Assessment of methods to estimate impairment of

Assessment of methods to estimate impairment of vagal and sympathetic innervation of the heart in diabetic autonomic neuropathy W. WTF:UNG, C. BORST***. J.J. VAN LIESHOUT, R.L.H. SPRANGERS, J.M. KAREMAKER**, J.F.M. VAN BREDERODE, G.A.

VAN MONTFRANS*

and

A.J. DUNNING*

Summary We examined the parasympathetic and sympathetic innervation of the heart in 36 type I diabetic patients by studying heart rate (HR) changes induced by standing, 70° head-up tilt, handgrip and the Valsalva manoeuvre. The HR changes during forced breathing were used to classify patients according to the degree of cardiac vagal neuropathy. A sequential pattern in cardiac denervation was identified, ranging from mild vagal damage to both parasympathetic and sympathetic impairment. Standing, handgrip and the Valsalva manoeuvre are superior to head-up tilt in testing vagal HR control. The HR responses induced by standing and the Valsalva manoeuvre are primarily but not exclusively vagally mediated and depend on intact adrenergically mediated vasoconstriction. Of these four tests, handgrip is best suited to assess instantaneous cardiac vagal inhibition. However, both rapid vagal inhibition and stimulation can only be tested by respiratory sinus arrhythmia during forced breathing, as has been shown previously. Measurement of HR responses evoked by forced breathing and standing up is the best strategy to assess incidence and severity of parasympathetic and sympathetic disorders in HR control in clinical practice. Neth J Med I985;28:383.

Introduction

Cardiovascular autonomic neuropathy in patients with diabetes mellitus has been documented in a large number of studies. A variety of disturbances in circulatory control have been described 1-9 • Previously, we studied cardiovascular parasympathetic control by measuring heart rate (HR) variations during forced breathing, and sympathetic function by monitoring changes in blood pressure and catecholamines in response to standing 8 • Impaired sympathetic cardiovascular control was found only in patients with severely diminished or even absent parasympathetic HR control 8 • We now report on HR responses induced by standing, 70° head-up tilt, handgrip and the Valsalva manoeuvre. The aim of

the study was to establish the usefulness of these four tests for estimating impairment of vagal and sympathetic innervation of the heart. The HR changes during forced breathing were used to classify the patients according to the degree of cardiac vagal neuropathy.

Methods Subjects Thirty-six insulin-dependent diabetic patients participated in the study after giving informed consent. They were divided into three groups according to the HR variation during forced breathing, expressed as inspiration-expiration (1-E) difference 10-11 • Group I (n=9): patients with severe impairment of vagal HR control documented by an 1-E difference of < 5 beats/min 8 • Clinical data are listed in table I. Six patients were almost blind. Four out of 9 patients were in the haemodialysis or peritoneal dialysis programme. Of the remaining five, four had proteinuria (Albustix at least 1 + on several occasions). Symptomatic autonomic neuropathy was found in 6 patients. Symptomatic autonomic neuropathy was indicated by at least one of the following symptoms or signs: delayed gastric emptying, bladder atony, symptomatic postural hypotension, abnormal sweating, or unawareness of hypoglycaemic episodes 4 ·5 • Group 2 (n=w): patients with an 1-E difference of ~ 5 beats/min, but less than the lower 2.5 percentile in healthy subjects taking age into account 10 • Group 3 (n=17): patients with an 1-E difference~ 2.5 percentile in healthy subjects. They had no long-term diabetic complications. Two patients in group I were treated with diuretics. No other drugs influencing the cardiovascular system were used. Group I patients were older and had a longer history of diabetes than those in group 3. Group 2 patients were in between groups I and 3 as to age, duration of diabetes and long-term complications (table I).

Departments of Internal Medicine, *Cardiology and **Physiology, Academic Medical Centre, Meibergdreef 9, I 105 AZ Amsterdam; ***Department of Cardiology, University Hospital, Utrecht. Neth J Med 28 (1985)

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cardiac denervation in diabetes TABLE J: CLINICAL DATA ON DIABETIC SUBJECTS

Group (n

I-E difference (beats/min) Age (years) Sex Percentage of ideal body weight Duration of diabetes (years) Glucose at the start of the study (mmol/1) Glycosylated haemoglobin ( % ) Retinopathy Proteinuria Symptomatic autonomic neuropathy

2

I

= 9) ±

I

Group 2 (n = IO)

8±

I

Group 3 = 17)

(n

27 ± 3

p

versus 2,3 p versus 3 p 1 versus 3 p 2 versus 3 p 1

2

43 ± 5

40 ± 3

29 ± 3

3M 6F 97 ± 6 22 ± 3 13 ± 2

5M 5F ro5 ± 4 14 ± 3 II ± 2

SM 9F 97 ± 3 8± I II ± 2

I2 ± I

9/9 4/5 6/9

I2

±

I

II±

< 0.001 < 0.001 < 0.02

< 0.005 NS

I

versus 3

p < 0.001 NS NS

I

5/rn

Results are expressed as mean ± SEM 10 I-E difference = heart rate variation during forced breathing, expressed as inspiration-expiration difference

Measurements Subjects were examined in the morning at least 2 hours after their normal insulin dose and breakfast. All subjects were requested to abstain from coffee and cigarettes on the day of testing. Blood was sampled for glucose and glycosylated haemoglobin at the start of the examination. The instantaneous HR was determined from a cardiotachometer as described before 12. A push-button-activated event marker identified onset and duration of the manoeuvres listed below. Heart rate changes induced by standing, 70° headup tilt, supine hand grip and the Valsalva manoeuvre We used a tilt table with a foot support and an anti-slip mattress 12. The 70° position was reached in 3-5 sec. Standing was accomplished in 3-5 sec in groups 2 and 3 patients, but took longer in group 1 patients (mean 7 sec, range 4-10 sec). Handgrip was performed supine at maximal voluntary force for 5 sec 12. The Valsalva manoeuvre was performed according to Levin 14. Patients were studied in semirecumbent position; they were trained to maintain an expiratory pressure of 40 mm Hg for IO sec, using a mercury manometer with a mouthpiece. The HR response to standing, head-up tilt, handgrip and Valsalva manoeuvre was determined at times t=-10,-5,-1 ,0,1 ,2,3,5,7 ,10,12,15,20,22, and 30 sec. The choice of these sample points was prompted by results reported in previous studies7'12'13. The magnitudes of .6.HRmax,.6.HRmin,Tmax, 12 and Tminwere determined as described previously . The definition of these variables is illustrated in figure I. We also measured the latency to cardioacceleration after the start of standing, handgrip and 70° head-up tilt, and the latency to cardiodeceleration after release of the Valsalva strain 15 to the

nearest I sec (fig. 1). The 70° head-up sample points were taken at the same moments as during standing1,12 _ Each test was performed three times. Subjects remained in the vertical position for two minutes. Two minutes of supine rest were taken between the various runs. A correction of 1 sec was made to allow for the reaction time of the subject and the one-beat lag of the cardiotachometer output. Control values were computed as average over 10 sec prior to the manoeuvres. The median HR response was determined at the various sample points and expressed as percentage deviation from the resting HR. Group results are presented as average changes in ,6.HR % 7. Parasympathetic blockade - One healthy subject was studied after complete blockade of efferent parasympathetic HR control by intravenous administration of atropine (0.04 mg/kg). Influence of supine rest _: The influence of the period of supine rest prior to standing on the magnitude of the initial HR response was examined in group 2 and 3 patients by comparing resting periods of 1 and 20 min 12·13. Testing orthostatic tolerance - Arterial pressure was measured by cuff and sphygmomanometer at rest and after 1 min standing. Phase 5 of the Korotkoff sounds was taken as diastolic pressure. Orthostatic hypotension was defined as a fall of> 20 mm Hg in systolic and/or > 5 mm Hg in diastolic pressure 8•16. In order to assess excessive postural tachycardia, we measured the HR increase after 2 min standing. A HR increase > 25 beats/min was considered abnormally high. This value was obtained by calculating the upper limit of the 95% confidence interval for changes in HR after the change in position from supine to standing in 37 Neth J Med 28 (1985)

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cardiac denervation in diabetes

.1HR 50

8-HANDGRIP

A-STANDING I

C-VALSALVA

I I

I I

I

40

30 20

10

.,,..,·· :'

J'--···" __;_ - -

0

-10

0

Tmax

r

I

30

I

I

I

20S

10

40S

Tmin

Tmax

I

I

0

30

I

40S

TmaxTmin

Fig. r. Examples of the heart rate (HR) changes evoked by standing (A), handgrip (B) and Valsalva manoeuvre (C) in a 33-year-old male volunteer. The definition of the variables LHRmax, LHRmin, Tmax and Tmin is illustrated in this figure. Pharmacological parasympathetic blockade with atropine(- - - -) abolished the large transient HR changes. A sluggish HR increase starting after > 1 sec remained.

healthy subjects of the same age range as the group 3 diabetic patients 8 • Statistical analysis Results are expressed as mean and standard error of the mean (SEM). The paired or unpaired Student t-test was employed to compare group means. A p < 0.05 was considered to indicate a significant difference.

Results

Baseline HR and systolic and diastolic blood pressure prior to the four manoeuvres did not differ in the three groups. Resting HR was lower in groups 2 and 3 than in group 1. Supine systolic and diastolic blood pressures were higher in group I than in groups 2 and 3 patients (table II).

TABLE II: CHANGES IN HEART RATE AND BLOOD PRESSURE AFTER l AND 2 MIN STANDING, COMPARED WITH RESTING VALUES IN THE THREE PATIENT GROUPS

Group I (n = 9) severe vagal impairment

Resting heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LSystolic blood pressure ( 1 min standing) 6 Diastolic blood pressure ( 1 min standing) LHeart rate ( 1 min standing) LHeart rate (2 min standing)

Group 2 (n mild vagal impairment

= IO)

Group 3 (n = 17) no apparent vagal impairment

Significance (p) 3

2

vs 3

I VS 2

I VS

< 0.05