of 40 healthy volunteers (controls), aged

AUTONOMIC

NEUROPATHY

IN DIABETIC

PATIENTS

38.0 _t 1.7 years. A standard electrocardiogram with 12 leads was normal in both the patients controls.

181

(ECG) and the

Procedure. The standard tests for CAN were carried out as previously described.‘,j Briefly, three tests, mainly depending on cardiac parasympathetic control (Valsalva, deep breathing, and lying-to-standing tests), were performed with the microcomputer-based system AUTOCAFT (AUTOmated Cardiovascular Autonomic Function Test) used on a BBC Master system (Acorn Computers Ltd, Cambridge, UK).ll The Valsalva test, conducted with the patient seated, consisted in forced exhalation and maintaining a pressure of 40 mm Hg for 15 sec. The result was expressed as the ratio RR maximum/RR minimum. It was done three times consecutively, and the mean value for the Valsalva ratio (VR) was taken. The deep breathing test was performed in a previously trained subject and consisted in taking six deep breaths in 1 min in a lying position. The result was expressed as the mean value for the difference between maximal and minimal heart rate (AHR&. During the lying-to-standing test heart rate variation was determined by calculating the difference between maximal rate (about the 15th beat) and minimal rate (about the 30th beat) (AHR30-‘i). The two tests for cardiovascular sympathetic control consisted in detecting orthostatic hypotension and measuring heart and blood pressure response to an isometric muscular contraction of the hand (handgrip) maintained at one-third of the maximal contraction for 5 min. Blood pressure was measured every minute with a mercury sphygmomanometer, and heart rate was recorded on an ECG. Both tests were given to 16 of the 40 controls. Evaluation of the other complications of diabetes consisted of an ophthalmoscopic examination and a retinal angiofluorography. The angiography showed evidence of retinopathy in 20 patients and was normal in the other 80. The 24 h urinary albumin excretion rate (UAER) was measured by laser immunonephelemetry, with an albumin detection threshold of 1.5 mg/L’” and revealed incipient nephropathy (UAER > 30 mg/24 h) in 23 patients. A peripheral neurophysiological test was carried out in 90 of the 100 diabetic patients. It consisted in examining two peripheral nerves on the dominant side, the peroneal nerve and the sural nerve with assessment of nerve-conduction velocity (NCV) and action potential amplitude, and also the Hoffman reflex with assessment of Hmax/Mmax on both sides. Peripheral neuropathy was confirmed if the NCV of one or both of the nerves was below 40 m/set or if the action potential amplitude of one or both of the nerves was below 3 and 10 pV, respectively, or if Hmax/Mmax was lower than 0.30 according to

TABLE 1. PARASYMPATHETIC TESTS IN DIABETIC PATIENTS (RESULTS ACCORDING TO AGE) <30

Age (years) VI< AHR[,” (b/min) AHRWe15 (b/min)

AND CONTROLS ... 50

30-50

Controls

Diabetics

Controls

Diabetics

Controls

Diabetics

(n = 13)

(n = 18)

(n = 17)

(n = 42)

G = 7)

(n = 40)

1.46 -e 0.04 32.0 -c 2.3” 20.7 2 1.4”

1.57 % 0.09 18.4 2 2.1’” 13.8 2 2.5’”

1.59 +- 0.06 20.7 -t 1.2* 18.4 -c 1x+*

1.60 -e 0.05 16.9 -e 1.3# 14.6 2 2.0

1.51 I 0.09 14.1 2 0.7 Y.8 z I .o

1.56 I!I 0.05 11.2 2 1.1) 7.3 2 1.o

VR. Vulsalua

ratio; AHRIjfi,

Cmrifxwisons

vs. i5O

Cornpnrison~

vs. >50 ,y<‘ar diabetic

ymr

deep brenthinx awtrols:

test; AHR,,

p < 0.005, patients:

“p

!?, lying-to-starrding

test.

< 0.001.

‘p i 0.005,

“r i

0.001

‘p c: 0.05; t p < O.UUl w. <30 yeur cof~tmls.

Bouche’s criteria.16 Such was the case in 59 of 90 patients (65.5%). The results were expressed as the means -+ SEM. The statistical analysis consisted of comparison of the means by the unpaired Student’s test, the x2 test, a study of the correlations according to a linear regression model, and multivariate analyses according to the stepwise regression analysis. RESULTS Tests for Parasympathic

Control. lnj7uence of age. The controls gave results that were comparable to those found in our previous study.’ We found a negative correlation between age and AHDIx, (r = -0.773, y < O.OOl), a non significant correlation between age and AHRN-15 (r = -0.282, p = 0.06) and an absence of correlation between age and VR (r = 0.130, p > 0.05). Different age groups (before 30 years, between 30 and 50, and over 50) gave a very similar mean VR value. AHRDs and AHRm- 15were significantly lower after 50 years than before 30 and between 30 and 50 (Table 1). On the basis of these results we considered a VR value below 1.10 (regardless of age) to be abnormal, for the deep breathing test, a AHRnu value below 19 beats/mm between 17 and 30 years, 12 beats between 30 and 50, and 10 beats after 50 to be abnormal, and a HRlo I.i value below 15 beats/min before 30 years, 11 beats between 30 and 50, and 7 beats after 50 years to be abnormal for the lying-tostanding test. These thresholds corresponded to the lowest values obtained in the respective age group of control subjects. A correlation was found in the diabetic patients, between AHRDB and AHR1(l-,j (r = 0.416, p < 0.001) and VR (r = 0.350, p < O.OOl), and also between AHRX+iF, and VR (I = 0.254, p = 0.01). A significant negative correlation was found between age and AHRI,r, (r = -0.371, ~7 < 0.001) and AHRN, ,; (r = -0.306, p < 0.01) but not between age and VR (r =

-0.02). Like the controls, the diabetic subjects had significantly lower AHRDB and AHRwm15 after the age of 50 than they did before 30 or between 30 and 50 years. (Table 1).

According to age group, AHRDB and AHRX)-,5 were significantly lower in the diabetic patients under 30 years of age than in the controls under 30 (Table 1). With age taken into account, the lying-to-standing test was abnormal in 52 of the 100 diabetic patients, the deep breathing test was abnormal in 40 cases, and the Valsalva test in 6 cases. Thirty-four patients had an early impairment of parasympathetic control defined by one of these three tests being abnormal: 23 had an abnormal lying-to-standing test and 11 had an abnormal deep breathing test. Twenty-three patients had a definite impairment of parasympathetic control defined by both the deep breathing and lying-to-standing tests abnormal, and 6 had a severe impairment defined by an abnormal Valsalva test as well. Thus cardiac autonomic neuropathy, present as an impairment in at least one of the three tests for parasympathetic control, affected 63 patients (63%).

Frequency of cardiac parasympathetic neuropathy.

influence of gender and smoking. The mean values for the tests mainly based on parasympathetic control did not significantly differ in men and women, or in the 36 smokers (>5 cigarettes/day) as compared with the nonsmokers. Likewise, the number of patients with CAN was not influenced by the gender (63.5% for men and 62.0% for women) or smoking (66.7% and 60.9%, respectively, for the smokers and nonsmokers). Influence of type, duration of diabetes,and metabolic control. A comparison of the 63 patients with CAN with

the 37 patients with the three parasympathetic tests normal showed no significant difference to the type of diabetes (Table 2). The known duration of diabetes was significantly higher in patients with CAN (Table 2) or in those with an abnormal lying-to-standing test

] Diab Camp

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2997; 11:180-187

TABLE

2. COMPARISON

AUTONOMIC

OF PATIENTS WITH AND WITHOUT CARDIAC AUTONOMIC NEUROPATHY (CAN) CAN

Diabetestype (I/II) Duration of diabetes(years) HbA1, (%) Microangiopathy (yes/no) Retinopathy (yes/no) Nephropathy (yes/no) Peripheral neuropathy (yes/no) u According

to electrophysidogical

NEIJROPATHY

investigation

No CAN

(n = 63)

(?I = 37)

28/35 9.3 ? 0.9 9.95 + 0.35 32/31 (50.8%) 20/43 (31.7%) 17/46 (27.0%) 46/11 (78.0%)

E/22 5.8 t 0.9 8.17 -c 0.42 6/31 (16.2%) o/37 (0%) 6/31 (16.2%) 13/20 (35.5%)

which was performed

(data not shown). There was a significant negative correlation between the duration of diabetes and AHR30-15 (Y = -0.255, p < 0.05) but not with AHRDB (r = 0.160) or VR (r = -0.03). The number of patients with CAN who had diabetes diagnosed for more than 12 years (19/25 = 76%) was significantly higher than that of patients whose diabetes was diagnosed for less than a year (6/15 = 40%) (x’ = 5.2, ~7< 0.05). The HbA1, levels were significantly higher in patients with CAN than in patients with all three parasympathetic tests normal (Table 2) and also higher in patients with an abnormal lying-to-standing test than in those with a normal one (data not shown). The number of patients with CAN was greater among those with HbA1, greater than 9.3% (37/46 = 80.4%) than with HbA1, of 9.3% or less (26/54 = 48.1%) (x2 = 11.11, p < 0.01). AHR30--15correlated negatively with HbA1, (r = -0.248, p < 0.05), whereas the HbA1, level did not significantly correlate with AHRDB or VR. There was no significant correlation between fasting and postprandial blood sugar, plasma cholesterol, and triglycerides, and the results of the three tests for parasympathetic control. The multivariate analysis, carried out with AHRzoe15as dependent variable and age, duration of diabetes and I&AI, as independent variables, showed that AHR,,P15 was independently correlated to these three factors (r = 0.463, p < 0.001). The combined influence of duration of diabetes and the HbA1, level appears on Table 3, showing that the number of patients with CAN was 2.5-times higher among the patients with known diabetes for less than 8 years and HbA1, of 9.3% or less than among those with a diabetes duration of more than 8 years and HbA,, greater than 9.3% (Table 3). lnj7uence of the associatedcomplications. Retinopathy detected by angiofluorography was significantly present more often in patients with CAN than in patients without it (p < 0.001) (Table 2). Of the 20 patients with retinopathy, 19 had an abnormal lying-to-standing test and12 an abnormal deep-breathing test. The number of abnormal deep breathing or lying-to-standing tests

IN DIABETIC

183

PATIENTS

PARASYMPATHETIC Statistical Test

Significance

x2 = 0.14 t = 2.52 t = 3.18 x2 = 11.83 x2 = 14.60 x2 = 1.5 x2 = 15.6

NS co.01 CO.005 CO.001 co.001

NS
in 90 patients.

was also significantly higher in the patients with retinopathy than in those without it (x2 = 4.15, p < 0.05 and x2 = 18.4, p < 0.001) and the results of the three autonomic tests were significantly lower in the patients with retinopathy (Table 4). CAN was present in all of the 20 patients with retinopathy, but it should be noted that 43 of the 80 patients who had a normal angiofluorography had CAN (Table 2). The frequency of CAN was however not significantly different between patients with nephropathy (UAER > 30 mg/24 h) and those with a normal UAER. It should be noted that 46 of the 77 patients with a normal UAER had CAN (Table 2). No significant correlation was found between the UAER and the results of the tests for parasympathetic control. Eighteen patients (6 IDDMs) with normal angiofluorography and UAER, diabetic for less than 2 years, had CAN. The frequency of CAN, or of only an abnormal lyingto-standing test, was significantly higher in patients with peripheral neuropathy, detected by an electrophysiologic assessment(Table 2). It should be noted, however, that the three tests for parasympathetic control were normal in 13 of the 59 patients (22.0%) with peripheral neuropathy, detected by an electrophysiologic investigation and conversely, 11 of the 31 patients (35.5%) with a normal electrophysiologic investigation had CAN (Table 2). AHR30-15and AHRDBwere signifi-

TABLE 3. INFLUENCE OF GLYCATED HEMOGLOBIN AND DURATION OF DIABETES ON THE FREQUENCY OF CARDIAC PARASYMPATHETIC AUTONOMIC NEUROPATHY (CAN)

Hb&c (%)

G9.3 >9.3

Duration of Diabetes (years)

~8 >8 ~8 >8

Number

29 25 26 20

CAN n (%)

11 (38) 15 (60) 18 (69) 19 (95)

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VALENSI

ET AL.

TABLE

4. RESULTS

OF THE CARDIAC WITHOUT -~ With Retinopathy (n = 20)

Tests

AHRu)-,i

AUTONOMIC TESTS IN PATIENTS RETINOPATHY .Without Retinopathy (n = 80)

3.2 1 2.5 10.2 5 1.5 1.35 2 0.10 16.9 -c 1.5

AHR,x

VR Handgrip VR, Valsalva

ratio; AHRDB, deep breathing

Seventeen patients in the first group increase in heart rate at the 5th minute.

13.8 16.2 1.61 20.3

test; AHR,,-,,,

were able to complete

lying-to-standing the handgrip

cantly lower in the patients with peripheral neuropathy (Table 5).

5. RESULTS

AHL

1s

1.2 0.9 0.04 1.0


test, and 67 in the second group;

OF THE CARDIAC AUTONOMIC TESTS WITHOUT PERIPHERAL NEUROPATHY

IN PATIENTS

VR Handgrip

1.54 t 0.04 18.8 2 1.0

1.65 C 0.06 21.3 2 1.6

ratio; AHRDB, deep breathing

test; AHR30-15,

was assessed by electrophysiological

Fifty patients in the first group in heart rate at the 5th minute.

were able to complete

WITH

as percent

of

OR

Without Peripheral Neuropathy (n = 31) 16.7 17.8

neuropathy

are expressed

There was a significant correlation between the heart rate acceleration percentage at the 5th minute and AHRDB (Y = 0.30, ~7< 0.01) and AHR30-15(Y = 0.239, p < 0.05). The heart rate acceleration percentage at the 5th minute of the handgrip test was not significantly different with regard to the absence or presence of retinopathy or nephropathy.

8.9 t- 1.2 13.8 2 1.1

VR, Valsalva

results

Table 6.

AH&m

Peripheral

p Value

test.

With Peripheral Neuropathy (n = 59)

Tests

OR

(n = 9; 12.6% 2 1.4) than in the diabetic patients without cardiac parasympathetic neuropathy (n = 34; 21.9% Ir 1.3, p < 0.005) and the control (n = 16; 22.1% t 1.7, p < 0.001). Of the patients with orthostatic hypotension, five had a lower heart rate acceleration percentage at the 5th minute of the handgrip test than the lowest value for the controls (~12%). Nine diabetic patients in all had an insufficient acceleration percentage (~12% at the 5th minute). They also had cardiac parasympathetic neuropathy and peripheral neuropathy detected by an electrophysiologic assessment.Of the 84 diabetic patients able to complete the handgrip test, 15 had orthostatic hypotension and/or an abnormal handgrip test; they also had parasympathetic neuropathy consisting of two or three abnormal parasympathetic tests. The final results of the five tests investigating parasympathetic and sympathetic controls are shown in

Tests for Sympathetic Control. Eleven diabetic patients had orthostatic hypotension as defined by at least a 20 mm Hg drop in systolic arterial pressure after standing for 1 min. The handgrip test, performed by 16 controls and the diabetic patients always brought about a rise in arterial pressure of at least 20 mm Hg systolic and 10 mm Hg diastolic. Eighty-four diabetic patients were able to perform the test up to the 5th minute. Nine of the 16 patients releasing their grip before the 5th minute were over 60 years old. No relation was found between the percentage of heart rate acceleration during the handgrip test and the controls’ and diabetic patients’ age. In the diabetic patients, the percentage of heart rate acceleration did not differ significantly between men and women, smokers and nonsmokers, and the types of diabetes. It did not correlate significantly with the duration of diabetes, fasting and postprandial blood sugar, and HbA,,. Heart rate acceleration was lower in the diabetic patients with at least one abnormal parasympathetic test and particularly in the 11 diabetic patients with orthostatic hypotension (Figure 1). The heart rate acceleration at the 5th minute was significantly lower in the diabetic patients with orthostatic hypotension

TABLE

+ t i2

WITH

lying-to-standing

p Value

5 2.4 2 1.4

CO.005 CO.05

NS NS

test.

investigation. the handgrip

test and 27 in the second group;

results are expressed

as percent

of increase

1 Diab Camp 2997; 17:180-287

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AUTONOMIC

NEUROPATHY

IN DIABETIC

PATIENTS

185

into four separate categories: normal, early, definite, and severe CAN. The authors thus found 55% prevalence of CAN.’ The lying-to-standing and deep breathing tests were also more frequently abnormal than the Valsalva test, like in the present study. In addition, assessment of the blood pressure response to the handgrip test and to standing up has suggested that cardiac sympathetic impairment seems to occur after parasympathetic impairment. However, we found that assessmentof the cardiac response to the handgrip appeared to be much more sensitive than the assessmentof the blood pressure response. In the patients able to complete the test, a heart rate acceleration at the fifth minute of less than 12% should be considered to be a criterion for sympathetic impairment. Our findings, which show evidence of lower acceleration of the heart rate during the handgrip test in cases of parasympathetic impairment and even lower acceleration in cases of orthostatic hypotension since the 2nd to the 5th minutes of the test, suggest that the impairment is similar in cardiovascular parasympathetic and sympathetic control inasfar as the acceleration after the first minute results from sympathetic activation.‘s Spectral analysis of the heart rate variability at rest suggests the same phenomenon.‘9 We found a significant negative correlation in the diabetic patients, as in the healthy subjects,“,?“&?? between the deep breathing and lying-to-standing test FIGURE 1 Heart rate response to the handgrip test. A-A Conresults and age. This shows the importance of interpretrols, A-A diabetic patients with normal cardiac parasympathetic ting the test results according to age. tests; 0-U diabetic patients with cardiac parasympathetic neuropaThe patients with at least one of the three tests for thy; and n -m diabetic patients with postural hypotension. Comparparasympathetic control abnormal, particularly the lyison with controls: *p < 0.05, **p ~0.02, ***p < 0.005,“““p < ing-to-standing test, had known diabetes for a longer 0.001. period of time than the patients with normal results for the three tests. A negative correlation between these tests and duration of diabetes has been reported by DISCUSSION some authors,“,23 but not by others.‘O However CAN The results of this study confirm our previous finding can occur very early in diabetes. Indeed, 18 of our on the frequency of subclinical CAN (5), evidence of patients (6 IDDM) had no signs of microangiopathic which was detected by means of standardized tests.17 complications and a known diabetes duration of less They can also be compared with the study by Ewing than 2 years. These results can be compared with two et al.’ on more than 500 patients, where the results previous studies, which reported that, after treatment were not analyzed according to age, but were divided of the initial ketosis24and in both IDDM and NIDDM with diabetes known for less than 2 years,*j there is often evidence of an abnormality in the spontaneous variation in heart rate. TABLE 6. RESULTS OF THE FIVE TESTS FOR CARDIOVASCULAR PARASYMPATHETIC AND With regard to a possible relationship between test SYMPATHETIC CONTROLS IN THE 100 results for parasympathetic control and metabolic conDIABETIC PATIENTS trol, in this study the I-IbAi, level was found to be significantly higher in the patients with one abnormal Deep breathing, lying-to-standing, Valsalva normal 37 test, particularly the lying-to-standing test. In the first Deep breathing or lying-to-standing abnormal 34 Both deep breathing and lying-to-standing Diabetes Control and Complications Trial (DCCT) abnormal phase there was a correlation between RR variations All three tests abnormal and the Valsalva test results and the HbA1, levels.*” ‘IFifteen of thesepatients had postural hypotension and/or reduced heart This supports the metabolic hypothesis for autonomic rate acceleration during the handgrip test. neuropathy, which suggests metabolic modifications

186

VALENSI

ET AL.

of the nerve fibers following chronic hyperglycemia, involving a metabolic cascade following an increase in aldose-reductase activity. 27,28 The improvement in the heart rate variability, after the metabolic improvement of the recently diagnosed diabetes again pleads in favor of the metabolic hypothesis.24 There are few studies on the association of CAN with the other chronic complications of diabetes.“rz6 A high frequency CAN has been reported in patients with proliferative retinopathy or clinical nephropathy.26 A strong association between proliferative retinopathy and CAN, considered to be present if one cardiac autonomic function test was abnormal, like in our study, has also been reported in juvenile-onset IDDM patients.2y We have found here a significant association between the presence of retinopathy detected by angiofluorography and the presence of CAN. But more than one-half the patients without retinopathy or with normal urinary albumin excretion had CAN, which supports the hypothesis than CAN usually precedes microangiopathic complications. An assessment of the factors associated with the peripheral neuropathy found on clinical examination and by electrophysiologic assessment also revealed a significant independent association between peripheral neuropathy and the clinical signs of microangiopathy,30 which suggests that vascular factors may play a role in the development of the peripheral nerve lesions. Detection of CAN in more than one-half the patients without retinopathy and the more severe impairment observed with the cardiac parasympathetic tests in patients with retinopathy suggest that impairment of cardiovascular autonomic functions occurs early and could contribute to the onset of microangiopathy. Recently, an impairment of vagal function has also been found associated with diabetic nephropathy.3’ While the association of CAN with microangiopathic complications may indicate the same underlying pathological process without cause and effect relationship, these data suggest that CAN may induce changes in regulation of microcirculatory blood flow. The reduction in peripheral sympathetic vasoconstrictive tonus can increase microcirculatory flow, inducing or aggravating capillary permeability impairment,“3 thus facilitating glycosylated protein deposits in particular, on the basal membrane and capillary lesions. Although a significant association was observed in this study between the presence of CAN and electrophysiologic evidence of peripheral neuropathy, as other authors have found4rX it is not surprising that these two complications are not concomitant in a given patient as small nerve fibers are involved in cardiovascular autonomic control, whereas fibers assessedby electrophysiology are on the contrary large myelinated fibers. The diagnosis of peripheral neuropathy was here

] Did

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1997; 11:1813-187

based on a reduction in the conduction velocity and/ or the action potential amplitude of a peripheral nerve during a test on two nerves and/or on an abnormal Hoffmann reflex. Another study, on the preinclusion phase of diabetic patients likely to have an aldosereductase inhibitor treatment for peripheral neuropathy confirmed by a reduction in the conduction velocity of the peroneal nerve, showed that all these patients had at least one abnormal cardiac autonomic parasympathetic test, after taking age into account.2 But the nerve-conduction velocities are reduced later than the action potential amplitudes and the abnormality of the Hoffmann reflex.35,3hIn the present work, the fact that only 46 of the 59 patients with peripheral neuropathy detected by electrophysiologic assessment had CAN may probably be explained by a less serious peripheral nerve impairment, which was only confirmed in some casesby an axonal lesion (revealed by a reduction in the action potentials) or an abnormal Hoffmann’s reflex. In conclusion, CAN is a frequently early complication of diabetes. It probably occurs most often before the signs of microangiopathy. Metabolic factors could play a more important role than microcirculatory factors. The impairment of the autonomic control of peripheral microcirculatory flow might be a contributive factor in the formation of microvascular lesions. CAN could therefore be a prognostic marker in the course of diabetes, predicting the presence of peripheral neuropathy and the other microangiopathic complications. ACKNOWLEDGMENTS The authors are grateful to Mrs. Marion Sutton-Attali for help in revising the Englishmanuscriptand Mrs. Anne-Marie Del Negro for secretarialassistance. REFERENCES 1.

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